Practical Manual of Pharmacology
Practical Manual of Pharmacology
Dinesh Badyal
MBBS, MD (PGI)
Associate Professor
Department of Pharmacology
Christian Medical College
Ludhiana, Punjab
India
®
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Practical Manual of Pharmacology
© 2008, Jaypee Brothers Medical Publishers
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First Edition: 2008
ISBN 978-81-8448-362-8
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Printed at Ajanta Offset & Packagins Ltd., New Delhi
To
My beloved students
(who have been my teachers too)
and
My daughter
Anvi
Preface
We are what we repeatedly do,
excellence then is not an act,
but becomes a habit.
—Aristotle
To impart skills to budding doctors practical pharmacology is an essential area of teaching.
This practical manual describes what you do with your own hands which will help you
throughout the life. This manual has been written keeping in view the desired shift in the
pharmacology practical teaching from pharmacy based redundant experiments to more
meaningful, clinically relevant problem based exercises. The topics covered in the manual
have been carefully selected based on the most recent (2007) improvised problem based
curriculum design for pharmacology (Appendix I). The book covers all essential components
to impart the necessary required skills to students in the subject of pharmacology as per
prevailing regulations in the country. The manual highlights the important skills to be imbibed
by budding doctors which will aid in rational therapeutics.
The manual covers all feasible exercises in pharmacology. The manual is flexible enough
to suggest various modifications for various medical colleges as per availability of material
for practicals. A time schedule is also included (Appendix II), which can be modified as per
requirements. The exercises vary from simple demonstrations to computer simulation models.
Special care is taken to keep the cost of material needed for practicals as low as possible.
There are sufficient examples for students to apply the concepts learned in practicals. There
are also new topics like ethics, which has become very important now after implementation
of consumer protection Act to doctors.
I am thankful to all my students for sharing their concern about existing pharmacology
practicals and for their views on modifications in pharmacology practical training. That in a
way, encouraged me to write this manual. I am thankful to Mr Tarun Duneja of M/s Jaypee
Brothers Medical Publishers (P) Ltd, New Delhi for expediting the publication. I hope that
students and teachers would benefit from this manual. Suggestions for improvements from
teachers and students are most welcome.
Dinesh Badyal
dineshbadyal@rediffmail.com
Contents
Section 1: Clinical Pharmacy
1.
2.
3.
4.
5.
6.
7.
Introduction to Clinical Pharmacy ........................................................................ 3
Weights, Measures and Abbreviations ............................................................... 7
Labeling of Drugs ....................................................................................................13
Pharmacy Preparations ..........................................................................................21
Common Dosage Forms and Routes of Administration-I .............................30
Common Dosage Forms and Routes of Administration-II ............................39
Common Dosage Forms and Routes of Administration-III ..........................54
Section 2: Experimental Pharmacology
8.
9.
10.
11.
12.
13.
14.
Introduction to Experimental Pharmacology ....................................................73
Effects of Drugs on Rabbit Eye ............................................................................75
Effect of Drugs on Frog Heart ...............................................................................80
Effect of Drugs on Rabbit Intestine ....................................................................86
Effect of Drugs on Dog Blood Pressure .............................................................90
Short Experiments for Efficacy and Safety .......................................................94
Ethics and Animals ................................................................................................. 98
Section 3: Clinical Pharmacology
15. Introduction to Clinical Pharmacology ........................................................... 103
16. Pharmacokinetic Parameters and Calculations ............................................ 104
x  Practical Manual of Pharmacology
17. Prescription Writing Through Problem Based Learning
(Rational Prescribing) .......................................................................................... 112
18. Critical Evaluation of Prescription (Audit of Prescriptions) ..................... 157
19. Problem Based Drug Interactions .................................................................... 162
20. Adverse Drug Reaction (ADR) Monitoring ................................................... 178
21. Therapeutic Drug Monitoring (TDM) ............................................................. 187
22. Drug Use in Special Population/Diseases/Physiological Conditions ...... 194
23. Critical Appraisal of Drug Promotional Literature ..................................... 207
24. Therapeutic Follow-up Cases/Problems ......................................................... 215
25. New Drug Development ..................................................................................... 219
26. Calculation of Drug Doses and Dilutions ...................................................... 223
27. Evaluation of Drug Formulations ..................................................................... 232
28. Ethics and Humans .............................................................................................. 238
29. Management of Some Common Poisonings .................................................. 243
30. Objective Structured Practical Examination (OSPE) ................................... 253
Appendix I ............................................................................................................... 257
Appendix II ............................................................................................................. 259
Appendix III ............................................................................................................ 261
Appendix IV ............................................................................................................ 262
Terminologies Used in Pharmacology ............................................................... 283
Index ......................................................................................................................... 287
Section 1
Clinical Pharmacy
CHAPTER
1
Introduction to Clinical Pharmacy
Earlier, pharmacy used to be typically related to preparing and dispensing of drugs only. In
those days, a doctor would himself prepare or formulate the drug in his dispensary and
dispense it to his patients. This practice is now almost obsolete. These days doctor gets all
the drugs in ready-made form. The pharmaceutical industry (Ranbaxy, Cipla, etc.) are now
manufacturing these drugs on mass scale. The doctor’s job is to rationally prescribe and use
these drugs. With this, there is now shift in pharmacy practicals. The redundant practicals
comprising of preparing and dispensing can be replaced by more clinically relevant clinical
pharmacy practicals. That’s why this chapter focusses on clinical pharmacy and not just
pharmacy.
I feel that a budding doctor needs to be trained better in recognizing various dosage
forms available to be used for patients, correct way of administration of these drugs and
interpretation of information on drug labels. A number of medical colleges have reduced/
deleted pharmacy preparation practicals from the course. The MCI also insists on replacing
unnecessary pharmacy practicals with more relevant clinical pharmacy practicals. Some people
are still continuing with pharmacy preparation practicals as they find no alternative available.
However, we can generate alternatives with the available resources in the department. These
alternatives can be easily arranged with no cost involved.
To achieve this, total number of pharmacy practicals can be divided into 12 practical
sessions assuming that there is one practical session per week, so this comes out to be initial
three months of pharmacology practical course (Appendix 2).
Conventional pharmacy is art of preparation, compounding and dispensing of drugs. It
also includes interpretation and evaluation of prescriptions. Some hospitals have their own
pharmacies. Usually it is managed by a qualified pharmacist. There can be main pharmacy
and satellite pharmacies throughout the hospital. These hospitals usually follow a computerised
coded system for drugs. The common source to get drugs is usually chemist shops which can
be labeled as retail pharmacies. There is a difference between functioning of pharmacies in
hospitals and chemist shops. The pharmacies in hospitals, these days do not manufacture/
prepare a large number of drugs. Only few preparations related with dermatological sciences
are prepared. In chemist shops only ready-made drugs are available. The common functions
of both is to advise proper use of drugs and other precautions to patients. At some places
they also provide information to doctors, nurses and other health care providers.
4  Practical Manual of Pharmacology
Instruments which are used in pharmacy are:
DISPENSING BALANCE
It is meant for weighing of more than 100 mg of a substance, i.e. sensitivity is 100 mg. Left
pan is made up of metal (for putting weights). Right pan is made up of glass/metal for
putting substances to be weighed. Advantages of glass pan is that it is inert, non-reactive,
can be easily washed and anything sticking to it can be seen. A butter paper can be used to
weigh salts, salts do not stick to butter paper. This balance is sensitive for most of pharmacy
work for common preparations (Fig. 1.1). It can be dismantled and packed in a small wooden
box.
These days electronic balances (Fig. 1.2) are available which can be conveniently used to
measure even a very small quantity of drugs. The information about balance will help a
doctor in clinics when you need to give a small dose to a child or when you want to divide
one dose into multiple doses. Usually pharmacist/pharmacologist is approached by pediatric
department to divide the dose into small multiple fractions.
WEIGHTS
Students are provided with a box containing weights ranging from 1 to 100 gm. There is one
additional small box containing very small weights ranging from 1 to 500 mg.
MEASURING CYLINDERS AND FLASK (FIG. 1.3)
The capacity can vary from 5 to 1000 ml. They are used for measuring liquid or solution, but
they are less accurate as compared to pipettes. They are safer as compared to pipettes. With
pipettes there are chances of contact of liquid with oral cavity, hence manual pipettes are not
recommended.
MORTAR AND PESTLE
It is made up of porcelain. It is used to grind the drug to powder form and also used to mix
ingredients of powders, liquid or semiliquid, ointments, mixtures, suspensions, etc. These
days glass mortar and pestle are available (Fig. 1.4). An advantage is that less drug sticks to
glass and they are easy to clean.
Fig. 1.1: Dispensing balance and weights
Introduction to Clinical Pharmacy  5
Fig. 1.2: Electronic Balance
Fig. 1.3: Measuring cylinder and flask
Fig. 1.4: Mortar and Pestle
CONTAINERS (FIG. 1.5)
Prescription bottle is used for liquids of low viscosity like mixtures, suspensions and solutions.
It is made up of glass or plastic. Wide mouth bottle is used for solutions of high viscosity like
ointment, etc. Amber coloured bottle prevents degradation of solution inside by absorption
of UV rays, e.g. calamine lotion.
SPATULAS
They are used to mix various chemicals, e.g. powders or ointments. They are formed of
plastic or metal (Fig. 1.6).
PILL TILE
It is used to mix the powders or ointments.
WASH BOTTLE
It contains tap or demineralised water.
Fig. 1.5: Dispensing bottle
Fig. 1.6: Spatula
6  Practical Manual of Pharmacology
PHARMACEUTICAL CONTAINERS
The basic requirement for a container is that it should not interact with the formulation.
Glass, plastics are commonly used components of containers.
Glass containers have some disadvantages, e.g. leaching of alkali and insoluble flakes
into the formulation. These can be offset by the choice of an appropriate glass material, e.g.
phenytoin has the ability to (in dilute solution) to react with glass. When added to glass
infusion bottles much of the drug remains stuck to the glass and does not reach the patient.
Plastic containers are convenient to handle but the major disadvantage is the two-way
permeation or ‘breathing’ through the container walls. Volatile oils, perfumes and flavouring
agents can permeate through plastics to some extent. Components of emulsions and creams
have been reported to migrate through the walls of some plastics causing either a deleterious
change in the formulation or collapse of the container. Loss of moisture from a formulation
is also common, e.g. paraldehyde (a hypnotic) is one example. This liquid dissolves plastic so
it must be injected parenterally using glass syringe.
Closure must form an effective seal for the container. It must not react chemically or
physically with the formulation. Rubber is a common component of stoppers, cap liners, and
parts of dropper assemblies. Absorption of the active ingredients, preservatives into the
rubber and the extraction of one or more components of rubber into the formulation is a
common problem.
The application of an epoxy lining to the rubber closure reduces the amount of leached
extractives but has no effect on the absorption of the preservative from the solution. Tefloncoated rubber stoppers may prevent most of the leaching and absorption.
OBJECTIVES
At the end of this session a student shall be able to:
1. Identify various instruments used in pharmacy.
2. Describe uses of instruments used in pharmacy.
CHAPTER
2
Weights, Measures
and Abbreviations
These are important to know dose and other details about administration of drugs. The
drugs and solutions can be measured by using various units. Metric or decimal system of
measure is usually used to measure due to two advantages:
i. Its tables are simple as they are based on decimal system of notation
ii. Its tables of length, volume and weight are conveniently correlated.
METRIC SYSTEM
In metric system:
• Base for weight is kilogram (kg)
• Base for volume is litre (l)
Measures of weight (mass) in metric system
1
1
1
1
1
1
kilogram (kg)
gram
milligram (10-3 g)
microgram (10-6 g)
nanogram (10-9 g)
picogram (10-12 g)
=
=
=
=
=
=
1000 grams (G or g)
1000 milligrams (mg)
1000 micrograms (μg or mcg)
1000 nanograms (ng)
1000 picograms (pg)
1000 femtograms (fg)
Measures of capacity (volume) in metric system
1 liter (L)
1 ml
=
=
1000 milliliters (ml)
1000 μl
Another less commonly used system is imperial system. It can be:
a. Avoirdupois system
Standard for weight = pounds (lb)
1 lb = 7000 grains
1 lb = 16 ounce (oz)
8  Practical Manual of Pharmacology
b. Apothecary system (UK)/Troy system
Standard for weight is grains
1 oz = 480 grains
1 lb = 12 oz
Measure for volume in both these system is Gallon
1 gallon (C. or gal.) = 4 quarts = 8 pints
1 quart (qt.) = 2 pints = 32 fluid ounces
1 pint (pt.) = 16 fluid ounces (fl. oz. or )
CONVERSION BETWEEN SYSTEMS
Weight
2.2 pounds = 1 kilogram (kg.)
1 grain (gr.) = 60 milligrams (mg.)
Fluid Measure
1 fluid ounce (fl. oz.) = 30 milliliters
1 pint = 473 milliliters
There are also domestic measures to measure:
Domestic weights and measures
Domestic measures
1 drop
1 teaspoonful
1 dessertspoonful
1 tablespoonful
1 glassful
1 tumblerful
=
=
=
=
=
=
Metric equivalent
1/20 ml, 1 ml = 20 drops (approx.)
5 ml
10 ml
15 ml
150 ml
240 ml
PHARMACEUTICAL CALCULATIONS
1. Percent Calculation
The word percentage can have different meanings under different circumstances. In solution,
we are dealing with solids that are weighed and liquids that can be weighed or measured.
There are three different percentage solutions.
a. Percentage weight in weight (w/w)—expresses the number of grams of solute in 100
ml of solution.
b. Percentage weight in volume (w/v)—expresses the number of grams of solute in 100
ml of solution, regardless of whether water or another liquid is used as the solvent.
c. Percentage volume in volume (v/v)—expresses the number of milliliters of solute in
100 ml of solution.
a. Percent weight in volume (%w/v)
It is a solution of solid in liquid and represents number of solutes per 100 ml of
solution.
Weights, Measures and Abbreviations  9
1% w/v is 1 g of solute in a total of 100 ml of solution.
1% w/v means 1 part by weight, whereas the solvent is added upto 100 parts.
1% = 10 mg/ml
e.g. To calculate the quantity of CaCl2 required for 200 ml preparation of 1%
solution in distilled water
1% means 1 g/100 ml
for 100 ml volume, CaCl2 = 1 g
For 200 ml CaCl2 = 1/100 × 200 = 2 g
b. Percent by weight (%w/w)
It represents number of grams of solute per 100 gm of solution.
1% w/w is 1 g of solute in 100 g solution.
Add solid 1 part by wt and then add upto 100 parts, ensuring uniform mixing
(Highly viscous substances like glycerin are considered solids and are measured
in grams)
e.g. To prepare 25 g of 10% of a drug
10% means 10 g/100 g of the preparation
if 100 g has drug = 10 g
25 g of preparation will have drug = 10/100 × 25 = 2.5 g
c. Percent by volume (%v/v)
It is a preparation of a liquid in liquid and represents number of millilitres of
solute per 100 ml of solution.
1% v/v is 1 ml of a liquid constituent in 100 ml of solution, e.g. To make 2% v/v,
to 2 part of volume of the constituent add upto 100 parts by volume.
2. Proportion Calculation
Involves mixing of 2 similar preparations of different strength to produce a preparation
of intermediate strength.
Proportions are equations containing ratios of equal value.
For example 3:4 = 6:8. This may also be written as fractions, 3/4 = 6/8. (see chapter 27 for
more).
3. Others
i. Units
Potency of certain drugs like heparin, insulin either cannot be determined by chemical
or physical methods or these methods are very costly. The measurement of these
drugs is expressed in units. The unit is based on the effect/ amount of effect produced
by a particular amount of drug in biological systems, i.e. isolated tissues of animals or
whole animals, e.g. 40 units of insulin.
ii. Molality: It is the number of moles of solute in 1000 grams of solvent.
iii. Normality: It is the number of gram equivalents of solute dissolved in 1000 ml of
solution.
10  Practical Manual of Pharmacology
ABBREVIATIONS USED IN PRESCRIPTIONS
A prescription should be written in simple and/or in regional language without using
abbreviations, however, certain abbreviations are still in use as under:
A. Time of Drug Administration
Phrase
Abbreviation
ante cibum
ac
post cibum
pc
hora somni
hs
opus in die
od
bis
bis
bis in die
bid
ter in die
tid
ter die sumendum
tds
quarter in die
qid
quaque
q
quarta quake
qqh
omni mane
om
omni nocte
on
si opus sit
sos
statim
stat
ad libitum
Ad lib
omni die
od
repetatur
Rep
Meaning
before meals
after meals
at bedtime
once a day
twice
twice daily
three times a day
three times a day
four times a day
every 6 hour
every 4 hour
every morning
every night
when required
immediately
freely, use as much as one desires
every day
let it be repeated
B. Formulations
Phrase
capsula
tabella
liquor
mistula
injectio
ampoule
syrupus
gutta
nebula
Meaning
capsule
tablet
solution
mixture
an injection
an ampoule
syrup
drops
spray
Abbreviation
cap
tab
liq
mist
inj
amp
syr
gtt
nebul
Weights, Measures and Abbreviations  11
C. Routes of Drug Administration
Phrase
Abbreviation
intramuscular
IM
intravenous
IV
subcutaneous
sc
per os
po
per vaginam
PV
bolus
bol
Meaning
by Intramuscular injection
by Intravenous injection
by subcutaneous injection
by mouth
by vaginal route
as a large single dose (usually IV)
D. Others
Phrase
Ad
aqua
receipe
signa
aurio dextra
aurio laeve
auris utrae
oculus dexter
oculus sinister
oculus uterque
ex modo prescripto
misce
dispensa
signa
tablespoon
teaspoon
Meaning
to, up to
water
(you) take
you write
right ear
left ear
both ears
right eye
left eye
both eyes
as directed
mix
Dispense
you write
tablespoon
teaspoon
Abbreviation
Ad
aq
R
sig
ad
al
au
od
os
ou
emp
M
Disp.
sig
tbsp
tsp
OBJECTIVES
At
1.
2.
3.
the end of this session a student shall be able to:
Understand meaning of all abbreviations used in Pharmacology.
Convert various measurements given.
Understand percent and proportion calculations.
12  Practical Manual of Pharmacology
Exercise in examination based on these practical can be:
1. Expand the following:
a. Cap. Rifampicin 600 mg od ac
b. Tab. diazepam 5 mg hs
c. Syr. Amoxycillin 5 ml tid po
d. Tab. FeSO4 200 mg 2 bd pc
e. Tab. PCM 500 mg sos
f. Inj. Ampicillin 0.5 g IM qid
2. What do you understand by:
a. 1% NaCl solution
b. 15% tannic acid glycerin
c. 5% lignocaine ointment
C H A P T E R
3
Labeling of Drugs
If you pick up a strip of any medicine, you will find a lot of information on it, regarding drug
name, manufacturer, expiry date, etc. as shown below in Figure 3.1.
Fig. 3.1: Labels on premanufactured medicines
Let us discuss in detail what various components of these labels are.
COMMERCIAL PREPARATIONS
Label of the given dosage form consists of
Name and quantity of the drug
Pharmacopeias used for preparation
14  Practical Manual of Pharmacology
Batch No
Manufacturing and expiry date
Manufacturing license number
Maximum retail price (MRP)
Schedule of the drugs, i.e. H, L, P, X, etc.
Instructions about use of drugs
Address of the pharmaceutical company
To explain these terms let us discuss some general points:
A. DRUGS ARE CLASSIFIED INTO VARIOUS CATEGORIES
1. Prescription-only Drugs:
These drugs are dispensed by pharmacist only when you have a prescription from a
registered medical practitioner (RMP), e.g. diazepam, morphine and antimicrobials.
Prescription is a written order from physician for pharmacist. Registered medical
practitioner is a doctor registered with regional or central medical council. An
allopathic RMP can not prescribe drugs from homeopathic stream and vice versa, e.g.
an allopathic doctor can not prescribe Liv 52.
These drugs are covered under Schedule 'H' in India
(Fig. 3.2). These drugs are considered to be unsafe for
general use, except under medical supervision. They are
dispensed only on physician's prescriptions.
2. Over-the counter (OTC) drugs:
These are non prescription drugs, i.e. these can be
purchased from pharmacies or chemist shops without a Fig. 3.2: Schedule H warning
prescription. These drugs are considered safe and medical
supervision is not required; e.g. Paracetamol. The drugs
which are mainly used as OTC drugs are:
• H2-antihistamines
• NSAIDs
• Oral contraceptives
• Hydrocortisone cream
• Nicotine-cessation of smoking
OTC drugs may lead to adverse drug reactions (ADRs) because of:
• Incorrect self-diagnosis and choice of incorrect therapy
• Incorrect route of administration
• Excessively prolonged use
• Risk of dependence and abuse
• Food and drug interactions
• Storage in incorrect conditions
Labeling of Drugs  15
• Failure to recognise
o Contraindications
o Interactions
o Warnings
o Precautions
So to avoid these, whenever you use an
over-the-counter (OTC) medicine, reading the
drug label is important for taking care of
yourself and your family. This is especially true
because you probably take OTC medicines
without first seeing a doctor. The label tells you
what a medicine is supposed to do, who should
or shouldn't take it, and how to use it. The OTC
medicine labels have always contained usage
and safety information for consumers, but now
the information will be more uniform and easier
to read and understand (Fig. 3.3).
All nonprescription, over-the-counter (OTC)
medicine labels have detailed usage and warning
information so consumers can properly choose
and use the products. You'll find this
information:
• Active Ingredient: Therapeutic substance
in product; amount of active ingredient
per unit.
• Uses: Symptoms or diseases the product
will treat or prevent.
• Warnings: When not to use the product;
conditions that may require advice from
a doctor before taking the product;
possible interactions or side effects; when
to stop taking the product and when to
contact a doctor; if you are pregnant or
breastfeeding, seek guidance from a
health care professional; keep product
out of children's reach.
Fig. 3.3: Labeling of OTC medicine
• Inactive Ingredients: Substances such as
colors or flavors.
• Purpose: Product action or category such as antihistamine, antacid, or cough
suppressant.
16  Practical Manual of Pharmacology
• Directions: Specific age categories, how to take, how much, how often, and how long.
• Other Information. How to store the product properly, and required information
about certain ingredients such as the amount of calcium, potassium, or sodium the
product contains.
• The expiry date, when applicable (date after which you should not use the product).
• Lot or batch code (manufacturer information to help identify the product).
• Name and address of manufacturer, packer or distributor.
• Net quantity of contents (how much of the product is in each package).
• What to do if an overdose occurs.
B. DRUG NOMENCLATURE
You will frequently find existence of multiple names for a single drug. These names are:
1. Chemical name: It indicates full name according to chemical constituents. It is lengthy,
complicated and not commonly used, e.g. 4-[2-Hydroxy-3-[(1-methyl ethyl) amino]
propoxy] benzene acetamide for atenolol.
2. Non proprietary name/Generic name/Approved name: Name in official books which
is accepted worldwide, e.g. aspirin. It allows identification of different products with
the same ingredient to be identified, although there are few exceptions, e.g. adrenaline
in India is known and epinephrine in United States of America. Drugs if prescribed
by generic name are cheaper as promotional expenditure is avoided, but quality control
is difficult for generic drugs.
3. Proprietary name/Trade name/Brand name: Names given by innovative
manufacturing company, e.g. Crocin for paracetamol. Patent protection enables
innovative pharmaceuticals to market the drug exclusively till the patent expires.
After that the same drug is available under various brand names, e.g. paracetamol
brand names are crocin, acemol, bepamol, calpol and dolopar. Brand names are popular
names of the drug and are easy to remember, but so many brand names for a single
drug can create confusion in prescribing. Brand names are expensive also as
advertisement cost is added.
The drugs can have strikingly similar names leading to prescription errors or
medication errors. To overcome these WHO has initiated a programme on selection
of International non-proprietary names (INN) for assigning a unique, globally accepted
and recognized name.
C. PHARMACOPOEIA
Name is usually followed by the reference according to which drug was prepared, e.g. IP
means Indian pharmacopoeia. Pharmacopoeia is a class of DRUG COMPENDIA (official
books of summarized information sources). The term pharmacopoeia is derived from two
Greek words—Pharmakon (means drug) and poiein (means make). Pharmacopoeia contains
formula or other standards required for preparation and testing of drugs to ensure uniform
purity and potency. The description of preparation given in pharmacopoeia is known as
Labeling of Drugs  17
monograph. These monographs describes drug, characteristics for identification, standards
of purity and strength limits of impurities, assay method of drugs, storage and instructions.
Drug and the information mentioned in pharmacopoeia are official. It also includes official
range of dosage for drugs, system of weights, measures and the formulations and the methods
used for sterilization of pharmaceutical products. Most of the countries have their own
pharmacopoeia.
Other source for this type of information is National Formulary. These are the books of
standards for drugs and devises. These are compilations of those drugs, which have been
recognized as legal standards of purity, quality and strength by government agency of that
country.
Official reference books of India:
Indian Pharmacopoeia (IP)
National Formulary of India (NFI)
Chemical and Medical Formulary of India
Drug Bulletins
International official books:
British Pharmacopoeia (BP)
British Pharmaceutical Codex (BPC)
United States Pharmacopoeia (USP)
International Pharmacopoeia (By WHO for those countries who do not have their own
pharmacopoeia)
Others:
British National Formulary
Martin Dale's Extra Pharmacopoeia
Physician's Desk Reference
D. THESE DAYS YOU MAY FIND A DRUG NAME CARRYING A POST SUFFIX.
These are:
D-dispersible, e.g. Doxycycline-D
CR-controlled release, e.g. Indomethacin-CR
SR-sustained release, e.g. Diclofenac-SR
E. DRUGS SCHEDULES AND ACTS
Sometimes you will find drug names followed by a boxed warning, e.g. Schedule H drug.
These are based on drugs schedules and acts.
There are various drug schedules and acts in India. The important ones are as per Drugs
and Cosmetics Act (1940) as amended in 2001 are:
18  Practical Manual of Pharmacology
DRUG SCHEDULES
Schedule A: gives specimen of prescribed form.
Schedule B: gives fees for test and analysis of drugs.
Schedule C: gives details with biological and other special products.
Schedule D: is concerned with exemption regarding drug import.
Schedule FF: gives details of standard ophthalmic solutions.
Schedule G: deals with details of drugs to be labeled 'CAUTION-it is dangerous to take
this medicine except under medical supervision'.
Schedule H: deals with drugs and medicine to be sold on prescription-only.
Schedule I: lists all ailments for which no cure can be claimed, e.g. AIDS.
Schedule Q: deals with cosmetics.
Schedule R: deals with standards for contraceptives.
Schedule W: gives details of drugs which should be marketed under generic name only.
Schedule X: deals with psychotropic drugs which require special license for manufacturing
and sale.
Schedule Y (new addition): specifies the requirements and guidelines on conduct of clinical
trials, import and manufacturing of new drugs.
FDA (USA) SCHEDULES ARE:
Schedule I (C-I)
• High abuse potential
• No accepted medical use in the United States
• Examples: heroin, marijuana, LSD (lysergic acid diethylamide), peyote
Schedule II (C-II)
• Potential for high abuse with severe physical or psychological
• dependence
• Examples: narcotics such as meperidine, methadone, morphine, oxycodone,
amphetamines and barbiturates
Schedule III (C-III)
• Less abuse potential than schedule II drugs
• Potential for moderate physical or psychological dependence
• Examples: nonbarbiturate sedatives, nonamphetamine stimulants, limited amounts of
certain narcotics
Schedule IV (C-IV)
• Less abuse potential than schedule III drugs
• Limited dependence potential
• Examples: some sedatives and anxiety agents, nonnarcotic analgesics
Labeling of Drugs  19
Schedule V (C-V)*
• Limited abuse potential
Examples: small amounts
Drugs which are prepared and dispensed by pharmacist usually have different label
than the ones prepared by pharmaceutical industry. The label is divided into two:
1. Primary Label
2. Secondary Label
PRIMARY LABEL
It is the main label used on pharmacy preparations. It should be proportional to the size of
container and it usually should occupy middle 1/3rd of the container. It should cover less.
This label should have following information:
Title of preparation, e.g. The Powder
Name :
Age/Sex :
Reg. No. :
Directions :
Date/Signature
Registration no.
Directions/instructions to patients for proper use of drug.
Name of the pharmacy laboratory from which the drugs have been dispensed.
SECONDARY LABEL
As obvious from the name, it is the other label than the primary label. It is smaller in size and
is usually put above the primary label with a small gap in between.
This label usually contains some important precautions about the use of drug in capital
letters, for example:
Shake Bottle Well Before Use
The number of secondary labels may be more than one.
OBJECTIVES
At
1.
2.
3.
the end of this session a student shall be able to:
Understand all information written on label of drugs.
Understand primary and secondary labels.
Knows drug nomenclature.
20  Practical Manual of Pharmacology
Exercise in examination bases on these practical can be:
1. Enumerate all the information written on the label of drugs:
A strip of tablets
A container of liquid
An ampoule
A vial
2. What do you understand by the following terms? Mention the clinical importance of
each of them.
a. Manufacturing Date
b. Expiry Date
c. Batch Number
d. MRP
e. Schedule H
CHAPTER
4
Pharmacy Preparations
To give an idea to students about how drugs are prepared in pharmacy, a few pharmacy
preparations practicals can be demonstrated in two session.
Exercise 1: To prepare and dispense 50 ml of Calamine lotion
Formula:
Calamine
Zinc oxide
Bentonite
Liquefied phenol
Sodium citrate
Glycerine
Purified water ad
For 100 ml
15 gm
5 gm
63 gm
0.5 ml
5 gm
5 ml
100 ml
PROCEDURE
• Weigh out the calculated quantities of calamine, zinc oxide and bentonite. Mix them
thoroughly in a mortar.
• Take 20 ml of purified water in graduated flask and add the required quantity of
sodium citrate.
• Pour a little of water from flask into mortar containing calamine, bentonite and zinc
oxide. Triturate to make homogenous paste. Add required amount of glycerin and
phenol to this mortar and triturate.
• Transfer the mixture to the flask. Rinse the mortar with a little quantity of purified
water and transfer this rinsing into the flask. Add sufficient quantity of water to make
up the final volume 50 ml. Transfer it to an amber coloured bottle, label and dispense.
HOW TO APPLY
• Wash and completely dry the affected area before applying the lotion. Shake lotion
well before use.
22  Practical Manual of Pharmacology
• Apply this medication to the affected area of skin, generally three to four times daily or
as directed by your physician.
• Do not dilute or mix with other lotions.
LABELING
FOR EXTERNAL USE ONLY
SHAKE WELL BEFORE USE
Name
Rajesh Singh
Age/Sex 35 M
Address
145, BRS Nagar, Ludhiana
Directions: Apply on the affected part with cotton swab.
Do not rub.
Sign and Regd No. of
24-05-2007
Pharmacist
Pharmacy, ABC Delhi
Secondary Labels
←
Primary Label
←
PHARMACOLOGICAL ACTIONS
Calamine: Calamine is a mixture of zinc oxide (ZnO) with about 0.5% iron (III) oxide (Fe2O3).
It is the main ingredient in calamine lotion and is used as an antipruritic to treat sunburn,
eczema, rashes, poison ivy, chickenpox, insect bites and stings. It is used as a mild antiseptic
to prevent infections that can be caused by scratching the affected area. It is also used to dry
weeping or oozing blisters and acne abscesses. It is also used as colouring agent in various
cosmetics.
Zinc oxide: It is insoluble in water, used as dusting powder, ointment, lotion and paste.
It has soothing and protective action in eczema. It is also used as mild astringent for skin.
Bentonite: It is colloidal aluminum silicate insoluble in water but swells into a homogenous
mass. It is used as suspending agent because it increases the viscosity of the vehicle. It is also
used as a bulk laxative. It should be sterilised before using on open wounds.
Sodium citrate: It helps in the dispersion of solids in this preparation and reduces the
viscosity of this preparation.
Liquefied phenol: It has an antiseptic and mild local anesthetic effect. However, in the
amount used, it acts as a preservative in this preparation. It is particularly required as glycerin
promotes the growth of microorganisms.
Glycerine: When applied locally it acts as an emollient and helps in penetration of
ingredients by making the skin moist and soft. Due to its viscous nature, the lotion stays for
a longer time at the site of application. It is hygroscopic in nature, so prevents drying up and
cracking of skin and the lesions.
Pharmacy Preparations  23
THERAPEUTIC USES
1.
2.
3.
4.
5.
In pruritis: used as soothing and protective lotion.
To allay pain and swelling of sun burns.
For prickly heat
Any other irritating skin condition
It is also used in herpes zoster and chickenpox.
PRECAUTIONS
• Avoid contact with the eyes, on the inside of your nose, mouth or genital area
• Contraindicated if known sensitivity or allergy to any ingredient
• Ask a doctor before using calamine lotion on children younger than 6 months of age.
Exercise 2: To prepare and dispense 25 ml of Mandle's throat paint
Formula for 100 ml:
Iodine
Potassium iodide
Mentha oil
Water
Alcohol 90%
Glycerine upto
For 100 ml
1.24 gm
2.48 gm
0.40 ml
2.48 ml
3.76 ml
100 ml
PROCEDURE
• Weigh out the required amount of iodine and potassium iodide and transfer to a glass
jar. 10 drops of water and 5 ml of glycerin. Stir the contents. When contents are completely
dissolved, add required amount of Mentha oil and dissolve it.
• Transfer the contents into a measuring cylinder and add glycerin to make volume upto
25 ml. Transfer contents into amber colored bottle, label and dispense.
LABELING
FOR EXTERNAL USE ONLY
Name
Rajesh Singh
Age/Sex 35 M
Address
145, BRS Nagar, Ludhiana
Directions: Apply on the affected part with cotton swab.
3 times a day.
Sign and Regd No. of
24-05-2008
Pharmacist
Pharmacy, ABC Delhi
←
Secondary Label
←Primary Label
24  Practical Manual of Pharmacology
PHARMACOLOGICAL ACTIONS
Iodine: It is nonmetallic component. It acts locally and has antiseptic properties. It is an
oxidising agent and acts as bactericidal.
Potassium iodide: It is used to dissolve iodine as iodine is highly soluble in aqueous
solution.
Water acts as solvent for potassium iodide. Mentha oil acts as flavouring agent and is
volatile. Alcohol is used to dissolve mentha oil and glycerin. It also acts as preservative,
antiseptic and astringent. Glycerine helps iodine to stick to affected area for longer period.
It also has antiseptic action and reduces edema.
THERAPEUTIC USES
1. Tonsillitis
2. Pharyngitis
PRECAUTIONS
Do not take food/water half an hour before and after the application of the paint.
Exercise 3: To prepare and dispense 1:5000 solution of Potassium Permanganate with
directions to dilute it to 1:15000 before use.
Calculations
Prepare 1% stock solution
1% stock solution is
1 gm in 100 ml
or 1000 mg in 100 ml
or 100 mg in 10 ml
or 100 mg in 1 ml
For 1:5000 solution of KMnO4 we need:
1g in 5000 thousand ml
or 1000 mg in 5000 ml
or 10 mg in 50 ml
Procedure
1. Measure accurately 100 mg of KMnO4 crystals. Dissolve it in 10 ml of distilled water
(1% stock solution). Stir with a glass rod to mix potassium permanganate solution.
2. Take 1 ml of solution and add 49 ml of water to make volume 50 ml. This is 1:5000
solution.
3. Label and dispense it in an amber coloured bottle to privet oxidation.
Pharmacy Preparations  25
LABELING
FOR EXTERNAL USE ONLY
Name
Rajesh Singh
Age/Sex 35 M
Address
145, BRS Nagar, Ludhiana
Directions: Dilute the solution before use by mixing 1
part of solution with 2 parts of water.
Use it for gargles and mouth washes 3-4 times
in a day.
Sign and Regd No. of
24-05-2009
Pharmacist
Pharmacy, ABC Delhi
←
Secondary Label
←Primary Label
STORAGE CONDITIONS
It should be stored in a tightly corked container in a cool dark place away from the sunlight.
PHARMACOLOGICAL ACTIONS
Potassium permanganate has bactericidal and fungicidal activity. Potassium permanganate,
on contact with organic matter, liberates nascent oxygen that oxidizes enzymes essential for
living microorganisms and their metabolism, thus producing antiseptic effects. It also acts as
astringent. It is readily soluble in water.
THERAPEUTIC USES
The
1.
2.
3.
major uses of this preparation are:
As disinfectant for water and utensils-1 in 100 solution.
As a cleansing application to ulcers and abscesses-1 in 1,000 solution.
As mouthwash (in gingivitis and steatites), gargles (Condyl's gargles), for washing
wounds and for vaginal irrigation-1 in 4,000 solution.
4. Sitz's baths given in hemorrhoids, piles and fissures.
5. As gastric lavage in the treatment of morphine, opium, strychnine, aconitine and other
alkaloid poisonings (but not for cocaine and atropine because they are not easily oxidised
by potassium permanganate)-1 in 5,000 solution is employed as applications for weeping
skin lesions and for urethral irrigation-1 in 5,000 and 1 in 10,000 solutions.
6. Treatment of snake bite (effective only if the venom is on the skin). It oxidize venom
(within 1-2 minutes of bite).
26  Practical Manual of Pharmacology
ADVERSE EFFECTS
• The crystals and concentrated solutions of KMnO4 are caustic and can cause corrosive
burns.
• Higher concentration can cause skin irritation, edema and mucous membrane turns
brown.
• There can be staining of clothes
• Do not disinfect surgical instruments, rusting can happen.
Exercise 4: To prepare and dispense one dose of oral rehydration powder for 1000 ml of
oral rehydration solution (ORS)
ORS is a simple, cheap and effective treatment for diarrhea-related dehydration, e.g. cholera
or rotavirus. It consists of a solution of salts and other substances such as glucose, sucrose,
citrates or molasses, which is administered orally. It is used around the world, but is most
important in the Third World, where it saves millions of children from diarrhea, still their
leading cause of death.
WHO FORMULA (FOR 1 LITRE ORS)
Sodium chloride
Sodium citrate
Potassium chloride
Glucose anhydrous
3.5
2.9
1.5
20.0
gm
gm
gm
gm
OBJECTIVE OF ORS
• To prevent dehydration
• To reduce mortality.
PROCEDURE
• Weigh the required quantities of sodium chloride,
sodium citrate, potassium chloride and glucose.
• Mix them on a paper placed over pill tile by using
powder spatula.
• Put the powder in a packet (Fig. 4.1).
• Label the packet and dispense.
Fig. 4.1: Folding of packet for powder
Pharmacy Preparations  27
Name
Akash
Age/Sex 20 M
Address
132, BRS Nagar, Ludhiana
Directions: Dissolve the contents of powder in 1000 ml of freshy
boiled and cooled water and take frequent sips.
Sign and Regd No. of
24-05-2007
Pharmacist
Pharmacy, ABC Ludhiana
The frequency of sips will depend on level of dehydration.
PHARMACOLOGICAL ACTIONS
In diarrhea loss of water and electrolytes leads to dehydration. Hence, both water and
electrolytes are given for treatment of dehydration. If water alone is given it will dilute the
salts present in body and aggravates the condition.
WHO ORS (for 1 litre) provides following salts as mEq/L:
Na+ 90.0
K+ 20.0
HCO3– 30.0
Glucose 111.0
Cl-80.0
Osmolarity of 311 mOsm/l
215 calories
PHARMACOLOGICAL ACTION OF SALTS
Sodium chloride
As you know, sodium is the main ion involved in various processes in the body, e.g. action
potential generation. It helps to maintain muscle tone. Symptoms associated with hyponatremia
are fatigue, muscle weakness, abdominal cramps, confusion, hypotension, weak pulse,
cyanosis, oliguria, tachycardia, loss of skin elasticity and dryness of mucous membranes.
Glucose
Glucose is the source of energy. Apart from that it helps in absorption of sodium. Molar
ratio of glucose is more than sodium in ORS. Sodium is absorbed through facilitated diffusion
or cotransport with the help of glucose.
Other contents provide sufficient amount of potassium, chloride and bicarbonate lost in
diarrhea. Sodium citrate is the source of HCO3– and also provides stability to the solution.
Potassium chloride influences the muscle action and ameliorates the cramps. Chloride helps
to maintain the fluid balance and production of gastric acid.
28  Practical Manual of Pharmacology
THERAPEUTIC USES
1. Diarrhoea
Oral rehydration therapy is widely considered to be the best method for combating the
dehydration caused by diarrhea and/or vomiting. Rehydration does not stop diarrhea,
but keeps the body hydrated and healthy until the diarrhea passes. ORS is recommended
in mild to moderate cases of diarrhea. Intravenous fluids are required in severe cases
of dehydration.
The amount of rehydration that is needed depends on the size of the individual and
the degree of dehydration. Rehydration is generally adequate when the person no
longer feels thirsty and has a normal urine output. A rough guide to the amount of ORS
solution needed in the first 4-6 hours of treatment for a mildly dehydrated person is:
• Up to 5 kg (11 lb): 200-400 ml
• 5-10 kg (11-22 lb): 400-600 ml
• 10-15 kg (22-33 lb): 600-800 ml
• 15-20 kg (33-44 lb): 800-1000 ml
• 20-30 kg (44-66 lb): 1000-1500 ml
• 30-40 kg (66-88 lb): 1500-2000 ml
• 40 plus kg (88 lb): 2000-4000 ml
The degree of dehydration can be assessed by following parameters:
— Pulse in dehydration has low volume and is thready.
— No tears, dry mouth in case of moderate to severe dehydration.
— Urine output is decreased in dehydration.
2. Heat stroke.
3. In patients of burns/surgery to maintain hydration.
4. Change from parenetral to enteral therapy.
5. High grade fever.
HOME MADE ORS
In a glassful of water, add I teaspoonful of sugar and a pinch of salt. You can also add half a
lemon.
Rice water and dal water can also be used.
or
An inexpensive home-made solution consists of 8 level teaspoons of sugar and 1 level
teaspoon of table salt mixed in 1 liter of water. A half cup of orange juice or half of a mashed
banana can be added to each liter both to add potassium and to improve taste.
SUPER-ORS
In this amino acids are added, e.g. alanine and glycine.
Pharmacy Preparations  29
NEW WHO ORS
Because of the improved effectiveness of reduced osmolarity ORS solution, especially for
children with acute, non-cholera diarrhoea, WHO and UNICEF now recommend that
countries use and manufacture the following formulation in place of the previously
recommended ORS solution.
REDUCED OSMOLARITY ORS
Ingredient
(grams/litre)
ion (mmol/litre)
Sodium chloride
(2.6)
Sodium (75)
Glucose, anhydrous
(13.5)
Glucose, anhydrous (75)
Potassium chloride
(1.5)
Chloride (65)/Potassium (20)
Trisodium citrate, dihydrate
(2.9)
Citrate (10)
Total Osmolarity = 245. In the human body, the plasma osmolality is about 285 mOsm/l.
PRECAUTIONS
• Hot water should not be used as it may lead to breakdown of bicarbonate and alteration
in flavor
• Do not use if the solution is coloured.
• Always use freshly prepared solution.
• The solution made should not be used 24 hours after its preparation.
• Use clean utensils to make solution.
Today, the total production is around 500 million ORS sachets per year, with the children's
rights agency UNICEF distributing them to children in around 60 developing countries. ORS
represents a cheap and effective way of reducing the millions of deaths caused each year by
diarrhea.
OBJECTIVES
At the end of this session a student shall be able to:
1. Understand how preparations are made in hospital pharmacy.
2. Various parts of a label on hospital pharmacy preparations.
CHAPTER
5
Common Dosage Forms and
Routes of Administration-I
Various dosage forms of drugs are used in therapy. Before discussing dosage forms let's see
what are the various sources of drugs.
SOURCES OF DRUGS
Plants: One third of allopathic drugs are still derived from plants. Problem associated with
a plant drug are: identification of plant, conditions of storage, standardization of active
principle, purity and maintenance of supply line, e.g. morphine, codeine
Animals: Some drugs are still obtained from animals due to expensive and cumbersome
synthesis, e.g. gonadotropins, heparin
Microorganisms: Antimicrobials are obtained, e.g. penicillin, erythromycin
Minerals: Some minerals are important for body and given prophylactically or for treatment
of deficiency, e.g. Zinc
Synthetic: Most of the drugs in use today are synthetic in origin. These drugs are chemically
pour and it is easy to maintain their supply, e.g. oral antidiabetics
Semisynthetic: Changes are made after synthesis, e.g. insulin
Biosynthetic: Recombinant technology is used to produce drugs, e.g. recombinant insulin
Drugs need to be presented in a form that can be administered to an organism. Formulation
is a recipe by which a drug is prepared. Drug formulation can allow specific tissue sites to be
selectively targeted or systemic absorption of the drug to be avoided. Formulation is not
only about a small amount of a drug that needs to be encapsulated or bottled for easy
delivery but it is also about how to present a drug for administration so that it is guaranteed
to reach the target area. The administration of drugs is one of the most important and
exacting duties performed in caring for sick and injured patients. The appropriate drug
given in the correct dosage will very often hasten a patient's recovery. On the other hand, an
inappropriate drug or dosage may worsen a patient's condition or even result in his death.
Common Dosage Forms and Routes of Administration-I  31
To discuss formulation we will discuss route of administration of drugs, dosage forms
used and their advantages and disadvantages.
Various routes of drug administration are:
A. For systemic effects
1. Enterable-oral, sublingual, etc.
2. Parenteral (which bypasses GIT)-i.v, i.m. etc.
B. For local effects
3. Local, e.g. topical application
C. Special preparations, e.g. controlled release
Remember that there are six "rights" in the administration of drugs:
1. Right patient
2. Right drug
3. Right dose
4. Right route
5. Right time
6. Right documentation
ORAL
The drug is given through mouth. It is the commonest and most acceptable method of drug
administration.
ADVANTAGES
1.
2.
3.
4.
Most convenient and cheapest
Non-invasive, painless and no assistance is required.
Aseptic precautions are not required.
Both, solid and liquid dosage forms can be given
• Solid preparations are: tablets, capsules, moulded tablets, powders, spansules,
etc.
• Liquid preparations are: syrups, mixtures, elixirs, emulsions, etc.
ORAL-TABLETS
A tablet is a disc, containing one or more medications, prepared
by compressing a granulated powder (Fig. 5.1). As most drugs
are presented in small quantities (sometimes less than a
milligram), other materials (excipients) must be added to make
them easy to handle, to be seen and to compress. Tablets must
have property to disintegrate in the gastrointestinal tract.
Fig. 5.1: Tablets
32  Practical Manual of Pharmacology
Capsules and tablets should be swallowed with a glass of water with the patient in upright
posture either sitting or standing, as this enhances the passage into the stomach and permits
rapid dissolution. Giving drugs orally to a recumbent patient should be avoided if possible,
especially in the case of drugs which can damage the esophageal mucosa, e.g. doxycyline,
iron salts, etc. Oesophagitis induced by these drugs is very difficult to treat. Tablets may be
scored i.e. a line demarcation is there to divide tablet into two equal parts (Fig. 5.2).
DISADVANTAGES
1.
2.
3.
4.
5.
6.
Action is slow so it is not suitable for emergency
Unpalatable drugs (e.g. paraldehyde) are difficult to administer
It may cause gastrointestinal adverse effects e.g. nausea and vomiting (e.g. emetine)
It can not be used for non cooperative/unconscious/vomiting patients
Certain drugs are not absorbed if given by this route (e.g. streptomycin)
Certain drugs are destroyed by gastric juices (penicillin G, insulin) or extensively
metabolized during first pass in the liver or GIT (e.g. nitroglycerine, testosterone,
lidocaine).
ORAL-CAPSULES
They can be of two types:
1. Hard gelatin type: It contains the drug as solid. It can be opened. Capsules can come in
many colors for easy identification. Hard capsule consists of 2 cylinders which fit into
one another (Fig. 5.3), e.g. amoxycillin capsules.
2. Soft gelatine type: It contains the drug in liquid or semi-liquid form. They are completely
sealed (Fig. 5.4). They are useful for liquid drugs and for drugs which are water insoluble,
e.g. nifedipine
Gelatin is heterogenous mixture of water soluble proteins of high molecular weight.
Pearls are transparent or translucent capsules that contain liquid or semisolid drugs,
e.g. vitamin A capsules.
Fig. 5.2: Tablets
Fig. 5.3: Capsules
Fig. 5.4: Soft Capsules
Common Dosage Forms and Routes of Administration-I  33
ADVANTAGES
1. Masks the bad smell and taste of drugs.
2. Avoids destruction by gastric juice and avoids gastric irritation.
DISADVANTAGE
More expensive than tablets.
ORAL-Pills means round or ovoid body, usual coated with sugar or even silver or gold
paint, e.g. oral contraceptives.
Tablets, capsules and pills are packed in the plastic coated paper or aluminum strips or in
blister packing (Fig. 5.5).
ORAL-powder: Powder is a solid form of drugs, which is finely divided and intimately
mixed (Fig. 5.6). They are mainly of three types. (i) Simple powders: contain one ingredient
only, e.g. glucose powder. (ii) Compound powders: contain more than one ingredients, e.g.
ORS powder. Simple powder - ORS and (iii) Effervescent powder, e.g. Antacid effervescent
powder, Seidlitz. Powders are packed in sachets.
ADVANTAGES
1. They are flexible in compounding.
2. Powders have a good chemical stability.
DISADVANTAGES
1. Needs proper instruction for preparing.
2. Time consuming to prepare.
3. It is not suitable for dispensing bitter drugs.
For effective use of this dosage form, required amount of powder to be dissolved in
required amount of water prior to administration and then to be taken orally.
Fig. 5.5: Packed tablets, capsules
Fig. 5.6: Powder
34  Practical Manual of Pharmacology
ORAL-LIQUIDS
Liquid oral formulations include syrups, mixtures, solutions, reconstituted oral solutions,
elixirs and gels (Fig. 5.7).
These two preparations (suspension and emulsion) have tendency to separate and requires
a thorough mixing before administration. Liquids for oral use are usually dispensed in plastic
or glass bottles.
ADVANTAGES OF LIQUID PREPARATIONS
1. They are more quickly acting than pills or tablets, which require previous disintegration
before absorption.
2. Certain substances can only be given in the liquid form, e.g. liquid paraffin.
3. Certain chemical substances, e.g. potassium chloride can cause gastric irritation if taken
in the form of powder or tablet.
4. Patients are sometimes prone to doubt the efficacy of the treatment they are receiving
unless it includes something in the bottle (e.g. placebo effect).
5. Usefulness of some substances are largely dependent upon administration of diffusible
form, e.g. magnesium sulphate in the form of suspension.
Syrups: They are liquid oral preparations in which the vehicle is concentrated aqueous
solution of sucrose or other sugar.
ADVANTAGES
1. They are sweet in taste so masking the bad taste of drugs, especially suitable for children.
2. Quicker effect than tablets which require previous disintegration.
DISADVANTAGES
1. Maintenance not easy.
2. They are costlier than tablets.
PRECAUTION
Close the bottle properly after use.
Elixir: Some drugs are insoluble in water, they are dissolved
in alcohol. These preparations are termed elixirs. They are clear
liquid oral preparations containing hydroalcoholic vehicle, e.g.
bromhexine, promethazine.
ADVANTAGE
Potent or nauseous drugs are pleasantly flavored and usually
attractively coloured so patient compliance is better.
Fig. 5.7: Syrup
Common Dosage Forms and Routes of Administration-I  35
DISADVANTAGES
1. Maintenance not easy.
2. They are costlier than tablets.
PRECAUTION
Close the bottle properly after use.
Suspension: A liquid preparation that is made from a drug in solid form but not dissolved
in alcohol is refers to as a suspension. It is a liquid medicament containing insoluble (diffusible
or indiffusible) solid substances which are homogeneously distributed throughout the vehicle
with or without the help of a suspending agent (Fig. 5.8).
ADVANTAGES
1. They are chemically more stable than the syrup.
2. Mask the unpleasant taste and odor of the drugs.
3. Insoluble solids can be given in liquid form.
DISADVANTAGES
1. A suitable preservative is required to avoid microbial contamination.
2. For effective use of this dosage form, shake the bottle well before use.
Emulsions: They are liquid medicaments containing two immiscible liquids, one of which
is broken into minute globules, each globule being surrounded by a thin film of emulsifying
agent and then dispersed throughout the other liquid, e.g. liquid paraffin emulsion.
ADVANTAGES
1. Oily drugs can be given in this form
2. Oil in finely dispersed state is quickly absorbed.
3. Emulsifying agents mask the unpleasant taste and smell of the drugs.
DISADVANTAGES
1. A suitable preservative is required to avoid microbial
contamination.
2. For effective use of this dosage form, shake the bottle well
before use.
Factors affecting oral route of administration:
1. Drug characteristics
2. Luminal pH along the GI tract
3. Destruction in GIT
4. Surface area per luminal volume
5. Blood perfusion
6. The presence of bile and mucus
Fig. 5.8: Suspension
36  Practical Manual of Pharmacology
7.
8.
9.
10.
The nature of epithelial membranes
Presence of food
Gut motility
First pass metabolism
DRUG CHARACTERISTICS
1. Unionised drugs are lipid soluble, hence absorption is better.
2. Most of the drugs are absorbed from small intestine due to large surface area, longer
contact time and rich vascular supply.
3. Presence of food usually delays absorption.
4. Some drugs are destroyed by gastric juices e.g. insulin, so these can not be given by
oral route.
5. First pass metabolism decreases bioavailability of drugs by oral route e.g. propranolol.
6. Gut motility and gastric emptying time also affect absorption of orally administered
drugs.
ORAL- SPECIAL PREPARATIONS
Coated preparations
Sometimes a drug needs to be disintegrated not in the stomach but in the intestine. The
tablets are coated with material which does not disintegrate in the acidic conditions of the
stomach but only in the alkaline conditions of the intestine, e.g. enteric coated aspirin to
avoid local toxicity in stomach.
• Coated tablets: Tablets may be sugar-coated or film-coated to disguise bad-tasting
drugs, e.g. Chloroquine tablet.
• Dispersible tablets: Tablets may be dispersible to avoid loss of disintegration in stomach
or to avoid local toxicity in oesophagus, e.g. doxycyline. These dispersible tablets are
to be dissolved in water prior to administration
• Chewable tablets: When chewed it disintegrates due to its creamy base, e.g. antacid
tablets, antihelminthic tablets and vitamin C tablets. It is useful to
children who have difficulty in swallowing and to the adults who
dislike swallowing, but tablet is expensive.
• Effervescent tablets: Prepared by compressing granular effervescent
salts. It disintegrates fast when added to water and acts by releasing
carbon dioxide (Fig. 5.9). Effervescence masks the bad taste of drug.
It may give psychological effect to patient, e.g. alkaline tablet,
antacid tablet, aspirin tablet. The tablet is very sensitive to moisture
and expensive also. The tablet to be dissolved in a glass of water
and the same to be taken orally while effervescence is present. Fig. 5.9: Effervescent
Take in upright posture either standing or sitting.
tablets
Common Dosage Forms and Routes of Administration-I  37
• Lozenges: These are disc shaped solid dosage forms, e.g. menthol, dextromethorphan.
They have local action in oral cavity. There is slow and continuous effect of the drug
on the mucous membrane of the throat.
SUSTAINED RELEASE (SR) PREPARATIONS
Drug is enclosed within device in such a way
that the rate of drug release is controlled
by its permeation through a membrane wall
(Fig. 5.10). These preparations release drug
slowly providing longer duration of action,
e.g. diclofenac sodium SR.
These are also known as retard or
controlled release preparations, e.g.
pilocarpine-releasing ocular insert for 4-day
continuous glaucoma treatment.
Fig. 5.10: SR
ADVANTAGES
1. It modifies the rate of release of drug into the gastrointestinal tract.
2. It prolongs the effect of drug and also reduces the frequency of administration.
3. Patient compliance is better.
DISADVANTAGES
1. It is expensive as compared to uncoated tablets.
2. Dose dumping at one site producing local toxicity/systemic and loss of control release
mechanism.
Sustained release preparations can be formed by various techniques as follows:
1. Membrane system—drug enclosed in polymers from where it is released slowly.
2. Matrix system—drug is incorporated in a porous matrix.
3. Coated granules—drug molecules are coated, which release drug at different rates
(Fig. 5.11).
RECTAL
Drugs in the form of suppositories are inserted into the anal canal, e.g. diazepam in children
suffering from status epilepticus. Rectum has rich vascular supply, so absorption is quick.
ADVANTAGES
1.
2.
3.
4.
5.
Unconscious, vomiting patient
Swallowing problems
In case of a difficulty to find the vein for intravenous injection
Uncooperative children
Unpleasant drugs
38  Practical Manual of Pharmacology
Fig. 5.11: Delivery systems and drug release
DISADVANTAGES
1.
2.
3.
4.
Anal or rectal irritation.
Inconvenient, aesthetic considerations.
Absorption slow, irregular and unpredictable.
They are made to melt at body temperature, so needs to be kept refrigerated. They can
even melt on the hand before insertion.
The patients need to be educated about the best position for insertion and also to remove
the plastic cover.
OBJECTIVES
At
•
•
•
•
the end of this session a student shall be able to:
Write down the name dosage form of the drug displayed at the various stations.
Give instructions to patients on the proper usage of each dosage form.
Write two important advantages of the dosage form.
Write two important disadvantages of the dosage form.
Exercises for this session can be arranged in stations. Each station has various dosage
forms. The stations can have the above mentioned dosage forms like:
Tablets–dispersible, sustained release, controlled release, enteric coated, sublingual
tablets, pills
Capsules–soft/hard gelatine capsules, pearls, spansules
Liquid oral formulations (mixtures)–syrups, mixtures, solutions, reconstituted oral
solutions, elixirs, suspensions, etc.
C H A P T E R
6
Common Dosage Forms and
Routes of Administration-II
Any method of drug administration that avoids the gastrointestinal tract is termed parenteral
administration. Parenteral is derived from combination of 2 words:
Par = beyond
Enteral = intestinal
Transdermal, intranasal, rectal are, therefore, parenteral methods. However, the usual
term parenteral is reserved for drug injections.
ADVANTAGES
1. They can be employed in an unconscious or an uncooperative patient.
2. They can be employed in cases of vomiting and diarrhoea and in the patients unable to
swallow.
3. Drugs which might irritate the stomach or which are not absorbed orally can be
administered, e.g. aminoglycosides.
4. They avoid drug modification by the alimentary juices and liver enzymes e.g. Insulin,
nitroglycerine.
5. Rapid action and accuracy of dose are ensured.
DISADVANTAGES
1.
2.
3.
4.
5.
Less safe, once given the action of given drug will become irreversible
More expensive
Inconvenient for use, self-medication being difficult
Liable to cause infection if proper care is not exercised
Likely to injure important structures such as nerves and arteries if not given properly.
Strict aseptic precaution should be taken while giving injection in order to prevent
infections due to HIV and Hepatitis B virus. Disposable syringe and needle should be
used and should be purchased from an authentic source. Needle should be broken
down and syringe should be discarded after use.
Injections: An injection is a method of putting liquid into the body with a hollow needle
and a syringe which is pierced through the skin long enough for the material to be forced
into the body. Preparations meant for parenteral administration must be sterile. Depending
40  Practical Manual of Pharmacology
upon the volume, they are supplied in sealed glass ampoules, e.g. streptomycin or rubber
capped multi-dose vials, e.g. multivitamins or large infusion bottles, e.g. 5% dextrose or in
polypropylene pouches, e.g. metronidazole.
DOSAGE FORMS FOR INJECTIONS
i. Aqueous or clear solution for subcutaneous/intramuscular/intravenous use.
ii. Suspension for intramuscular/intravenous use.
iii. Emulsion for intravenous use. Oily solution for intramuscular use long-acting forms of
subcutaneous/intramuscular injections are available for various drugs; these are called
depot injections.
iv. Powder to be reconstituted for intramuscular/intravenous use. Powder has to be
dissolved or suspended in colloidal form before injecting by adding an adequate quantity
of a suitable solvent (e.g. streptomycin) because reconstitution of drug reduces the
shelf life and stability.
PARENTERAL
Intravenous injections (IV)
An intravenous infusion is a liquid administered directly into the bloodstream via a vein.
Drug is given in one of the superficial veins.
Drug is either given as:
1. Bolus IV injection, e.g. adenosine in PSVT (immediate action is required), furosemide in
acute pulmonary edema.
2. Slow IV injections over 5-10 minutes, e.g. calcium gluconate in arrhythmias (to avoid
toxicity of calcium on heart).
3. Slow IV infusion, e.g. oxytocin in induction of labour (slow and sustained action is
required) (Fig. 6.1). This is done by dissolving drug in 50-100 ml of isotonic glucose or
saline.
4. Rapid IV infusion is sometimes used, e.g. fluids in shock.
Drug is usually in aqueous form (Fig. 6.2). It should be nonirritant to vascular endothelium.
Fig. 6.2: IV infusion
Fig. 6.2: IV fluid
Common Dosage Forms and Routes of Administration-II  41
ADVANTAGES
1.
2.
3.
4.
5.
6.
100% bioavailability
Immediate onset of action, so it can be used in emergencies
Titration of dose can be done
First pass metabolism bypassed
GIT adverse effects not present
Can be used in unconscious, uncooperative and vomiting patients.
DISADVANTAGES
1.
2.
3.
4.
5.
6.
7.
8.
Aseptic precautions are mandatory
Vital organs are exposed to high concentration of drug
Thrombophlebitis
Expensive
Invasive
Painful
Trained person is required
If the drug extravasates there may be necrosis and sloughing, e.g. with pentothal sodium,
quinine.
Before learning technique of IV injection it is important to learn to fill the syringe with
drug. Drug can be available as liquid or powder form. It can be present in single dose
ampoule or multidose vial.
Exercise: How to aspirate drug from ampoule into syringe?
REQUIREMENTS
Syringe of appropriate size, ampoule with required drug or solution, needle of right size,
disinfectant, gauze (Fig. 6.3).
TECHNIQUE
1. Wash your hands properly with soap and water.
2. Take out syringe and needle from disposable pack taking care not to touch naked end
of syringe.
3. Put the needle on the syringe.
4. Remove the liquid from the neck of the ampoule by flicking or tapping it or swinging it
fast in a downward spiralling movement.
5. File around the neck of the ampoule.
6. Carefully break off the top of the ampoule. Protect your fingers with gauze if ampoule
is made of glass.
7. For a plastic ampoule twist the top.
8. Remove cover from needle.
42  Practical Manual of Pharmacology
9. Aspirate the fluid from the ampoule.
10. Remove any air from the syringe.
11. Clean up, dispose of working needle safely and wash your hands.
Exercise: How to aspirate drug from vial into syringe?
REQUIREMENTS
Vial, syringe of the appropriate size, needle of right size, disinfectant, gauze.
TECHNIQUE
1. Wash your hands properly with soap and water.
2. Take out syringe and needle from disposable pack taking care not to touch naked end
of syringe. Use a syringe with a volume of twice the required amount of drug or solution.
3. Put the needle on the syringe.
4. Remove protective covering from vial cap. Disinfect the top of the vial with a cotton
swab soaked in disinfectant (Fig. 6.3).
5. Remove cover from needle.
6. Suck up as much air as the amount of solution needed to aspirate.
7. Insert needle into vial through rubber cap and push down and then mix.
8. Pump air into vial (creating pressure).
9. Aspirate the required amount of solution and 0.1 ml extra. Make sure the tip of the
needle is below the fluid surface (Fig. 6.4).
10. Pull the needle out of the vial.
11. Remove the air from the syringe.
12. Clean up, dispose of waste safely and wash your hands.
Fig. 6.3: Ampoule
Fig. 6.4: Aspiration
Common Dosage Forms and Routes of Administration-II  43
Exercise: How to dissolve dry medicine in vial and aspirate drug solution into syringe?
Antibiotic drugs such as penicillins, streptomycin and the tetracyclines often are manufactured
and supplied to you in the form of a sterile powder in a vial which must be reconstituted
with sterile water for injection, normal saline solution, or other suitable diluent (solvent)
REQUIREMENTS
Vial with dry medicine to be dissolved, syringe of the appropriate size, needle of right size,
disinfectant, gauze.
TECHNIQUE
1. Wash your hands properly with soap and water.
2. Take out syringe and needle from disposable pack taking care not to touch naked end
of syringe.
3. Put the needle on the syringe.
4. Aspirate solvent into syringe from the ampoule.
5. Remove protective covering from cap of vial. Disinfect the rubber cap (top) of the vial
containing the dry/powdered medicine.
6. Insert the needle into the vial, hold the whole unit upright.
7. Suck up as much air as the amount of solvent already in the syringe.
8. Inject only the fluid into the vial, not the air.
9. Shake well.
10. Turn the vial upside-down.
11. Inject the air into the vial (creating the pressure).
12. Aspirate the total amount of solution.
13. Remove any air from the syringe.
14. Clean up, dispose of waste safely and wash hands.
It is recommended that all antibiotics that are reconstituted and are to be used later,
should be labeled in the following way (see example):
1. Hour and date reconstituted.
1400 hrs 9 Mar 07
2. Strength of reconstituted antibiotic.
50,000 units/ml
3. Initials of the preparer.
Exercise: How to inject by Intravenous route?
REQUIREMENTS
Syringe, drug, needle 20G, liquid disinfectant, cotton wool, adhesive tape and tourniquet.
PROCEDURE
1. Wash your hands properly with soap and water
2. Reassure the patient and explain the procedure
3. Uncover arm completely
44  Practical Manual of Pharmacology
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Have the patient relax and support his arm below the vein to be used
Apply tourniquet, tell patient to clinch fist and look for a suitable vein
Wait for the vein to swell. Disinfect skin
Stabilize the vein by pulling the skin taut in the longitudinal direction of the vein. Do
this with the hand you are not going to use for inserting the needle.
Insert the needle at an angle of around 35° (Fig. 6.5)
Puncture the skin and move the needle slightly into the vein (3-5 mm)
Hold the syringe and needle steady
If blood appears hold the syringe steady, you are in the vein. If it does not come, try
again
Loosen tourniquet. Withdraw needle swiftly. Check for pain, hematoma
Press sterile cotton wool onto the opening. Secure with adhesive tape
Check the patient's reactions and give additional reassurance, if necessary
Clean up, dispose of waste safely and wash your hands.
Exercise: Model for IV injections for students in laboratory
REQUIREMENTS
A simple model for IV administration can be used to teach the students about the process of
IV injection. Model of hand with vein (made of latex glove stuffed with mattress foam and a
rubber tube filled with red ink placed under the latex glove on top of the cotton), IV infusion
sets, butterfly needles, IV fluid bottles.
Follow same procedure as described forIV injection.
GENERAL PRINCIPLES
Apart from the specific technique of injecting, there are a few general rules that you should
be kept in mind.
1. Expiry dates: Check the expiry dates of each item including the drug. If you make
housecalls and keep stock of injections, check the drugs in your medical bag regularly
to make sure that they have not passed the expiry date.
2. Drug: Make sure that the vial or ampoule contains the right drug in the right strength.
3. Sterility: During the whole preparation procedure, material should be kept sterile. Wash
your hands before starting to prepare the injection. Disinfect the skin over the injection
site.
4. Prudence: Once the protective cover of the
needle is removed extra care is needed. Do
not touch anything with the unprotected
needle. Once the injection has been given take
care not to prick yourself or somebody else.
6. Waste: Make sure that contaminated waste is
disposed of safely.
Fig. 6.5: IV injection
Common Dosage Forms and Routes of Administration-II  45
7. Do not use plastic tubing for glyceryl trinitrate, paraldehyde.
8. Protect nitroprusside from light by covering infusion set with brown paper.
PARENTERAL-IM
Intramuscular injections
Drug is injected in one of the large skeletal muscles of the body, i.e. deltoid, gluteus and in
infants in anterolateral region of the thigh in middle third region. Skeletal muscle is highly
vascular and its capillaries contain small pores which enable substances of small molecular
weight to pass through into the bloodstream. Several muscles of the body have considerable
mass and can be injected with quantities of up to several millilitres of fluid without inducing
discomfort to the patient. Generally, intramuscular injections are not self-administered, but
rather by a trained medical professional, e.g. many vaccines, antibiotics, and long-term
psychoactive agents.
Aqueous solutions better absorbed than oily solutions. Depot preparations in oil can be
given to prolong duration of action. The degree of tissue perfusion and condition of the
injection site will influence the rate of drug absorption.
ADVANTAGES
1.
2.
3.
4.
5.
Rate of absorption is reasonably uniform.
Less painful.
Onset of action-fairly rapid.
Depot preparations can be given.
In addition to soluble substances, mild irritants, suspensions and colloids can be injected
by this route.
DISADVANTAGES
1.
2.
3.
4.
5.
Aseptic precautions are mandatory.
Danger of injecting into blood stream.
Intramuscular absorption is not always faster than oral absorption.
The volume of injection should not be more than 10 ml.
Pain at the site of injection, irritation, abscess formation or
tissue and nerve damage may occur. Rapid absorption may
cause even death.
PRECAUTIONS
1. Do not inject in gluteal region in a child until child starts
walking. Inject into lateral part of thigh.
2. Heparin should not be given IM (hematoma).
3. Injury to nerves leading to paresis of muscles can occur. Never
give IM injection to child with suspected poliomyelitis.
Fig. 6.6:
Sites for IM
injection in adults
46  Practical Manual of Pharmacology
4. A healthy well developed person can tolerate 3.0 ml in large muscles, this does NOT
include the deltoid. For elderly, thin clients or children the total amount should not
exceed 2.0 ml. No more than 1.0 ml should be given to young children and older infants.
Exercise: How to inject drug by intramuscular route?
REQUIREMENTS
Syringe filled with the drug to be administered (without air), needle 22G, liquid disinfectant,
cotton wool, adhesive tape.
PROCEDURE
1. Wash your hands properly with soap and water
2. Reassure the patient and explain the procedure
3. Uncover the area to be injected (lateral upper quadrant major muscle lateral side of
upper leg, deltoid muscle Fig. 6.6)
4. Disinfect the skin and tell the patient to relax the muscle
5. Insert needle swiftly at the angle of 90° (watch depth)
6. Aspirate briefly, if blood appears withdraw needle. Replace it.
7. Inject slowly (less painful)
8. Withdraw needle swiftly
9. Press sterile cotton wool onto the opening. Fix with adhesive tape Check the patient's
reaction and give additional reassurance, if necessary
10. Clean up, dispose of waste safely and wash your hands.
Exercise: How to inject drug by intramuscular route in an orange model?
REQUIREMENTS
Syringe filled with the drug to be administered (without air), needle 22G, liquid disinfectant,
cotton wool, adhesive tape, Orange.
Orange peel gives resistance and feeling of injecting through skin. When needle enters
inside orange it gives feeling of injecting in muscle.
PROCEDURE
Same as above.
PARENTERAL-SC
A subcutaneous injection is administered into the subcutis, the layer of
skin directly below the dermis and epidermis, collectively referred to as
the cutis. Subcutaneous injections are highly effective in administering
such medications as insulin, morphine, diacetylmorphine or goserelin
(Fig. 6.7). Drug is injected into loose subcutaneous tissue. Hyaluronidase
can increase absorption, which breaks down intracellular matrix. A person Fig. 6.7: SC injection
Common Dosage Forms and Routes of Administration-II  47
with type I diabetes mellitus typically injects insulin subcutaneously. Places on the body
where people can inject insulin most easily are:
• The outer area of the upper arm
• Just above and below the waist, except the area right around the navel (a 2-inch circle)
• The upper area of the buttock, just behind the hip bone
• The front of the thigh, midway to the outer side, 4 inches below the top of the thigh to
4 inches above the knee.
Subcutaneous—the volume to be administer is 1.0 ml or less.
ADVANTAGES
1. Self-administration possible.
2. Drugs in oil or implants can be given.
3. Action of the drug is sustained and uniform (Fig. 6.8).
Fig. 6.8: ROA and concentration time curve
DISADVANTAGES
1. Painful
2. Onset of action-slower
3. Only non-irritant substances can be injected by this route.
Subcutaneous drug implants can act as depot therapy, e.g. Medroxyprogesterone.
Exercise: How to inject drugs subcutaneously?
48  Practical Manual of Pharmacology
REQUIREMENTS
Syringe with the drug to be administered (without air), needle 25G, liquid disinfectant,
cotton wool, adhesive tape.
PROCEDURE
1.
2.
3.
4.
5.
6.
7.
Wash hands with soap and water.
Reassure the patient and explain the procedure.
Uncover the area to be injected (upper arm, upper thigh, abdomen).
Disinfect skin, "Pinch" fold of the skin.
Insert needle in the base of the skin-fold at an angle of 20 to 30°.
Release skin.
Aspirate briefly, if blood appears: withdraw needle, replace it with a new one, if possible,
and start again from point 4.
8. Inject slowly (0.5-2 minutes).
9. Withdraw needle quickly.
10. Press sterile cotton wool onto the opening. Fix with adhesive tape.
11. Check the patient's reaction and give additional reassurance, if necessary.
12. Clean up, dispose of waste safely and wash hands.
Insulin is administered only using an insulin syringe. Most insulin vials contain 100 units/
ml. Insulin may be administered subcutaneously, intramuscularly (rarely used) and
intravenously. Regular insulin is the only type that may be given IV since it does not contain
any additives to prolong the action. Regular insulin is clear. If the vial is cloudy, it has been
contaminated and should be discarded. Longer acting insulin is cloudy and may have a
precipitate on the bottom of the vial. Be sure to mix the vial well by rotating it between the
hands.
PARENTERAL-INTRADERMAL INJECTION
Drug or substance is injected into the dermis using a fine needle. The absorption is very slow
and only small quantities of the drug can be given by this route. This route is used for
specific purpose only. Intradermal—the volume to be administered is 0.1 ml or less, e.g.
BCG vaccine.
Other less commonly used injectable routes are:
Intra-thecal injectons are made into the cerebrospinal fluid. This drug are given to get
drugs directly into the central nervous system by avoiding the blood brain barrier commonly
used for spinal anesthesia and chemotherapy.
Epidural injections is just like intrathecal but the drug is deposited above the dura and
not in the cerebrospinal fluid. Local anesthetics are often given this way during surgical
procedures, specially for procedures involving the pelvic and inferior regions, to block.
Intra-arterial injections: To deliver high concentration of anticancer drugs in malignancy,
e.g. vasodilator drugs in the treatment of vasospasm and thrombolytic drugs for treatment
of embolism.
Common Dosage Forms and Routes of Administration-II  49
Intra-articular injections: are used to inject drugs directly into joint. But strict aseptic
precautions are a must (Fig. 6.9).
PARENTERAL- SUBLINGUAL
Highly lipid soluble drugs can be absorbed from sublingual and buccal mucosa, e.g.
Nitroglycerin, a potent vasodilator, used in angina.
ADVANTAGES
• This form of administration avoids the mixing of drug with food and/or gastric juices
which may impede absorption.
• Immediate action, can be used in emergency.
• Action can be terminated by spitting the remaining drug.
• Bypasses hepatic first pass metabolism (Fig. 6.10).
Fig. 6.9: Intraarticular injection
Fig. 6.10: Circulation
DISADVANTAGES
1. Drug taste must be pleasant.
2. Irritant drugs cannot be given.
Can produce ulcers in mouth.
PARENTERAL-TRANSDERMAL
The skin is relatively more impermeable to drugs than other
stratified epithelia. The skin is useful to administer drugs which
are very lipophilic and active in very small amounts. Drug is present
in patches (Fig. 6.11) which release drug at constant and predictable
rate. No peaks or troughs of drug concentration are seen. Site used
are-chest, abdomen, upper arm, buttocks. Transdermal drug
delivery avoids problems such as gastrointestinal irritation,
Fig. 6.11: Patch
50  Practical Manual of Pharmacology
metabolism, variations in delivery rates and interference due to the presence of food. It is
also suitable for unconscious patients. The technique is generally non-invasive and aesthetically
acceptable and can be used to provide local delivery over several days.
Examples are:
• Nicotine patches-help stop smoking.
• Oestradiol-prevent menopausal symptoms.
• Fentanyl cytrate-prevent severe pain.
• Nitrate patches-for angina.
Transdermal delivery system (patches) can be of various types (Fig. 6.12) as follows:
1. Membrane controlled
The drug in solution or bound to polymer is held in a reservoir between an occlusive
backing film and a rate controlling micropore membrane. The drug is absorbed into
systemic circulation by diffusion.
2. Matrix controlled
The drug is homogeneously mixed with rate controlling polymer and rate of release is
controlled by its diffusion through polymer matrix.
3. Sandwich type
Combination of membrane and matrix type. Matrix is coated with a rate controlling
polymer membrane.
Rate of absorption depends on:
Fig. 6.12: Transdermal delivery
Common Dosage Forms and Routes of Administration-II  51
• Degree of hydration.
• Keratinisation.
• Rate of blood flow through skin.
ADVANTAGES
1.
2.
3.
4.
5.
6.
Bypasses first pass metabolism.
Maintains constant plasma levels for a longer period.
Less side effects.
Easy to discontinue if toxicity appears.
No GIT side effects.
Convenient to use, compliance improves.
DISADVANTAGES
1.
2.
3.
4.
5.
6.
Local irritation, erythema.
Onset of action-slower.
Can not achieve high concentration in plasma.
Can not deliver drugs in a pulsatile manner.
Development of tolerance.
Expensive.
Methods to increase permeation
• Physical, e.g. iontophoresis.
• Chemical, e.g. sorption promoters.
• Biological, e.g. skin metabolism inhibitors.
Instructions for correct use of this dosage form:
1.
2.
3.
4.
5.
6.
7.
Do not apply over bruised or damaged skin.
Do not wear over skin folds or under tight clothing and change spots regularly.
Apply with clean, dry hands.
Clean and dry the area of application completely.
Remove patch from package, do not touch 'drug' side.
Place on skin and press firmly. Rub the edges to seal.
Remove and replace according to instructions.
OBJECTIVES
At the end of this session a student shall be able to:
• Write down the dosage form of the drug displayed at the various stations.
• Administer the drug properly by required method.
52  Practical Manual of Pharmacology
• Understand and describe precautions required during use of each dosage form.
• Write two important advantages of the given dosage form.
• Write two important disadvantages of the given dosage form.
Exercises for this session can be arranged in stations. Each station has various dosage
forms. The stations can have the above mentioned dosage forms like:
Ampoules, vials, IV set, syringes, needles, patches.
DEMONSTRATE
1. How you will aspirate drug from an ampoule/vial?
2. How you will make solution of dry drug for injection?
3. How you will inject drug through IV route/ IM route?
Exercise 1:
Inject 0.1 ml of saline intravenously into the model provided.
Check-list
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Wipes area with spirit from centre to periphery.
Waits for the spirit to dry.
Positions needle with bevel facing upwards.
Holds syringe in correct manner (without touching needle).
Inserts needle into skin first.
Withdraws to check whether in vein.
Pushes plunger smoothly and completely.
Withdraws and wipes area with cotton.
Disposes needle (without recapping) and syringe correctly.
Completes procedure smoothly without disruption.
Exercise 2:
Give clear instructions on the proper use of a transdermal nitroglycerine patch to this patient.
Check-list
1.
2.
3.
4.
5.
6.
7.
8.
Greets the patient.
Offers a seat.
Opens pack.
Right side has to be on skin.
Over the lateral chest wall.
Change every day.
Do not place on exactly same site.
If irritation or redness - come to doctor.
Common Dosage Forms and Routes of Administration-II  53
9. Not more than two patches in a day.
10. Check whether it is there after bath.
Exercise 3:
You have decided to put this 24 years female going to get married, on oral contraceptives
after having taken a history and done a physical examination. Give instructions on the use of
this packet of contraceptive pills which contain low dose combination pills.
Check-list
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Explains that she will be on a contraceptive.
To start on fifth day of menstrual cycle.
To start a new packet at end of this without gap.
If pill is missed to take it next day.
If more than 2 pills are missed additional contraceptive cover.
Additional methods for first cycle.
Explains withdrawal bleeding.
Explains breakthrough bleeding.
To take at same time each night.
When to return - next visit.
C H A P T E R
7
Common Dosage Forms and
Routes of Administration-III
LOCAL
This refers to the application of a drug to an area of the body for direct treatment. Usually
there is inefficient absorption (1-15%). High local tissue levels nevertheless achievable, often
higher than by systemic route. Toxicity usually not a problem.
DROPS
Eye and nose drops are made isotonic to avoid pain or discomfort. Ear drops are formulated
as oily solutions to coat and adhere to the aural cavity.
EYE DROPS
They are aqueous or oily solutions for instilling into conjunctival sac (Fig. 7.1). They are used
as anesthetics, anti infective or anti inflammatory agents, miotics, mydriatics and artificial
tears.
For example atropine sulphate (mydriatic), pilocarpine nitrate (miotic), timolol maleate.
ADVANTAGES
1. Local effect at required place.
2. Easy to apply.
3. Drug interactions can be avoided.
DISADVANTAGES
1.
2.
3.
4.
It requires repeated application.
Systemic effects can occur following absorption.
May cause irritation.
Once seal is broken, should be used within 1 month.
PROCEDURE
1. Wash your hands.
2. Do not touch the dropper opening.
3. Look upward.
Fig. 7.1: Eye drops
Common Dosage Forms and Routes of Administration-III  55
4.
5.
6.
7.
8.
9.
Pull the lower eyelid down to make a 'gutter' or pouch.
Bring the dropper as close to the 'gutter' as possible without touching it or the eye.
Instill the prescribed number of drops (usually 1 or 2) in the 'gutter'.
Close the eye for about two minutes. Do not shut the eye too tight.
Excess fluid can be removed with a tissue. Do not rub.
If more than one kind of eye drop is used wait at least five minutes before instilling the
next drops.
Eye-drops may cause a burning feeling but this should not last for more than a few
minutes. If it does last longer, consult a doctor or pharmacist.
EYE OINTMENT
They are semisolid preparations with a greasy base, to be applied in the eye, e.g. neomycin
eye ointment, chloramphenicol eye ointment, tetracycline eye ointment.
ADVANTAGE
They have longer duration of action.
DISADVANTAGE
Due to greasy base eyes may become sticky.
PROCEDURE
1.
2.
3.
4.
5.
6.
7.
8.
9.
Wash your hands.
Do not touch anything with the tip of the tube.
Tilt the head backwards a little.
Take the tube in one hand and pull down the lower eyelid with the other hand, to make
a 'gutter'.
Bring the tip of the tube as close to the "gutter" as possible.
Apply the amount (usually 1 cm length) of ointment.
Close the eye for two minutes.
Remove excess ointment with a tissue.
Clean the tip of the tube with other tissue.
EAR DROPS
They are aqueous or oily solutions instilled in the ear, e.g. wax softeners, sodium bicarbonate.
ADVANTAGE
Avoid systemic side effect due to its local action.
DISADVANTAGE
Local irritation can occur.
56  Practical Manual of Pharmacology
PROCEDURE
1.
2.
3.
4.
5.
Lie on one side with the ear upward.
Gently pull the lobe to expose the ear canal.
Instill the amount (usually 4-5) of drops.
Wait for five minutes before turning to the other ear.
Use cotton wool to close the ear canal after applying the drops only if the manufacturer
explicitly recommends this.
6. Ear drops should not burn or sting longer than a few minutes (Fig. 7.2).
NASAL DROPS
They are aqueous solutions of drugs instilled into the nose with a dropper, e.g. Xylometazoline,
ephedrine, etc.
ADVANTAGE
Local and quick action.
DISADVANTAGES
1. Absorption can occur producing systemic effect.
2. May cause local irritation.
PROCEDURE
1. Blow the nose.
2. Sit down and tilt head backward strongly or lie down with a pillow under the shoulders;
keep head straight.
3. Insert the dropper one centimeter into the nostril.
4. Instill the number of drops prescribed (usually 3-4 drops).
5. Sit up after a few seconds, the drops will then drip into the pharynx.
6. Repeat the producer for the other nostril, if necessary.
7. Rinse the dropper with boiled water.
NASAL SPRAYS
These are drugs or combinations of drugs (Fig. 7.3) which by virtue of their high vapor
pressure, can be carried by an air current into nasal passage and exert their effect, e.g.
Beclomethasone, calcitonin, vasopressin, etc.
ADVANTAGES
1. Easy to use.
2. It covers large surface area so quick absorption.
DISADVANTAGE
Explosion may occur in hot environment as the contents are under pressure.
Common Dosage Forms and Routes of Administration-III  57
PROCEDURE
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Blow the nose.
Sit with the head slightly tilted forward.
Shake the spray. Insert the tip in one nostril.
Close the other nostril and mouth.
Spray by squeezing the vial (flask, container) and sniff slowly.
Remove the tip form the nose and bend the head forward strongly (head between the
knees).
Sit up after a few seconds; the spray will drip down the pharynx.
Breath through the mouth.
Repeat the procedure for the other nostril, if necessary.
Rinse the tip with boiled water.
SUPPOSITORIES
A suppository (Fig. 7.4) is a drug delivery system that is inserted either into the rectum
(rectal suppository), vagina (vaginal suppository) or urethra (urethral suppository) where it
dissolves. They are used to deliver both systemically acting and locally acting medications.
They are solid, uniformly medicated masses of medicaments, e.g. glycerin, bisacodyl.
ADVANTAGES
1. Local application for systemic as well as local effect
2. Especially helpful for unconscious or in a patient who can not take orally.
DISADVANTAGES
1. Inconvenient and some times irritant
2. Aesthetic concerns
3. Local irritation.
Fig. 7.2: Ear drops
Fig. 7.3: Nasal spray
Fig. 7.4: Suppository
58  Practical Manual of Pharmacology
PROCEDURE
1. Wash your hands.
2. Remove the covering (unless too soft).
3. If the suppository is too soft let it harden first by cooling it (fridge or hold under cold
running water, still packed) then remove covering.
4. Remove possible sharp rims by warming in the hand.
5. Moisten the suppository with cold water.
6. Lie on your side and pull up your knees.
7. Hold the suppository by the non pointed end and insert the tip into the anal opening.
8. Now just gradually push, keep pushing (it may be further than you imagine) and at
some point the suppository will be pulled into the rectum by the anal sphincter. Remain
lying down for several minutes.
9. Try not to have a bowel movement during the first hour.
VAGINAL PESSARIES
It is the term applied to suppository shaped medications for vaginal administration. This is
a topical treatment and it is important that the drug coats all the vagina mucosa. Vaginal
medications whether in pessaries or cream come with applicators which are designed to
reach the upper parts of the vaginal canal. Vaginal preparations which are left in situ are best
used at night because the vagina has no means of retention like sphincters and the medication
can run out.
Vaginal tablet (Pessary) with applicator
They are vaginal suppositories intended for introduction into vagina, e.g. nystatin,
metronidazole.
ADVANTAGES
1. Local application
2. Avoid systemic effect.
DISADVANTAGES
It may cause staining and irritation.
PROCEDURE
1.
2.
3.
4.
5.
Wash your hands.
Remove the wrapper from the tablet.
Place the tablet into the open end of the applicator.
Lie on your back, draw your knees up a little and spread them apart.
Gently insert the applicator with the tablet in front into the vagina as far as possible, do
not use force.
Common Dosage Forms and Routes of Administration-III  59
6.
7.
8.
9.
Depress the plunger so that the tablet is released.
Withdraw the applicator.
Discard the applicator (if disposable).
Clean both parts of the applicator thoroughly with soap and boiled lukewarm water (if
not disposable).
Without applicator
1.
2.
3.
4.
5.
Wash your hands.
Remove the wrapper from the tablet.
Dip the tablet in lukewarm water just to moisten it.
Lie on your back, draw your knees up and spread them apart.
Gently insert the tablet into the vagina as high as possible, do not use force.
OINTMENTS
These are lipid-based. They have a greasy appearance and feel. The drug is trapped under
the dressing and, the layer of the skin is soften from sweating, enabling the drug to penetrate
deeply into the tissues. Eye ointments are formulated to melt quickly so that vision is not
impaired.
PASTES
They have a very high powder content. They are useful in protecting areas of skin from
moisture, being water repellent.
GEL AND LOTIONS
They are used on the hairy areas of the body. Alcoholic gels or lotion are less messy than
ointments or creams, but the evaporation of carrier is rapid, therefore, there is little penetration
of the drug (Fig. 7.5).
JELLIES
For urethral application.
DUSTING POWDER
They are free flowing very fine powders having particle size < 150 µm for external use. They
are used to treat superficial skin conditions.
They are sterilized by dry heat and supplied in
airtight glass or plastic jars with reclosable
perforated lid or sprinkler holes at top.
Commonly used dusting powders are purified
talc, magnesium sulphide powder, neomycin
powder, sulphacetamide sodium, sulphadiazine
Fig. 7.5: Gel
powder.
60  Practical Manual of Pharmacology
ADVANTAGES
1. Systemic side effects of drugs are avoided because of local application.
2. It provides greater stability.
DISADVANTAGE
It requires repeated application.
LOTIONS
They are liquid preparations meant for local application to the skin or mucous membrane
without rubbing for providing soothing or antiseptic effects. These medications are preferably
supplied in amber or blue coloured bottles to protect them from sunlight, e.g. potassium
permanganate lotion (0.1%), cetrimide lotion (1%), calamine lotion.
ADVANTAGE
Systemic side effects of drugs are avoided because of local application.
DISADVANTAGE
Patient may experience a gritty feeling.
PROCEDURE
1. Shake the bottle well before use
2. Apply without rubbing, on the affected part with the help of cotton swab.
LINIMENTS
They are liquid or semiliquid preparations intended for external application by rubbing and
may contain substances possessing analgesic, rubefacient, soothing or stimulating properties.
They may be either emulsions or solutions, e.g. liniment turpentine.
ADVANTAGE
Systemic side effects of drugs are avoided because of local application.
DISADVANTAGE
Patient may experience a burning sensation.
PROCEDURE
Apply with rubbing on the affected part.
OINTMENTS
They are semisolid preparations in a greasy base used for external application by inunction.
They are of such consistency that they soften but not necessarily melt when applied to the
skin, e.g. Whitfield's, salicylic acid, calamine ointment.
Common Dosage Forms and Routes of Administration-III  61
ADVANTAGES
1. They increase the hydration of the skin.
2. The duration of action is prolonged due to occlusive dressing.
DISADVANTAGES
1. They stain the clothes.
2. Inconvenient to the patient due to greasy base.
PROCEDURE
To be applied on the affected part with inunction.
CREAMS
They are semi solid preparations consisting of opaque emulsions for external use (Fig. 7.6).
The term cream is most frequently applied to a soft cosmetic type of preparation. Creams
are used in treatment of skin conditions like eczema, pruritis as astringent, emollient, and
antiseptics. They are dispensed in collapsible metal or plastic tubes, glass or plastic pots.
ADVANTAGE
They are cosmetically more acceptable due to their less greasy nature.
DISADVANTAGE
They are easily washed out so requires repetitive application.
SPRAYS
They are preparations of drugs in aqueous, alcoholic or glycerin containing media, e.g.
adhesive sprays.
ADVANTAGE
Easy to use and cover a larger surface area.
DISADVANTAGE
Explosion may occur in hot environment as the contents are under pressure.
PAINTS
They are simple solutions containing medicaments in semisolid solvents like liquid paraffin
or glycerin, e.g. povidone iodine.
Fig. 7.6: Cream
62  Practical Manual of Pharmacology
ADVANTAGE
Retain the medicament in situ for longer period.
DISADVANTAGE
May cause staining and irritation.
LOCAL-inhalation
Drug administered by nasal or oral respiratory route. Action is either on bronchial tree or
systemic due to absorption through lungs, e.g. salbutamol and beclomethasone in bronchial
asthma. Drugs are delivered to bronchial musculature in asthma. Aerosols are formed as
drug solution or microionised drug powder is converted into mist/dust respectively.
Particle size which is absorbed in between 3 to 5 µm. If size < 3 µm-particles are not
retained, they come out with expiration. If size > 5 µm particles are not absorbed. Preparations
used for inhalation route are:
1. Dry powder inhalers.
2. Metered dose aerosol-drug is delivered through pressurized canister equipped with a
valve through which only metered dose is discharged. Medication is most commonly
stored in solution in a pressurized canister. The canister is attached to a plastic, handoperated pump. The standard metered dose inhaler (MDI) on activating releases a
fixed dose of medicine in aerosol form (Fig. 7.7).
3. Nebuliser—In children and other patients who can not inspire forcefully while
coordinating with inhaler opening, nebulisers are used (Fig. 7.8). The air pressure
required for aerosol formation is generated by an electric pump. A nebuliser, or
"breathing machine," is another way to take inhaled medicines. A nebuliser treatment is
given with an air compressor machine. Pressurized room air is used to create a mist of
the medicine solution, which is inhaled for approximately 5-10 minutes.
4. Rotahalers—The device is loaded with rotacapsules and then drug is inhales with forceful
inspiration. Only capsules specifically made for rotahalers are used with rotahalers
(Fig. 7.9).
Fig. 7.7: MDI
Fig. 7.8: Nebuliser
Fig. 7.9: Rotahaler
Common Dosage Forms and Routes of Administration-III  63
Only a small portion of drug (10%) reaches respiratory tract a small fraction of this
amount penetrates mucosa.
ADVANTAGES
1.
2.
3.
4.
5.
Systemic effects including toxicity is less, e.g. steroids in asthma
Targeted delivery of drug
Easy to use
Less amount of drug is needed
Onset of action is fast.
DISADVANTAGES
1. Reflex bronchospasm
2. Candida growth in oral cavity
3. Patient has to learn the technique.
PROCEDURE FOR CORRECT USE (FOR MDI) (FIGS 7.10 AND 7.11)
1. Cough up as much sputum as possible.
2. Shake the inhaler before use.
3. Hold the inhaler as indicated in the manufacturer's instructions (this is held usually
upside down).
4. Fully exhale.
5. Place the lips tightly around the mouthpiece.
6. Tilt the head backward slightly.
7. Breathe in deeply and activate the inhaler (press the metallic bottle), keeping the tongue
down. The co-ordination between activating the inhaler and breathing in is critical for
effective delivery of the drug into the lungs.
8. The aerosolized medicine is drawn into the
lungs by continuing to inhale deeply before
holding the breath for 10 seconds to allow
absorption into the bronchial walls.
Fig. 7.10: Absorption through lungs
Fig. 7.11: Use of Inhaler (MDI)
64  Practical Manual of Pharmacology
9. Hold the breath for ten to fifteen seconds.
10. Breathe out through the nose.
11. Rinse the mouth with warm water.
PROCEDURE (FOR ROTAHALER)
1. Check the mouthpiece for foreign objects.
2. Twist the barrel in either direction until it stops.
3. Take a capsule (designed for rotahaler) and insert the clear (thinner/white) end into
the raised hole of rotahaler. Push the new capsule in until it is level with the top of the
hole (Fig. 7.12).
4. Hold the Rotahaler vertically, turn the lower end as far as it will go in the opposite
direction. This will open the capsule.
5. Cough up as much sputum as possible and gently breathe out.
6. Place the lips tightly around the mouthpiece.
7. Tilt the head backward slightly.
8. Breathe in through your mouth as quickly and deeply as possible. Continue to take a
full, deep breath.
9. Hold your breath for upto ten seconds. This allows the medication time to deposit in
the airway.
10. Resume normal breathing.
11. After each use, pull the two halves of the rotahaler apart and throw away the loose
capsule shell.
12. Reassemble the rotahaler. Repeat steps 1-7 when more than one rotacap is prescribed.
CARE OF FOR THE ROTAHALER
Clean the rotahaler once every two weeks or sooner
if needed. Regular cleaning will prevent powder
accumulation inside the rotahaler.
1. Remove the empty capsule shell before
washing the rotahaler.
2. Rinse the two halves of your rotahaler in warm
water.
3. Shake off any excess water.
LOCAL-ORAL
Gargles and Mouthwashes
They are aqueous solutions used for throat
infections and hygienic purpose, e.g. saline gargles,
potassium permanganate solution, povidone
iodine, betahexidine.
Fig. 7.12: Parts of rotahaler
Common Dosage Forms and Routes of Administration-III  65
ADVANTAGE
Local soothing and antiseptic action.
DISADVANTAGE
May cause staining and irritation.
PROCEDURE
1. Use with proper instruction that is written on the label. Swish mouthwash around in
the mouth for at least 30 seconds and then spit it out. Do not swallow it.
2. Keep away from children.
NEW TECHNIQUES FOR DRUG DELIVERY
Conventional Drug Delivery Systems
Tablets, capsules, pills, suppositories, creams, ointments, liquids, aerosols, and injectables.
New drug delivery systems (NDDS)
Most of the marketed drugs these days are new delivery systems of older drugs only,
hence, you will find a lot of OD, CR, SR and patches in the market. The reason is that an old
drug can be given a new life by putting it into new delivery system, it is less expensive and
time consuming as compared to discovering a new molecule. The profits are almost similar.
There is now a growing realisation that innovative delivery of drugs would not only increase
safety and efficacy levels but also improve the overall performance of the drug.
WHY NDDS?
• These days a consumer (patient) demands more efficacious, safe, convenient and low
cost drugs, e.g. cipro-OD, intranasal insulin.
• The provider spends less money in new drug delivery system as compared to new
drug. New drug development takes approximately $800 million and 12 years. NDDS
development takes only 20% cost of new drug and only 6-8 years.
Advances in drug delivery systems are also expected to offer a host of additional
advantages such as ease of administration, increased patient compliance, decreased side
effects and cost reduction. Multiple injections required per week or day could be replaced
by once a month dosages or even longer intervals, which would stabilise blood levels of the
medication, thereby enhancing treatment outcomes and patient compliance.
New delivery systems are usually offer following advantages
1.
2.
3.
4.
Targeted drug delivery.
Maximum efficacy/minimum adverse effects.
Maintain steady state plasma conc.
Longer duration and patient compliance.
66  Practical Manual of Pharmacology
NDDS-ORAL
• Programmed drug delivery
• Sustained release and controlled release (SR/CR), e.g. theophylline SR, Indomethacin
CR
• Prodrugs
• Cyclodextrins.
PRODRUGS
Also known as "Smart Drugs", these compounds are designed to work only when activated
by certain components in the body. For example, a smart drug designed to be activated by a
certain enzyme will be activated only in tissues that produces that specific enzyme. These
are drugs which are inactive outside body and get activated through metabolism in the
body, e.g. Enalapril. So these drugs have.
• Inactive precursors
• Have active metabolites.
ADVANTAGES
1. Better bioavailability
2. Increased stability
3. Less side effects
4. Targeted delivery, e.g. Cyclophosphamide, Levodopa, Zidovudine.
SUSTAINED VS. CONTROLLED RELEASE
Sustained release, a pharmaceutical dosage form formulated to retard the release of a
therapeutic agent such that its appearance in the systemic circulation is delayed or prolonged
and its plasma profile is sustained in duration. These forms also limit fluctuation in plasma
drug concentration, providing a more uniform therapeutic effect. Absorption rate is slowed
by coating drug particles with wax or other water-insoluble material, by embedding the
drug in a matrix that releases it slowly during transit through the GI tract, or by complexing
the drug with ion-exchange resins. Most absorption of these forms occurs in the large bowel.
Crushing or otherwise disturbing a controlled-release pill can often be dangerous. Alcohol
can also disturb this delivery system, leading to dose dumping at one point only.
Controlled release, goes beyond the scope of sustained drug action. Implies a
predictability and reproducibility in drug release kinetics.
NDDS-OTHERS
•
•
•
•
Transdermal therapeutic systems
Inhalation route
Coated implantable devices
Antibody tagging
Common Dosage Forms and Routes of Administration-III  67
• Non viral vectors for gene therapy
• Special forms of subcutaneous route
Demoted
Pellet implantation
Sialistic and biodegradable implants
• Tissue specific drug delivery systems
Bone specific
Colon specific
Lung and liver specific
• Biomolecular engineering, protein drugs
• Gene gun, gene pills
• Nanotechnology
• Microfabrication
• Oral vaccines ( in banana)
• Liposomal delivery.
OBJECTIVES
At the end of this session a student shall be able to:
• Write down the dosage form of the drug displayed at the various stations.
• Administer the drug properly by required method
• Understand and describe precautions required during use of each dosage form
• Write two important advantages of the given dosage form
• Write two important disadvantages of the given dosage form
Exercises for this session can be arranged in stations. Each station has various dosage
forms. The stations can have the above mentioned dosage forms (Flow Chart 7.1) like:
Eye drops, ear drops, eye ointments, vaginal pessaries, inhalers, nasal sprays,
suppositories, prodrugs.
DEMONSTRATE
Explain the use of inhaler to a patient.
CHECK-LIST
1.
2.
3.
4.
5.
Greets the patient.
Offers a seat.
Open the mouthpiece.
Breath normally thrice.
Start inhaling mid inspiration.
68  Practical Manual of Pharmacology
Flow Chart 7.1: Depicting various dosage forms
6. Hold breath for 20 secs.
7. Wipe mouthpiece.
• What precautions you will give to patients to take drug through nebulisers
• What precautions you will give to patients to take drug using rotahalers
• What precautions you will give to patients to take drug vaginaly/rectally
PRECAUTIONS FOR STORAGE OF DOSAGE FORMS (FIG. 7.13)
• Most of the commercial preparations are labeled with expiry dates.
• The longevity of a medicament is governed by its shelf-life. Shelf-life of a drug is the
duration from the time the product is manufactured till the
potency of the drug has been reduced by 10%.
• This limit is usually considered acceptable in practice; more
stringent standard is required if the degradation products are
more toxic or irritative than the parent drugs. This can happen
with tetracycline antibiotics.
• Products with a shelf-life of more than 3 years are considered
to be stable as these are expected to sold and used within his
period.
• Products with a shorter half-life should be labeled with
Fig. 7.13: Storage of drugs
expiration date.
Common Dosage Forms and Routes of Administration-III  69
• As a guide to good pharmaceutical practice it is suggested that mixtures recommended
to be 'freshly prepared' should be prepared not more than 24 hours before issue to the
patient.
• Mixtures recommended to be 'recently prepared' should be stored in unopened bottles
in the dispensary for not more than 3 months.
• Should there be any doubt, the pharmacist should be consulted.
ENVIRONMENTAL FACTORS AFFECTING DOSAGE FORM
• pH: Affect rate of chemical reaction and hence, longevity of a drug.
• Temperature: An increase in temperature usually increases the rate of chemical reaction.
Storage of a medicine in a cool place (below 15°C) will prolong the shelf-life. Refrigeration
may prolong shelf-life of a medicament that is unstable in room temperature but solid
particles may grow and precipitate in a suspension. The temperatures suitable for storage
of topical drugs lies in the range of 15-25°C.
• Environmental factors affecting dosage form.
• Oxygen: Many drugs show slow oxidation in the presence of atmospheric oxygen, e.g.
adrenaline, glyceryl nitrate is so prone to oxidation, the shelf-life is only about 3 months
after the bottle has been opened.
• Light: Can induce photochemical degradation. This can be reduced by the use of lightresistant containers or more effectively, by storage in the dark. Sodium nitroprusside
very light sensitive, must be kept in darkened glass ampoules, wrapped in black plastic.
• Humidity: Low humidity may be responsible for the powdering of granular solids
containing effervescent salts and for the 'drying out' of creams. High humidity brings
about the deterioration of effervescent tablets and solid preparations that contain
hygroscopic materials. The adverse effects of humidity can be avoided by the use of
moisture-proof containers. Aspirin hydrolyses readily to acetic acid and salicylic acid
in the presence of moisture (most people store medicine and their aspirin tablet in
bathrooms).
Section 2
Experimental Pharmacology
CHAPTER
8
Introduction to Experimental
Pharmacology
Today's pharmacology teaching is much different from yesterday's teaching of Materia
Medica. For better healthcare and to provide more effective, safe and affordable medications
research is continuously being carried on new chemicals. This continuous search for new and
better drugs starts from animal experimentation, i.e. preclinical testing before clinical testing
in human subjects. There is enormous change in research methodology due to new high-tech
instruments and methods available to us.
Just as medicine cannot be taught or learnt without going towards and clinics, similarly
pharmacology cannot be taught without experimentation. But animals should not be
sacrificed just to gain skills about exact methodology and the techniques of animal experiments.
Animals are not easily available nowadays due to animal welfare regulations and ethics.
Animal experiments are expensive, time consuming and tedious. Thus with the changing
scenario alternative methods of teaching pharmacology experiments have been developed
along with the advances in computer technology. Animal experiments can be substituted by
demonstrations using computer simulated learning programs. Students can be taught to use
these programs. Give them exercises to analyse the results obtained from experiments,
interpret them and apply them in different clinical situations. To analyse the results of any
experiment or drug trial and draw conclusions is good learning experience for developing
clinical judgement skills.
A number of animal experiments can be demonstrated to students, but important ones
are:
1. Effects of various drugs on the Rabbit Eye
2. Effects of various drugs on the Frog Heart
3. Effect of various drugs on Rabbit Intestine
4. Effects of various drugs on the Dog Blood Pressure.
These experiments can be carried out on animals (Fig. 8.1) or
these can be demonstrated with computer simulation models.
Wherever animals are sacrificed, those experiments can be demonstrated with computer simulation models. In those experiments where
animals are not sacrificed or tortured and if animals are available in
Fig. 8.1: Albino rat
the institute, then animals can be used in experiments.
74  Practical Manual of Pharmacology
Various softwares are available for computer simulation demonstrations. Exercises in
the form of graphs, tables obtained from various animal experiments can be used to teach
students. They will analyse and interpret them applying different methods, formulae and
statistics whenever necessary. After the discussions they will draw conclusions, correlate
them clinically and answer the various questions given with graphs, tables and other exercises.
Exact simulation of real animal experiments on a computer is not easy because the
biological responses are very complex. Many factors come control an organ or a system.
Hence, the results obtained with these simulated models may not be very accurate. But
remember that the aim of the software is to teach the students about major facts that have
practical utility in their future life.
The purpose of demonstration of these models by a teacher would be of great help to
students to understand the experimental procedure and the theory behind it. These programs
may be used for self-learning later on.
Understanding of autonomic nervous system pharmacology is essential for planning
rational drug therapy of diseases like asthma, hypertension, parkinsonism, glaucoma, etc.
Theoretical discussion alone may not suffice for the same, while discussion of experimental
exercises may provide a sound background for enhancing the understanding. This will give
to the students a general idea about how experiments are conducted, how results are
interpreted and applied clinically.
CHAPTER
9
Effects of Drugs on Rabbit Eye
INTRODUCTION
The Iris is composed of two types of muscle fibres, the circular and the radial muscles. The
circular fibres are supplied by parasympathetic nerve fibres (cholinergic) and the radial
ones are innervated by sympathetic nerve fibres (adrenergic). The stimulation of sympathetic
and parasympathetic nerves produces mydriasis and miosis respectively and their paralysis
produces opposite effects. Drugs which simulate the effects of autonomic nervous system
can produce the above mentioned effects. This experiment uses a few such drugs on the
rabbit eye (Figs 9.1 and 9.2).
Sphincter Pupillae
(Circular Muscle Fibers)
Muscarinic (cholinergic receptors-M3)
Fig. 9.1: Structure of eye
Dilator Pupillae
(Radial Muscle Fibres)
Sympathetic (adrenergic receptors-α1)
Fig. 9.2: Muscle fibres of eye
76  Practical Manual of Pharmacology
REQUIREMENTS
1.
2.
3.
4.
5.
6.
Rabbit
Scissors
Measuring scale
Droppers
Torch
Cotton wool.
DRUGS AND SOLUTIONS
A. Normal saline
B. Mydriatic drugs:
Active
Phenylephrine
C. Miotic drugs:
Active
Pilocarpine
D. Local anaesthetic:
Lignocaine hydrochloride
20%
Passive
Atropine sulphate
4.0%
Passive
Phentolamine (not used)
1.0%
1-2%
PROCEDURE
• Handle rabbit with care.
• Clip off eyelashes of both the eyes
• Use pouch method to instill drugs into eye. Pinch lower eyelid to make a small pouch.
Instill 1-2 drops of saline/drug in it using dropper. Pull the lower eyelid upwards and
keep it in contact with conjunctiva for 1-2 minutes
• You can also press medial canthus for 5 seconds after instillation of drug
• Keep one eye (either right or left eye) as control and the other as test
• Apply saline in the control eye and a drug in the test eye.
Following parameters are measured at 5-15 minutes after instillation of drug (Fig. 9.3):
1. Size of pupil
2. Light reflex
3. Touch reflex (Corneal reflex)
1. Size of Pupil
Measure the diameter of both the pupils. This can be measured
with a pupilometer made up of cardboard or hard paper. Take
a hard paper, cut it approximately equal to a 6 inch ruler.
Then cut holes in it having increasing order of diameter in
millimeters. You can start with 1mm then mark upto 10 mm.
You can also measure with the help of a simple scale. It will
Fig. 9.3: Instillation
look like this:
Effects of Drugs on Rabbit Eye  77
It is difficult to force open eyes of rabbit. Hence, with pupilometer it becomes easy to
measure diameter. Keep pupilometer close to eye through which you can see pupil, match
the hole in pupiolometer with size of pupil and note down the size in mm written on the
matched hole.
2. Light Reflex
Light reflex is checked with a torch. A pencil torch is best suited for this purpose. Always
put the light from side (back) and bring it to the front. Do not put the light from the front
side of the rabbit. Observe the changes in the diameter of pupil when light is put into
eye. Note any decrease or increase in pupillary diameter. Take 3 readings.
3. Corneal Reflex
It is tested with a fine cotton wool wick. Wick is made in such a manner that there is no
protruding part of cotton. Touch peripheral part of cornea with tip of cotton wick. Always
bring forward the cotton wool from the side (back). Rabbit should not be able to see
cotton wool or your hand. Blinking represents presence of corneal reflex. Do not forget
to note down the 3 readings.
Precaution: Do not touch central part of cornea it can cause corneal ulcers/opacities.
This can lead to blindness as central part of cornea is the main part of cornea used for
visibility.
Computer Simulation Model (CSM) Procedure: The teacher will show the students the
various instruments used for this experiment. Then he/she will describe the procedure and
steps in setting up the experiment. Then the whole batch for a particular day is shown the
experiment using LCD projector. Students are told about the various options available and
how to operate the software. Then the batch is divided into groups and each group is
provided with a computer which has been pre-loaded with software. Then demonstrator/
instructor will then guide students to operate the software and students are allowed to
work on their own. An instructor/demonstartor is always there to help the students. Students
are expected to write down the procedure and effect of drugs and tabulate findings giving
reasons for the changes in heart rate, respiration or increase or decrease in BP. They have to
draw the graph obtained and find out the nature of the unknown drug given in the program
(Table 9.1).
78  Practical Manual of Pharmacology
Table 9.1. Effect of drugs on rabbit eye
DRUGS
LIGHT REFLEX
Right
Left
+++
+++
+++
--+++
+
+++
+
+++
+++
Phenylephrine
Atropine
Pilocarpine
Physostigmine
Lignocaine
CORNEAL REFLEX
Right
Left
+++
+++
+++
+++
+++
+++
+++
+++
+++
---
PUPIL SIZE mm
Right
Left
4
8
4
8
4
1.4
4
1
4
4
ADDITIONAL INFORMATION
Active and passive miotics and mydriasis (Table 9.2)
When miosis occurs as a result of active contraction of the sphincter pupillae (circular muscle
of the iris), it is known as active miosis. This usually occurs as a result of action of
cholinomimetics. When miosis occurs as a result of (passive) relaxation of the dilator pupillae
(radial muscle of the iris), it is known as passive miosis. It usually results from action of
adrenergic blockers. Similarly with mydriatics also, there is active and passive mydriasis
due to active contraction of the dilator pupillae or relaxation of sphincter pupillae.
Table 9.2. Classification of miotics and mydriatics
Drugs
Miotics
Mydriatics
Centrally acting
Active
Cholinomimetics:
Pilocarpine
Carbachol
Anticholinesterases
Physostigmine
Neostigmine
Sympathomimtics
1Phenylephrine
Morphine
Indications of Miotics
1.
2.
3.
4.
Cataract
Anterior chamber surgery
Wide angle glaucoma
To break adhesions between lens and iris
Passive
Adrenergic blockers
Phentolamine
Anticholinergics
Atropine
Homatropine
Cyclopentolate
Tropicamide
Effects of Drugs on Rabbit Eye  79
5. Reversal of mydriatic effects of anticholinergics
6. Xerostomia.
Indications of mydriatics
1. Fundoscopy for visualisation of the periphery of retina.
2. Retinoscopy in those who are unable to relax their eyes, e.g. children, very old patients.
3. To break and prevent adhesions between iris and lens in iridocyclitis (alternate miotics
and mydriatics)
4. Chronic simple glaucoma
5. Corneal ulcer/uveitis
6. Preoperative: Cataract surgery/Vitrectomy/Retinal surgery
7. Fluorescent fundus or Indocyamine green angiography.
LOCAL ANAESTHETICS (LAs)
LAs reversibly block impulse conduction along nerve axons and other excitable membranes
that utilises the Na+ Channels as primary means of action potential generation.
Procaine is not a surface anaesthetic (Poor penetration). Cocaine is not used because of
corneal sloughing (protoplasmic poison). LAs block corneal reflex in the rabbit eye.
OBJECTIVES
At the end of the practical class the student shall be able to:
1. Explain effect of drug A on rabbit eye.
2. Identify the nature of unknown drug B instilled into rabbit eye.
3. Name three miotics/mydriatics used clinically and their important uses and
contraindications.
4. Explain difference between active and passive miosis/mydriasis.
Demonstrate on animals
1. Instill drugs carefully into the rabbit's eye by making pouch without injuring the
cornea.
2. Study the effect of given drug on the rabbit's eye.
3. Record, analyze and interpret the observations obtained during this experiment.
Exercise in examination
These days LCD projectors are available in which you can project only a part of computer
screen. This type of projector it is very easy to use these softwares for examination purpose.
On your projector screen everything is visible including name of drugs, but you can project
only eye in which drug is instilled.
C H A P T E R
10
Effect of Drugs on Frog Heart
Many drugs act on the heart. Adrenergic and cholinergic drugs produce opposite effects on
it. These drugs act through their respective receptors. Some drugs act directly on the heart.
This experiment demonstrates the effects of drugs and ions (agonists, antagonists, calcium
and potassium) on the frog heart.
Requirements
1. A medium sized frog, frog board and
frog tray.
2. Starling's heart lever (Fig. 10.1).
3. Venous cannula attached through drip
set to a reservoir containing ringer
perfusion fluid.
4. A kymograph with drum and smoked
paper or physiograph with chart
recorder.
5. A pithing needle, 2 pairs of scissors, 2
pairs of forceps, 1cc syringe with a
needle, scale and pencil.
Fig. 10.1: Starling heart lever
Procedure
A frog is pithed and dissected to expose the
heart (Fig. 10.2). Pericardium is removed.
Heart is lifted up. Sinus venosus is cannulated
using a glass cannula (Syme's cannula) and
secured with thread. Then the heart is
perfused with Ringer solution through the
sinus venosus. Perfusion rate is adjusted at
30-40 drops/minute. A curved needle is
inserted in the apex and attached to a heart
lever for recording contractions on the
Fig. 10.2: Dissected frog
smoked paper pasted over the drum of a
kymograph. Starling heart lever is used. It
has a spring to record fast contractions.
Effect of Drugs on Frog Heart  81
Lever should be horizontal. Normal contractions are recorded followed by effect of
drugs (Table 10.1). Students are demonstrated this experiment in batches of 5-6 students
and then they are supposed to conduct the same experiment themselves in batches of 5-6
students.
[Instead of heart lever, drum and kymograph, a physiograph can be used (Fig. 10.3).
Transducer replaces the heart lever and is connected to the heart. Chart paper and pens are
used for recording].
CSM Procedure: The teacher will show the students the apparatus and other instruments
used for this experiment. Then he/she will describe the procedure and steps in setting up
the experiment. Then the whole batch for a particular day is shown the experiment using
LCD projector. Students are told about the various options available and how to operate the
software. Then the batch is divided into groups and each group is provided with a computer
which has been pre-loaded with software. Then demonstrator/instructor will guide
students to operate the software and students are allowed to work on their own. An
instructor/demonstartor is always there to help the students. Students are expected to write
down the procedure and effect of drugs and tabulate findings giving reasons for the changes
in heart rate, respiration or increase or decrease in BP. On screen is seen graph recording
contractions. You can choose drugs from a drop down menu. You can also select dose of the
drug. Then press inject button and observe changes in graph. There is also provision of use
of blockers to find out nature of action of drug, i.e. whether it is direct acting or indirect
acting.
The students have to draw the graph obtained and find out the nature of the unknown
drug given in the program.
• There is NO CORONARY CIRCULATION
Facts About Frog Heart!
to the heart. Heart derives its energy
• Heart is three chambered—there are two
from atmospheric oxygen and directly
atria, but only one ventricle.
from the blood contained in it.
• Ventricle contains mixed blood.
• Heart rate is 20-80 beats /minute.
• Superior and inferior venae cava open
into sinus venosus. Venous blood flows
from sinus venosus to right atrium and
from right atrium to ventricle. Arterial
blood comes from left atrium into the
ventricle. Ventricle pumps mixed blood
to bulbous aorta. Bulbous aorta have
spiral valve that directs arterial blood
to body and venous blood to lungs
through pulmonary arteries.
• There is no specialised conducting tissue
in the heart. There is muscular continuity
in all the chambers of the heart and
Fig. 10.3: Physiograph
there is NO VALVES in the heart.
82  Practical Manual of Pharmacology
Table 10.1: Drugs and solutions used in frog heart experiment
Drugs
Dose
(µg)
2
Concentration
(µg/ml)
10
2. Norepinephrine
(Noradrenaline)
2
10
3. Isoprenaline
2
10
4. Propranolol
200
1 mg/ml
5. Acetylcholine
2
10
6. Atropine sulphate
20
100
7. Calcium Chloride
2000
10 mg/ml
8. Potassium Chloride
µg = micrograms
2000
10 mg/ml
1. Epinephrine
(Adrenaline)
9. Frog Ringer solution
Volume of above solutions to be injected = start with 0.1 ml, if sufficient response is not
there increase dose to 0.2 ml and so on.
Procedure
Inject drugs one by one. Observe the following parameters before and after drug
administration:
a. Force of contraction–amplitude (normal, increased or decreased)
b. Tone (normal, increased or decreased)
c. Heart rate (beats per minute).
Parameter (a) and (b) are assessed by observing the recording (Figs 10.4 and 10.5). Tables
10.2 and 10.3 shows the effect of various drugs on frog’s heart (recording 1 and recording 2
respectively). The amplitude of contractions reflect the force. Shift in the mid point of systolic
and diastolic contractions indicate the change in tone. Heart rate is assessed by counting
movements of lever or directly by observing the heart.
Fig. 10.4: Effect of various agonists of frog heart contractions (Recording 1)
Effect of Drugs on Frog Heart  83
Fig. 10.5: Effect of various agonists in presence of antagonists on frog heart contractions (Recording 2)
The above parameters must be recorded in a sheet or record book. Tabulate the data.
Interpret the data and record your conclusions.
Precautions
a. Give sufficient time for the heart to recover between drug administrations.
b. Always note the parameter readings before and after giving drugs.
c. Record heart rate when there is maximum effect of drug.
Table 10.2. Effect of drugs on frog heart (Recording 1)
S.NO.
1
2
3
4
5
6
7
DRUG
Control
Epinephrine
Norepinephrine
Isoprenaline
CaCl2
Acetylcholine
KCl2
HEART RATE
87
92
83
115
1
67
1
AMPLITUDE
Normal
Increased
Increased
Increased
Decreased
Decreased
Decreased
TONE
Normal
Increased
No change
Increased
Increased
No change
Decreased
Procedure to Inject Drugs
Inject 0.2 ml of drugs 1-4 in succession (cardiac stimulants) in the tube through which the
heart is being perfused and record the responses. A control reading (without addition of
any drug) should be taken before and after each drug response. All the parameters mentioned
above should be recorded during the control and drug responses respectively. The heart
rate, drug name and the dose should be mentioned in the recording during the control and
drug responses. The next drug response should be recorded only after the heart rate has
returned to the approximate original value. Inject stimulants and depressants. In case the
heart stops because of systolic or diastolic arrest restart only when the heart is contracting.
In case adequate response is not observed use a higher dose.
Inject 0.2 ml of propranolol (depressant) and note its response. Stop the drum for 3
minutes. After 3 minutes inject adrenaline (same dose as injected previously) and note whether
84  Practical Manual of Pharmacology
Table 10.3. Effect of drugs on frog heart (Recording 2)
S. NO. DRUG
1
2
3
4
5
6
7
8
Control
Propranolol
followed by
Epinephrine
Propranolol
followed by
Norepinephrine
Propranolol
followed by
Isoprenaline
Propranolol
followed by
CaCl2
Control
Atropine
followed by
Acetylcholine
Atropine
followed by
KCl
HEART RATE
AMPLITUDE
TONE
86
76
Normal
Decreased
Normal
Decreased
76
72
No change
Decreased
No change
Decreased
72
69
No change
Decreased
No change
Decreased
69
72
No change
Decreased
No change
Decreased
1
85
89
Decreased
Normal
No change
Increased
Normal
No change
89
85
No change
No change
No change
No change
1
Decreased
Decreased
its effect is adequately blocked. In case sufficient blockade is not obtained repeat the procedure
with 0.4 ml propranolol.
Inject calcium chloride immediately after adrenaline effect has been blocked and note
whether its effect has been blocked or not. In case the typical increase in rate and/or
systolic arrest is not observed use higher dose.
Inject 0.2 ml of cardiac depressants, i.e. acetylcholine and potassium chloride after taking
control readings in between drug responses. Note also the condition of the heart during
diastolic arrest. Diastolic arrest is due to hyperpolarisation.
Inject 0.2 ml of atropine and note its response. Normally no response is seen because it is
an in vitro preparation and moreover atropine has no intrinsic activity of its own. Stop the
drum and wait for 3 minutes, inject acetylcholine (same dose as given earlier) and note
whether effect is completely blocked. In case sufficient blockade is not obtained, repeat the
same procedure with 0.4 ml of atropine.
Effect of Drugs on Frog Heart  85
Finally inject potassium chloride after the effect of acetylcholine has been blocked by
atropine and note whether the effect is blocked. There should be no blockade of KCl effect.
OBJECTIVES
At the end of the practical class the student shall be able to:
CSM
1. Interpret effect of various drugs on heart rate, amplitude and tone
2. Describe mechanism of action of various drugs
3. Comment on nature of unknown drugs given.
Exercise in Examination
These days LCD projectors are available in which you can project only a part of computer
screen. With this type of projector it is very easy to use these softwares for examination
purpose. On your computer screen everything is visible including name of drugs, but you
can project only recording showing effect.
CHAPTER
11
Effect of Drugs on Rabbit Intestine
Many drugs act on the intestine. Adrenergic and cholinergic drugs produce opposite effects
on it. These drugs act through their respective receptors. Some drugs act directly on the
intestine. This experiment demonstrates the effects of various drugs on the rabbit intestine.
Requirements
1. A medium sized rabbit.
2. Frontal writing lever. It does not stick to writing paper on drum and gives straight
lineas compared to simple lever (Figs 11.1 and 11.2).
3. A water bath having temperature control unit, organ bath with aeration tube.
4. A kymograph with drum and smoked paper or Physiograph with chart recorder.
5. 2 pairs of scissors, 2 pairs of forceps, 1cc syringe with a needle, scale and
pencil.
Procedure
A rabbit is sacrificed and dissected to expose the intestines. A part of ileum is taken 10 cm
away from ileocaecal valve. An optimal length of tissue (5-6 cm) is cut and a thread is tied to
antimesenteric border on both sides. Then one end is tied to a fixed point inside organ bath
and other point is attached to the lever for recording contractions on the smoked paper
pasted over the drum of a kymograph (Fig. 11.3). Lever should be horizontal. Normal
contractions are recorded followed by effect of drugs. Students are demonstrated this
experiment in batches of 5-6 students and then they are supposed to conduct the same
experiment themselves in batches of 5-6 students.
Fig. 11.1: Frontal writing lever
Fig. 11.2: Simple lever
Effect of Drugs on Rabbit Intestine  87
[Instead of heart lever, drum and
kymograph, a physiograph can be used. Force
transducer replaces the heart lever and is
connected to the heart. Chart paper and pens
are used for recording].
CSM Procedure: The teacher will show
the students the apparatus and other
instruments used for this experiment. Then
he/she will describe the procedure and steps
in setting up the experiment. Then the whole
batch for a particular day is shown the
experiment using LCD projector. Students are Fig. 11.3: Organ bath with intestine attached to lever
told about the various options available and how to operate the software. Then the batch is
divided into groups and each group is provided with a computer which has been preloaded with software. Then demonstrator/instructor will guide students to operate the
software and students are allowed to work on their own. An instructor/demonstartor is
always there to help the students. Students are expected to write down the procedure and
effect of drugs and tabulate findings giving reasons for the changes amplitude, tone and
frequency of intestinal movements. You can choose drugs from a drop down menu. You can
also select dose of the drug. Then press inject button and observe changes in graph. There is
also provision of use of blockers to find out nature of action of drug, i.e. whether it is direct
acting or indirect acting.
The students have to draw the graph obtained and find out the nature of the unknown
drug given in the program.
Table 11.1. Drugs and solutions used in rabbit intestine experiment
Drugs
Dose
(µg)
2
Concentration
(µg/ml)
10
2. Propranolol
200
1 mg/ml
3. Acetylcholine
2
10
4. Atropine sulphate
20
100
5. Barium chloride
2000
10 mg/ml
1. Epinephrine
(Adrenaline)
6. Kreb’s solution
Volume of above solutions to be injected into organ bath = start with 0.1 ml, if sufficient
response is not there increase dose to 0.2 ml and so on.
88  Practical Manual of Pharmacology
Procedure
Inject drugs one by one (Table 11.1). Observe the following parameters before and after
drug administration:
a. Force of contraction—amplitude (normal, increased or decreased)
b. Tone (normal, increased or decreased)
c. Frequency of contractions (per minute).
Parameters (a) and (b) are assessed by observing the recording. The amplitude of
contractions reflect the force. Shift in the mid point of contractions indicate the change in
tone. Rate is assessed by counting movements of lever.
The above parameters must be recorded in a sheet or record book. Tabulate the data
(Table 11.2). Interpret the data and record your conclusions.
Precautions
a. Give sufficient time for the intestine to recover between drug administrations.
b. Always note the parameter readings before and after giving drugs.
c. Record frequency of contraction when there is maximum effect of drug.
Table 11.2. Effect of drugs on rabbit intestine
S. NO.
1
2
3
4
5
6
Drug
Control
Epinephrine
Acetylcholine
Atropine
BaCl2
Ephedrine
Frequency
Normal
Decreased
Increased
Decreased
Increased
Decreased
Amplitude
Normal
Decreased
Increased
Decreased
Increased
Decreased
Tone
Normal
Decreased
Increased
Decreased
Increased
Decreased
Procedure to Inject Drugs
Inject 0.1 ml of drugs 1-4 in succession (spasmogenic) in the organ bath and record the
responses. A control reading (without addition of any drug) should be taken before and
after each drug response. All the parameters mentioned above should be recorded during
the control and drug responses respectively. The drug name and the dose should be
mentioned in the recording during the control and drug responses. The next drug response
should be recorded only after the rate and amplitude have returned to the approximate
original value. Inject spasmogenics and spasmolytics. In case adequate response is not
observed use a higher dose.
Inject 0.2 ml of propranolol (depressant) and note its response. Stop the drum for 3
minutes. After 3 minutes inject adrenaline (same dose as injected previously) and note whether
its effect is adequately blocked. In case sufficient blockade is not obtained repeat the procedure
with 0.4 ml propranolol.
Effect of Drugs on Rabbit Intestine  89
Inject barium chloride immediately after adrenaline effect has been blocked, and note
whether its effect has been blocked or not.
Inject 0.1 ml of atropine and note its response. Atropine produces relaxation. Stop the
drum and wait for 3 minutes, inject acetylcholine (same dose as given earlier) and note
whether effect is completely blocked. In case sufficient blockade is not obtained, repeat the
same procedure with 0.4 ml of atropine.
Finally inject ephedrine after the effect of acetylcholine has been blocked by atropine
and note whether the effect is blocked. There should be no blockade of ephedrine effect.
OBJECTIVES
At the end of the practical class the student shall be able to:
CSM
1. Interpret effect of various drugs on rabbit intestine.
2. Describe mechanism of action of various drugs.
3. Comment on nature of unknown drugs given.
CHAPTER
12
Effect of Drugs on Dog
Blood Pressure
This experiment should be demonstrated using computer simulation model only. Experiments
on large animals require permission from subcommittee of CPCSEA.
Procedure
A dog is anesthetized with pentobarbital 3% intravenously (30 mg/kg). Trachea and carotid
arteries are exposed. A ‘Y’ shaped tracheal cannula is put in cut trachea. Through one limb
artificial respiration can be given with a respiratory pump if required or secretions can be
cleaned. Other limb can be attached to a tube to record respiratory movements. Carotid
artery on one side is cannulated. The cannula prefilled with sodium citrate solution is attached
to a mercury manometer to record blood pressure. A butterfly cannula is inserted into leg
vein to inject drugs. Drugs (Table 12.1) are injected and there effect is recorded on a smoking
drum. The arterial cannula may be connected to a mercury manometer or to a pressure
transducer, which is connected to a polyrite or physiograph (Fig. 12.1). Heart rate is recorded
by observing movements of lever.
Fig. 12.1: Dog BP and respiration recording
Effect of Drugs on Dog Blood Pressure  91
Table 12.1. Drugs and solutions used in dog BP experiment
Drugs
Dose
(µg/kg)
Concentration
(µg/ml)
1.
Epinephrine
(Adrenaline)
1-8
10
2.
Norepinephrine
(Noradrenaline)
1-8
10
3.
Isoprenaline
2
10
4.
Propranolol
1mg
1 mg/ml
5.
Acetylcholine
1-5
10
6.
Atropine sulphate
0.5 mg
1 mg/ml
7.
Dopamine
1-5
10
8.
Histamine
0.2-5
1-10
9.
CaCl2
0.1
1%
KCl
µg = micrograms
0.1
1%
10.
Volume of above solutions to be injected = start with 0.1 ml, if sufficient response is not there
increase dose to 0.2 ml and so on.
CSM
The model usually have an on screen recording. You can choose drugs and record their
effect (Table 12.2).
The recordings will look like as:
Actual dog experiment (Fig. 12.2).
Fig. 12.2: Dog BP recording with agonists
92  Practical Manual of Pharmacology
CSM (FIG. 12.3)
Fig. 12.3: Dog BP recording
Table 12.2. Effect of drugs on dog BP
S. NO.
1.
2.
3.
4.
5.
6.
7.
8.
9.
DRUG
Control
Epinephrine
Norepinephrine
Isoprenaline
CaCl2
Acetylcholine
KCl2
Dopamine
Histamine
HEART RATE
62
71
57
91
1
37
1
35
40
BP
Normal
Increased
Increased
Increased
Decreased
Decreased
Decreased
Decreased
Decreased
Epinephrine (Fig. 12.4): Produces biphasic response because of its actions on all
adrenergic receptors. Initially there is α1 stimulation leading to increase in BP, this followed
by β2 action leading to decrease in BP. It is followed by β1 action leading to increaser in BP,
after this there is compensatory decrease in BP.
Fig. 12.4: Biphasic response with adrenaline
Norephinephrine: Produces greater rise in BP as compared to equivalent dose of
adrenaline. This is because there is no vasodilatory component (β2).
Isoprenaline: Decreases BP, as it has predominant β2 action.
Effect of Drugs on Dog Blood Pressure  93
Dopamine: There is decrease in BP with 1-5 µg dose, but BP increase with 5-20 µg dose.
Histamine (Fig. 12.5): Produces fall in BP.
Acetylcholine (Fig. 12.5): Produces fall in BP.
Fig. 12.5: Effect of depressors on Dog BP
Blockers can also be used to identify nature of unknown.
OBJECTIVES
At the end of the practical class the student shall be able to:
CSM
1. Interpret effect of various drugs on dog BP and heart rate
2. Describe mechanism of action of various drugs.
3. Comment on nature of unknown drugs given.
Exercise in examination
These days LCD projectors are available in which you can project only a part of computer
screen. With this type of projector it is very easy to use these softwares for examination
purpose. On your computer screen everything is visible including name of drugs, but you
can project only recording showing effect.
CHAPTER
13
Short Experiments for
Efficacy and Safety
These experiments are demonstrated to students so that they get an idea of how efficacy
and safety of drugs is tested in animals. The following experiments can be shown to students
1. Evaluate analgesic effect of drugs on rats
2. Evaluate antidepressant effect of drugs on mice
3. Evaluate adverse effects of drugs on mice
4. Evaluate Antianxiety effect of drugs.
DEMONSTRATION I
Evaluate analgesic effect of drugs on rats using Tail flick method
Pain is an unpleasant sensation localized to a part of the body. Tail flick method is used to
evaluate analgesic activity of narcotic analgesics. Tail flick method evaluates sharply localized
pain and measures the threshold for an escape response.
Procedure
In this method radiant heat is used. A wire
heated upto 55°C is used for radiant heat.
The apparatus used is analgesiometer
(Fig. 13.1). The animal is put in rat restrainer.
The tail is cleaned. The tail is placed on a level
surface, a radiant heat is applied to the tail
and the latency of the mouse to remove its
tail from the heat is recorded. To avoid the
heating of surrounding metallic parts due to
radiant heat, cold water is circulated through
hollow metallic portion of the apparatus
surrounding the hot wire.
Animal are screened on the apparatus and
cut off time is 5 seconds. If an animal does
not flick tail after > 5 seconds, the animal is
excluded from the experiment.
Wistar rats can be used for this
experiment. After screening 8 animals are
selected for this experiment. There are
divided into 2 groups. Four animals are given
normal saline (group A) by intraperitoneal
Fig. 13.1: Analgesiometer
Short Experiments for Efficacy and Safety  95
route (i.p.) other 4 are given test drug (e.g. morphine 2 mg/kg i.p.-group B). Tail flick is done
at 30 minutes, 1 hour and 2 hours after the drug administration. Everytime 3 readings are
taken.
Mean of group is taken for calculations (Table 13.1).
Calculations
% antinociception =
Test latency – control latency
× 100
Cut off time – control latency
or
The maximum possible analgesia (MPA) can be calculated as:
MPA =
Exercise
What is the % antinociception or MPA of the given drug using analgesiometer?
Table 13.1. To record your findings
30 minutes
Group A
Group B
P value
Mean tail flick time
Test reaction time – Saline reaction time
1 hour
2 hours
15 – Saline reaction time
DEMONSTRATION II
Evaluate antidepressant effect of drugs on mice using despair behaviour test
Depression involves decreased self-esteem of the person. It is usually caused by reaction to
some exogenous stimuli or may be due to an endogenous emotional cause.
Procedure
In this method mice are put in a glass jar containing water.
The dimensions of glass jar can be 40 cm height and 18 cm
diameter. Water can be upto 15 cm. This is an inexpensive
methods, you need not buy any expensive instrument.
Animals are trained for swimming for 15 minutes.
Mice when left in water start swimming (Fig. 13.2). When
depression sets in, they stop swimming. This is counted
as immobility period. In this period mouse does effort
only to keep the head above the water. There is no active
swimming. Test is conducted 24 hours after training.
Fig. 13.2: Mouse swimming
96  Practical Manual of Pharmacology
After training 8 animals are selected for this experiment. There are divided into 2 groups.
Four animals are given normal saline (group A) by intraperitoneal route (i.p.) route 4 are
given test drug (e.g. imipramine 10mg/kg i.p.-group B). Total immobility period is noted
for each mice.
Mean of group is taken for calculations (Table 13.2). Statistical test can be applied to see
any difference in score.
Exercise: Evaluate the effect of the given drug on despair behaviour test.
Table 13.2. For your recordings
Total immobility period (mean)
Group A
Group B
P value
DEMONSTRATION III
Evaluate adverse effects of drugs on mice using Rota Rod apparatus (Fig. 13.3)
This experiment is a measure of strength and coordinated movements of the animal. The
apparatus is known as rota rod treadmill. It consists of a rotating rod (diameter 3 cm). Rod
is suitably machined to provide grip for animals. Five flanges divide the rod into 4 partitions
and 4 animals can be placed simultaneously. The rod is rotated by a electric motor at 6-10
rpm. There is digital display at bottom of each partition. It shows time the animals spends
on the rod. It is run by solid state clock running at one second interval. When a animal falls
off the rod on to the plate below, it trips the corresponding circuit for that partition. The
clock stops and you can note the reading of endurance time of animal on rod.
Procedure
Wistar rats or albino mice can be used for this
experiment. Animal are trained on rota rod. The
animals are placed on rod and made to walk.
Each time animals falls down, keep it again on
the rod. Training for an animal ended when an
animal remained on rod continuously for 180
seconds or completed 20 trials, whichever is
earlier. If the animal failed, it was excluded.
Test is conducted 24 hours after training.
After training 8 animals are selected for this
experiment. There are divided into 2 groups.
Four animals are given normal saline
(group A) by intraperitoneal route (i.p.) route 4
are given test drug (e.g. diazepam 3mg/
kg i.p.-group B). The time spent on rod
(endurance time) by each animal is noted.
Fig. 13.3: Rota rod
Short Experiments for Efficacy and Safety  97
Mean of group is taken for calculations (Table 13.3). Statistical test can be applied to see
any difference in score.
Exercise: Evaluate the effect of given drug on motor functions using rota rod.
Table 13.3. For your recording
Mean endurance time
Group A
Group B
P value
DEMONSTRATION IV
Evaluate antianxiety effect of drugs on rats using hole board test (Fig. 13.4)
This experiment is a measure of anxiolytic activity of a drug. The apparatus is an inexpensive
wooden platform. Its dimensions are 0.5 × 0.5 m and it has 16 holes of 3 cm diameter each.
Holes are large enough for animal to dip their head into holes. Head dip is calculated as one
if it dips till eyes. Head dips are counted by a counter for 30 minutes.
Procedure
Wistar rats can be used for this experiment. Eight
animals are selected for this experiment. There are
divided into 2 groups. Four animals are given normal
saline (group A) by ip route 4 are given test drug (e.g.
diazepam 3mg/kg ip-group B). The head dip count
was noted for each animal after 30 minutes of drug
administration.
Mean of group is taken for calculations (Table
13.4). Statistical test can be applied to see any difference
in score.
Exercise
Evaluate the effect of given drug using hole board test.
Table 13.4. For your recordings
Mean head dip count
Group A
Group B
P value
Fig. 13.4: Hole board test
CHAPTER
14
Ethics and Animals
Ethics is whatever you do when no one is observing you. These days it is very important to
understand ethical issues when we are dealing with research on animals and humans. The
four principles of ethics are:
• Autonomy: Right to decide
• Beneficence: One must remember that whatever we do should be done for benefit of
patients.
• Do no harm.
• Justice: Best treatment and justice to all as far as possible.
The guidelines for performing experiments on animals are given by CPCSEA ( committee
for purpose of control and supervision on experiments on animals). The guidelines regarding
maintenance of animal house are also given by CPCSEA (http://medind.nic.in/ibi/t03/i4/
ibit03i4p257.pdf).
Animals are used in pharmacology in:
1. Undergraduate teaching to show effects of various drugs.
2. Postgraduate teaching to show effects of various drugs, to find out the nature of unknown
drug and for bioassay.
3. Research to conduct screening for drugs, bioassay and for preclinical testing.
For all new drugs, it is mandatory to do toxicity studies in animals.
ANIMAL TOXICITY STUDIES
These are done before drug can be tested in human beings.
The toxicity studies are divided into three stages:
1. Acute toxicity studies (single dose studies): Acute
toxicity studies should be carried out in at least two
species, usually mice and rats using 2 routes of
administration. One of the routes should be same as
intended for humans. The effect of drug is observed
for 24 hours.
Fig. 14.1: Rat in cage, ethical!
Ethics and Animals  99
2. Subacute toxicity studies (repeated dose studies): These studies last for 3 weeks-3 months.
Three doses and 2 species are used.
3. Chronic toxicity studies (long term studies): Long-term toxicity studies should be carried
out in at least two mammalian species, of which one should be a non-rodent. These
studies can continue upto the life time of animal (1-2 years). Effects of drugs are studies
even in next generation.
SPECIAL TOXICITY STUDIES
1. Fertility studies
2. Teratogenicity studies
3. Carcinogenicity studies.
Rodents (rats, mice) and non-rodents (rabbits) are used in these studies.
There is a lot of unnecessary pain and trauma to animals during these experiments, hence to
reduce this the following principle of 3Rs is recommended:
1. Refinement: Refine experimental methods to decrease unnecessary pain and trauma to
animals.
2. Reduction: Reduce the number of animals used in these experiments.
3. Replacement: Replace the animal experiments with appropriate alternative methods,
e.g. computer simulation models, in-vitro methods, cell culture techniques.
Whenever you think of animal experiments, critically analyse following:
1. Is the animal, the best experimental system for the problem (Fig. 14.1)?
2. Can the pain and discomfort be lessened?
3. Is the problem under review is worth solving?
Debate on use of animals in teaching and research:
Full class is divided in two batches.
(If you get class in batches for practical, you can use one theory lecture for this activity)
One batch speaks for the use of animals and other against the use of animals in teaching
and research. Each batch is given fifteen minutes to discuss the issue in their respective batch
and then choose a group leader to speak on behalf of group. The speaker gets 10 minutes
time to speak. Ten minutes are allowed for questioning and comments. This if followed by
concluding remarks by a faculty member.
Visit to animal house: central animal house as well as departmental animal house:
This can be done on day of practical by dividing students into small batches.
This is done after debate to avoid any enthusiastic, biased reaction of students to use of
animals. This is done because first time they are exposed to animal experiments as well as
animal house, most of them might feel too concerned about animals by looking at cute looking
animals (especially guinea pigs, rabbits).
100  Practical Manual of Pharmacology
Depending upon facilities available in animal house, the following points can be discussed
during the to animal house:
1. Maintenance of stock, types of animals kept
2. Why they are required (name of experiments)
3. Breeding of animals
4. Separation of pregnant, just delivered pups
5. Maintaining room temperature, humidity, air flow, light-dark cycle
6. Feeding practice (pellets, greens, etc.)
7. Care of sick animals
8. Disposal of animal waste.
OBJECTIVES
At the end of the session the student shall be able to:
1. Understand principles of ethics.
2. Realize the importance of ethics when using animals for experiments.
3. Justify the need for adhering to proper standards of maintenance and care in the use of
animals for research and teaching.
Section 3
Clinical Pharmacology
CHAPTER
15
Introduction to
Clinical Pharmacology
Clinical pharmacology is study of drugs in clinical material, i.e. human beings. Clinical
pharmacology is also the science of prescribing the correct drug at the correct dose at the
right price to the right patient, i.e. rational drug utilisation. It includes clinical trials of drugs,
postmarketing surveillance, pharmacokinetics, pharmacodynamics, toxicity, drug interactions,
etc. The focus of pharmacology teaching has shifted more to clinical pharmacology. In clinical
pharmacology, a student is expected to know the appropriate indication, dose, route of
administration, frequency adverse effects, contraindications, potential drug interactions, how
to reported adverse effects and above all explain these salient features to patient. Prescribing
and therapeutics are important areas of clinical pharmacology. It is proposed that teaching
of clinical pharmacology should be extensive for undergraduates. They should be taught
more about clinical pharmacology of drugs. There should be a problem based approach to
teach clinical pharmacology. Learning through curiosity, the exploitation of knowledge and
critical evaluation of evidence should be encouraged. To learn this aspect of pharmacology,
it is essential to learn some basic principles of pharmacology. A sound knowledge of basic
principles of clinical pharmacology allows students to take a logical approach to learning
about any of the drugs they are likely to encounter during the course. This section deals
with the above mentioned issues. This branch of pharmacology is most demanding these
days. With the shift of a number of clinical trials of new drugs to India, the training and
demand has increased tremendously in this area.
Most of the aims of clinical pharmacology are general requirements for the safe and
effective use of dugs in most areas of clinical practice. Inculcate the attitude and behaviour
required by a professional competent doctor. Prescription load can be decreased by using
essential drug list. A student who is able to effectively learn these aspects of clinical
pharmacology, should be able to cope safely and effectively with most of the prescribing
challenges that he/she is likely to face in early postgraduation or practice.
Clinical Pharmacology learning should produce graduates who are competent to prescribe
safely and effectively. They should learn to assimilate information about new drug
developments that will occur throughout a professional carrier.
CHAPTER
16
Pharmacokinetic Parameters
and Calculations
Pharmacokinetics is what the body does to the drug. The knowledge of kinetics is very
important for budding doctors to understand how dosage schedules are formed for various
patients and diseases.
Basically the process of pharmacokinetics involves 4 steps, i.e. ADME as follows:
Step 1: Absorption of drugs from various route of administration
Step 2: Distribution of drugs into body
Step 3: Metabolism of drugs into body
Step 4: Elimination of drugs or their products from body.
The ADME process can be depicted as (Fig 16.1):
Various body fluids and organs involved in ADME are (Fig. 16.2):
The knowledge about pharmacokinetic principles and their clinical significance is very
important for doctors to generate dosage schedules, to monitor therapy, to modify schedules
in case of diseases, etc. Clinical pharmacokinetics is the name assigned to science discipline
dealing with the application of pharmacokinetics to the safe and effective therapeutic
management of the individual. Let us discuss important pharmacokinetic parameters.
BIOAVAILABILITY
Bioavailability refers to the extent and rate at
which the active moiety (drug or metabolite)
enters systemic circulation, thereby accessing the
site of action. It is denoted as "f". Bioavailability
is the amount of the administered drug that is
available to have an effect. Bioavailability of a
drug is largely determined by the properties of
the dosage form (which depend partly on its
design and manufacture), rather than by the
drug's physicochemical properties.
Fig. 16.1: Plasma concentration time curve
Pharmacokinetic Parameters and Calculations  105
Fig. 16.2: Various organs, tissues involved in pharmacokinetics
SALIENT FEATURES
1. Drugs given intravenously may be considered to be 100% bioavailable as they are
administered directly into the circulation.
2. Administration of highly lipid soluble drugs by oral route means that some of the drug
molecules will be lost due to first pass metabolism and thus bioavailability is reduced.
For calculating bioavailability (f) drug is give by IV route and by intended route of
administration.
Plasma concentration curves are plotted and area under plasma concentration curve
(AUC) is measured for each mode of administration (Fig. 16.3).
f=
AUC oral × 100
AUC IV
For new preparations of the same drug, bioavailability can be compared to see their bioequivalence.
Bioequivalence is whether both preparations give
same bioavailability in the body or not.
Clinical significance:
1. Oral dose is more as compared to IV Dose.
2. Marked interindividual variation in first pass
metabolism, hence dose required.
3. Hepatic diseases affect first pass metabolism,
hence concentration achieved will be high.
Fig. 16.3: AUC
106  Practical Manual of Pharmacology
4. Drug interactions can occur when 2 drugs compete for same pathway of first pass
metabolism.
AUC
It is area under plasma concentration-time curve. It tells about total amount of drug present
in the body. The most commonly method used to calculate AUC is trapezoidal rule.
AUC is a measure of quantity of drugs in the body.
From AUC one can determine bioavailability (f) of a drug and the relative bioavailability.
AUC can be calculated by the following methods:
1.
2.
3.
4.
Square counting method
Cutting and weighing method
Planimetery
Trapezoidal rule: This is considered to be the best method. A blood concentration,
time curve can be described by a series of trapezoids that are determined by each
concentration time point. In Figure 16.4, A is triangle and B-F are trapezoids. Calculate
area of all and add up. This will give you AUC0-6.
AUCt-α = Kel
Last observed concentration
AUC0-α = AUC0-6 + AUCt-α
Relative bioavailability (Bioequivalence) =
Other formulae for AUC:
AUC =
AUC =
AUC =
CL = Clearance, Vd = Volume of distribution
Kel = Elimination rate constant.
VOLUME OF DISTRIBUTION (VD)
It is defined as "apparent or hypothetical volume
of body fluids that can accommodate the total
amount of drug administered so that the concentration achieved is equal to concentration in
the plasma.
Fig. 16.4: Trapezoids
Pharmacokinetic Parameters and Calculations  107
If total amount of administered drug = 1000 mg
And plasma conc. achieved = 50 mg/l
Then Vd will be calculated as given in Figure 16.5.
Fig. 16.5: Vd calculation
Vd gives an idea about distribution of drug as given in Tables 16.1 and 16.2.
Table 16.1. Vd as related to drug present in body
If vd is
10-20 L
20-40 L
Drug is present in
Plasma and extracellular
fluid
Intracellular fluid
> 40 L
Concentrated in tissues
Example
Streptomycin
Lipid insoluble
Phenytoin
Lipid soluble
Chloroquine
Highly lipid soluble
Table 16.2. Vd of common drugs
Drug
WARFARIN
LIGNOCAINE
DIGOXIN
NORTRIPTYLINE
Vd (L/Kg)
0.1
1.5
7
20
Vd depends on the following factors:
• Blood flow rate in different tissue
• Lipid solubility of drug
• Partition coefficient of drug and different types of tissues
• pH
• Binding to biological material.
Vd is often proportional to body weight.
In obesity Vd is lower than expected from the body weight.
In edema, Vd is larger than expected for the body weight.
108  Practical Manual of Pharmacology
Other formulae for Vd
Vd =
CL =
Vd =
Vd =
Clinical significance
1. Hemodialysis in drug poisoning:
Drugs with low Vd can be easily removed by hemodialysis, e.g. Salicylates
2. Calculation of loading dose (LD)
LD = Vd × CL (IV Route) CL = clearance
LD =
f = bioavailability.
HALF-LIFE
The half-life (t½) is the time taken for the circulating plasma concentration of a drug to fall to
50% of original/peak concentration.
Kel = elimination rate constant
t½ =
Kel =
so t½ =
For example: Aspirin 15 minutes
Phenobarbital 2-6 days.
Salient features
1. Half-life is a derived parameter that changes as a function of both clearance and volume
of distribution. Half-life is constant in first order kinetics. Half-life increase with increase
in concentration in zero order kinetics
2. Plasma protein binding increase half-life
3. Drug widely distributed and sequestrated in tissues got longer half-life, e.g. amiodarone
4. Approximately 4-5 half-lives are required for complete elimination of drug from the
body:
Pharmacokinetic Parameters and Calculations  109
one
two
three
four
t½
t½
t½
t½
=
=
=
=
50% drug is eliminated
75% (50 + 25) drug is eliminated
87.5% (75 + 12.5) drug is eliminated
93.75% (87.5 + 6.25) drug is eliminated.
Clinical significance
1. Half-life determines frequency of administration or dosing interval of drug, e.g. If t½
is 12 hours, then drug is given twice a day.
2. When rate of absorption equals rate of elimination steady state is said to be achieved.
3. The clinician usually wants to maintain steady-state concentrations of a drug within a
known therapeutic range (gl), assuming complete bioavailability.
4. Approximately 4-5 half-lives are required to reach steady state (Fig. 16.6).
5. In most clinical situations, drugs are administered in a series of repetitive doses or as a
continuous infusion in order to maintain a steady-state concentration of drug in plasma
within a given therapeutic range. At steady state the rate of drug administration is
equal to drug elimination and the mean concentration remains constant.
CLEARANCE
Clearance is the most important concept to be considered when a rational regimen for longterm drug administration is to be designed.
Clearance is defined as the volume of the plasma cleared of the drug in a unit time. It is
expresses as ml/minute. If given clearance is 5 ml/minute, it means that 5 ml of plasma is
cleared of the drug.
Most of the drugs follow first order kinetics for clearance.
Total body clearance is:
CL = CLrenal + CLhepatic + CLother
Other formulae for clearance
CL = Vd * Kel
CL =
CL =
Cp = Plasma concentration
Salient features
1. If a drug is only excreted by glomerular
filtration, CLrenal can not exceed GFR
(120 ml/min), e.g. Aminoglycoside antimicrobials.
Fig. 16.6: Steady state
110  Practical Manual of Pharmacology
2. If a drug is completely removed by tubular secretion, CLrenal can not exceed renal
plasma flow (700 ml/min), e.g. Penicillin.
3. Reabsorption can decrease CLrenal to as low as 1ml/min.
4. Clearances is constant in zero order kinetics. Zero order kinetics are saturable kinetics,
e.g. Phenytoin. It is also known as non-saturable kinetics. Most of the drugs follow first
order kinetics.
5. Clearance increase with increase in concentration in first order kinetics.
Clinical significance
1. Most of the drugs got unsaturable enzyme system for their hepatic biotransformation,
hence most of the drugs are metabolised in liver. In this instance, the concentration of
drug in the blood leaving the liver will be low (Cv = 0). Extraction ratio (ER) will
approach unity
2. The rate limiting step will become hepatic blood flow. These drugs are known as high
extraction ratio (HER) drugs, e.g. Lidocaine imipramine (Fig. 16.7).
3. In contrast, changes in intrinsic clearance and protein binding will affect.
4. The clearance of drugs with low extraction ratios, but changes in blood flow should
have little effect.
5. Maintenance dose is calculated with the help of CL
MD = CL × Cp.
LOADING DOSE
The "loading dose" is one or a series of quickly repeated doses that may be given at the onset
of therapy with the aim of achieving the target concentration rapidly (Fig. 16.8). The
appropriate magnitude for the loading dose is:
LD =
, e.g. 20L*20 mg/L = 200 mg, Cp = plasma concentration required
• Loading dose depends on extent of
distribution. If a drug is widely
distributed in the body a large loading
dose is required to fill the distribution
sites.
• A loading dose may be desirable if the
time required to attain steady state by
the administration of drug at a constant
rate (four elimination half-lives) is long
relative to the temporal demands of the
condition being treated.
Example: The half-life of lidocaine, an
antiarrhythmic, is usually more than 1 hour.
One cannot wait for 4 to 6 hours to achieve a
Fig. 16.7: Hepatic extraction
Pharmacokinetic Parameters and Calculations  111
therapeutic concentration, arrhythmias
encountered may be life threatening, hence,
a loading dose of lidocaine is used.
Maintenance dose
To maintain steady state a maintenance dose
is required.
MD =
Maintenance dose depends on clearance.
Whatever dose is lost in clearance is replaced
by maintenance dose.
Fig. 16.8: Loading dose
OBJECTIVES
At
1.
2.
3.
the end of this session a student shall be able to:
Define the various pharmacokinetic parameters
Calculate various pharmacokinetic parameters from given data
Explain clinical significance of these parameters.
C H A P T E R
17
C H A P T E R
Prescription Writing Through
Problem Based Learning
(Rational Prescribing)
A prescription is a written order by a physician to a pharmacist to dispense a therapeutic
agent to a patient. This therapeutic transaction is the sum of the physician's evaluation of the
problem (the history, physical examination, diagnostic tests, decision on treatment, and
prognosis). On this single sheet of paper are the final results of the physician's education,
experience, and diagnostic acumen.
Prescriptions are typically handwritten on preprinted prescription forms that are
assembled into pads, or alternatively printed onto similar forms using a computer printer.
Preprinted on the form is text that identifies the document as a prescription, the name and
address of the prescribing provider and any other legal requirement such as a registration
number. The word "prescription" can be decomposed into "pre" and "script" and literally
means, "to write before" a drug can be prepared.
It is estimated that 3 billion prescriptions were written in the United States in 2002. This
number has grown from 1.5 billion in 1989 and is expected to continue to grow. Drugs
should be prescribed only when they are necessary for treatments following clear diagnosis/
indication. Not all patients or conditions need prescriptions for drug. In certain conditions
simple advice and non-drug treatment may be more suitable.
All written prescriptions should contain
•
•
•
•
•
•
•
Patient's full name and address
Prescriber's full name, address, telephone number and registration number
Date of issuance
Signature of prescriber
Drug name, dose, dosage form, amount
Directions for use
Refill instructions.
A prescription has various parts. Predating modern legal definitions of a prescription, a
prescription traditionally is composed of four parts: a "superscription", "inscription",
"subscription" and "signature".
Prescription Writing Through Problem Based Learning (Rational Prescribing)  113
Superscription: it has
• Name and address of doctor.
• Name, age, sex and address of patient (age is desirable for safety purposes) and date.
• The symbol "L" separates the superscription from the inscriptions sections. L is a
traditional esoteric symbol, for the word recipe 'take thou' (Latin "recipe") the imperative
form of "recipere", "to take". It should not be interpreted as instructions to the patient
to "take thou" as patient instructions are in a later section. Some the literal exhortation
to the pharmacist is "take thou this recipe".
Significance of superscription is to expedite the handling of the prescription and to
avoid confusion with the medications intended for some one else. It is also the duty of
pharmacist to verify the patient's name and age to monitor the prescribed dose.
Inscription: The inscription section defines what the medication is.
It has name of drug, its dose, frequency, duration, route of administration
• Choice of drug name: best is to use generic names or non-proprietary or official names
rather than using brand names. This eliminates necessity for memorising multiple drug
names.
• The name, strength of drug and its inert additives should be mentioned, both for the
single ingredient drug and fixed dose drug combinations (FDCs). This helps in rapid
identification of drug and a quick estimate of the amount consumed and can help in the
initiation of appropriate therapy in case of adverse drug reactions (ADRs) or accidental
or deliberate over dosage.
• Frequency and duration of administration.
• One should avoid using abbreviations since it frequently leads to errors.
• For decimals a zero should precede the decimal point where there is no other value,
e.g. 0.5 ml not .5 ml.
• Do not abbreviate microgram, nanogram
• Prescription orders should always be written in metric system. Home/domestic
measures or convenient kitchen utensils should not be used to measure as they are not
uniform and accurate to indicate the metric unit of weight or volume desired for liquid
drugs. Instead a calibrated dropper, moulded plastic cylinders, measuring oral syringe,
and graduated caps have been designed for administering liquid medications.
Subscription: It has dispensing directions to the pharmacist, e.g. send such number of
capsules/send such number of tablets.
Importance of subscription is to reduce the communication gap between patient and
physician and direct the pharmacist to detect any overdose of potent drugs for safety of
patient and educate the patient about compliance and how to take medication.
Transcription or signature: The "signature" section contains directions to the patient and
is often abbreviated "Sig." or "Signa". It also obviously contains the signature of the prescribing
doctor though the word "signature" has two distinct meanings here and the abbreviations
are sometimes used to avoid confusion. It has instruction or direction to the patient regarding
114  Practical Manual of Pharmacology
the use of medications prescribed. Here brevity, clarity and accuracy are especially important.
This is required to improve patient's compliance and to explain the patient about his or her
illness and how the prescribed medication will alter the disease process. Only the registered
medical practitioner can prescribe the drug.
Prescribe drug therapy for a male patient age 55 years, suffering from myasthenia gravis
An example of prescription:
Superscription
Inscription
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name: Amit Sharma
Age/Sex: 55 Male
Address: H.No 445, Model town, Ludhiana Tel: 5058677
Unit No. C-238567
Date. 27-6-2007
L
Tab. Pyridostigmine 30 mg
Tab. Prednisone 60 mg
Dispense 45 tablets of Pyridostigmine
Dispense 15 tablets of Prednisone
Subscription
Take 1 tab. of pyridostigmine 3 times a day for 15 days
Take 1 tab. of prednisone once a day for 15 days
Transcription
Revisit after 15 days
Regd.No 24456 (Punjab Medical Council)
Signature
Name Dr Ankur Sharma, MD
In conventional curriculum, practice of prescription writing becomes mechanical. Most
of the times the students copy the prescribing behavior of their seniors or teachers on existing
standard treatment guidelines, without explanation as to why certain treatments are chosen
and prescribed. The need of improvement with supplementing sufficient background
information and proper orientation is felt. Prescription writing through problem-based
pharmacotherapy teaching is one such way, which can help the students appreciate the
relevance of acquired information for appropriate or rational prescribing in a better way. It
provides step by step guidance to the process of rational prescribing.
Prescription Writing Through Problem Based Learning (Rational Prescribing)  115
To develop self-learning and thinking process in the medical students early in their
career while learning pharmacology is the best way to inculcate these habit of rational
prescribing. The students will be learning how to prescribe effectively and judiciously for
any given situation and also the skill of choosing and prescribing drugs logically and rationally.
For this we can use the WHO concept of "P" drug.
WHO has introduced the concept of "P" drugs. As a doctor you may see 50 patients per
day or more, many of whom need treatment with a drug. How do you manage to choose the
right drug for each patient in a relatively short time? This can be achieved by using "P"drug
concept. "P"drugs or personal drugs are the drugs you have chosen to prescribe regularly
and with which you have become familiar. They are your priority choice for given indications.
They will differ from country to country and between doctors. In general, the list of drugs
registered for use in the country and the national list of essential drugs contain many more
drugs than you are likely to use regularly. Most doctors use only 40-60 drugs routinely. It is,
therefore, useful to make your own selection from these lists and to make this selection in a
rational way. In fact, in doing so you are preparing your own essential drugs list. The Pdrug concept is more than just the name of a pharmacological substance, it also includes the
dosage form, dosage schedule and duration of treatment. Students will be taught to make
an inventory of possible treatments of any common disorder resulting in a set of first choice
drugs called P (personal) drugs on the basis of their efficacy, safety, suitability and cost.
Steps in choosing a P-drug:
Step
Step
Step
Step
Step
(i)
i: Define the diagnosis
ii: Specify the therapeutic objective
iii: Make an inventory of effective groups of drugs
iv: Choose an effective group according to criteria
v: Choose a P-drug
Define diagnosis:
When selecting a P-drug, it is important to remember that you are choosing a drug of
first choice for a common disorder. Knowledge about pathophysiology of the disease
will help you to choose drug of first choice. Treating symptoms without really treating
the underlying disease/pathology is known as symptomatic treatment.
(ii) Specify the therapeutic objective:
It is very useful to define exactly what you want to achieve with a drug. For example,
to control the blood pressure to a certain level, to cure an infectious disease or prevent
occurrence of hepatitis. If you are sure about therapeutic objective, it becomes easier to
select P drug.
(iii) Make an inventory of effective drugs:
In this step you link the therapeutic objective to various available drugs. Efficacy is the
first criterion for selection of drugs. Initially, you should look at groups of drugs rather
than individual drugs. There are tens of thousands of different drugs, but only about
70 pharmacological groups.
116  Practical Manual of Pharmacology
(iv) Choose an effective group:
There are two ways to identify effective groups of drugs. The first is to look at formularies
or guidelines or standard treatment guidelines that exist in your institution/state/
country, or at international guidelines, such as the WHO treatment guidelines for certain
common disease groups, or the WHO model list of essential drugs. You can also take
help from the index of a good pharmacology reference book and determine which
groups are listed for your diagnosis or therapeutic objective. In most cases you will
find only 2-5 groups of drugs which are effective.
(v) Choose a P-drug:
Out of these shortlisted drugs choose a P-drug for a common condition.
After choosing a P drug this concept can be extended to rationally treat patients. There are
6 steps:
(i) Define patient's problem:
Make right diagnosis based on clinical history, sign symptoms as well as investigations
Patient's complaints are mostly linked to his/her symptoms. A symptom is not a diagnosis
in itself, although it will usually lead to it, e.g. all patients with symptoms of sore throat
will not need the same treatment even when they have same diagnosis.
(ii) Define therapeutic objective:
Before choosing a treatment it is essential to specify your therapeutic objective. What
do you want to achieve with the treatment?
(iii) Verify the suitability of your P-drugs:
You have chosen a P drug as first drug of choice for common condition. You cannot
assume that 'first-choice' treatment will always be suitable for everyone. You must
verify whether your P-drug is suitable for this individual patient or not.
It is to be remembered here that P drug for a condition may not always be the most
appropriate drug for every patient. A number of patient specific factors like extremes
of age, pregnancy and lactation, concurrent medications, existing diseases (hepatic or
renal disease) may require a different P drug for a particular patient.
The process of "personal drug" selection is centered around the drug and indication.
But for patient treatment, even if the disease is same, the patient related factors become
important and need to be considered. There might be some factors or characteristics
peculiar to the patient that renders the personal drug unsuitable for him/her.
(iv) Write a prescription:
Write legibly and completely as described in various parts of prescription.
(v) Give information, instructions and warnings:
It has been seen that, 50% of patients do not take prescribed drugs correctly, take them
irregularly or not at all. The most common reasons cited are that symptoms have ceased,
side effects have occurred, the drug is not perceived as effective or the dosage schedule
is complicated for patients, particularly the elderly. Hence, it is very important to talk
to your patients. Explain them about treatment, specific instructions and warnings about
medications.
Prescription Writing Through Problem Based Learning (Rational Prescribing)  117
(vi) Monitor and/or stop the treatment:
After rational treatment of your patient, you would be interested to know what happened
to patient's condition. For that you can monitor of follow up the patient. You can decide
whether treatment is effective or not.
P-DRUGS AND P-TREATMENT
There is a difference between P-drugs and P-treatment. The key point is that not all diseases
need to be treated with a drug. Not every P-treatment includes a P-drug!
Electronic prescriptions
Softwares are available to write prescriptions. But more and more, doctors are writing
prescriptions electronically in developed countries, but it is not so popular in our country
due to various reasons.
OBJECTIVES
At the end of this practical, a student shall be able to:
1. Acquire cognitive, motor and communication skills that are necessary throughout a
clinical career for rational therapeutics.
2. Choose an appropriate drug from P-drug list, deciding what information or instruction
is (or not) to be given and to monitor the result of treatment.
3. Write appropriate prescription for a given case.
Exercises in class
Anil Verma, 42 years old male is found to be diabetic during routine medical examination.
He does not experience any symptoms related to increased blood glucose (PPBS 160 mg/dl).
Physical examination reveals- his BP 160/130 mm of Hg, weight 76 kg, height 5 ft. 10 inches.
No other abnormality is found.
Exercise:
Q1. What is the patient's problem?
Q2. What is the goal of treatment in this patient?
Q3. Prepare a list of effective groups of drugs for the given condition/s.
Q4. Choose the effective group/groups of your choice for the given condition/s giving
justification.
Q5. Choose the most appropriate drug/drugs from your chosen group/s of drugs based
on efficacy, safety, suitability and cost, for this patient.
Q6. Write the prescription with suitable instructions and follow up plan for this patient.
118  Practical Manual of Pharmacology
Examples of prescriptions for common diseases:
1. Anemia (microcytic hypochromic)
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
•
Tab. Ferrous sulphate (60 mg elemental iron) 1od × 1 month
•
Tab. Albendazole 400 mg stat
Direction: Dispense 30 such tablets of ferrous sulphate and 1 tablet of albendazole
Sig: Take one tablet of ferrous sulphate every day before food for 1 month. Take one
tablet of albendazole. Revisit after 1 month for hemoglobin estimation.
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Prescription Writing Through Problem Based Learning (Rational Prescribing)  119
2. Angina pectoris
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Isosorbide dinitrate 5 mg sublingually as and when required
• Tab. Isosorbide mononitrate 50 mgSR 1od × 15 days
• Tab. Atenolol 50 mg 1 od × 15 days
• Tab. Aspirin 100 mg 1 od × 15 days
Direction: Dispense 10 tablets of isosorbide dinitrate, 15 tablets of isosorbide
mononitrate, atenolol and aspirin.
Sig: Take these tablets after breakfast
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Other measures:
•
•
•
•
•
•
Life style change is recommended, e.g. work stress, smoking, etc.
Stop working and sit down at the earliest indication of pain in chest
Avoid tea, coffee, nasal decongestant drops
Atenolol contraindicated in asthmatics
Do not take aspirin empty stomach
Revisit after 2 weeks or earlier in case of any distress or breathlessness, fainting or
palpitations.
120  Practical Manual of Pharmacology
3. Acute asthma
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Salbutamol MDI
2 puffs (100 µg/puff) SOS
Direction: Dispense one MDI of Salbutamol
Sig: Use inhaler whenever needed as described in attached pictorial diagram.
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Prescription Writing Through Problem Based Learning (Rational Prescribing)  121
4. Acute severe asthma
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Oxygen inhalation
• Inj. Hydrocortisone hemisuccinate
100 mg iv stat, repeat 100 mg every 6 hourly
• Nebuliser salbutamol
2 ml diluted to 5 ml with normal saline over 30 minutes
• Inj. Terbutaline - 5mg/ml
1 ampoule SC immediately
• Review the patient every 2 hourly
Direction: Dispense 10 vials of hydrocortisone, nebuliser salbutamol and 5
ampoules of terbutaline.
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Other measures:
• Hospitalise the patient
• If patient is not in hospital, give salbutamol inhaler (100 ug/puff) 2 puffs every 10
minutes till patient reaches hospital
• Admit and keep the patient in propped up position.
122  Practical Manual of Pharmacology
5. Hypertension (Essential hypertension with no associated disease)
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Salt restriction
• Exercise/meditation to relief stress
• Tab. Atenolol 50 mg 1 od × 15 days
• Revisit after 15 days.
Direction: Dispense 15 such tablets
Sig: Take one tablet every day, regularly do aerobic exercises, restrict salt intake.
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Other measures/additional information:
• Dose of atenolol may be increased upto 100 mg/day
• The choice of drug may vary depending on age and associated diseases. Alternative
drugs are: enalapril (hypertension with CHF or diabetes), thiazide diuretics,
amlodipine (hypertension with asthma).
• Combination therapy with more than one agent can be used if the patient does not
respond to single drug therapy.
• Advice to reduce/eliminate smoking/alcohol intake.
Prescription Writing Through Problem Based Learning (Rational Prescribing)  123
6. Status epilepticus
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Inj Lorazepam 0.1 mg/kg at rate of 2 mg/ml iv
Can be repeated after 10 min (max 3 doses)
If seizures persist then give
• Inj Phenytoin 15-20 mg/kg slow iv infusion
• Review the situation every 15 minutes
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Additional measures:
•
•
•
•
Admit the patient in casualty
Maintain patent airway, breathing, circulation
Phenytoin can be repeated at 5-10 mg/kg (max 30 mg/kg)
If seizure still persist then give Inj. Phenobarbitone 20 mg/kg iv at 50-100 mg/min. It
can be repeated. If seizures are not controlled then give midazolam or propofol.
124  Practical Manual of Pharmacology
7. Peptic ulcer
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Omeprazole 20 mg I od
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Additional measures:
• Test for H pylori, if positive then prescribe for H pylori eradication.
• Avoid alcohol, smoking, stress, caffeinated drinks, chillies and drugs like steroids,
NSAIDs.
Prescription Writing Through Problem Based Learning (Rational Prescribing)  125
8. NIDDM
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Glibenclamide 5 mg ½ tablet every day before breakfast
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Additional measures:
• Dose can be titrated up based on blood glucose levels.
• Advice diet modification and exercise.
126  Practical Manual of Pharmacology
9. Acute abdomen
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Inj. Dicyclomine HCl 10 mg IM stat
• Tab. Dicyclomine HCl 10 mg 1 sos
Direction: Dispense 1 ampoule of dicyclomine and 4 tablets of dicyclomine
Sig: Take one tablet whenever needed
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Additional measures:
• Narcotics may be given in severe pain
• If pain due to soft tissue trauma give NSAIDs
• Advise semisolid diet.
Prescription Writing Through Problem Based Learning (Rational Prescribing)  127
10. Dysmenorrhoea
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Ritu Sharma
Age/Sex: 35 Female
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Mefenamic acid 250 mg tds × 3 days
• Tab. Dicyclomine HCl 10 mg tds × 3 days
Direction: Dispense 9 tablets of mefenamic acid and dicyclomine
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
128  Practical Manual of Pharmacology
11. Acute attack of migraine
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Aspirin 650 mg stat, repeat after 4 hours if needed
• Tab. Ergotamine (1mg) + caffeine (100 mg) 2 tab stat
Then 1 tablet half hourly (max 6 in a day)
If nausea/vomiting
• Tab. Metoclopramide 10 mg stat and sos
Direction: Dispense 4 tablets of aspirin, 6 tablets of ergotamine + caffeine and 6 tablets
of metoclopramide
Sig: Take tablet of aspirin immediately. Take ergotamine + caffeine 2 tab, then take 1
tablet half hourly. Take metoclopramide immediately and then whenever required.
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Additional measures:
• Alternative to tablet aspirin are paracetamol and ibuprofen.
Prescription Writing Through Problem Based Learning (Rational Prescribing)  129
12. Allergic Conjunctivitis
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Betamethasone eye drops (0.1%)
• Ketorolac eye drops (0.5%) q6h till symptoms subside
Direction: Dispense 1 vial of betamethasone and 1 vial of ketorolac
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
130  Practical Manual of Pharmacology
13. Herpes zoster
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Acyclovir 800 mg 5 times a day × 7 days
• Tab. Ibuprofen 400 mg tds till symptoms subside
Direction to pharmacist: Please dispense 35 tabs of tablets of acyclovir and 10 tablets of
ibuprofen.
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Prescription Writing Through Problem Based Learning (Rational Prescribing)  131
14. Oral candidiasis (Thrush)
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Fluconazole 100 mg 1 od × 14 days
or
• Clotrimazole mouth paint 1% 2-3 times/day × 7 days
Direction: Dispense 14 tabs of fluconazole
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
132  Practical Manual of Pharmacology
15. Vaginal candidiasis (Vulvovaginitis)
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Ritu Sharma
Age/Sex: 35 Female
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Fluconazole 150 mg stat
Direction: Dispense 1 tab of fluconazole
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Prescription Writing Through Problem Based Learning (Rational Prescribing)  133
16. Hepatic amoebiasis
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Tinidazole 300 mg 2 bd × 7 days
• Tab. Chloroquine 250 mg 2 bd × 1day then 1 bd × 19 days
Direction: Dispense 14 tabs of tinidazole and 42 tabs of chloroquine.
Sig: Take 2 tablets of tinidazole two times in a day. Take 2 tablets of chloroquine two
times in the day on day 1 then 1 tablet two times in a day.
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Additional measures:
• Metronidazole can be given in place of tinidazole
• If severe, give metronidazole IV
134  Practical Manual of Pharmacology
17. Intestinal amoebiasis
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Tinidazole 500 mg bd × 3 days
• Tab. Diloxanide furate 500 mg tds × 10 days
Direction: Dispense 6 tabs of tinidazole and 30 tabs of diloxanide furate
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Additional measures:
• Tinidazole can be taken as 2 g single dose
• In place of tinidazole secnidazole 2 g single dose can also be taken.
Prescription Writing Through Problem Based Learning (Rational Prescribing)  135
18. Primary syphilis
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Inj. Benzathine penicillin G.2.4 M Units IM stat AST (1.2 M Units in each
buttock)
Direction: Dispense 1 vial of inj. benzathine penicillin
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Additional measures:
• AST-after sensitivity test
• If patient allergic to penicillin give tab. Doxycycline 100 mg bd × 10 days.
136  Practical Manual of Pharmacology
19. Typhoid
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Ciprofloxacin 500 mg 1 bd × 14 days
• Tab. Paracetamol 500 mg tds × 5 days
Direction: Dispense 28 tabs of ciprofloxacin and 15 tablets of paracetamol
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Additional information:
• Dose of ciprofloxacin is 750 mg if weight of patient > 50 kg
• Paracetamol is for headache and fever, but if there is any bleeding episode stop
paracetamol
• If patient is hospitalized start with inj. ciprofloxacin 200 mg IV bd
• If no response within 5 days or condition worsens earlier shift to following therapy:
Inj. Ceftriaxone or Inj. Ofloxacin or combination of both.
Prescription Writing Through Problem Based Learning (Rational Prescribing)  137
20. Acute gouty arthritis
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Aspirin 300 mg 2 q4h
• Tab. Colchicine 0.6 mg 1 q4h till pain is there
After that
• Tab Allopurinol 100 mg tds × 7 days
• Low purine diet
Direction: Dispense 24 tabs aspirin, 12 tablets of colchicines and 21 tablets of allopurinol
Sig: Take 2 tablets of aspirin 4 hourly and 1 tablet of colchicines 4 hourly till pain subsides.
After that take 1 tablet of allopurinol three times in a day for 7 days.
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
138  Practical Manual of Pharmacology
21. Multibacillary leprosy
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
Day 1- Tab. Clofazimine 300 mg once in month supervised
Tab. Rifampicin 600 mg once a month supervised
Tab. Dapsone 100 mg 1od × 1 month
Then 2-28 days
Tab. Clofazimine 50 mg 1od × 1 month
Tab. Dapsone 100 mg 1od × 1 month
Direction: Dispense 1 tab of rifampicin, 30 tabs of dapsone and 36 tab of clofazimine
(50 mg).
Sig. Tablets on day 1 to be taken under supervision of doctor.
Special instruction: Regular follow up every month. Repeat the same treatment every
month and continue the treatment for 2 years. To report immediately in case of skin reaction.
There might be red hypopigmented patches on skin due to clofazimine. There may be
orange discolouration of body secretions due to rifampicin.
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Prescription Writing Through Problem Based Learning (Rational Prescribing)  139
22. Paucibacillary leprosy
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
Day 1-Tab. Rifampicin 600 mg once a month supervised
Tab. Dapsone 100 mg 1od × 1 month
Then 2-28 days
Tab. Dapsone 100 mg 1od × 1 month
Direction: Dispense 1 tab of rifampicin, 30 tabs of dapsone.
Special instruction: Regular follow up every month. Repeat the same treatment every
month and continue the treatment for 6 months. To report immediately in case of skin reaction.
There may be orange discolouration of body secretions due to rifampicin.
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
140  Practical Manual of Pharmacology
23. Tuberculosis
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Isoniazid (300 mg) 1 od × 30 days
• Tab. Rifampicin (600 mg) 1 od × 30 days
• Tab. Pyrazinamide (750 mg) 1bd × 30 days
• Tab. Pyridoxine (10 mg) 1 od × 30 days
• Tab. Ethambutol (1000 mg) 1 od × 30 days
Direction: Please dispense 30 tablets of isoniazid, rifampicin, ethambutol, pyridoxine
and 60 tabs of pyrazinamide
Sig: Take tab. Rifampicin once daily empty stomach for 30 days. Take tab. Pyrazinamide
two tab. once daily for 30 days. Take tab. Ethambutol and pyridoxine once daily for 30 days
Special instruction: Regular follow up every month on the same day. To undergo sputum
smear examination at the end of 2 months of treatment. To undergo ophthalmic examination
prior to starting tab ethambutol. The colour of body secretions may turn orange with intake
of tab. rifampicin.
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Additional information:
• If sputum is negative after 2 months, start continuation phase
Tab. Isoniazid 300 mg
Tab. Rifampicin 600 mg
Tab. Pyridoxine 10 mg all 1 od × 4 months
• The drugs can be given 3 times in a week, but dose is more.
Prescription Writing Through Problem Based Learning (Rational Prescribing)  141
24. Chloroquine sensitive malaria
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Chloroquine (250 mg) 4 stat then 2 after 8, 24 and 48 hours
• Tab. Primaquine 45 mg stat*
Direction to pharmacist: Please dispense 10 tablets of chloroquine phosphate and 1 tablet
of primaquine.
Sig. Take 4 tablets at once, then 2 tablets after 8, 24 and 48 hours. Take single table of
primaquine.
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Additional information:
• Dose of chloroquine is 10 mg/kg followed by 5mg/kg
• 1 tablet of 250 mg chloroquine phosphate contains chloroquine base 150 mg, hence
above dose of chloroquine is 600 mg stat followed by 300 mg after 8, 24 and 48 hours
• Each 5 ml of suspension contains 50 mg base
• *For Falciparum malaria
• For vivax/mixed malaria tab primaquine 15 mg 1 od for 5 days is given.
142  Practical Manual of Pharmacology
25. Chloroquine resistant malaria
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Mefloquine (250 mg) 3 tab stat then 2 tab after 8 hours
• Tab. Pyrimetahamine + suladoxine (25 + 500 mg) 3 stat
Direction: Dispense 5 tab. of tab. of mefloquine and 7 tab. primaquine
Direction to patient: Take 3 tabs of mefloquine 250 mg at once followed by 2 tabs after 8
hrs. Take 3 tab of pyri + sufa together.
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Other measure:
• To conduct test to assess the G-6 PD status before starting tab. primaquine.
• Other alternative drugs are:
Tab. Quinine sulfate (600 mg) tds × 7days plus
Tab. Doxycycline (100 mg) 1od × 7days
or
Tab. Pyrimetahamine + suladoxine (25 + 500 mg) 3 stat
or
Tab Mefloquine + Tab. Artesunate 80 mg 2 tab-day1, 1 tab od × 5 days.
Prescription Writing Through Problem Based Learning (Rational Prescribing)  143
26. Cerebral malaria
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Inj. Quinine sulphate (600 mg in 1 ml) 10 mg/kg iv q8h
• Inj. 5% Dextrose (100 ml)
Direction to pharmacist: Please dispense such 24 ampoules of Inj. quinine and 24 Infusions
of 5% dextrose.
Sig. Inj. Quinine (20 mg/kg) loading dose to be mixed in 5% dextrose (20 ml) and given
slowly over 20 minutes. Then inj. Quinine (10 mg/kg) mixed in 5% dextrose every 8 hours.
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Additional information
• Infusion should continue for 4 hours
• Once the patient attains consciousness start tab. quinine (10 mg/kg) to make total duration
of therapy 7 days.
144  Practical Manual of Pharmacology
27. Upper respiratory tract infection
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Paracetamol 500 mg 1 tds × 3 days
• Tab. Cetrizine 10 mg 1 od hs × 3 days
Direction: Please dispense such 15 tablets of paracetamol and 3 tablets of cetrizine
Sig. Take cetrizine at bedtime, avoid driving and operating heavy machinery.
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Prescription Writing Through Problem Based Learning (Rational Prescribing)  145
28. CHF
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Enalapril 2.5 mg 1od × 7 days
• Tab. Chlorthiazide 250 mg 1 od om × 7 days
• Salt restriction
Direction: Please dispense such 7 tablets of enalapril and chlorthiazide
Sig. Take chlorthiazide in the morning.
Name: Dr Ankur Sharma, MD
Regd.No 24456 (Punjab Medical Council)
Additional measures:
• In severe cases add Inj. furosemide 40 mg iv stat and repeat if required after 2-3 hours
• Digoxin can be given if associated with atrial fibrillation.
146  Practical Manual of Pharmacology
29. Generalised tonic clonic and partial seizures
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date. 27-6-2007
L
• Tab. Carbamazepine 200 mg tablets 1tds × 1 month
Dispense 90 tablets
Revisit after 30 days
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Additional measures:
• Dose of carbamazepine to be increased to 800-1200 mg/day gradually
• Alternative to carbamazepine are phenytoin and sodium valproate.
Prescription Writing Through Problem Based Learning (Rational Prescribing)  147
30. Depression
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Cap. Fluoxetine 10 mg bd × 1 month
Direction: Dispense 30 capsule
Revisit after 30 days
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
148  Practical Manual of Pharmacology
31. Bipolar disorder
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Lithium carbonate 300 mg 1tds x15 days
Direction: Dispense such 45 tablets
Revisit after 15 days
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Prescription Writing Through Problem Based Learning (Rational Prescribing)  149
32. Parkinsonism
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 65 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Levodopa (100 mg) + Carbidopa (10 mg) 1tds × 15 days
Dispense 45 tablets
Sig: Take tablets after meals
Revisit after 15 days
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Additional measures:
• Dose of L-dopa to be increased gradually to 2-3 g/day.
150  Practical Manual of Pharmacology
33. Myasthenia gravis
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Pyridostigmine 60 mg 1tds × 15 days
• Tab. Prednisone 30 mg 1 od × 15 day
Direction: Dispense 45 tablets of pyridostigmine and 15 tablets of prednisone
Sig: Take prednisolone early in the morning
Revisit after 15 days
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Prescription Writing Through Problem Based Learning (Rational Prescribing)  151
34. Insomnia
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Zolpidem 10 mg tablets 1od hs
Direction: Dispense such 15 tablets
Revisit after 15 days
Sig: Do not take more dose than recommended
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Additional measures:
• Advise nonpharmacological methods for sleep
• Do not take medication in more than recommended doses and beyond the prescribed
duration
• Alternative drugs are-Tab. diazepam or alprazolam.
152  Practical Manual of Pharmacology
35. Erectile dysfunction
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Sildenafil 25 mg 1 tablet I hour before intercourse
Direction: Dispense such 10 tablets
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Additional measures:
• Check CVS status of patient
• Check which other drugs are being taken.
Prescription Writing Through Problem Based Learning (Rational Prescribing)  153
36. Chronic simple glaucoma
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Pilocarpine (2%) eye drops tds × 1month
• Timolol (0.5%) eye drops bd × 1month
• Tab. Acetazolamide 250 mg bd × 1month
Revisit after 1 month
Direction: Dispense 1 eye drops of timolol and pilocarpine and 30 tablets of acetazolamide.
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Additional measures:
• Revisit earlier if any deterioration in vision or persistent headache is there.
154  Practical Manual of Pharmacology
37. Aphthous ulcer
Dr Rakesh Kumar
MBBS, MD
115, Civil Lines, Ludhiana
Phone: 0161-5030987
Name:
Amit Sharma
Age/Sex: 55 Male
Address: H. No 445, Model Town, Ludhiana Tel: 5058677
Unit No. C-238567
Date 07-07-2007
L
• Tab. Vitamin B-complex 1 bd × 1 month
• Tab Ferrous sulphate (60 mg elemental iron) 1 tds × 1 month
• Tab Albendazole 400 mg single dose
• Metronidazole cream for local application × 7days
• Lignocaine (2%) viscous for local application × 7days
Direction to Pharmacist: Please dispense 60 tab. Vit B-complex, 90 tablets of ferrous
sulphate, 1 tab of albendazole 250 mg, one metronidazole cream and 1 lignocaine.
Name: Dr Ankur Sharma, MD
Regd. No 24456 (Punjab Medical Council)
Prescription Writing Through Problem Based Learning (Rational Prescribing)  155
Exercises in class:
After going through solved examples of prescription for common diseases, students are
advised to solve the following:
Choose a P drug and write appropriate prescription in the following conditions:
1. A 55-year-old farmer (Kulwant Singh), was admitted in emergency department with
irritation and watering of eyes, increased salivation, sweating, blurring of vision and
abdominal pain. History revealed accidental exposure to heavy amount of an insecticide.
2. Tonometric examination of a 48-year-old Ram Singh patient showed raised intraocular
pressure (55 mm of Hg). He was complaining of severe pain, redness in eye and nausea/
vomiting and headache.
3. A female aged 38 years (Kamlesh Kaur) came with complains of easy fatigability,
weakness, dizziness and soreness of the tongue. Investigations reported reduced
hemoglobin level (6.5 gm/dl) and blood film reported megaloblastic cells.
4. A 26 years pregnant female (Nisha Agarwal) patient complained of headache and
visual disturbances in 2nd trimester. On examination edema of feet was present. Her
BP was 160/130 mm of Hg. Urine examination reported albuminuria.
5. A 55 years Arun Kumar was brought to ICU with persistent severe chest pain for last
one hours. The pain persists at rest and was radiating to left shoulder. Pain is associated
with vomiting and profuse sweating.
6. Ashok Kumar, 48-year-old male, complained of dyspnoea, cough, easy fatigability and
swelling over lower limbs. His BP was 170/130 mm of Hg.
7. A 22-year-old, Anushka a medical student reported loss of sleep due to examination
stress for last two days.
8. Buta Singh, 55-year-old male, developed tremor, rigidity and disturbed gait following
haloperidol therapy for last 1 month.
9. Anita Rani, 56-year-old female, complained of joint pain (small joints of fingers and
toes) and joint stiffness. He reported that stiffness was more in the early morning. Pain
increases on movement of affected joint.
10. Kanta, a 45 years, fair, fatty female complained of sudden onset of pain in epigastric
region lasting for about 3 hours and some times upto 6 hours. A plain abdominal
ultrasonograph reported presence of gall stones.
11. A 35-year-old Rajesh Singh complained of purulent urethral discharge, dysuria and
meatal erythema. His blood smear showed leukocytosis and urethral swab culture
reported neisseria gonococci.
12. A 28-year-old Kanta Kumari, complained of fever with chills, burning micturition,
increased and frequency of urination. Microscopic examination of urine reported plenty
of pus cells and epithelial cells.
13. A 20-year-old Sharad Gupta, complained of malaise, decreased appetite, itching all
over body, abdominal discomfort and diarrhoea with mucus and blood for the last one
week. Investigations revelaed high eosinophil count and stool examination reported,
occult blood positive and presence of ova of both roundworm and hookworm.
156  Practical Manual of Pharmacology
14. A 20-year-old female (Sunayna), is known to vomit during journey. She approached
you for help. She wants to travel for about 4 hours in bus from Chandigarh to Shimla.
15. A 35-year-old Amar Kaur, presented with history of palpitation, weight loss, increased
appetite and swelling of the thyroid region for past 2 months. On clinical examination
there were tremors in hands and investigations revealed raised serum T3 and T4 levels.
16. A 23-year-old female Charu, is recently getting married. She has come to you to take
advice for contraception.
CHAPTER
18
Critical Evaluation of Prescription
(Audit of Prescriptions)
Irrational prescribing is seen every where (developing and developed countries), at all levels
(senior consultants and junior students) and in all categories (specialists, superspecialists).
As drug treatment is the essence of therapeutics, it become extremely important to audit
prescriptions. Wrong prescriptions can be fatal. With consumer protection Act (CPA) in
force, you need to be careful when writing prescriptions.
Common errors in prescription writing
• Dosage form: Tab, cap, inj missing, hence difficult to dispense. Sometimes pharmacist/
patient decides on their own what can be the dosage form. Suppose patient is prescribed
an injection for an spreading infection, but he takes only tablets or a patient is prescribed
tablet to decrease his BP, but he takes injection.
• Quantity: This is very common. You reach a pharmacist/chemist, give him prescription,
but he asks which one you want 250 mg or 500 mg. Missing quantity can play havoc
with lives of patients. Similarly error in dose when prescribing to children can lead to
serious adverse effects. Sometimes you will find a prescription for an amount that
doesn't exist. Do not assume anything, always write on prescription.
• Length of therapy: This is a common error with most of the prescriptions. The result is
that most of patients decide on their own when to stop or when to restart. This leads to
irrational use especially with antimicrobials. With antimicrobials you need to be very
specific about duration.
• Patient allergies: Usually a missing part on prescriptions.
• Date: Very important to track back when medication was started, how much time has
passed and to refill prescription.
• Signature: Missing on prescriptions. This mistake is now increasing, may be because of
CPA.
• Registration number: Again a serious omission.
• Directions: A busy physician will not explain or explain in such a hurry that the patient
does not understand or understand in incorrect way, e.g. a lady took methotrexate
daily which was to be taken weekly. She died because of severe bone marrow
suppression.
158  Practical Manual of Pharmacology
• An error in reading the prescription by the pharmacist so that the wrong drug or dose
is dispensed, e.g. cotrimoxazole-cotrimazole.
• Substitution: Usually physician does not write substitution in case drug is not available.
It is only when you go back ant tell them that a particular drug is not available then he/
she will write substitution.
• Bad handwriting leading to confusion of drug name, e.g. similar names, e.g.
Acetazolamide and acetohexamide
• Drugs may be administered incorrectly, especially in institutions. A drug may be given
to the wrong patient, at the wrong time or by the wrong route. Certain drugs must be
given slowly when given IV, and some drugs cannot be given simultaneously.
• Use of expired/outdated drugs is common. For some drugs (e.g. aspirin, tetracycline)
risk of harm is great when outdated drug is used.
• Most commonly, drug error results from a patient's confusion about how to take drugs.
Tips for avoiding prescribing errors
a)
b)
c)
d)
e)
f)
g)
h)
Keep all blank prescription pads in a safe place
Minimizing the number of prescription pads in use
Write in ink
Write out the amount prescribed in addition to the numerical number
Avoid large quantities
Only use prescription pads for prescriptions
Don't sign prescriptions in advance
Put only one prescription on a blank prescription form.
Precautions for controlled or unscheduled medications, e.g. morphine
a)
b)
c)
d)
e)
f)
g)
h)
i)
Put the patient's diagnosis or the purpose of therapy on the prescription
Print
Include the patient's age and weight if relevant on the prescription
Use the metric system unless dealing with units
Avoid uncommon abbreviations
Be consistent
Sign your own prescriptions
Inform patient about medications
Never leave a decimal point naked.
Prescription audit is part of medical audit. Medical audit is an objective and systematic
way of evaluating the quality of care provided by physicians. It is conducted mainly in the
hospitals, assesses only the technical aspects of medical care, and often falls short in its
objectives.
Critical Evaluation of Prescription (Audit of Prescriptions)  159
Parameters of Prescription Audit :
1. Format of the prescription: Superscription, Inscription, Subscription, Transcriptioncomplete/incomplete.
2. Whether the diagnosis is recorded? Final or provisional.
3. Number of drugs prescribed.
4. Whether drugs prescribed are by official/pharmacological or brand names.
5. Choice of drugs for the given condition.
First choice/Second choice/Third choice/Placebo.
6. Unnecessary/Irrational/Hazardous drugs.
Unnecessary drug or injection: means a category of drugs or formulations not
recommended for that particular condition in the standard text books. However, rational
alternatives should not be considered unnecessary.
Irrational drug or drug combinations, i.e. a drug or drug combination not
recommended in the standard text books of pharmacology or other reputed scientific
medical literature.
Hazardous drugs: Drugs listed under the heading 'Banned and bannable drugs'.
7. Dose regime: Dosage form, dose, frequency and duration of treatment.
8. Prescription cost is calculated using the prevailing prices of drugs given in the latest
volumes of Indian Drug Review, MIMS, CIMS or Drug Index.
9. Status of the prescription: Rational/Semirational/Irrational.
10. Date.
11. Signature of doctor, registration number.
12. Patient's particulars are right.
Tips for writing a good prescription
1. Write or print the prescription legibly. If the physician has poor writing, preprinted or
typed prescriptions may help.
2. Spell the name(s) of the drug(s) correctly, especially in view of the number of "lookalikes" and "sound-alikes." Get in the habit of writing both the trade and generic names.
3. Write the prescription in proper English grammar. Latin abbreviations such as qid may
be interpreted as qd or od and are no longer recommended. Avoid phrases such as "as
directed" or "as needed." Specify exact times to be taken: daytime hours, around the
clock and relationship to meals.
4. Careful use of decimal points to avoid ambiguity:
a. Avoid unnecessary decimal points: 5 ml instead of 5.0 ml to avoid possible
misinterpretation of 5.0 = 50
b. Always zero prefix decimals: For example 0.5 instead of .5 to avoid
misinterpretation with .5 = 5
160  Practical Manual of Pharmacology
5.
6.
7.
8.
9.
10.
11.
12.
13.
c. Never have trailing zeros on decimals: For example use 0.5 instead of .50 to avoid
misinterpretation with .50 = 50
d. Avoid decimals altogether by changing the units: 0.5 g = 500 mg.
Directions should be written out in full in English.
Quantities can be given directly or implied by the frequency and duration of the
directions.
Where the directions are "as needed" the quantity should always be specified
Where possible, usage directions should specify times (7 am, 3 pm, 11 pm) rather than
simply frequency (3 times a day) and especially relationship to meals for orally consumed
medication
Avoid unspecified or "as needed" instructions-limits and indicators should be provided,
e.g. "every 3 hours pain"
For refills, minimum duration between repeats and number of repeats should be
specified
Provide the indication for all prescriptions even when obvious to the prescriber so that
the pharmacist may identify possible errors
Avoid non-standardized units such as "teaspoons" or "tablespoons"
Write out numbers as words and numerals ("dispense #30 (thirty)") as in a bank draft or
cheque.
Exercises:
Critically analyse following prescription and rewrite the correct prescription.
Example 1:
L
• Injection L-Dopa l0 mg IV Stat
• Tab B complex 1 tab twice daily
• Tab Benzhexol hydrochloride 2-5 mg. initially and then dose increased to 300
mg daily in divided doses.
Dr ABC
Reg No. 456
Comments:
1. Format of prescription is not proper, i.e. superscription is not given. Further the duration
of drugs is not specified.
2. In the Inscription : Route and dose of L-Dopa mentioned is wrong.
3. Pyridoxine which is present in B complex tablet is dopa decarboxylase enzyme stimulator,
so that very little amount of dopamine will reach the brain, further deteriorating the
clinical condition.
Critical Evaluation of Prescription (Audit of Prescriptions)  161
4. Tab Benzhexol is increased to only 10-50 mg/day and also in divided doses. Such high
doses can lead to toxic anticholinergic side effects.
Example 2: Comment on the following prescription:
Date 12/9/88
L
Name: Mr Kulwant Singh
Age: 47
Sex: M
Occupation: Business executive, Address: Mahim (Bombay)
Diagnosis: Status asthmaticus
Tab Cetrizine 10 mg stat
Injection pethidine 10 mg LM. 6 hourly
Tab salbutamol 20 mg tds.
Injection adrenaline hydrochloride 1:1000 IV, sos
Comments: (write your comments)
C H A P T E R
19
Problem Based Drug Interactions
Drug interactions deserve a special mention because interactions are one of the leading
causes of the adverse drug effects. It is estimated that drug-drug interactions represent
from 3 to 5% of all in hospital medication errors. Drug interactions are also an important
cause of patient visits to emergency department of hospitals.
Drug interactions are often recognized only when serious toxicity occurs. Sufficient
knowledge regarding effective and safe use of drugs is possible only if there is adequate
knowledge understanding of pharmacokinetic and pharmacodynamic of drugs. This will
enable physicians to select proper drug combinations. A number of drugs have been
withdrawn from market because of drug interactions. Few important ones are:
• Terfenadine February 1998
• Mibefradil June 1998
• Astemizole July 1999
• Cisapride January 2000.
Hence, drug interactions between drugs represent a major concern for the pharmaceutical
industry, for drug regulatory agencies and clinically for health care professionals and their
patients. Drug interactions may be synergistic or antagonistic, desired or undesired, beneficial
or harmful.
Drug interaction can occur at 3 levels (Table 19.1):
A. Pharmaceutical: These are interactions before administration of drugs. These interactions
can occur in vitro (IV fluid, syringe, vial-outside the body) due to chemical interaction.
Example: Heparin should not be mixed with tetracyclines, penicillins and hydrocortisone
in the same syringe. Inactivation of these drugs may occur.
When phenytoin is added to solutions of dextrose, a precipitate can and the phenytoin
falls to the bottom of the IV bag as an insoluble salt. When this happens, it is no longer
available to control convulsions. Amphotericin is still used widely as a urinary bladder
perfusion to treat aggressive fungal infections. If it is administered in saline, the drug
precipitates and can erode through the bladder wall if not removed. The clinical presentation
of such cases is an acute abdomen due to perforation of the bladder. Lastly, it is recommended
Problem Based Drug Interactions  163
that aminoglycosides should not be mixed in IV fluids with betalactam antibiotics (penicillins,
cephalosporins). This can markedly reduce antibiotic activity.
Table 19.1. Sites of adverse drug interaction
Site
In vitro
Oral
Intestine
Plasma
Liver
Kidney
Receptor
Mechanism
Chemical interaction
Altered bioavailability
Altered absorption
Protein binding displacement reactions
Enzyme induction/inhibition
Reabsorption, secretion, altered pH
Competition/antagonism
B. Pharmacokinetic: Usually the cause of drug interactions is an alteration in pharmacokinetic
properties of one drug by another drug. Pharmacokinetic properties can be altered during
absorption, distribution, metabolism or excretion of drugs.
1. Absorption
Drug interactions can occur during absorption of drugs in the gastrointestinal Tract.
Examples:
a) Aluminum-containing medicines such as sucralfate and antacids to reduce the
absorption of expensive and potentially life-saving antibiotics like ciprofloxacin
and azithromycin.
b) Women taking iron supplements often do not consider them as medicines and
should be specifically questioned about whether they are taking iron if they are
to be prescribed a quinolone or azithromycin.
c) Drugs such as ketoconazole and delavirdine require an acidic environment to be
in the unionised form that is preferentially absorbed. Solubility is drastically
reduced in neutral or basic medications such as omeprazole, lansoprazole or H2antagonists that raise the stomach pH.
The following drugs/food products, i.e.
• Sucralfate, some milk products, antacids and oral iron preparations
• Omeprazole, lansoprazole and H2-antagonists
• Didanosine (given as a buffered tablet)
• Cholestyramine.
CAN
•
•
•
•
Block absorption of quinolones, tetracycline and azithromycin
Reduce absorption of ketoconazole, delavirdine
Reduces ketoconazole absorption
Binds raloxifene, thyroid hormone and digoxin respectively.
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Distribution
Displacement of highly protein bound drug (warfarin) by another drug (e.g. NSAIDs) could
lead to an increase in the free plasma concentration of first drug and an adverse effect
(bleeding tendency). But most of the drug interactions due to plasma protein displacement
reactions are not clinically significant, because the displaced drug (free drug) is eliminated
faster, i.e. more free drug is now available to kidneys for excretion.
Metabolism
Drug interactions involving metabolism are the most important drug interactions clinically.
Some important preventable drug interactions are due to their effects on drug metabolizing
enzymes, resulting in either inhibition (reduced activity) of the enzyme or induction (increased
activity) of the enzyme. There are many potential consequences of changes in drug metabolism
for a given drug. It is made more complex by the fact that there are multiple pathways of
metabolism for many drugs.
The major group of enzymes in the liver that metabolize drugs can be isolated in a
subcellular fraction termed the microsomes. The largest and most important of these enzymes
are the cytochrome P450(CYP450) family of enzymes, which mediate phase I reactions. Since
Phase II reactions generally result in conjugation of a drug to a water-soluble group like a
sugar, peptide (glutathione) or sulfur group, and because there is a large excess of these
groups in well nourished cells, these reactions are rarely rate-limiting. Thus, they are rarely
involved in drug interactions. In contrast, the Phase I reactions carried out by cytochrome
P450 enzymes, flavin monooxygenases and reductases are more frequently rate limiting.
These are the target of clinically significant drug interactions, such as the inhibition of
cyclosporine metabolism by erythromycin.
Although there are other enzyme systems that perform similar functions, the cytochrome
P450 system is important because it is involved in most clinically relevant metabolic drug
interactions. Six CYP450 isoforms are clinically important. These days drug interactions can
be predicted if we know by which isoenzyme it is metabolized. The following Table 19.2 can
help to predict mechanism of interaction of few important drugs.
Problem Based Drug Interactions  165
Table 19.2: Cytochrome P450 isoenzymes, their substrates, inhibitors and inducers
Isoenzyme
Substrates
Inhibitors
Inducers
3A
Most calcium channel blockers
Most benzodiazepines
Most HIV protease inhibitors
Statins
Cyclosporine
Ketoconazole
Fluconazole
Cimetidine
Erythromycin
Troleandomycin
Carbamazepine
Rifampicin
Rifabutin
Ritonavir
St. John's wort
2D6
Codeine
Many tricyclic antidepressants
SSRIs
Haloperidol
Amiodarone
Dexamethasone
Rifampicin
2C9
Most NSAIDs (including COX-2)
S-warfarin (the active form)
Phenytoin
Fluconazole
Fluvastatin
Isoniazid
Sulfamethoxazole
Rifampicin
Secobarbital
2C19
Diazepam
Phenytoin
Omeprazole
Omeprazole
Isoniazid
Ketoconazole
Carbamazepine
pentobarbital
Rifampicin
1A2
Theophylline
Imipramine
Propranolol
Clozapine
Many
fluoroquinolone
antibiotics
Fluvoxamine
Brussel sprouts
Char-grilled meat
Omeprazole
Tobacco
INHIBITION (FIG. 19.1)
Fig. 19.1: Drug interaction by inhibition of metabolism
Warfarin is anticoagulant and cimetidine is used in treatment of peptic ulcers.
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Fig. 19.2: Drug interaction by induction of metabolism
INDUCTION (FIG. 19.2)
Rifampicin is an antitubercular drug.
Excretion
Drugs can compete for excretion, hence, there can be inhibition of excretion of one of the
drugs. This leads to increased concentration, prolonged action or toxicity.
Examples:
• Sulfinpyrazone inhibits excretion of tolbutamide and increases its toxicity.
• Probenecid inhibits excretion of penicillins and increases their duration of action.
C. Pharmacodynamic: Pharmacodynamic interaction occurs at site of action.
Examples:
a) The combined inhibitory effects of propranolol and verapamil or diltiazem on
atrioventricular node represent potential site of an adverse interaction.
b) Alteration of compensatory mechanisms could also lead to such interactions. Beta
blockers prolong the recovery from hypoglycemic effects of antidiabetics.
c) Drugs with sedative potential can aggravate sedation when given together especially
in the elderly, e.g. tricyclic antidepressants and antiepileptics.
Effects of drug interactions
1.
2.
3.
4.
5.
6.
7.
8.
9.
Diminished therapeutic response
Enhanced side effects
Relative overdosage toxicity
Intensified allergic reactions
Increased secondary effects
Severe idiosyncratic reactions
Greater teratogenicity
Additive addiction potential
Miscellaneous.
Problem Based Drug Interactions  167
Food-drug interactions
Several drugs are known to interact with foods.
a) Reduced absorption of tetracycline when taken with milk products. The chelation of
tetracycline by calcium prevents it from being absorbed from the intestines.
b) Dietary sources of vitamin K, such as spinach or broccoli, may increase the dosage
requirement for warfarin by a pharmacodynamic antagonism of its effect. Patients should
be counseled to maintain a consistent diet during warfarin therapy.
c) Grapefruit juice contains a bioflavonoid that inhibits CYP3A and blocks the metabolism
of many drugs. This was first described for felodipine but has now been observed
with several drugs. This interaction can lead to reduced clearance and higher blood
levels when the drugs are taken simultaneously with grapefruit juice. Grapefruit juice
(GFJ) is often taken at breakfast in the western countries when drugs are also often
taken. GFJ contains bioflavonoids mainly naringin and furacoumarin which cause
mechanism based inhibition of presystemic elimination of a number of drugs and increase
their bioavailability and toxicity.
d) Cheese reaction (hyperadrenergic crisis) can occur when a patient on MAO inhibitors
consumes cheese or cheese containing preparations, e.g. cheese tomato. This is because
of tyramine present in cheese that leads to release of catecholamines in the body. Since
the patient is on MAO inhibitors there is already decreased metabolism of catecholamines
in the body, hence, there is exaggerated response.
It is impossible to remember all of the drug interactions that can occur. It is, therefore,
important to develop a stepwise approach to prevent drug interactions. First, taking a
good medication history is essential. The following stepwise approach can help health
care practitioners to develop good habits when performing this task.
1. Take a medication history
2. Remember high risk patients
a. Any patient taking 2 medications
b. Anticonvulsants, antibiotics, digoxin, warfarin, amiodarone, etc.
3. Check pocket reference
4. Consult pharmacists/drug info specialists
5. Check up-to-date computer program.
OBJECTIVES
At the end of this session, a student shall be able to:
1. Identify type of drug interaction in a given problem
2. Explain mechanism of drug interaction
3. Provide preventive and curative treatment for the interaction.
168  Practical Manual of Pharmacology
Exercises in class: Problem based exercises can be designed for this activity. These are
given in the form of a statement of a case for class exercises. Students are divided into
batches. Each batch has 5-6 students. In examination, these can be given on cards and a short
viva can be conducted. They can also be given this activity with prescription writing as is
done usually. A short viva can be held on the answer written by the student. This can be
done in labs where students are doing experiments.
Examples of problem based drug interactions:
1. A 35-year-male was prescribed astemizole and erythromycin together for sore throat.
Next day he was admitted in cardiac casualty with arrhythmias.
a) What happened to the patient?
b) Which other drugs can lead to similar situation?
c) How this can be prevented?
2. A 35-year-male on taking MAO inhibitors. He consumed cheese tomato during a
wedding party of his friend. Next day he was admitted in casualty with a BP of 190/
110 mm of Hg.
a) Why his BP increased?
b) How this can be prevented?
c) How this can be treated?
Problem Based Drug Interactions  169
3. A 26-year-female was using oral contraceptive pill for the last 2 years. He was
prescribed antitubercular drugs for the tuberculosis. She became pregnant after 2
months.
a) Why she became pregnant even when she was on oral contraceptives?
b) How this can be prevented?
c) Which other drugs can produce similar situation?
4. A 4-year-old child was prescribed iron syrup for anemia (Hb 9.5 gm). To avoid bad
taste, his mother used to give milk with iron syrup. After 4 months of iron therapy
the Hb was still 9.5 gm.
a) Why there was no increase in Hb?
b) How this can be prevented?
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5. A 30-year-male patient was stable with warfarin therapy. He was prescribed cimetidine.
After 1 week he was admitted to hospital with intracranial bleeding.
a) What happened to patient?
b) Which other drugs can lead to similar situation?
c) How this can be prevented?
6. A 40-year-male epileptic patient was stable with phenytoin. He was prescribed
ketoconazole. After 1 week he was admitted to hospital with slurred speech and
dizziness.
a) What happened to patient?
b) Which other drugs can lead to similar situation?
c) How this can be prevented?
Problem Based Drug Interactions  171
7. A 50-year-male was taking azathioprine for the last 2 months. He was prescribed
allopurinol for gout. After 1 week he was admitted to hospital with bleeding from
gums.
a) What happened to patient?
b) Which other drugs can lead to similar situation?
c) How this can be prevented?
8. A 30-year-lady was taking oral contraceptives for the last 1 year. She was prescribed
ampicillin for an infection. She became pregnant after 1 month inspite of taking oral
contraceptives regularly.
a) What she became pregnant?
b) Which other drugs can lead to similar situation?
c) How this can be prevented?
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9. A cardiac CHF patient was taking metoprolol. He was prescribed verapamil by another
cardiologist without asking what he was already taking. Next day patient was
admitted in ICCU with severe bradycardia.
a) What happened to patient?
b) Which other drugs can lead to similar situation?
c) How this can be prevented?
10. A 45-year-old male hypertensive patient was stable on metoprolol for the last one
year. He was prescribed diclofenac for joint pains. After 2 months his BP increased
even when he was taking metoprolol regularly.
a) What happened to patient?
b) Which other drugs can lead to similar situation?
c) How this can be prevented?
Problem Based Drug Interactions  173
11. A 45-year-old male epileptic patient was stable on carbamazepine for the last one
year. He was prescribed clarithromycin for throat infection. After 1 month he
complained of diplopia and ataxia.
a) What happened to patient?
b) Which other drugs can lead to similar situation?
c) How this can be prevented?
12. A 55-year-old male patient was stable on lithium for the last 6 months. He was
prescribed chlorthiazide for CHF. After 1 month his complained of persistent nausea/
vomiting and blurred vision.
a) What happened to patient?
b) Which other drugs can lead to similar situation?
c) How this can be prevented?
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13. A 45-year-old male hypertensive patient was stable on enalapril for the last one year.
He was prescribed spironolactone for CHF. After 5 days he complained of palpitations
and restlessness.
a) What happened to patient?
b) Which other drugs can lead to similar situation?
c) How this can be prevented?
14. A 34-year-old male consumed alcohol during a wedding party. He felt abdominal
discomfort in the morning and took metronidazole. In the evening he developed a
rash on the body, throbbing headache and respiratory difficulty and nausea.
a) What happened to patient?
b) Which other drugs can lead to similar situation?
c) How this can be prevented?
Problem Based Drug Interactions  175
15. A 65-year-old male Parkinsonian patient was stable on L-dopa last one year. He was
prescribed pyridoxine. After 1 month his condition deteriorated.
a) What happened to patient?
b) How this can be prevented?
16. A 40-year-old male diabetic patient was stable on chlorpropamide for the last one
year. He was prescribed probenecid. After 1 month he was admitted in ICU with in
unconscious state.
a) What happened to patient?
b) Which other drugs can lead to similar situation?
c) How this can be prevented?
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17. A 40-year-old male diabetic patient was stable on gliclazide for the last one year. He
was prescribed chlorthiazide for hypertension. After one month his fasting blood
sugar increased to 180 mg/dl.
a) What happened to patient?
b) Which other drugs can lead to similar situation?
c) How this can be prevented?
18. A 45-year-old male diabetic patient was stable on glibenclamide for the last 6 months.
He was prescribed propranolol for migraine. After one week he was admitted in ICU
with in unconscious state.
a) What happened to patient?
b) Which other drugs can lead to similar situation?
c) How this can be prevented?
Problem Based Drug Interactions  177
19. A 52-year-old male was taking nitrates for angina for the last one year. He was
prescribed sildenafil for erectile dysfunction. On next day, at 11pm he was admitted
in ICU with aggravation of angina.
a) What happened to patient?
b) Which other drugs can lead to similar situation?
c) How this can be prevented?
CHAPTER
20
Adverse Drug Reaction (ADR)
Monitoring
It took many decades before the deleterious effects of aspirin on the gastro-intestinal tract
became apparent and almost as long before it was recognised that the protracted abuse of
phenacetin could produce renal papillary necrosis; 35 years elapsed before it became clear
that amidopyrine could cause agranulocytosis; and several years before the association of
phocomelia with thalidomide became obvious. The recent withdrawal of a very successful
drug 'Rofecoxib' highlights the importance of ADR monitoring. Hence, systematic collection
of information on adverse drug reactions is essential to provide much needed information
regarding patients at risk, drug interactions and adverse reactions to new drugs not detected
in studies conducted before marketing of the drug. The ADR monitoring is also known as
pharmacovigilance. WHO defines pharmacovigilance as "the science and activities relating
to the detection, assessment, understanding and prevention of ADRs or any other, medicinerelated problem". Pharmacovigilance plays a major role in pharmacotherapy decision-making,
be it individual, regional, national or international.
What is an adverse drug reaction?
1. Adverse reaction: A response to a drug which is noxious and unintended, and which
occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of
disease or modifying a physiological function.
2. Side effects: Any unintended effect of a pharmaceutical product occurring at doses
normally used in man which is related to pharmacological properties of the drug.
3. Toxic effect: A direct action of the drug, often at high dose damaging cells, e.g. liver
damage from paracetamol overdose.
Types of ADRs:
A. (Augmented)—directly related to pharmacolgical action of drug, e.g. hypokalaemia
with digoxin
B. (Bizarre)—idiosyncratic and genetically determined, e.g. acute intermittent porphyria
due to sulphonamides in patients with G-6 PD deficiency.
C. (Continues use)—associated with long term use of drugs tardive dyskinesia with
neuroleptics.
Adverse Drug Reaction (ADR) Monitoring  179
D. (Delayed)—Teratogenicity or carcinogenicity, e.g. phenytoin-teratogenicity
E. (End of dose)—abrupt stoppage of drug, e.g. beta blockers, corticosteroids.
Severity:
Minor
:
Moderate :
no treatment/antidote or hospitalization required. Drug is continued.
change in drug therapy required, specific treatment, increase in
hospitalization by at least for one day.
Severe
: potentially life threatening, caused permanent damage or require intensive
medical care.
Lethal
: directly or indirectly contributed to death of the patient.
Causality: It is determination that the event is due to drug and that there is no other
alternative explanation for it.
The Naranjo algorithm is one means to assign the likelihood of a drug causing an untoward
event. This simple ten-item questionnaire uses specifically assigned numerical values to arrive
at an overall total score for probability assignment. Probability is assigned via a score termed:
1. definite
2. probable
3. possible or
4. doubtful.
Advantages of the Naranjo algorithm include its ease and widespread use. However,
tests of its reliability as a tool for serious cases of adverse drug reactions have not been
performed. The Naranjo algorithm can be used to assess the likelihood that a change in
clinical status is the result of an ADR rather than the result of other factors such as progression
of disease. Answer each of the ten items in the assessment and enter the value of the answer
in the column labeled Score. Sum the scores of the ten items to determine the total score, and
apply the interpretation rules that appear at the bottom of the page (available at http://
mqa.dhs.state.tx.us/QMWeb/MedSim/Naranjo.htm).
Health professionals are in the best position to report on suspected ADRs observed in
their every day patient care. All healthcare providers (physicians, pharmacists, nurses, dentists
and others) should report ADRs as part of their professional responsibility, even if they are
doubtful about the precise relationship with the given medication. You can reduce the suffering
and save thousands of patients lives by doing this. ADR monitoring is to help ensure that
patients obtain safe and efficacious products. The results of ADR monitoring have also a
very important educational value. The aim is to obtain data of scientific quality for rational
and safe use of drugs.
Several methods used for collection of information on adverse reactions to drugs have
been reported in literature. The main methods are as follows:
180  Practical Manual of Pharmacology
A. Premarketing Clinical trials
Before marketing of drug, animal studies and human trials (Phase I, II, III and IV) are done
to detect ADRs. Animal studies include acute, subacute, chronic toxicity studies and specialized
toxicity studies. But, it has been proved again and again that tests in animals are insufficient
to predict human safety. Clinical trial done in humans to look for ADRs, but number of
patients is limited and there trials detect ADR with an incidence of 1:200 only. The declared
purpose of 'pre-marketing' clinical trials is to discover:
• If a drug works and how well
• If it has any harmful effects
• If there is potential harm how serious is it and how does it weigh against the benefits.
There are concerns about these premarketing studies because of two reasons:
1. Before marketing drugs are evaluated for toxicity in animals. These studies produce an
overall picture of toxicology of the drug and indicate organs which are at highest risk
of damage. However, it is difficult to draw direct parallels between toxicity in animal
models and potential risks to man.
2. After animal toxicity studies drug undergoes clinical trials in humans. For a new drug
pre-marketing clinical trials are generally carried out in less than 3000 patients. Type A
reactions can thus be identified. Subgroups at particular risks are occasionally identified.
However, type B reactions with incidence of 1:1000 are generally missed.
By the time of licensing, exposure of less than 5000 human subjects to a drug allows only the
more common ADR to be detected. At least 30,000 people need to be treated with a drug to
be sure that you do not miss at least one patient with an ADR which has an incidence of 1 in
10,000 exposed individuals. Susceptible population like elderly, children, lactating mothers
are unlikely to be included in these studies. However, within a short time after entering the
market, the drug may be administered to several million patients. That means that for drugs
that cause rare toxicity, their toxicity can only be detected after, not before, marketing.
So, the safety profile for new drugs that come into the market is never totally defined
because new drugs are studied only in relatively small and homogenous patient populations.
The complete safety profile of a new drug will be defined only after it has been approved
and is in use in the market.
Clinical trials generally do tell a good deal about how well a drug works for a defined
disease and what potential harm it may cause. However, they provide no information for
larger populations with different characteristics from the trial group—age, gender, state of
health, ethnic origin and so on.
Therefore, for many medicines and particularly new, complex products, safety monitoring
does not stop at the manufacturing stage, it must be followed by careful patient monitoring
and by further scientific data collection. This aspect of drug monitoring is called postmarketing
B. Postmarketing methods
In these methods ADRs are observed epidemiologically under conditions of normal use in
the community. Thus, post-marketing surveillance is important to permit detection of less
Adverse Drug Reaction (ADR) Monitoring  181
common, but sometimes very serious ADRs. Therefore, health professionals worldwide
should report on ADRs as it can save lives of their patients and others. The various methods
used are:
Case Reports: This has the advantage of speed and sensitivity, however, the reports
need to be validated. Case reports have been the first means by which some of the type B
reactions have been identified, e.g. Practolol induced dermatitis and keratoconjunctivitis,
benoxaprofen induced photosensitivity which is dose related.
Cohort Studies: Cohort of patients receiving a drug under investigation are prospectively
studied and compared with control population. The cohort studies are excellent methods of
quantifying ADRs, e.g. Royal College of General Practitioner's oral contraceptive study. The
contraceptive study quantified the risk of cardiovascular diseases and excess mortality due
to oral contraceptives. However, cohort studies are expensive and slow and do not
necessarily, prove causal link.
Prescription event monitoring: Patients who have received specific drugs are identified
from prescription (in UK prescription pricing authority). The general practitioner is then
asked to report any adverse event detected. The method has the advantage of enhancing
detection of new adverse reactions and incidence of event can be calculated. Prescription
event monitoring has identified deafness associated with enalapril.
Case control studies (Retrospective): In this prospective method patients who have the
identified disease are matched with a control group who have similar potentially confounding
factors but who do not have the disease. The drug histories are then compared. The association
between aspirin and Reye's syndrome was confirmed using this method and resulted in
recommending removal of the pediatric formulation of aspirin from the market.
Spontaneous Reporting-Yellow card system: Spontaneous reporting of ADRs to a central
body was started in UK in 1964. However, it is estimated that out of even serious and fatal
ADRs, only 10% are reported so there is gross underreporting. Reporting may be biased and
limited to serious ADRs. Advantages of this system are that numbers are large, personal
details are kept confidential and early alerts are available. The yellow card system identified
the risk of urticaria and confirmed the occurrence of cough due to captopril and enalapril. It
is recommended that a physician for newer drugs a physician must report all suspected
ADRs and for established drugs, he should report all serious suspected ADRs. Advantages
of this system are that it acts as early alerting system.
1. Record linkage: The health records of a defined population are correlated with data on
the use of drugs. This technique is not very sensitive compared to other methods but
can generate hypotheses for further investigation. This method covers large sample
size and there is no recall bias.
Phase-IV clinical studies (Post Marketing surveillance): Post marketing surveillance (PMS)
is a regulatory requirement and done for all the drugs after marketing. This surveillance
provides information of long term safety of drug, safety in extremes of ages, safety in special
population, e.g. pregnant and lactating females. Severe ADRs may lead to withdrawal of
drugs. In India it is now mandatory to submit results of postmarketing surveillance within 2
182  Practical Manual of Pharmacology
years of marketing the drug. Sometimes after this surveillance warnings on ADRs are inserted
on labels of drugs.
This monitoring can be done as regional or national level. Other way to monitor is to
monitor disease, rather than drugs, especially in case of Type B bizarre ADRs, that will help
in identifying many serious adverse effects in different subspecialties of medicine and surgery,
e.g. carcinoma in young females showed unusual clear cell carcinoma like histopathological
features, only in these mothers who received stilbesterol during pregnancy, similarly biopsy
revealed pseudomembranous colitis in those treated with tetracycline lead to the path of
drugs induced adverse effect in the gastroenterology department, while ophthalmic
department could observe a different kind of dry eye in those treated with controlled care
studies. Thus, orientation and participation of physicians can help identifying the new drugs
reaction, as well as minimizing the adverse effect of dugs through regularly updating their
own knowledge.
WHO promotes drug safety through its International Drug Monitoring Programme, which
began to operate in 1968. Initially a pilot project in 10 countries with established national
reporting systems for ADRs, the network has expanded significantly as more countries
worldwide develop national pharmacovigilance centers for the recording of ADRs. Currently,
81 countries are members in the programme.
The Uppsala Monitoring Centre (UMC, WHO), Sweden is maintaining the international
database of adverse drug reaction (ADR) reports received from several National Centers.
By June 2006, the database had 3.67 million adverse drug reaction reports. Vigibase online
(web based) system is used for submission of ADR reports. Although, India is participating
in this programme, its contribution to UMC database is very little. This is essentially due to
the absence of a vibrant ADR monitoring system and also the lack of a reporting culture
among health care workers.
Special need for ADR monitoring in India
Due to huge population, unorganized health sector, use of alternative medicine there is an
urgent need for monitoring ADRs in India.
There is variation in ADRs between different countries on account of variation in genetic,
environmental, dietary factors and disease patterns and drug used. The reported incidence
of drug induced hepatotoxicity is low in India compared to developed countries. The common
drugs incriminated were antitubercular drugs in India as opposed to halothane reported to
be the commonest in the Danish registry.
In India, in rural areas, over 50% of children are malnourished and 45-70% of population
is iron deficient, which may affect incidence of ADR. There are very few functioning ADR
centers in India. Adequate information is not available even on adverse reactions to old
drugs. There is lack of data on ADR in specialised populations like pregnant, women and
children.
Due to the increased prevalence of certain diseases in this country certain drugs are used
in a population where they are not recommended, e.g. Ciprofloxacin in children. Many patients
tend to use modern drugs along with traditional remedies. Interactions that can result could
Adverse Drug Reaction (ADR) Monitoring  183
lead to adverse reaction and loss of efficacy. Traditional drugs are considered safe but may
not necessarily be safe.
Organization of ADR monitoring system in India
Appreciating the importance and benefits of pharmacovigilance, Central Drugs Standard
Control Organization (CDSCO), Ministry of Health and Family Welfare, Govt. of India
launched the National Pharmacovigilance Programme (NPP) in November, 2004. It is largely
based on the recommendations made in the WHO document titled "Safety monitoring of
medicinal products-guidelines for setting up and running a pharmacovigilance centre".
The immediate aim of NPP is to foster the culture of ADR notification by health care
workers in India. Subsequently, it seeks to generate broad based ADR data on the Indian
population and share this with WHO database. This would ensure optimum safety of drugs
in the Indian market.
Under this programme, the whole country is divided into zones and regions for
operational efficiency. CDSCO, New Delhi is at the top of the hierarchy followed by two
zonal pharmacovigilance centers, Seth GS Medical College, Mumbai and AIIMS, New Delhi.
There are 5 regional pharmacovigilance centers located at Kolkata (IPGMR-SSKM Hospitals),
Mumbai (TN Medical College & BYL Nair Charitable Hospital), Nagpur (Indira Gandhi
Medical College), New Delhi (Lady Hardinge Medical College) and Pondicherry (JIPMER).
Twenty eight peripheral centers, spread country-wide, are attached to their nearest peripheral
centers. ADR reports can be sent only by health care workers (doctors including dentists,
nurses, pharmacists) to any one of the nearest pharmacovigilance centre. The full list of
centers is available at CDSCO website (www.cdsco.nic.in). ADR reports sent by lay public
are not acceptable. Data received at the peripheral centers are forwarded to the respective
regional centers which will carry out the causality analysis. This information will be forwarded
to the zonal centers. From there the data will be forwarded to the CDSCO and UMC database.
The ADR form for reporting ADRs in India is given in Appendix-III.
The various factors contribute to poor ADR reporting from India. Doctors feel that they
are trained to treat patients and not monitor ADRs. There is no guarantee of confidentiality
of a reported ADR by a doctor and government has no effective machinery to monitor
ADRs. Patient communities can not report an ADR and population is not educated about
ADRs and interprets it as doctor's negligence.
How to recognize ADRs?
Since ADRs may occur through the same physiological and pathological pathways as different
diseases, they are difficult and sometimes impossible to distinguish. However, the following
step-wise approach may be helpful in assessing possible drug-related ADRs:
1. Ensure that the medicine ordered is the medicine received and actually taken by the
patient at the dose advised.
2. Verify that the onset of the suspected ADR was after the drug was taken, not before
and discuss carefully the observation made by the patient.
184  Practical Manual of Pharmacology
3. Determine the time interval between the beginning of drug treatment and the onset of
the event.
4. Evaluate the suspected ADR after discontinuing the drugs or reducing the dose and
monitor the patient's status. If appropriate, restart the drug treatment and monitor
recurrence of any adverse events (dechallenge and rechallenge).
5. Analyse the alternative causes (other than the drug) that could on their own have
caused the reaction.
6. Use relevant up-to-date literature and personal experience as a health professional on
drugs and their ADRs and verify if there are previous conclusive reports on this reaction.
The National Pharmacovigilance Centre and Drug Information Centers are very
important resources for obtaining information on ADR. The manufacturer of the drug
can also be a resource to consult.
7. Report any suspected ADR to the person nominated for ADR reporting in the hospital
or directly to the National ADR Centre.
What should be reported?
• For "new" drugs - report all suspected reactions, including minor ones. (In many countries
drugs are still considered "new" up to five years after marketing authorization)
• For established or well-known drugs - report all serious or unexpected (unusual)
suspected ADRs
• All life threatening and serious adverse effects
• Report all suspected ADRs associated with drug-drug, drug-food or drug-food
supplements (including herbal and complementary products) interactions
• Report ADRs in special fields of interest such as drug abuse and drug use in newborns,
pregnancy and during lactation
• All reactions to vaccines, report ADRs occurring from overdose or medication error
• All drug interactions.
Thus, report all suspected adverse reactions that you consider of clinical importance as
soon as possible!
How to report ADRs?
ADR reporting usually occurs retrospectively. Local case report forms (CRF) should be
obtained from the National Drug Regulatory Authority. Some countries have included CRF
in their National Formularies (British National Formulary, Formularies of South Africa,
Zimbabwe, etc.). There are different Case Report Forms in different countries. The ADR
reporting form for India is attached as Appendix I. Send filled form to regional centre. In
any case of doubt, you may send this form to the National Pharmacovigilance Centre at:
Central Drugs Standard Control Organization, Directorate General of Health Services,
Ministry of Health and Family Welfare, Nirman Bhawan, New Delhi-110 011. All forms have
at least four sections which should be completed.
Adverse Drug Reaction (ADR) Monitoring  185
Sample ADR format
1. Patient information
• Patient identifier
• Age at time of event or date of birth
• Gender
• Weight
2. Adverse event or product
• Problem date of event date of this report
• Description of event or problem
• Relevant tests/laboratory data (if available)
• Other relevant patient information/history
• Outcomes attributed to adverse event
3. Suspected medication(s):
• Name (INN and brand name) dose frequency route used
•
•
•
•
Therapy date
Diagnosis for use
Event abated after use stopped or dose reduced
Batch number
expiration date
• Event reappeared after
• Reintroduction of the treatment
• Concomitant medical products and therapy dates
4. Reporter
• Name, address and telephone number
• Specialty and occupation
OBJECTIVES
At the end of the practical group work the student shall be able to:
1. Appreciate the importance of ADR monitoring
2. Enumerate methods used for ADR monitoring
186  Practical Manual of Pharmacology
3.
4.
5.
6.
Identify which adverse effects should be reported
Find out severity and causality
Fill ADR monitoring form
Report an ADR to a monitoring centre.
Exercises in class:
Simulated cases can be given for exercises:
The form in Appendix II can be given as exercise to students. The students are divided
into batches and sent to hospital to investigate and report ADR on preselcted cases. The
information collected can be discussed in a larger group explaining the importance of all
parameters of ADR monitoring.
Example
The patient is a 42-year-old woman who presents to the emergency department with an
erythematous rash and audible wheezing. She presented to the medicine OPD days ago for
a second evaluation for elevated blood pressure. She was started on benazepril 5 mg po bd.
After taking the second dose, she noticed a rash on her torso and upper arms. Shortly
thereafter, she began experiencing difficulty in breathing as well as some facial swelling.
Her past medical history was notably only for high blood pressure for 4 years that was
previously controlled by diet and exercise. She has no history of tobacco use or alcohol use.
She has no known drug or food allergies. Her current medication is benazepril and she has
not taken any other prescription or OTC medications for more than 3 weeks. On physical
exam, she is a well developed, well nourished woman in moderate distress. Her vital signs
are as follows: blood pressure 100/80 mmHg, heart rate 78 beats per minute, respiratory
rate 32 beats per minute and afebrile. She weighs 62 kg and is 5 feet 5 inches. On examination,
she had notable edematous swollen face, inspiratory and expiratory wheezing and a red,
maculopapular rash on trunk and upper extremities. She was alert and oriented. Her serum
chemistries and complete blood count were within normal limits.
Exercise:
1. Has the patient suffered an ADR? If yes, explain severity and causality.
2. Did a drug precipitate a reaction in this patient?
3. Let's complete an ADR form on this patient.
CHAPTER
21
Therapeutic Drug Monitoring
(TDM)
Therapeutic drug monitoring is a branch of clinical chemistry that specialises in the
measurement of medication levels in blood. It is also part of chemical pharmacology. Its
main focus is on drugs with a narrow therapeutic index, i.e. drugs that can easily be under or
overdosed.
In pharmacology, many medications are used without monitoring of blood levels, as
their dosage can generally be varied according to the clinical response that a patient gets to
that substance, e.g. dosage adjustment can be done by monitoring the blood pressure for
antihypertensives (pharmacodynamic monitoring).
However, in a small group of drugs, this is impossible, as insufficient levels will lead to
undertreatment or resistance and excessive levels can lead to toxicity and tissue damage.
But for some drugs, there is either no readily available measure of effect or it is not sufficiently
sensitive. For example, clinical effects do not serve as a good guidance indicator when drugs
are used prophylactically (e.g. anticonvulsants) or when drug effects develop slowly (e.g.
antidepressants) or when drug effect cannot be differentiated from the complications of
disease process (e.g. digoxin). For such drugs, measurement of plasma concentration is very
useful (pharmacokinetic monitoring).
For these drugs, plasma concentration indicates the dose required to achieve therapeutic
levels for safe and effective outcome. Thus, TDM involves measurement of drug concentration
in body fluids and adjusting the dose in individual patients.
TDM is defined as "individualization of dosage by maintaining plasma or blood
concentrations within a target range (therapeutic range/therapeutic window). It is pragmatic
manipulation of the dose of a drug using plasma concentration as a guide to optimize its
efficacy, to avoid or identify toxicity and to detect or confirm poor compliance."
The characteristics of drugs which make them suitable for, or make them require,
therapeutic drug monitoring are:
• marked pharmacokinetic variability
• concentration related therapeutic and adverse effects
• narrow therapeutic index
• defined therapeutic (target) concentration range
• desired therapeutic effect difficult to monitor.
188  Practical Manual of Pharmacology
The indications for TDM are listed in Table 21.1.
Table 21.1: Indications for TDM
Indication
Drug/s
Narrow therapeutic range drugs
Lithium
Drugs with non-linear (zero order)
pharmacokinetics
Phenytoin
Drugs showing interindividual
variation in metabolism
Tricyclic antidepressants
Prophylactic use
Antiepileptics
To check toxicity
Aspirin
To check compliance
Antiepileptics, antidepressants
To check bioequivalence
Two or more brands of the same drug
To check drug interactions
Two or more drugs
To check effect of concomitant
pathological/physiological condition
on drugs, e.g. pregnancy, organ
dysfunction
Phenytoin
Efficacy failure
Antiepileptics
The important steps in TDM are
TIME OF SAMPLING
Drug concentrations are usually measured in serum or whole blood. Saliva can be used if it
is difficult to get blood sample. For example, in children for phenytoin. The timing of sampling
influences the interpretation of a drug concentration measurement. Hence, the correct time
of sampling is very important. Drug concentrations vary over the dosing interval and with
the duration of dosing in relation to achieving a steady state. This is unlike most physiological
parameters such as serum creatinine or serum sodium which change relatively slowly.
Generally, samples are collected after the steady state levels have been reached which takes
approximately five half-lives. This does not apply to drugs such as amiodarone and perhexiline
with very long half-lives and which can cause severe toxicity. Steady state may take months
to be reached and dose adjustments need to be made along the way. With all drugs, if a
sample is taken before steady state is reached, allowance needs to be made for this in
interpreting the concentration.
The pre-dose or trough concentration is commonly used for antiepileptics and peak
concentrations may be used for antimicrobials. Antimicrobials are classed as "time dependent"
where the aim is to maintain concentration above minimum inhibitory concentration (MIC)
throughout the dosage or "concentration dependent" where the aim is to achieve peak
Therapeutic Drug Monitoring (TDM)  189
concentration, but allow the concentration to fall to low levels in between doses. Vancomycin
exhibit time dependant activity, hence steady state levels are measuresd. Aminoglycosides
are concentration dependant, hence sampling is recommended 1 hour after dose (peak
concentration). Immediate sampling is recommended in cases of suspected toxicity. In general
for therapeutic failure, sample should be taken half an hour before next dose and for toxicity
sample should be taken half an hour after the last dose.
Drug estimation methods
The sensitivity, specificity and reproducibility of the laboratory method are important. Most
high-volume drug assays are now carried out by automated immunoassay methods which
have these characteristics. The most commonly used methods are:
1. High performance liquid chromatography (HPLC, e.g. antiepileptics)
2. Liquid Chromatography Mass Spectroscopy [LC-MS]
3. Gas Chromatography Mass Spectroscopy [GC-MS, GC/MS]
4. Gas liquid chromatography (GLC, e.g. amiodarone, perhexiline)
5. Immunoassay (e.g. antiepileptics)
6. Spectrophotometry (e.g. Salicylates).
All methods if used correctly are acceptable. Participation in international quality control
programmes will ensure laboratory validity. Recurring cost for HPLC is least of all. However,
it requires technical expertise. Usually, plasma or serum is used for drug assays, depending
on the equipment used. However, with cyclosporin there are large shifts of drug between
red cells and plasma with storage and temperature change so whole blood is assayed. Some
blood collecting tubes, especially those containing a gel to separate cells and plasma, may
not be suitable for all drugs due to drug adsorption by the gel or other components in the
tube. All analytical methods estimate total drug (free + bound) levels. Although it is the free
drug which has direct access to the site of action. In patients with normal plasma protein
levels, total drug concentration correlates well with drug effects. However, sometimes it is
necessary to estimate metabolites especially when the metabolite is active and the
concentration is high (e.g. carbamazepine epoxide in children).
Interpretation of plasma concentration data
The concentration measured must always be interpreted in the light of clinical response, the
demographic and clinical status of individual patient, dosage regimen and concomitant drugs
used. Ideally interpretation and advice should be there with each report. If the levels exceed
90% of therapeutic concentration, the dosage is halved. Dosage is further reduced by 50% if
plasma levels exceed therapeutic concentrations at 4 half-life interval. If the first concentration
is not too high, one can proceed with the same dose. With this procedure undue toxicity can
be avoided.
Therapeutic concentrations are average values and individual patients will show
satisfactory drug response at levels above and below the average values. Plasma concentration
data must always be considered along with the patient's clinical response.
190  Practical Manual of Pharmacology
Dosage adjustment
For drugs with linear kinetics increasing the dose leads to proportionate increase in plasma
concentration and can be safely carried out.
Revised dose rate =
Previous dose rate × target Css
Measured Css
For drugs with nonlinear pharmacokinetics, relatively small increase in dosage can result
in disproportionately large increase in plasma concentrations (e.g. phenytoin) for such a
drug it is advisable to use a nomogram.
A list of drugs for which therapeutic drug monitoring is commonly used is shown in
Table 21.2 with the target or therapeutic ranges. The ranges used are in most cases derived
from observation of therapeutic and adverse effects in small groups of patients. Therefore,
when applied to a wider population of patients, there will be individuals who achieve adequate
effects at lower concentrations or experience adverse events within the 'therapeutic range'.
Table 21.2. Drugs and therapeutic range
Drug
Digoxin
Amiodarone
Lignocaine
Salicylate
Theophylline
Phenytoin
Carbamazepine
Sodium valproate
Gentamicin
Amikacin
Vancomycin
Lithium
Time to steady state
7 days
2-6 months
12 hours
2-5 days
1-2 days
2-4 weeks
2 weeks
2-3 days
8 hours
8 hours
24 hours
3-6 days
Therapeutic range mg/L
0.5 - 2.1
1.0 - 2.5
2.0 - 5.0
150 - 300
10 - 20
10 - 20
5.0 - 12
50 - 100
trough 1-2; peak 5-10
trough 3-5; peak 20-30
trough 5-10; steady state 15-25
0.6 - 1.2
For rational therapeutics TDM can be followed in a stepwise pattern as:
Therapeutic Drug Monitoring (TDM)  191
Flow chart 21.1: TDM process at a glance
TDM procedure at a glance
With this background information let us now consider the important aspects of therapeutic
drug monitoring keeping in mind Flow chart 21.1.
Antiepileptic Drugs (AED)
Most antiepileptic drugs have a narrow margin of safety and there is considerable
interindividual variation in pharmacokinetics, dosage requirement and response obtained.
Phenytoin
Measurement of plasma levels, commuting with effect, and adjusting the dose as per
requirement is very important and rewarding for phenytoin. Phenytoin has a narrow margin
of safety. Levels below l0 μg/ml do not give good seizure control and those above 20 μg/ml
are usually associated with toxicity. However, do not consider plasma levels in isolation. It
is seen that about 20% patients achieve good seizure control despite phenytoin levels below
10 μg/ml on the other hand 3-5% patients are well controlled only with levels above 20 μg/
ml and show no sign of toxicity. Patient compliance is a very important variable in AED
treatment. When a patient shows subtherapeutic levels despite standard doses, compliance
must be checked before increasing the dose. In majority of the patients receiving 300 mg
phenytoin per day levels below 5 μg/ml were found to be simply due to non compliance.
Patient counseling, simpler drug and dosage regimens, and recording intake helps to control
seizures effectively in many patients.
192  Practical Manual of Pharmacology
Phenytoin has nonlinear kinetics and dose increments result in proportionately large
increases in plasma concentrations leading to toxicity. Hence, it is necessary to use a nomogram
for calculating dose requirement.
One of the limitations of phenytoin tablets and capsules available in India is their dosage
strength, all are of 100 mg strength (and syrup is 125 mg/5ml). On account of the nonlinear
kinetics, dose increments of 100 mg may lead to toxic levels in some patients. It is observed
that nearly 20% of the patients need dose increments of only 25 or 50 mg to achieve desired
therapeutic concentrations. Appropriate dosage adjustment and achieving therapeutic
concentration results in over 70% of patients getting good seizure control.
Carbamazepine
Therapeutic range of carbamazepine is 4-12 μg/ml. Samples should be collected after steady
state levels are reached. Some reduction in plasma concentration thereafter is to be expected
on account of autoinduction. In adults, fluctuations in carbamazepine plasma levels between
dosing intervals are not large and blood sample can be collected at trough or peak time. In
children due to short half-life and specially with liquid formulations which can be rapidly
absorbed, the difference between peak and trough levels can be substantial, requiring
measurement of both levels depending on indication. Drug monitoring is most useful in
deciding the extent to which dose can be increased in patients who are not responding to
standard dose inspite of good compliance.
Phenobarbitone
Therapeutic range for phenobarbitone is 10-40 μg/ml and monitoring is mainly useful for
deciding maximum increase in dose (side effect of drowsiness experienced by the patient is
most important limiting factor).
Is TDM cost-effective?
Therapeutic drug monitoring is has become very important in managing the difficulties in
using some drugs. While the digoxin therapeutic range is somewhat 'loose', the advent of
monitoring resulted in a far greater appreciation of the toxicity of digoxin and of the need
for rational dosing. Similarly, theophylline, while now falling out of favour for other reasons,
was rescued from oblivion when the advent of therapeutic drug monitoring in the 1970s
allowed its use largely without the serious toxicity previously associated with it. The use of
any of the drugs in Table 21.2 without monitoring would be difficult and often dangerous.
Emphasis should be placed not so much on whether monitoring is necessary as on how to
use it in the most cost-effective and clinically effective manner possible.
OBJECTIVES
At the end of the session the student shall be able to:
1. Understand and define therapeutic drug monitoring
2. List indications for TDM with examples
Therapeutic Drug Monitoring (TDM)  193
3. Suggest the timing of sampling for TDM depending on the given clinical situation.
4. Suggest modification of dosage/treatment by interpreting given plasma levels of drugs.
Exercises:
Exerices can be given in small groups to students. These exercises can be in the form of cases
on cards. Then the cases can be discussed in a bigger group.
Exercises:
1. When samples should be collected for following clinical conditions:
a) Failure of antiepileptic therapy
b) Suspected aspirin toxicity
c) Cyclosporine in organ transplantation
d) Starting gentamicin therapy
2. A 35-year-old male was given Tab. Theophylline 300 mg bd for bronchial asthma.
There was good clinical response as evidenced by pulmonary function tests, but patient
complained of tremor, anxiety and palpitations.
What would you advise the doctor on duty?
Investigations – Theophylline blood levels–7 mg/l
(Normal 5-15 μg/ml).
3. A 49-year-old male was prescribed phenytoin for seizure prophylaxis. After receiving
a 400 mg loading dose of phenytoin, the patient received 200 mg phenytoin qid, but
experienced disturbance in sensorium.
You are approached by neurologist to comment on. What you would advise?
Investigations-phenytoin blood levels 26 μg/ml.
(Normal levels of phenytoin 10-20 μg/ml, Toxic levels > 20 μg/ml).
C H A P T E R
22
Drug Use in Special Population/
Diseases/Physiological
Conditions
Certain pathological and physiological condition can change pharmacokinetics of a drug
affecting its action. Hence, dose adjustment is needed in these conditions. Let us discuss
them one by one.
A. CHILDREN
Very old are very young patients are more prone to adverse drug reactions (ADRs). When
the drug manufacturer does not provide adequate information about pediatric dosage, there
can be substantial risk in deriving a dose for children and infants from an adult dose. Children
and particularly neonates, differ from adults in their response to drugs. Special care is needed
in the neonatal period (first 30 days of life) and doses should always be calculated with care.
At this age, the risk of toxicity is increased by inefficient renal function, relative enzyme
deficiencies, differing target organ sensitivity and inadequate metabolism systems causing
delayed elimination.
Factors affecting drug disposition in children
• Absorption
o Variable gastric and intestinal transit time: in young infants, gastric emptying time is
prolonged and only approaches adult values at around 6 months of age. In older
infants, intestinal hurry may occur.
o Increased gastric pH: gastric acid output does not reach adult values until the second
year of life.
o Other factors: gastrointestinal contents, posture, disease states and therapeutic
interventions, such as drug therapy, can also affect the absorption process.
o Bioavailability of rifampicin, gentamicin, phenytoin, phenobarbitone and
acetaminophen is increased in children.
o Topical drugs are absorbed promptly in children.
• Distribution:
o Increased total body water: as a percentage of total body weight, the total body
water and extracellular fluid volume decrease with increasing age. Neonates require
higher doses of water soluble drugs on an mg/kg basis than adults.
Drug Use in Special Population/Diseases/Physiological Conditions  195
o Decreased plasma protein binding: plasma protein binding in neonates is reduced as
a result of low levels of albumin and globulins and an altered binding capacity, e.g.
increased free levels of aspirin. High circulating bilirubin levels in neonates may displace
drugs from albumin.
• Metabolism
o Enzyme systems mature at different times and may be absent at birth, or present in
considerably reduced amounts. Phase 2 reactions are not well developed, e.g. Gray
baby syndrome with Chloramphenicol in neonates.
o Altered metabolic pathways may exist for some drugs.
o Metabolic rate in children is often greater than in adults. Compared with adults,
children may require more frequent dosing or higher doses on an mg/kg basis.
• Excretion
o Complete maturation of renal function is not reached until 6-8 months of age.
Similarly pharmacodynamic vary in children. There is immaturity in receptor and
neurotransmitter development. Similarly ciprofloxacin can lead to tendon damage
and rupture and it is not recommended for children, but in our country there is no
restriction for its use in children.
Children are not mini-adults. Always calculate the appropriate dose for the child. Dose
can be calculated based on body weight, age or surface area. The commonly used method is
based on weight but the most accurate method is based on surface area. The following
methods can be used to calculate dose in children:
1. Young's formula
Dose in child =
Age × Adult dose
Age + 12
2. Clark's rule
Dose in child =
Adult dose × Weight (Pounds)
150
3. Fried's rule
Dose in child =
Adult dose × Age in months
150
4. Based on surface area
Dose in child =
Adult dose × Body surface area (m 2 )
Adult body surface area (1.7 m 2 )
Dosage form, compliance, vomiting, shaking of suspensions, measurements with
household measures, taste of drugs are some of the practical issues in children.
196  Practical Manual of Pharmacology
Golden rules in children are:
• Always calculate appropriate dose
• Do not use newer drugs, use only well established drugs
• Avoid polytherapy
Some drugs should be avoided as far as possible. These are given in Table 22.1:
Table 22.1. Drug to be avoided in children
S. No.
1
2
3
4
5
6
Drug
Aspirin
Chloramphenicol
Fluoroquinolones
Tetracyclines
Stunned growth
Aminoglycosides
Adverse effect
Reye's syndrome
Gray baby syndrome
Arthropathy
Teeth and bone abnormalities
Corticosteroids
Ototoxicity
B. ELDERLY
It is estimated that by the year 2020 elderly people will constitute 11-12% of total population.
In treatment of the elderly (geriatric) many variations are required from standard recognized
treatment due to both aging itself and common age related diseases. Variations occur in
pharmacokinetics and pharmacodynamic with age. Moreover elderly people often suffer
from multiple diseases and are treated with multiple drugs. Multiple drug use and altered
responsiveness expose elderly more to adverse drug reactions making it difficult to prescribe
rationally. Providing safe, effective drug therapy is one of the greatest challenges in geriatrics.
The following changes happen in the elderly:
Pharmacokinetic changes
Decreased first pass metabolism can lead to increased levels of propranolol. Decreased lean
body mass can lead to increased level of water soluble drugs, e.g. digoxin. Decreased plasma
protein binding can cause increased activity of highly plasma protein bound drugs, e.g.
warfarin. Impaired renal elimination can cause accumulation of digoxin. Impaired hepatic
elimination can lead to increased levels of theophylline.
Pharmacodynamic changes
Physiologic changes and loss of homeostatic resilience can result in increased sensitivity to
unwanted effects of drugs, such as hypotension from psychotropic medications and
hemorrhage from anticoagulants, even if dosage is appropriately adjusted to account for the
age. Drugs that depress the central nervous system produce increased effects at any given
plasma concentration.
Drug Use in Special Population/Diseases/Physiological Conditions  197
In addition, drug therapy should be employed only after nonpharmacologic means have
been considered or tried and only when the benefit clearly outweighs the risk. Once
pharmacotherapy has been decided upon, it should begin at less than the usual adult dosage
and the dose should be increased slowly. However, given the marked variability in
pharmacokinetics and pharmacodynamics in the elderly, dose escalation should continue
until either a successful endpoint is reached or an intolerable side effect is encountered. The
final dosage schedule should be kept as simple as possible, and the number of pills should be
kept as low as possible.
Other factors which affect therapy:
• Impaired memory
• Impaired eyesight
• Tremors in hands
• Constipation.
Compliance is often poor (60%) in the old patients particularly in persons taking too
many drugs. This may be due to forgetfulness, confusion (the patient takes too many doses),
deliberate and immobility lethargy. Be careful about following drug groups in elderly:
Sedative-Hypnotics
If nonpharmacologic treatment of insomnia is unsuccessful, use intermediate-acting agent
whose metabolism is not affected by age (e.g. oxazepam, 10 to 30 mg/d).
Antibiotics
Serum creatinine is not a good index of renal function in old people, concentrations of relevant
antibiotics should be measured directly.
Cardiac Drugs
In older patients, digitalis, procainamide and quinidine have prolonged half-lives and narrow
therapeutic windows. Toxicity is common at the usual dosages.
Antipsychotics and Tricyclic Antidepressants
These drugs can produce anticholinergic side effects in old people (e.g. confusion, urinary
retention, constipation, dry mouth. The newer potent antipsychotics (e.g. risperidone,
olanzapine, quetiapine, and clozapine) are relative exceptions to this rule.
Analgesics
Of the NSAIDs, indomethacin is most likely to induce confusion, fluid retention and
gastrointestinal bleeding. Each of these agents should be avoided in the elderly.
Cyclooxygenase 2 (COX-2) inhibitors are safer than nonselective NSAIDs for older adults.
However, they are more expensive and can cause fluid retention with consequent worsening
of hypertension and nocturnal incontinence.
198  Practical Manual of Pharmacology
Avoidance of Overtreatment
Drugs are frequently not indicated in some common clinical situations in elderly. For instance,
antibiotics need not be given for asymptomatic bacteriuria unless obstructive uropathy, other
anatomic abnormalities or stones are also present. Ankle edema is often due to venous
insufficiency, drugs such as NSAIDs or some calcium antagonists or even inactivity or
malnutrition in chairbound patients. Diuretics are usually not indicated unless edema is
associated with heart failure. Fitted, pressure gradient stockings are often helpful. For
claudication, regular exercise should be prescribed before cilostazol.
Golden rules in treatment of elderly are:
•
•
•
•
•
•
•
Start slow, go slow
One drug, one dose
Start at right time, stop at right time
Avoid certain drugs
Think about necessity of drug
Think about drug dose and dosage form
Check compliance.
C. PREGNANCY
Drugs given during pregnancy may affect fetus. Thalidomide is a classical example of
teratogenic effects. It was synthesized in 1954 in Germany and four years later was marketed
as sedative. It was widely used by pregnant females for nausea and vomiting. It was
considered safe because in toxicity studies in rodents, it did not produce any toxic effect.
Thalidomide led to birth of babies with seal like limbs (phocomelia). It is estimated that
approximately 20,000 babies suffered toxicity of thalidomide. It was withdrawn in 1961.
There are so many physiological changes during pregnancy which can affect drug action.
In pregnant state pharmacokinetics and pharmacodynamic of a drug change considerably.
Total body water increases by 8%, diluting the drugs in the body. Plasma protein binding
undergoes a considerable change. Some metabolic pathways may be induced. Renal plasma
flow is doubled during 3rd trimester, so clearance of some drurg may increase. This
predisposes a pregnant female to adverse drug reactions.
An important aspect of human teratology is that teratogenic medications administered
after the vulnerable period will not usually cause structural malformations but may induce
functional adversity. Thus, the timing of drug intake is crucial:
(a) Conception to about 17 days of gestation:
It is likely that the deleterious effects on the zygote will lead to abortion.
(b) From is 18 to 55 days of intra-uterine life:
It is the most susceptible period for adverse effects. The rapidly multiplying and
differentiating cells are vulnerable to any agent (Table 22.2) affecting division, enzymes,
protein synthesis or replication. As many organs are for concurrently, it is not surprising
Drug Use in Special Population/Diseases/Physiological Conditions  199
that a dysmorphogenic agent interferes with simultaneous organization of many systems
may produce a multiplicity of malformation various sites. It is recommended that no
drug should be given in first trimester of pregnancy.
(c) By the day-56 of gestation, most organs are well formed and drugs can no longer produce
malformations, but they may still impair the growth, development and functioning
particularly in organs which are not yet fully differentiated.
Drug given prior to labour: drugs can lead to adverse postnatal effects in infants,
e.g. CNS depressants can lead to neurological, respiratory or muscular dysfunction in
the neonate.
Drugs given during labour: Anaesthetics, analgesics, etc. used during labour can
suppress foetal respiration and prolong labour.
Drugs which are considered safe in pregnancy are: penicillin, pyrimethamine,
thiazides, atenolol, ACE inhibitors and prazocin.
According to their effect on fetus drug are classified into categories.
CATEGORY
A: Adequate, well-controlled studies in pregnant women have not shown an increased risk
of fetal abnormalities to the fetus in any trimester of pregnancy, e.g. Folic acid Thyroxine
B: Animal studies have revealed no evidence of harm to the fetus, however, there are no
adequate and well-controlled studies in pregnant women.
Or, Animal studies have shown an adverse effect, but adequate and well-controlled
studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester,
e.g. Amoxycillin, Paracetamol.
C: Animal studies have shown an adverse effect and there are no adequate and wellcontrolled studies in pregnant women.
Or, No animal studies have been conducted and there are no adequate and wellcontrolled studies in pregnant women, e.g. Morphine, Atropine.
D: Adequate well-controlled or observational studies in pregnant women have demonstrated
a risk to the fetus. However, the benefits of therapy may outweigh the potential risk.
For example, the drug may be acceptable if needed in a life-threatening situation or
serious disease for which safer drugs cannot be used or are ineffective, e.g. Aspirin,
Phenytoin.
E: Adequate well-controlled or observational studies in animals or pregnant women have
demonstrated positive evidence of fetal abnormalities or risks. The use of the product is
contraindicated in women who are or may become pregnant, e.g. Isotretinoin,
Ergometrine.
You must assess the benefit/risk ratio for the condition being treated.
200  Practical Manual of Pharmacology
Table 22.2. Common drugs that are teratogenic
ACE inhibitors
Alcohol
Amantadine
Antithyroid
Androgens
Anticonvulsants
Aspirin and other salicylates (third trimester)
Benzodiazepines
Chloramphenicol (third trimester)
Cyclophosphamide
Diazoxide
Diethylstilbestrol
Disulfiram
Ergotamine
Estrogens
Griseofulvin
Isotretinoin
Lithium
Methotrexate
Misoprostol
NSAIDs (third trimester)
Opioids (prolonged use)
Oral hypoglycemics
Progestins
Radioiodine
Reserpine
Ribavirin
Sulfonamides (third trimester)
Tetracycline (third trimester)
Thalidomide
Tobacco smoking
Trimethoprim (third trimester)
Warfarin and other coumarin
anticoagulants
Dosage adjustment and plasma level monitoring
Points to remember while prescribing in pregnancy:
• Dosage adjustment becomes difficult due to changes in pharmacokinetics and complex
nature of maternal-placental-fetal complex (Fig. 22.1). Be careful when narrow
therapeutic index drugs are given, e.g. phenytoin levels tend to fall during pregnancy,
hence dosage has to be increased.
• If possible counselling of women before a planned
pregnancy should be carried out including discussion of
risks associated with specific drugs.
• Drugs should be prescribed in pregnancy only if the
expected benefits to the mother are thought to be greater
than the risk to the fetus.
• All drugs should be avoided if possible during the first
trimester.
• Drugs which have been used extensively in pregnancy and
appear to be usually safe should be prescribed in preference
to new drugs and the smallest effective dose should be
used.
• Well known single component drugs should usually be
Fig. 22.1: Fetus in uterus
with placenta
preferred to multidrug therapy.
Drug Use in Special Population/Diseases/Physiological Conditions  201
D. LACTATION
Most drugs are secreted in breast milk in very small quantities. These do not affect suckling
infant. However, there are few drugs, which readily enters breast milk and adversely affect
nursing infant. Care should be taken while prescribing drugs to lactating mothers. Drugs
may be classified as per the following criteria:
a. Drugs undetected in breast milk: aminoglycosides
b. Drugs reach the baby but insignificant dose: non-narcotic analgesics, penicillin
c. Drugs reach the baby with significant dose: aspirin, benzodiazepines, barbiturates,
tetracyclines, carbimazole.
The following principles should be followed when prescribing for breastfeeding mothers:
• Avoid unnecessary drug use and limit use of over-the-counter (OTC) products, e.g.
opiates, benzodiazepines, Isoniazid, anticancer drugs
• Breastfeeding mothers should seek advice on the suitability of OTC products
• Avoid use of drugs known to cause serious toxicity in adults or children
• Neonates (and particularly premature infants) are at greater risk from exposure to
drugs via breast milk, because of immature excretory functions and the consequent
risk of drug accumulation
• Choose a regimen and route of administration which presents the minimum amount
of drug to the infant
• It is best to avoid long-acting preparations, especially those of drugs likely to cause
serious side effects (e.g. antipsychotic agents).
• Multiple drug regimens may pose an increased risk especially when adverse effects
such as drowsiness are additive
• Infants exposed to drugs via breast milk should be monitored for unusual signs or
symptoms
• Avoid new drugs if a therapeutically equivalent alternative that has been more widely
used is available. A robust assessment of the balance of benefit to risk requires data
both on the drug's passage into breast milk and its effects in infants: there is rarely
enough information available for new drugs to allow such an assessment to be made
• Assess the benefit/risk ratio for both mother and infant.
E. HEPATIC DISEASE
Drugs which are mainly eliminated by liver are affected. There can be accumulation of drug
or failure to get converted to active moiety (prodrug). Hence, Dose adjustment is needed.
Unfortunately, unlike renal disease where creatinine clearance can provide an indication of
the extent of renal dysfunction, there is no simple test to assess hepatic functions. Most of
the conventional liver function tests do not reflect the capacity of the liver to metabolise.
Hepatic blood supply: this decreases in old age and with use of beta blockers. Dosage
of drugs with high extraction ratio need to be decreased in this case, e.g. lignocaine,
imipramine.
First pass metabolism: dosage of drugs undergoing extensive first pass metabolism need
to be decreased, e.g. propranolol.
202  Practical Manual of Pharmacology
Prodrugs: these drugs get activated by metabolism in liver, hence in hepatic dysfunction
they might become ineffective, e.g. captopril.
Hepatotoxic drugs: avoid all drugs which are hepatotixic, e.g. tetracyclines, methotrexate.
Hypoalbiminaemia: this leads to increased concentration of highly plasma protein bound
drugs, e.g. warfarin.
Remember that in while prescribing for patients with hepatic disease:
• Avoid drugs which undergo extensive first pass metabolism
• Measure plasma levels
• Be careful about drug interactions
• Drugs mainly metabolized by kidneys can be used.
F. RENAL DISEASES
Drugs which are eliminated from body through kidneys are mainly affected. There can be
accumulation of drug at therapeutic doses, leading to toxicity. Elimination of a drug is linearly
and hence, predicably related to GFR (Table 22.3) which is best expressed clinically as the
creatinine clearance. Dose adjustment is done according to creatinine clearance (CLcr).
Creatinine clearance is calculated as (Cockroft Gault formula):
Wt
ml/min
72
140
CLcr– Age
100Ccr
Wt
Female = 0.85 ×
ml/min
×
72
Ccr is serum creatinine concentration in mg/dl
This formula is invalid with Ccr > 5 mg/dl
The loading dose is not changed. The maintenance dose is altered based on the clinical
condition. The maintenance dose of a drug can be reduced either by reducing the individual
dose amount leaving the normal interval between doses unchanged or by increasing the
interval between doses without changing the dose. The interval extension method may provide
the benefits of convenience and decreased cost, while the dose reduction method provides
more constant plasma concentration.
Male =
×
Based on CLcr, 2 methods to calculate the dosage can be used
a. Clearance method
b. Dose fraction method
a. Clearance method
It is the most accurate method, but clearance data of drug is needed. This method can be
used to determine:
i. Dose amount
DRF = D ×
Drug Use in Special Population/Diseases/Physiological Conditions  203
DRF – dose in renal failure
D – standard dose
ii. Dosage interval
DI (revised) = DI (standard) ×
iii. Infusion rate
DRF = CLRF × Cp
iv. Oral dose
DRF/F (fraction of absorption).
b. Dose Fraction method
It is less accurate as it uses renal clearance only, but it is more user friendly.
DRF = D ×
The known dose fraction (KRF/K) of a drug (at CLcr zero) is plotted on the Nomograsm,
against estimated CLcr and the required dose fraction in renal failure is obtained.
In adjusting the dosage for patients with renal failure the initial loading dose usually
needs little or no reduction. A few notable exceptions to this principle are digoxin and
morphine (because of changes in distribution volume
and sensitivity). After the initial dose
CL
KRF
achieves the peak plasma concentration, the plasma level will decrease more slowly, i.e. the
Clrf
K
half life will be prolonged in proportion to the severity of renal failure as reflected by the
plasma creatinine concentration. The prolonged half life means that the plasma concentration
will be higher than usual when the next dose is due.
A marked reduction in dosage will be required when the kidney is the only route of
excretion of a drug and renal failure is severe. Obviously the half lives of those drugs
eliminated predominantly by extrarenal routes will be affected little by renal failure and
intermediate effects will result when elimination is partially renal. The fractional elimination
by the kidney (the renal clearance as a fraction of total plasma clearance) determines the
extent of dosage adjustment required in renal failure.
Avoid all nephrotoxic drugs, e.g. aminoglycosides, NSAIDs
Remember that in while prescribing for patients with renal disease:
• Avoid/adjust dosage of drugs which undergo extensive renal elimination
• Measure plasma levels
• Be careful about drug interactions
• Drugs mainly metabolized in liver can be used.
For patients in whom renal function is compromised, dosing nomograms have been
developed to help achieve the usual therapeutic plasma concentrations of a drug.
Renal impairment is usually divided into three grades:
Mild—GFR 20 – 50 ml/minute
Moderate—GFR 10 – 20 ml/minute
Severe—GFR < 10 ml/minute
204  Practical Manual of Pharmacology
Table 22.3. Drugs requiring dose/interval adjustment in renal dysfunction
Drug
Aminoglycosides
Cefazolin
Amoxicillin
Lithium
Atenolol
Spironolactone
Famotidine
Adjustment
Dose reduction
Interval extension
Interval extension
Dose reduction
Dose reduction
Interval extension
Dose reduction
> 50
GFR (ml/min)
10-50
< 10
60-90%
8h
1h
100%
100%
6-12 h
100%
30-70%
12 h
6h
50-75%
50%
12-24 h
75%
20-30%
24-48 h
6-12 h
25-50%
25%
avoid
25-50%
G. GENETIC VARIATIONS
Sometimes dose adjustment is required due to genetic variations (Table 22.4).
Table 22.4. Drugs causing hemolysis in glucose 6 phosphate dehydrogenase
deficient individuals
o Definite association: primaquine, sulfanilamide, sulfacetamide, dapsone, nitrofurantoin,
nalidixicacid, niridazole, methylene blue, phenazopyridine, naphthalene, toluidine blue.
o Probable association: chloroquine, quinine,sulfadiazine, sulfisoxazole, aspirin,
paracetamol, phenacitin, ciprofloxacin, norfloxacin, L-dopa, chloramphenicol, vitamin
K analogs, probenecid,vitamin C
OBJECTIVES
At the end of the session the student will be able to:
1. Understand the modification in the pharmacokinetics of some common drugs in
children, elderly, pregnancy, lactation, hepatic and renal disease.
2. List and choose drugs based on efficacy, suitability, tolerability and cost in these
conditions.
3. Calculate dose of a given drug in children and in renal disease.
Exercises in class:
Exercises can be given in small groups. The problem is then discussed in a larger group.
Drug Use in Special Population/Diseases/Physiological Conditions  205
Examples:
a) Which drugs you will choose in following conditions. Explain with reasons.
1. Pregnant woman suffering from grand mal epilepsy.
2. Hyperthyroid pregnant female.
3. 70-year-old suffering from insomnia.
4. 40-year-old hypertensive with impaired renal function.
5. 42-year-old lady with hepatic dysfunction and suffering from tuberculosis.
6. 35-year-old male suffering from gram negative infection with renal dysfunction.
7. The creatinine clearance of a patient with renal failure is 35 ml/min. How would
you adjust the normal dosage of gentamicin for this patient using the nomogram
provided. (dose of gentamicin 80 mg three times a day).
8. Seven year child suffering from status epilepticus.
9. Can tetracycline be prescribed to children and pregnant females.
10. 70-year-old diabetic patient.
206  Practical Manual of Pharmacology
b) The parenteral dose of erythromycin injection is 10 mg/kg/24 hours. Calculate the
daily dose of this drug for a 20 kg child.
c) A 23 kg, 7-year-old girl of average height is to begin Griseofulvin therapy. The dose
of this drug is 10 mg/kg/24 -4 doses, orally. The average adult dose is 500 mg daily
in divided doses.
d) Each numbered term in column A below indicates a method of solving the daily
child's dose for the given data. Once you have solved the child's dose according to
each method, find it in column B and enter the corresponding letter in the blank.
Column A
Column B
(Method)
(Daily Dose)
1. Clark's Rule.
2. Young's Rule.
3. Calculation using mg/kg dose
4. Calculation as fraction of adult
5. Calculate based on surface area.
e) The child has a body surface area of 0.67 M2. The adult dose of drug A is 40 mg/day.
The physician prescribed 8 mg. Is the dosage correct?
C H A P T E R
23
Critical Appraisal of Drug
Promotional Literature
There seems to be a glamour about anything new. A new car or a new movie, you know
these days how these things are advertised. Similarly, pharmaceutical Industry has multitrack
approach for providing information to physicians. This is the commonest source of drug
information for physicians and available through all channels of communication, i.e. verbal,
written and computerised. These channels also include professional meeting, advertising in
journals, direct mailing, medical representatives, etc.
Advertising is paid, one-way communication through a medium in which the sponsor is
identified and the message is controlled. 15-20% of budget of a pharmaceutical industry is
for promotion of products. Out of those > 50% is spent on medical representatives. 90% of
the physicians see medical representatives (MRs). This is the easiest way to gather new drug
information. A substantial percentage of physicians heavily rely on representatives as source
of information about drugs (and gifts!). But, it has been observed that these representatives
emphasize only the positive aspects of products and overlook or give little coverage to the
negative aspects (ADRs). Most of the information is commercially driven. These
advertisements highlight the advantages of the drug in question and the disadvantages or
the limitations of the drug being suppressed. The general principles of advertising are also
applied to drug advertising. There is a huge difference in criteria when you want to select a
vehicle or mobile phone as compared to selecting a drug. Ethically speaking the criteria for
selection of drug should be entirely driven by patient's disorder or disease. For that a doctor
do not need advertisement but a scientifically validated information about drugs.
Whenever you are shown an advertisement about drugs by MRs, look carefully for the
size of the letters used for brand name, generic names, efficacy, and adverse effects. Critically
analyse the given advertisements for:
a) Validity of scientific claims
b) Content of scientific information
c) Relevance of references cited
d) Appropriateness of illustrations.
The following sources of drug information can be used for this purpose:
208  Practical Manual of Pharmacology
Source of drug information
Although pharma houses provide knowledge about the drug and their hazardous events
that may occur during their use in therapeutic indications with recommended dosage the
information given by these houses is often incomplete and hence the data loses its reliability.
There should be pooled information given by drug safety committee to be backed by WHO
and a regular update must appear especially on the adverse effect of newer drugs in the
leading medical journals, so that physicians remain comprehensively updated to face any
eventuality.
The typical example of how the information provided can change the concepts and beliefs
of the patients, doctors and community is information on new selective COX-2 inhibitor
NSAIDs. Many doctors also gained the false impression that selective drugs were also less
likely than conventional NSAIDs to have adverse effects on blood pressure and the kidneys.
This view was also held by some key opinion leaders, people who always have a major
influence on prescribing patterns and, for this reason, are invited by pharmaceutical companies
to talk to groups of prescribers. To complicate the situation, the media persuaded consumers
that the new 'wonder' drugs were more efficacious than older medications. Word of mouth
completed a marketer's dream situation. Certainly the drugs were heavily promoted by
both industry and the media, but why did prescribers fail to follow ethical principles? The
facts were all there in many independent sources of information. The present status is that
Cox-2 inhibitors are either being banned (nimesulide) or withdrawn voluntary by
manufacturer (rofecoxib). The manufacture is paying heavy claims to the patients who suffered
from adverse effects.
There is no merit in being among the first to prescribe a new drug whatever the pressures
from patients and drug companies. Of course industry puts the best possible spin on its
marketing messages, but doctors should be smart enough to see through the hype created.
They need to know that when a drug first appears on the market only limited safety data are
available and long term outcomes, both good and bad, can only emerge with time and
appropriately designed, prospective safety studies. It is well established that most prescribers
obtain the majority of their information from the pharmaceutical industry and they, therefore
need more training in how to evaluate the information and what questions to ask drug
representatives.
How doctors can get updated about drugs?
Knowledge and ideas about drugs are constantly changing. More and more new drugs are
coming on the market. New experience with existing drugs is expanding (side effects, new
indications/ways of using). A Physician is expected to know about new developments in
drug therapy. However, in many parts of the world, objective and unbiased information
about drugs is a luxury which is difficult for most of the physicians to access. It is difficult for
busy physicians to have satisfactory knowledge of all these drugs. Hence, selection and use
of right drug in an appropriate manner becomes a challenge.
How you can keep up-to-date about drug information inspite of your busy schedule?
Critical Appraisal of Drug Promotional Literature  209
The sources of information are:
1. Written form-journals, reference books, drug bulletins, books
2. Verbally-through discussions in CMEs, meetings, journal clubs in institutions
3. Tape/video/online-journals, CDs
4. Drug Information Centers
5. Pharmaceutical industry
6. Internet.
Others written forms which can be used are:
1. Drug compendia—these list the drugs available on the market
2. National list of essential drugs and standard treatment guidelines
3. General Pharmacological reference—Goodman and Gilman's: The Pharmacological basis
of Therapeutics
4. Martindale's The extra Pharmacopoeia—excellent reference book, gives all information
on all chemicals used with references
5. Avery' drug treatment—more specialised
6. Meyler's side effects of drugs
7. MIMS—monthly index of medical specialties—these provide information on:
• Generic/brand names
• Chemical composition
• Indications/contraindications
• Side effects, interactions
• Price.
[Current Index of Medical Specialties (CIMS), Indian Drug Review (IDR), Drug Index
(DI), Drugs Today, etc.]
Drug bulletins are preferred because they are:
• Critical source of new drug information
• Promote rational drug therapy
• Appear at frequent intervals
• Sponsors—government agencies, university departments, professional bodies, nonindustry sponsored.
Some drug bulletins available In India are:
Drug bulletins
Australian prescriber is available free of charge
Others are: Drugs and therapeutic bulletin (UK)
Medical letter (USA)
210  Practical Manual of Pharmacology
Medical Journals
The important ones are: The Lancet, New England Journal of Medicine, and British Medical
Journal. Tons of information is available in these journals. Thousands are published and they
vary enormously in quality.
• Only a small proportion publish scientifically validated articles
• Good journal are peer reviewed by independent experts, usually no advertisements
are there
• Define range of drugs available to prescriber
• Consensus on the treatment of choice for the most common diseases and complaints
• Index Medicus has list of major reputable journals.
Symposia/conferences
Symposia are useful for disseminating information. The objective scientific content of such
meetings should be paramount, and presentations by independent scientists and health
professionals are helpful to this end.
DIC (Drug Information Centre)
• Very useful
• Prescribers and general public can call
• Use reference books online.
Examples
• DIC-Philippines-Dept. of Pharmacology
• DIC-Kathmandu, Nepal
2 Clinical pharmacologists
1 Pharmacist.
Internet
Adverse effects are the prime health hazards of drugs. In order to manage an adverse drug
reaction it is important to be aware of all possible drug reactions and drug interactions.
However, given the current scenario of introduction of new drugs into market, it is impossible
to keep track of all reports of reactions. This is where the web comes to the rescue. Internet
is another source of drug information, but all the information available is not authentic.
Check the authenticity of the website.
Advantages
• A large number of sources
• Quick and easy.
Critical Appraisal of Drug Promotional Literature  211
Disadvantages
• Illegal advertising and complaints have increased
• Use catchy slogans, e.g. Scientific breakthrough, miraculous cure, secret formula, ancient
ingredients, antiageing, all natural
• Use case histories of successful consumers, authenticity of whom is questionable
Keeping up-to-date should not be too difficult for physicians in developed countries,
but it can be far from easy in some parts of the world where access to independent
sources of drug information is very limited. But wherever you live and work it is
important to develop a strategy to maximize your access to key information you need
for optimal benefit of the drugs you prescribe.
Ethical criteria for drug promotion
WHO has formulated ethical criteria for medicinal drug promotion. The main objective of
ethical criteria for medicinal drug promotion is to support and encourage the improvement
of health care through the rational use of medicinal drugs. The essential features are:
1. Ethical criteria for drug promotion provides the foundation for proper behaviour
concerning the promotion of medicinal drugs, consistent with the search for truthfulness
and righteousness. These criteria constitute general principles for ethical standards
which could be adapted by governments to national circumstances as appropriate to
their political, economic, cultural, social, educational, scientific and technical situation,
laws and regulations, disease profile, therapeutic traditions and the level of development
of their health system. They apply to prescription and non-prescription medicinal drugs
("over-the-counter drugs"). They also apply generally to traditional medicines as
appropriate, and to any other product promoted as a medicine.
2. "Promotion" refers to all informational and persuasive activities by manufacturers and
distributors, the effect of which is to induce the prescription, supply, purchase and/or
use of medicinal drugs. All promotion making claims concerning medicinal drugs should
be reliable, accurate, truthful, informative, balanced, up-to-date, capable of
substantiation and in good taste. They should not contain misleading or unverifiable
statements or omissions likely to induce medically unjustifiable drug use or to give rise
to undue risks. The word "safe" should only be used if properly qualified. Comparison
of products should be factual, fair and capable of substantiation. Scientific data in the
public domain should be made available to prescribers and any other person entitled to
receive it, on request, as appropriate to their requirements. Scientific and educational
activities should not be deliberately used for promotional purposes.
3. Information that such advertisements should usually contain, among others includes:
• The name(s) of the active ingredient(s) using either international nonproprietary names
(INN) or the approved generic name of the drug.
• Brand name.
• Content of active ingredient(s) per dosage form or regimen;
212  Practical Manual of Pharmacology
4.
5.
6.
7.
8.
• Name of other ingredients known to cause problems;
• Approved therapeutic uses;
• Dosage form or regimen;
• Side-effects and major adverse drug reactions;
• Precautions, contraindications and warnings;
• Major interactions;
• Name and address of manufacturer or distributor;
• Reference to scientific literature as appropriate.
To fight drug addiction and dependency, scheduled narcotic and psychotropic drugs
should not be advertised to the general public. While health education aimed at children
is highly desirable, drug advertisements should not be directed at children.
Medical representatives should have an appropriate educational background. They
should be adequately trained. They should possess sufficient medical and technical
knowledge and integrity to present information on products and carry out other
promotional activities in an accurate and responsible manner. Exposure of medical
representatives and trainees to feedback from the medical and allied professions and
from independent members of the public, particularly regarding risks, can be salutary.
Medical representatives should make available to prescribers and dispensers complete
and unbiased information for each product discussed, such as an approved scientific
data sheet or other source of information with similar content.
Free samples of legally available prescription drugs may be provided in modest quantities
to prescribers, generally on request. Free samples of non-prescription drugs to the
general public for promotional purposes.
Postmarketing scientific studies and surveillance should not be misused as a disguised
form of promotion.
Appropriate information being important to ensure the rational use of drugs, all
packaging and labeling material should provide information consistent with that
approved by the country's drug regulatory authority. Adequate information on the use
of medicinal drugs should be made available to patients.
Should you avoid representatives?
Medical representatives are criticized a lot, but there network is very huge and now they
have become an integral part of medical infrastructure in the country. Hence, make best use
of this huge network for getting drug information in a desirable way! Ask about publication
of drug safety in an authentic medical journal. Optimize the time spent with medical
representatives. Remember following points while dealing with a representative:
• Take control of the discussion
• You get the information you need
• Ask for officially registered drug information and compare it with what industry has
got printed
Critical Appraisal of Drug Promotional Literature  213
•
•
•
•
Comparison with standard treatment use
Particularly look for side effects and contraindications
Ask for published references on efficacy and safety
If it is 'me too' drug (analogue of same class, e.g. new proton pump inhibitor) ask about
price
• Do not start by using free samples on a few patients or family members
• Do not base your conclusions on the treatment of a few patients.
OBJECTIVES
At
1.
2.
3.
4.
5.
the end of the practical class the student shall be able to:
Understands concept of advertisement.
Critically analyze a given drug advertisement.
Identify unethical points in advertisement.
Enumerate authentic sources of drug information.
Appreciate the merits and limitations of the various sources.
Exercise in class
Drug promotional literature is given to batch of 4-5 students. They are given 15 minutes to
analyse and write their points. The group leader gets 5 minute to speak about advertisement
which is projected through LCD projector in front of whole class. In this way you can cover
a large number of advertisements and all aspects of advertisements.
Exercises
Find out the following information from the appropriate books and mention the source of
information:
1. What is the plasma half life of atenolol?
2. Does the clearance of gentamicin get altered in the renal insufficiency?
3. What is the Vd of amiodarone?
214  Practical Manual of Pharmacology
4. What is dose of paracetamol in children?
5. Select the cheapest preparation of ciprofloxacin (500 mg tablet).
6. Select the cheapest and costliest preparation of diclofenac (50 mg tablet).
7. What is the incidence of anaphylaxis with penicillin injection?
8. Can nimesulide be prescribed to a 3-year-old child?
9. What are precautions while taking doxycyline tablet?
10. Name 3 new antiepileptic drugs.
11. Why rofecoxib was withdrawn from market?
12. Write 5 brand names of enalapril tablet.
CHAPTER
24
Therapeutic Follow-up
Cases/Problems
Cases are identified in the hospital. Students are divided into batches. Each batch has 4-5
students. They are allotted cases. They go to their respective cases and work up on the case
and fill the following required information.
Clinical Pharmacology Exercise Form (Therapeutic follow-up for any case)
Student's Name
MBBS 2nd Prof.(Year)
Semester
Roll No.
Clinical Assignment of
INSTRUCTIONS
1. Fill up the Performa with appropriate data.
2. Write down the presenting complaint, chief complaints and other symptoms of disease
in this patient.
3. Write down the various parameters to follow improvement in this disease and enter
the observation daily/ periodically in the columns provided.
4. Write the name of the drug, dose, route, and frequency of administration. Tick (√) in
the appropriate date column when each drug is started and put (X) when the drug is
discontinued.
5. Any fresh sign/ symptom appearing during the treatment should be recorded. Tick (√)
when these appear and put (X) when these disappear.
Salient Features of the case:
Clinical
Department
Registration No.
DOA/DOD
Name of patient.
Body weight
Ht.
Age and Sex,
Pregnant
Smoking Y/N
Alcohol Y/N
Lactating
216  Practical Manual of Pharmacology
Major Sign and Symptoms: (Write down all the symptoms in chronological order)
Symptoms
Signs/ Diagnostic test
1.
2.
3.
4.
5.
6.
Drugs used
Name of drug
Dose
Route
Frequency
Res. Rate
BP
Change/Date
Daily cost
Parameters monitored
(General)
Day/time
Temp
Pulse
Others
Others
Others
Others
Therapeutic Follow-up Cases/Problems  217
Specific parameters
Investigation
Date
Day-
Day-
Day-
Day-
1
2
3
4
5
C. Investigations during treatment with date and rational/ reasons
1.
2.
3.
4.
5.
D. Fresh signs and symptoms/adverse effects (developed during treatment)
1.
2.
3.
4.
E. Comment on:
Common trade names of the drugs used
Cost
Shelf life/Storage
Schedule (H/X, etc.)
Method of administration (With/without food, milk, other drugs, posture, inhalation,
Dilution/Infusion, etc.)
Information to patient (About expected side effects which are not serious/when
consultation should be sought)
Specific Antidote (In case of poisoning)
Advice to attendant/family members to ensure compliance and assess improvement
F. Therapeutic follow-up
G. Advice on discharge
218  Practical Manual of Pharmacology
H. Other alternative drugs available for this case
II. Alternatives to be used in old/Children/Pregnant/presence of concurrent hepatic
or renal disease
III. Non-Pharmacological Measures to be taken. (Diet, exercise, smoking, alcohol,
etc.)
OBJECTIVES
1. Complete few therapeutic follow-up cases
2. Present these cases and highlight drug management.
Students will fix the copies of this performa in their practical notebook. The case will
be discussed during the presence of full class. The student will present the case and
other students would be allowed to comment/ask questions. The number of cases
covered can vary from 20 to 40 depending upon the schedule. Later on problem
based questions can be taken out from these cases. Put them on card along with 3-4
questions and make them as one of the OSPE stations.
Example: This is taken from history of a parkinsonism patient.
A 60-year-male was on phenothiazines therapy for psychotic illness. He developed
parkinsonism disease. He was given L-dopa 250 mg OD but there was no improvement.
The dose of which then increased to 750 mg OD but still there was no improvement.
Q1. Why he developed parkinsonism?
Q2. Why he was not benefited by increasing the L-dopa dose even?
Q3. What alternate should be given?
CHAPTER
25
New Drug Development
New drug development involves animal toxicity studies followed by clinical trial in humans.
Potentially useful compounds are studied in animals to evaluate desired effects and toxicity.
Animal toxicity studies are done to see whether the chemical is safe or not. Compounds that
appear effective and safe are candidates for human studies. For all new drugs, it is mandatory
to do toxicity studies in animals. After that the drug enters various phases of clinical trials.
The various phases of drug development are:
Drug development is an extremely arduous, highly technical, time-consuming and very
expensive process. The investment to produce one marketed drug is approximately US$800
million and 12-15 years. The idea starts from folklore or screening of natural products. But
nowadays drugs are designed on computer keeping in view the target, e.g. agonists and
antagonists are synthesized for receptors.
Chemical synthesis is done by chemists by using computer models these days. Various
combinations are designed using CADD (computer assisted drug designing) and then best
molecules are chosen for study in animals. They are given code numbers, e.g. M1001-M1210.
220  Practical Manual of Pharmacology
The molecules are synthesized and a formulation is made. It is tested in animals. Various
screening methods are available depending on the disease condition. Selected molecules
from screening are further subjected to animal toxicity studies. If the molecule is found to be
safe it enters clinical trials. It is estimated that to have one successful drug we need to start
with 10,000 molecules.
Clinical trial is defined as “a carefully and ethically designed experiment with the aim of
answering some precisely framed questions. To carry out each phase of clinical trial in India,
permission from Drug Controller General of India (DCGI) is required. In US the regulatory
authority is Food and Drug Administration’s (FDA).
Clinical trial is systematic study of pharmaceutical products on human subjects (whether
patients or non patient volunteers) in order to discover or verify the clinical, pharmacological
(including pharmacodynamics/pharmacokinetics) and/or adverse effects, with the object of
determining their safety and/or efficacy. There are five phases of clinical trials.
Phase 0
Phase 0 is a recent designation for exploratory, first-in-human trials conducted in accordance
with the FDA 2006 guidelines. Phase 0 trials are designed to expedite the development of
promising therapeutic or imaging agents by establishing very early on whether the agent
behaves in human subjects as was anticipated from preclinical studies. Distinctive features of
Phase 0 trials include the administration of single subtherapeutic doses of investigational
agent to a small number of subjects (10 to 15) to gather preliminary data on the agent’s
pharmacokinetic and pharmacodynamic properties and mechanism of action.
Phase I
The objective of phase I of trials is to determine the maximum tolerated dose in humans,
pharmacodynamic effect, adverse reactions, if any, with their nature and intensity and
pharmacokinetic behaviour of the drug as far as possible. These studies are often carried out
in healthy adult volunteers (20-25) using clinical, physiological and biochemical observations.
The main aim is to find out the safety of the drug in humans.
Phase I trials are usually carried out by investigators trained in clinical pharmacology
and having the necessary facilities to closely observe and monitor the subjects. These may be
carried out at one or two centres. The perquisite to start phase I trials is submission of
results of animal toxicity studies.
Phase II-Exploratory trials
In phase II trials a limited number of patients (20-200) are studied carefully to determine
possible therapeutic uses, effective dose range and further evaluation of safety and
pharmacokinetics. Normally 10-12 patients should be studied at each dose level. These studies
are usually limited to 3-4 centres and carried out by clinicians specialized on the concerned
therapeutic areas and having adequate facilities to perform the necessary investigations for
efficacy and safety. The perquisite to start phase II trials is submission of results of phase I.
New Drug Development  221
Phase III-Confirmatory trials
The purpose of these trials is to obtain sufficient evidence about the efficacy and safety of
the drug in a larger number of patients (250-1000), generally in comparison with a standard
drug and/or a placebo as appropriate. These are real life situations. These trials may be
carried out by clinicians in the concerned therapeutic areas, having facilities appropriate to
the protocol.
Data on ADRs observed during clinical use of the drug should be reported along with a
report on its efficacy in the prescribed format. The perquisite to start phase III trials is
submission of results of phase II. However, if the drug is already approved/marketed in
other countries, then you need to carry on directly phase III study (known as bridging
study) on at least 100 patients distributed over 3-4 centres primarily to confirm the efficacy
and safety of the drug, in Indian patients. The prerequisite is submission of data of marketed
drug in other countries. In this case you need to conduct bioequivalence studies also.
Phase IV
These are studies performed after marketing of the pharmaceutical product. Trials in phase
IV are carried out on the basis of the product characteristics on which the marketing
authorization was granted and are normally in the form of postmarketing surveillance,
assessment of therapeutic value, treatment strategies used and safety profile. Phase IV studies
should use the same scientific and ethical standards as applied in pre-marketing studies.
This phase has now become mandatory in India under Schedule Y.
After a product has been placed on the market, clinical trials designed to explore new
indications, new methods of administration or new combinations, etc. are normally considered
as trials for new pharmaceutical products.
A protocol for clinical trials has following information:
• Title:
• Introduction: (brief, justification and problem definition)
• Hypothesis:
• Aims and Objectives:
• Materials and Methods:
(a) Type of Study: prospective, observational
(b) Setting:
(c) Subjects: patients, healthy volunteers
(d) No. of Groups: Randomisation, blinding
(e) Sample size calculation: power of study
(f) Study design:
(g) Treatment:
(h) Primary outcome measures:
(i) Secondary outcome measures:
222  Practical Manual of Pharmacology
(j) Stopping rule:
(k) Analysis:
(l) Ethics:
OBJECTIVES
At the end of the session a student shall be able to:
1. Understand concept of new drug development.
2. Understand various phases of clinical trials.
C H A P T E R
26
Calculation of Drug Doses
and Dilutions
Posology is the science of dosage. It deals with the amount of drug necessary to produce a
desired physiological, therapeutic, or prophylactic effect.
Dose
It is the appropriate amount of a drug required to produce a certain degree of response in a
patient given at a time and which can be repeated at an appropriate interval to produce a
desired therapeutic effect or it is quantity of drug which is sufficient to diagnose, prevent or
cure a disease.
Dosage
It is schedule of dose, frequency and duration of administration of drug.
Dose may be:
1. Standard dose
The same average dose is given to all the patients, e.g. diclofenac 50 mg three times a
day.
a. The minimum dose is the smallest dose that produces a therapeutic effect.
b. The maximum dose is the largest dose that can be safely administered.
c. The toxic dose is the dose that produces harmful effects.
d. The lethal dose is the dose that will result in death. The minimum lethal dose
(MLD) is the smallest amount that will cause death.
e. The single dose is the amount of a drug taken at one time.
f. The daily dose is the total amount of a drug taken in 24 hours.
g. A continuous dose consists of small doses taken at short intervals.
2. Regulated or Titrated dose
Dose is adjusted based on measurement of a body function.
For example: antihypertensive drugs as per BP measurement
Antidiabetic drugs as per blood glucose measurement.
224  Practical Manual of Pharmacology
3. Target level dose
Plasma concentration of a drug is monitored for adjustment of dose, e.g. Phenytoin in
epilepsy based on plasma level achieved. Target concentration is 10-20 microgrms/dl.
Fixed-Dose Combinations (FDC)
The concomitant use of two or more drugs adds to the complexity of individualization of
drug therapy of a disease. The dose of each drug should be adjustable to achieve optimal
benefit. But patient compliance is more difficult to achieve. To obviate the latter problem,
many fixed-dose drug combinations have been marketed. The use of such combinations is
beneficial only if the ratio of the fixed doses of drugs corresponds to the needs of the individual
patient. Most of the FDCs are banned in India and other countries.
Drug doses may also be calculated based on body weight or surface area in adults.
Anticancer drugs are calculated based on body surface area.
Ratio-proportions
Ratios indicate a relationship between two numbers with a colon between the numbers. The
colon represents division. For example 3:4 = 3/4.
A ratio is the relation between like numbers or values, or a way to express a fractional
part of a whole. Ratios may be written:
As a fraction:
2
3
1.0
11 gm
200
1000
3 ml
As a division: 2 ÷ 3
The strength or concentration of various drugs can be expressed as a ratio.
First, read the label of the drug and find the strength or concentration. Express this
strength as a ratio in fractional form, as in the following examples.
Kanamycin injection, 1.0 gm/3 ml =
Isoproterenol inhalation, 1:200 =
Epinephrine injection, 1:1000 =
Proportions are equations containing ratios of equal value.
A proportion consists of two equal ratios and is essentially a statement of equality between
two ratios. For example 3:4 = 6:8. This may also be written as fractions, 3/4 = 6/8.
The value of the ratio on the right must always equal the value of the ratio on the left. A
proportion may be written with the double colon, or proportion sign (::), or with the sign of
equality (=).
Calculation of Drug Doses and Dilutions  225
Means
2 :5 :: 4: 10
or
Extremes
In a proportion, there are four numbers. The two middle numbers are known as MEANS
and the two end numbers are known as EXTREMES.
Example: You find a 10-ml vial of Aminophylline in supply labeled "25 mg per ml." Thus,
there are 250 mg of drug in this 10-ml vial.
(extreme) 25 mg = 250 mg (mean)
(mean)
1 ml = 10 ml (extreme)
Notice that when you multiply the two extremes and the two means, the products are
equal.
For example: 25 × 10 = 250 × 1.
Multiply the extremes: 25 × 10 = 250
Multiply the means: 1 × 250 = 250
In a proportion, the product of the means is always equal to the product of the extremes.
Therefore, when you do not know one value (x), you can determine it, if the other three
values are known. When setting up a ratio, the known factor (on hand) is stated first, the
2=4
desired is stated second.
5 = 10
When doing calculation, use the following steps to solve for X.
(1) Step 1. State problem in "if-then" form.
(2) Step 2. Convert the problem to an equation.
(a) Known information (labeled strength, and so forth) should be your IF ratio.
(b) The unknown ratio including X will be your THEN ratio.
(c) Put like units on the same side of each ratio. (For example, if the left side of the
equation is expressed in mg/ml, then the right side must also be expressed in
mg/ml).
(3) Step 3. Cross multiply means and extremes.
(4) Step 4. Solve for X.
Example 1:
Prescribed: 600,000 units of penicillin po q6h
Available: 400,000 units per scored tablet
How many tablets will you administer?
400,000 units : 1 tablet = 600,000 units : x
600,000 = 400,000x
600,000 = x = 1.5 tablets
226  Practical Manual of Pharmacology
400,000
or the formula method can be used:
D/H X Q = X
D - dosage desired or ordered
H - what is on hand (available)
Q - unit of measure that contains the available dose. When using solid products (tablets,
capsules) Q is always 1 and can be eliminated. Q varies when using liquid measures.
X - the unknown dosage you need to administer.
Example 2:
Prescribed: Potassium Chloride 20 mEq added to the IV.
Available: 40 mEq per 10 cc.
How much potassium will you add?
D = 20 mEq
H = 40 mEq Q = 10 cc
20 mEq X 10 cc = X
40 mEq
0.5 X 10 = X = 5 cc
It doesn't matter if you use ratios, fractions or the formula, the answer will be the same
Calculating dosages in units (insulin, heparin, pitocin, vitamins, some antibiotics).
Example 3:
Prescribed: Ampicillin 400 mg IM q6h
Available: Vial with powder.
Label reads: For IM injection, add 3.5 ml diluent (read accompanying circular). Resulting
solution contains 250 mg Ampicillin per ml. Use solution within one hour.
How many ml will you administer
Ratio-proportion method:
250 mg : 1 ml = 400 mg : x
400 = 250 x
400÷250 = 1.6 ml
Formula method:
D/H X Q = X
400 mg X 1 ml = X
250 mg
1.6 ml = X.
Calculation of Drug Doses and Dilutions  227
Example 4:
Prescribed: Heparin 8000 units subcutaneous q12h
Available: Heparin 10,000 units per ml
How much will you administer?
Formula: 8000 units X 1 ml = 0.8 ml 10,000 units
Ratio: 10,000 units : 1 ml = 8000 units : x
8000 units X 1 ml = 10,000 units x
8000/10,000 = x
0.8 ml = x.
Conversion within the metric system
To convert a quantity in the metric system to a larger unit, we divide or move the decimal
point to the left. To convert to a smaller unit, we multiply or move the decimal point to the
right. Alternatively, we can use ratio and proportion as illustrated in the following examples:
Example 1: Convert 0.3 mg to grams. (There are 1000 mg in 1 gram.)
IF 1000 mg THEN 0.3 mg
1 gm = X gm
1000 x X = 0.3 x 1
1000X = 0.3
X = 0.0003 gm (answer).
Example 2: Express 30 liters in terms of milliliters. (There are 1000 ml in 1liter.)
IF 1000 ml THEN X ml.
1 liter = 30 liters
1 x X = 1000 x 30 liters
X = 30,000 ml (answer).
The labeled strength of a 30 ml vial of Meperidine injection is 50 mg/ml. How many
milliliters must be injected to provide a 75 mg dose?
IF 50 mg THEN 75 mg
1 ml = X ml
50 x X = 1 x 75
50X = 75
X = 1.5 ml.
228  Practical Manual of Pharmacology
Calculate drop rate:
Example 1:
Prescribed: Infuse 2 L of Lactated Ringers solution in 24 hours.
The administration set has 12 gtts/ml.
How many gtts/min will you administer the IV?
2000 ml X 12 gtts/ml = x
24 hr
60 min/hr
24000 = x
1440
16.7 gtts/min or 17 gtts/min = x.
Example 2:
Ordered: Gentamicin 100 mg/100 ml IV q8h. The IV handbook states that it should be
given over 90 min. What rate will you set on your IV pump?
100 ml = x
90 min
60 min
90 x = 6000
x = 6000/90
x = 66.7 or 67 ml/hr.
Liquids
Example 1:
A three-month old boy who is 24.5 inches long and weighs 11 pounds, 8 ounces, is to receive
Phenobarbital elixir labeled 20 mg/5 ml. The anticonvulsant dose of Phenobarbital is 125
mg/m² dose.
(1) Calculate the single dose of Phenobarbital in mg.
SURFACE AREA = 0.31 m²
CHILD'S DOSE = 0.31 x 125 mg = 40 mg, approximately
(2) How many milliliters will be administered for each single dose?
IF 20 mg THEN 40 mg
5 ml = X ml
20 x X = 5 _ 40
X = 200 = 10 ml (answer)
20.
Example 2:
How many grams of potassium permanganate should be used in preparing 500 ml of a 1:2500
solution? 1:2500 = 0.04%
Calculation of Drug Doses and Dilutions  229
500x0.0004 = 0.2 gm or
1:2500 means 1gm in 2500 ml
2500:500 = 1xX
X = 0.2 gm.
OBJECTIVES
At the end of the session the student shall be able to:
1. Calculate the quantity of drug present in a given solution.
2. Appreciate the importance of calculating the total quantity of drug and its conversion
from percentage and molar solutions for individualization of therapy.
3. Calculate number of tablets, quantity of solution, drip rate for given condition.
Exercises in class:
These can be given to small groups on cards. Later on these cards can be used as one of the
stations in OSPE.
1. How many milliliters of promethazine hydrochloride injection labeled 25 mg/ml must
be administered to provide a dose of 12.5 mg?
2. A patient is prescribed 30 milligrams of furosemide intravenously. 10 milligrams in 1
millilitre of liquid for IV. Injection is available. How many millilitres will you administer?
3. A patient is prescribed 22 milligrams of gentamicin sulphate by intramuscular injection.
20 milligrams in 2 millilitres of liquid for IM. Injection is available. How many millilitres
will you administer?
4. A patient is prescribed 75 micrograms of fentanyl citrate intravenously. 0.1 milligrams
in 1 millilitre of liquid for IV. Injection is available. How many millilitres will you
administer?
5. A patient is prescribed 50 milligrams of sodium valproate orally. 200 milligrams in 5
millilitres of syrup is available. How many millilitres will you administer?
230  Practical Manual of Pharmacology
6. A patient is prescribed 200 milligrams of Amoxicillin trihydrate orally. 250 milligrams
in 5 millilitres of Syrup is available. How many millilitres will you administer?
7. A patient is prescribed 15 mg of stemetil. You have 2 ml of solution on hand which
contains 25 mg Stemetil. What volume of solution would you give?
8. A dose of 75 mg of pethidine has been prescribed. It is available in ampoules containing
100 mg in 2 ml. What volume must be administered?
9. Calculate the drip rate for 100 mls of IV fluids to be given over a half hour via a giving
set which delivers 10 drops/ml.
10. Calculate the drip rate for 500 ml of normal saline to be given over 4.5 hours via a
giving set which delivers 15 drops/ml.
11. Calculate the drip rate for 500 ml of dextrose 5% in water to be given over 4 hours via
a giving set which delivers 15 drops/ml.
12. A patient is prescribed 50 milligrams of amitriptyline. 25 milligram tablets are available.
How many tablets will you give?
13. A patient is prescribed 300 milligrams of carbamazepine. 200 milligram tablets are
available. How many tablets will you give?
Calculation of Drug Doses and Dilutions  231
14. A child weighing 12 kg has been prescribed syrup chloroquine (one bottle of 60 ml,
each ml containing 10 mg of chloroquine base). The initial dose of chloroquine is
10 mg/kg. Calculate the amount of syrup to be administered to the child.
15. A patient is prescribed 2.5 grams of neomycin sulphate. 500 milligram tablets are
available. How many tablets will you give?
16. Convert 93074 milligrams to grams.
17. Convert 64343 millilitres to litres.
18. Convert 97.196 micrograms to milligrams.
CHAPTER
27
Evaluation of Drug Formulations
Rational therapeutics is an important clinical aspect of applied pharmacology. Formulation is
an integral part of therapeutics.
Hence, following aspects of formulation for a given disease will be discussed
1. Labeling:
2. Cost:
3. Rational Therapeutic:
4. Essential drug concept:
Pharmaceutical companies manufacture the drugs. They usually provide the information
sheets/package inserts/brochures for their products. Though, they should provide the
scientific information for their products, largely such information is prepared from commercial
angle and for marketing of their products rather than giving scientific information.
Often the companies provide the information which is incomplete, irrelevant and having
tall claims. Therefore, it is necessary that these information sheets/brochures/literature
provided by the pharmaceutical companies should be evaluated on the basis of above points.
In addition to this one should pay special attention to the following points:
1. Physical presentation: quality of paper, print, colour, etc.
2. Figures, diagrams, tables, pictures, cartoon, etc.
3. Quality of statements made, i.e. broken, convenient statements and their source
4. References: their authenticity, time of publication, etc.
5. Cost, if mentioned.
The following aspects of labeling and package inserts should be considered:
1. Consumer information which is simple and not confusing
2. Indication of the item as a medicinal product
3. Composition of the product including international nonproprietary name (INN)/generic
name of the active substance
4. Uses for which the product is intended
Evaluations of Drug Formulations  233
5. Mode of use, including route of administration (systemic or local), maximum single
dose, maximum daily dose and duration of treatment
6. The product is intended for (children or adults)
7. Presentation of the most important precautions, contraindications and adverse effects
clearly stated in easily understandable language. The size of letters.
8. Specific warnings and information for use during physiological/pathological variations
such as pregnancy, lactation, the elderly, or in patients with renal or hepatic failure.
9. When medical advice should be sought
10. Duration of use
11. Information on storage conditions and shelf-life
12. Inactive ingredients listed
13. Expected benefit when the drug is used properly
14. Expiry date
15. Overdosage: Brief clinical description of symptoms, non-drug treatment and supportive
therapy and specific antidotes
Many developing countries including India, have a limited budget allocated to health
care especially for drug procurement. Therefore, it is imperative to optimize expenditures
for drug purchases by selecting an essential drug list and promoting the rational use of
drugs.
Rational drug use:
RUD means use of a right medicine, in the right manner (dose, route and frequency of
administration, duration of therapy), in right type of a patient, at a right cost, i.e. the rule of
right. Rational drug use also means using the drug when necessary (chloroquine in malaria)
and more importantly, not using it when unnecessary (expectorant mixture in common cold).
When the word 'right' is replaced by the word 'wrong' it becomes irrational drug therapy
which is more frequent than assumed.
Irrational use of medicines is a major problem worldwide. WHO estimates that more
than half of all medicines are prescribed, dispensed or sold inappropriately and that half of
all patients fail to take them correctly. Inappropriate, ineffective and inefficient use of drugs
commonly occurs at health facilities in developing and developed countries. Common types
of irrational use of drugs include:
• Non-compliance with health worker prescription
• Self-medication with prescription drugs
• Overuse and misuse of antibiotics
• Overuse and misuse of antidiarrhoeals for non-specific childhood diarrhea
• Multiple or overprescription
• Overuse of injections and overuse of relatively safe drugs
• Use of unnecessary expensive drugs and poor patient compliance
• Unnecessary use of tonics and multivitamins
• Short consulting time.
234  Practical Manual of Pharmacology
Many individuals or factors influence the irrational use of drugs such as patients,
prescribers, the workplace environment, the supply system including industry influences,
government regulation, drug information and misinformation.
In addition to optimizing the use of limited budget, promoting the rational use of drugs
aims to improve quality, increase accessibility and equity of health and medical care for the
community.
Essential drug concept:
The concept of essential drugs was first time mooted by the World Health Organisation
(WHO) in 1977 and the first list of essential list was published in 1977. The list is revised
every two years. Currently the 15th list (March, 2007) is in use (http://www.whoindia.org/
LinkFiles/Essential_Medicine_List_EML15.pdf). The essential drug list of India was
formulated in 1996 and revised in 2003. It has 354 drugs (Appendix IV). Many drugs included
in the list are preceded by a box in WHO list to indicate that they represent an example of a
therapeutic group and that various drugs could serve as alternatives. It is imperative that
this is understood when drugs are selected at national level, since choice is then influenced
by the comparative cost and availability of equivalent products.
Definition: Essential medicines are those that satisfy the priority health care needs of
the population.
Selection criteria: Essential medicines are selected with due regard to disease prevalence,
evidence on efficacy and safety and comparative cost-effectiveness. Essential drugs are
selected to fulfill the real needs of the majority of the population in diagnostic, prophylactic,
therapeutic and rehabilitative services using criteria of risk-benefit ratio, cost-effectiveness,
quality, practical administration as well as patient compliance and acceptance.
Purpose: Essential medicines are intended to be available within the context of functioning
health systems at all times, in adequate amounts, in the appropriate dosage forms, with
assured quality and at a price the individual and the community can afford.
Implementation: The implementation of the concept of essential medicines is intended
to be flexible and adaptable to many different situations; exactly which medicines are regarded
as essential remains a national responsibility.
Clinical guidelines and a list of essential medicines lead to better patient care and effective
prevention.
The principle of the concept is that a limited number of drugs lead to:
•
•
•
•
•
•
Better supply of drugs
More rational prescribing
Procurement of good quality drugs at lower costs
Easier storage, distribution and dispensing
Focused training and drug information
Prescribers gain more experience with fewer drugs and recognize ADR better.
Evaluations of Drug Formulations  235
Essential drugs are selected based on:
•
•
•
•
•
•
•
•
Morbidity pattern
Evidence of efficacy and safety
Relative cost effectiveness
Local manufacturing facilities
Pharmacokinetics considerations
Ensured quality, bio-availability, stability
Single compounds preferred over FDC
FDCs only if proven advantage of combination, decreasing emergence of resistance,
i.e. malaria, tuberculosis, HIV/AIDS.
Essential drug list should be:
• Evidence Based
Best balance of efficacy, safety, quality and cost
• Efficient
Focuses therapeutic, decision, professional training, public information, finances
• Flexible
Implemented from primary to tertiary health care
• Forward Looking
Regularly updated in accordance with new needs and information.
Rational drug use and essential drug concept are interdependent and interlinked.
Availability of essential drugs will undoubtedly lead to more rational drug use and rational
use of drugs shall promote more production and supply of essential drugs. There are three
broad categories of interventions to improve rational drug use. These have been classified
as educational approaches, managerial approaches and regulatory approaches. Educational
approaches attempt to inform or persuade prescribers, dispensers or patients to use drugs in
the proper, rational and efficient way. There are many types of this approach such as inservice training, face-to-face education, small group discussions, seminars, workshops and
printed education materials.
Managerial strategies attempt to improve drug decision-making by a variety of techniques
including use of specific processes, forms, packages and monetary incentives. The interventions
using this approach include developing and implementing Essential Drug Lists or Drug
Formularies, Standard Treatment Guidelines, implementing drug supply kit system,
monitoring and feedback, establishing representative Pharmacy and Therapeutics Committees,
establishing structured drug prescribing form, providing cost information, and set-up
financing. Essential Drug Lists or Drug Formularies provide prescribers with a list of the
drugs felt to be most effective and economic in treating important health problems.
Regulatory approaches attempt to restrict allowable decisions by placing absolute limits
on availability of drugs. These strategies rely on rules or regulations to change behavior.
236  Practical Manual of Pharmacology
Interventions using this approach are limiting or banning registration, changing product
registration status as well as prescribing and dispensing controls.
In general a combined intervention is likely to have a synergistic effect
Fixed-dose Drug Combinations (FDCs): They are produced and used to meet the following
objectives:
1. To produce drug synergism in order to achieve a better therapeutic response than each
drug used alone. Atleast they must have additive effect, for example, cotrimoxazole.
2. To reduce the incidence/severity of adverse effects of one drug by the other, for example,
atenolol + amlodipine, combinations of antitubercular drugs.
3. To provide convenience of administration and to reduce cost of drug, leading to better
patient compliance, for example, levodopa + carbidopa.
As against these, following are the demerits of majority of the currently available FDCs in
India.
1. dosage alteration of one drug is not possible without alternation of other drugs.
2. differing pharmacokinetics of constituent drugs pose the problem of frequency of
administration of the formulation.
3. overprescribing and polypharmacy leading to consumption of unnecessary drugs.
4. increased chance of adverse drug effects and drug interactions.
5. increased cost.
6. when an FDC has large number of ingredients (4 or more), as in the case of tonics,
haematinics and cough mixtures, a doctor may not know what are the ingredients in
the formulation he is prescribing.
WHO essential drug list has only 2.1% FDCs. As against this, according to a rough
estimate, approximately 1,00,000 drug formulations are marketed in India. According to a
conservative estimate nearly 70% of them are FDCs. A large majority of these FDCs are nonessential or useless at the best and irrational or harmful at the worst.
In India, doctors get information about various drugs largely from the medical
representatives visiting them or from the promotional literature mailed to them by the
pharmaceutical industry. More often a doctor consults various indexes like, Monthly Index
of Medical Specialties (MIMS), Current Index of Medical Specialties (CIMS), Indian Drug
Review (IDR) or Drug Index (DI) to get information on drugs. The claimed objective of these
publications is to share information but hidden agenda is to promote the commercial interest.
One gets lost in the 'therapeutic jungle'. It becomes virtually impossible to choose the right
medicine from plethora of drugs.
Therefore, it is essential for a doctor to develop the skill of critically evaluating the
available drug formulations for their rationality based on efficacy, safety, cost and convenience
of administration before embarking on their use.
Evaluations of Drug Formulations  237
OBJECTIVES
1. Work out the cost of drug treatment for the given condition. Compare the drug cost
for different brands.
2. Assign the status as rational/semirational/irrational to the given drug formulation as
a whole and giving reason(s) for the same.
3. Comment on the following FDC
a) Paracetamol + aspirin
b) Paracetamol + Nimesulide
c) Amoxycillin + clavulanic acid.
CHAPTER
28
Ethics and Humans
ETHICS
•
•
•
•
A discipline dealing with what is good and bad and with moral duty and obligation
A set of moral principles or values
A theory or system of moral values
The principles of conduct governing an individual or a group.
Ethics is the study of right conduct and a rational process for determining the best
course of action in the face of conflicting choices. Medical ethics is the science of moral values
that guides a medical practitioner in their relationship with their patients, the state and
professional brethren. It also includes ethical issues associated with providing health care or
perusing biomedical research.
The four essential principles of ethics are:
1. Autonomy of Patients: Patients body is his/her own. He/she has right to decide about
operations and procedures. When patients come to you it is implied consent for routine
procedures. It is better to explain patient about every procedure and them perform.
When special procedures are done stated/special consent is taken. Physician must guide
patients to take right decision.
2. Beneficence: One must remember that whatever we do, it should be done for benefit of
patients.
3. Non-maleficence: Do no harm.
4. Justice: Patient should get the best treatment and justice should be done to all as far as
possible.
You need not have ethical worries if you behave in a beneficent, nonmaleficant, just
manner, protecting autonomy and following consistent moral code.
Since ethics is an integral part of practice of medicine, its study should parallel that of
study of medicine. The purpose of this session is to make students start understanding of
principal moral values governing medical ethics. It should subsequently develop awareness
of frequent existence of ethical issues and dilemmas help develop the capacity for resolution
Ethics and Humans  239
of these issues through ethical reasoning and acquire understanding of the function of
institutional bodies concerned with ethics. As in every sphere of life, medical profession has
also moral duty and obligations, and so is in the field of pharmacology. Ethics in pharmacology
are most important when it comes to research on humans and the interaction of doctors and
medical representatives.
Earlier human beings were being used in research without their consent. History is full
of examples showing unethical use of human beings. Nurember code (1947) was the first
attempt to integrate ethics into research. The main emphasis of this code was to protect the
integrity of the research subject. This was followed by declaration of Helsinki in 1964 by
World Medical Association and International Guidelines for biomedical research involving
human subjects by WHO (1982). In India, there are guidelines from ICMR, New Delhi (2000)for
conduct of research on human beings. As per these guidelines it is mandatory to take written
informed consent from any human who is going to be involved in research. This consent
form is considered to be document of faith and trust. It safeguards autonomy, respect patient's
right to dignity.
Written Informed consent has following components:
1. Patient Information Sheet
Provides information to patient about the research work where he is going to be
involved.
2. Consent Form
Used to document consent in writing
Informed consent emerged from the ethical principle of Respect for Persons. These
principles state that:
• Individuals be treated as capable of taking decisions for themselves ("autonomy")
• Those with diminished autonomy be protected
• Language: The informed consent and information sheet must be available in local
languages in validated format.
Informed consent is a PROCESS and involves:
•
•
•
•
•
•
Providing all relevant information to the volunteer/patient
The patient/volunteer understanding the information provided
Voluntarily agreeing to participate
It should be in writing, there is no value of verbal consent
Basic right
Maintaining confidentiality.
The information on consent form includes:
a) Name and designation of investigator
b) Institute where the study will be carried out
240  Practical Manual of Pharmacology
c)
d)
e)
f)
g)
h)
i)
j)
Name and address of the patient
Age, sex and hospital registration number
Title of the study
Procedure in layman's language
Option to opt out of the study without reason
Care will not suffer if he opts out
Adverse effects (known and unknown)
Signatures.
Written informed consent is needed in following circumstances:
1. All research projects involving human beings.
Special care has to be taken about, double blinding, randomization, serious adverse
effects, whether to give placebo or not, cost of treatment, washout period, informed
consent form in writing, treatment after end of trial, insurance of subjects,
randomization, etc.
2. Cancer chemotherapy
3. Invasive procedures
4. HIV testing
5. Thalidomide prescription.
It is necessary to stress that taking informed consent should satisfy the letter and spirit
of the procedure. Special groups like pregnant women, children, mentally ill patients were
previously excluded from clinical trials. However, now the trend has changed to include
these groups in clinical trials so as not to deprive them of the benefits of new drugs and
therapies. Therefore, whenever possible the procedure is explained to the subject (during a
lucid interval or to a child using pictorial representations) and receiving the individuals
consent in addition to the guardian's consent is mandatory.
Example of an informed consent form:
PATIENT CONSENT DOCUMENT
Example 1
I_________________________ exercising my free power of choice, hereby give my consent
to be included in this study of "Drug A" and understand that I will be treated with this
drug for the disorder I am suffering from. I have been informed to my satisfaction by the
attending physician, the purpose of this and follow up including the laboratory
investigations required to monitor and safeguard my body functions.
I, have also been explained the risk profile of the drug and am giving consent that I be
included in the study. I am also aware of my right to opt out of the study at any time
during the course of the study without having to give reasons for doing so.
Patient Signature:
Date:
Signature of investigator:
Date:
Ethics and Humans  241
PATIENT CONSENT DOCUMENT
Example 2
Patient Consent Form
I
exercising my free power of choice, hereby
give my consent to be included in the study "Comparison of safety of Drug A and Drug B in
Indian patients." I have been informed to my satisfaction by the doctor, the purpose of this
study. I will not be given any new medication. I am diagnosed to be suffering from
and will be receiving standard treatment for this disease. I understand
that I will be evaluated for adverse effects of drugs in the OPD only. The information will be
kept confidential and will be used only for scientific purpose.
I am also aware of my right to opt out of the study at any time without having to give
any reason for doing so.
Patient Signature:
Date:
Signature of investigator:
Date:
Consent form need to be signed by a relative/guardian for mentally ill patients.
Other ethical issues are:
•
•
•
•
•
•
•
•
Meeting drug medical representatives (MRs)
Acceptance of gifts of equipment, travel, or accommodation from MRs
Attending at sponsored dinners and social or recreational events
Attending at sponsored educational events, continuing medical education, workshops,
conferences or seminars
Conducting drug company sponsored research
Company funding for medical schools, academic chairs, or lecture halls
Undertaking paid consultancy work for drug companies
Giving medication during pregnancy/lactation.
OBJECTIVES
At the end of the session a student shall be able to:
1. Understand importance of ethical issues in clinical research.
2. Understand the components of a written informed consent form and realize its medicolegal implications.
3. To recognize the specific groups (children, mentally ill patients, etc.) where informed
consent has to be sought from the legal guardian.
Example 1:
A new selective Cox-II NSAID has been launched to the market. You are invited on its
launch in a five star hotel in Mumbai. You deliver a lecture in its favour. Its adverse effect
242  Practical Manual of Pharmacology
profile has not been investigated adequately. The drug company marketing the NSAID
gives you 500 tablets as sample and asks you to try out the drug on 30 patients. You are also
informed that you can present your findings at an international conference to be held after
3 months in USA. There is no DCGI permission. The travel arrangement (along with family)
will be sponsored by drug company. You agree and start using the drug on patients who
attend the dispensary where you work but not on patients who come to your private clinic.
Comment on ethical issues.
Example 2:
You are conducting a clinical trial in Punjab on hypertension. The informed consent are in
English language and there is no information sheet attached to it. The patient is just told to
sign on it without giving any explanation. The patient is paying for all investigations done
during the trial.
Comment on ethical issues.
CHAPTER
29
Management of Some
Common Poisonings
How apt is the statement that,
"A medicine in large dose can act like a poison,
a poison in small dose can act like a medicine"
A poison or toxin is a substance that can cause temporary or permanent damage if taken
into the body in sufficient quantity. A poison may be swallowed, inhaled, injected, instilled
in the eye or absorbed through the skin. Once introduced into the body, a poison can quickly
be carried to all the tissues via the bloodstream. Signs and symptoms vary, depending on
the poison and its method of entry. Vomiting is common to many cases, with the attendant
risk of inhalation of the stomach contents.
Acute poisoning requires accurate assessment and prompt therapy may be needed. Hazard
is associated not only with the potency of the poison but also with the quantity ingested, the
duration of exposure and the presence of other ingredients in preparations, including solvents.
General principles:
It should be determined if the poisoning:
1. Is life-threatening and already compromising vital functions;
2. Poses a potential hazard or
3. Is essentially harmless.
Early identification of the toxic substance (or ingredients and their potential toxicities)
can save time and decrease the risk of toxicity and complications, particularly in instances
where a specific antidote could be lifesaving or prevent serious organ damage, e.g. methanol,
paracetamol, arsenic, iron poisoning, etc.
Early collection of blood, urine and other body fluid samples to establish baseline values
for monitoring the toxin, glucose, electrolytes, acid/base status and organ damage may be
valuable in the management of the poisoned patient.
Obtaining the original toxic substance or container is more valuable and reliable for
rapid and positive identification of the poison than depending on laboratory analysis of
blood, urine or other body fluids alone.
244  Practical Manual of Pharmacology
Supportive care:
• Contaminated clothing should be removed and the skin washed with soap and water.
If contaminated, the hair should be shampooed.
• Reliable venous access should be established in comatose patients.
Hypoventilation can be avoided by ensuring an adequate airway with suction, oxygen,
insertion of an airway and mechanical ventilation as required. Most poisons that depress
consciousness also impair respiration. An obstructed airway needs immediate attention.
Dentures and oral secretions should be removed and the jaw held forward with the patient
turned in a left semiprone position.
Volume depletion secondary to vomiting, diarrhoea and sweating is common and should
be corrected.
Hypoglycemia must be excluded in any comatose patient. If present, 50 ml of a 50%
dextrose solution should be administered intravenously. Hypoglycemia should be suspected
particularly in intoxication with oral hypoglycemics, salicylates and ethyl alcohol.
Hypotension is most common in severe barbiturate poisoning and whether due to volume
depletion or venous pooling, frequently necessitates monitoring of central venous pressure
to determine fluid requirements.
Hypothermia (< 35° C) may develop in comatose patients.
Cardiac conduction defects and arrhythmias may occur in acute poisoning with various
substances. ECG monitoring is advisable and attention should be given to aggravating factors
such as acidosis, hypoxia and electrolyte/fluid disturbances. Specific treatment will depend
on the toxin ingested and the type of arrhythmia.
Convulsions that are single and short-lived do not require immediate anticonvulsive
therapy. Diazepam, given slowly intravenously, should be administered if convulsions are
protracted or recur frequently, keeping in mind that it may produce CNS and particularly
respiratory depression.
Terminating exposure to ingested toxins:
The stomach should be emptied after the ingestion of most poisons, (there are some notable
exceptions, e.g. corrosives, volatile hydrocarbons and convulsants). Gastric emptying is clearly
unnecessary if the risk of toxicity is small or if the patient presents too late. Emptying the
stomach more than 4 hours after ingestion is of questionable value, although worthwhile
recovery of tricyclic antidepressants (and other drugs which delay gastric emptying, e.g.
anticholinergics, opiates, antihistamines and sympathomimetic amines) can be achieved 4-12
hours after ingestion.
Induced emesis may be preferred to lavage in alert patients with an active gag reflex and
is usually more efficient than lavage especially when large tablets or capsules have been
swallowed. Emesis is best induced with ipecacuanha.
Gastric lavage via a large-bore orogastric tube (32-40 F in adults and 16-28 F in children)
is preferred in patients with a depressed level of consciousness, but only after a cuffed
Management of Some Common Poisonings  245
endotracheal tube has been inserted to prevent aspiration. Warm water is instilled and after
a minute the water is removed. The procedure may have to be repeated 5-6 times until no
further drug is obtained.
Stomach emptying should be followed by the administration of activated charcoal, which
reduces absorption of many substances.
Activated charcoal
(WHO essential therapeutic group)
Activated charcoal is a powerful adsorbent of a wide spectrum of drugs and poisonous
substances thereby reducing absorption from the gut. It is used in cases of overdosage or
accidental poisoning by drugs and other non-corrosive substances, usually after the stomach
has been emptied by lavage or emesis and plays an important role in the management of
poisoning.
Since charcoal adsorbs ipecacuanha it should not be given before the emetic. Current
opinion favours the use of larger and more frequent doses of charcoal in all instances where
a potential for adsorbing intoxicants exists.
Binding of drugs in the lumen also creates a concentration gradient so that the drug or
poison passes continuously from the circulation into the gut lumen. There are indications
that this 'gastrointestinal dialysis' is valuable in hastening the elimination of numerous drugs
or toxins that have already been absorbed into the bloodstream.
It is recommended that 2-4 additional doses of 20-50 g be administered in severely
poisoned patients, in cases where slow release tablets have been ingested (e.g. theophylline),
in poisoning with drugs that are excreted into the bile, undergoing entero-hepatic recycling
(e.g. tricyclic antidepressants, estrogens and progestogens, digitoxin) as well as those secreted
into the intestine (e.g. digoxin, pethidine).
It is of no value in poisoning with strong acids or alkalis, iron salts, lithium, petroleum
products (including kerosene) and of questionable value in cyanide ingestion.
Activated charcoal may be mildly constipating, but is essentially safe and innocuous.
Mixing the suspended dose with 20 ml lactulose and 50% syrup (or sorbitol 70%) makes it
more palatable and prevents the constipating effect.
Adult dose: Usually oral or via gastric tube, 50-100 g, prepared as a thick slurry in 200500 ml water.
Paediatric dose: Under 6 years, 10 g in 50-100 ml water; older children, 20-50 g in
100-300 ml water.
Osmotic laxatives, e.g. saline purgatives (such as sodium sulphate), sorbitol 70% or lactulose may usefully assist in clearing the bowel of potentially absorbable poisonous material.
Rough estimates of the dose, the time elapsed since exposure and the physical state of
the patient determine whether emesis, gastric lavage, supportive care, or specific therapy is
required, as well as the sequence of such interventions.
246  Practical Manual of Pharmacology
Poisoning with drugs
1. Paracetamol poisoning
It is the commonest ingested toxin in UK causing > 300 deaths in the UK each year. It is
rarely taken alone. The liver is the main target organ in paracetamol poisoning. Doses of 7.515 g in an adult may cause severe centrilobular hepatic necrosis. Renal tubular necrosis may
also develop. Hepatic and renal failure typically manifest only after 3-5 days.
Clinical features: Within a few hours after the overdose (0.5-24 hours) patients experience
symptoms of gastrointestinal irritability with anorexia, nausea, vomiting, abdominal pain,
as well as pallor, malaise and increased sweating. During this phase the patient may, however,
appear normal or asymptomatic. During the next 24-48 hours symptoms and signs may become
less pronounced, but the blood chemistry starts to become abnormal. Very rarely coma and
severe metabolic acidosis develop in patients who have extremely high plasma paracetamol
concentrations (usually > 800 mg/L). Loin pain, haematuria and proteinuria after the first
24 hours strongly suggest incipient renal failure. Features of hepatic necrosis with right
subcostal pain and tenderness, recurrence of nausea, vomiting and jaundice can occur after
2-3 days.
Management
Start treatment depending on time elapsed since ingestion of paracetamol:
• If within 1 hour give activated charcoal.
• If < 4 hours wait for blood levels.
• If > 4 hours and >150 mg/kg don't wait for levels.
Emesis or gastric lavage is indicated if less than 6 hours have elapsed since ingestion.
Activated charcoal should be administered if the specific antidote is given by the i.v. route,
but is contraindicated if the antidote is given orally.
Acetylcysteine is the antidote of choice and is usually given intravenously. Although
more effective when administered within 8-12 hours of ingestion of paracetamol, recent
studies have indicated benefit if antidote therapy is initiated up to 96 hours after the overdose.
Acetylcysteine has not been shown to contribute to hepatic injury that is already present.
Acetylcysteine: Use with caution in patients with asthma or a history of asthma. Patients
should be observed carefully for the emergence of hypersensitivity reactions. The
hypersensitivity-type adverse reactions often tend to be due to histamine release and are
not necessarily true allergic reactions. Therefore, acetylcysteine may not need to be
discontinued in mild reactions. These reactions may be overcome by temporary cessation of
the infusion, IV administration of an antihistamine, followed by a slower infusion rate of
acetylcysteine. Acetylcysteine is incompatible with rubber and metals, silicone rubber and
plastic should be used.
Plasma potassium should be monitored. Hypokalaemia and ECG changes have been
associated with paracetamol overdosage irrespective of the treatment. Considered to be
relatively safe during pregnancy and breast feeding.
Management of Some Common Poisonings  247
Adult dose: i.v. infusion, initially 150 mg/kg in 200 mL 5% dextrose over 15 minutes;
then 50 mg/kg in 500 mL 5% dextrose over the next 4 hours by continuous infusion; followed
by 100 mg/kg in 1 litre 5% dextrose over 16 hours.
The manufacturer's dosage regimen covers only the first 20-24 hours. The recommended
dose for the second 24 hours is 150 mg/kg in 1 litre 5% dextrose water over 24 hours. The
above represents a minimum dosage requirement and is exceeded in some investigational
regimens.
Oral acetylcysteine is proven to be effective in the treatment of paracetamol overdose.
Loading dose of 140 mg/kg followed by 70 mg/kg 4 hourly for 17 doses (over a period of 72
hours). Solutions should be diluted to 5% in water or fruit juice/soft drink. Capsules or
powder should be taken with adequate amounts of fluid (250 mL).
If the initial paracetamol level is in the toxic range, full antidote therapy is necessary.
Liver damage is likely to occur in 90% of patients with paracetamol levels > 300 mcg/mL at
4 hours or > 45 mcg/mL at 15 hours post ingestion. Levels below 120 mcg/mL at 4 hours are
unlikely to cause hepatotoxicity. For reliable hepatotoxicity risk assessment, blood for plasma
levels must be drawn after the drug has peaked (at least 4 hours post ingestion).
Patients presenting 24 hours or later after an overdose of paracetamol and having
detectable plasma levels or biochemical evidence of hepatotoxicity must be given
acetylcysteine. Patients taking drugs that induce hepatic enzymes, e.g. barbiturates, phenytoin,
carbamazepine, rifampicin and meprobamate, or alcohol abusers may develop paracetamol
toxicity at lower plasma concentrations; a lower threshold for instituting specific antidote
therapy should be used (50-70% of the potential toxic levels).
If paracetamol levels are in the potentially toxic range, liver and kidney function tests
should be performed daily.
Fatality at below mentioned levels
< 150 mg/kg Unlikely
> 250 mg/kg Likely
> 12 g total
Potentially fatal
Carbocysteine and methionine can be used as alternative to acetylcysteine.
2. Opioid poisoning
Respiratory depression is the most important toxic effect of the opioid analgesics. Death
from morphine poisoning is nearly always due to respiratory arrest.
Clinical features: Poisoning with morphine and other opioids produces central nervous
system depression ranging from drowsiness to deep coma, respiratory depression with
shallow respiration or apnoea, cyanosis, miosis (pin-point pupils), hypotension and
hypothermia. If hypoxia is severe, the pupils may be dilated. In some cases there is spasticity,
muscle twitching, convulsions and non-cardiogenic pulmonary oedema. The onset of
pulmonary oedema may be rapid, but in the comatose patient it may be delayed for up to 24
hours after recovery from coma (following administration of an opioid antagonist).
248  Practical Manual of Pharmacology
Management
Stomach emptying using gastric lavage should be performed in the comatose patient via an
orogastric tube after a cuffed endotracheal tube has been inserted to prevent aspiration.
(Gastric emptying may be delayed because of opioid-induced pylorospasm.)
Activated charcoal should be administered to adsorb opioid in the intestine and may be
followed by a saline cathartic such as sodium sulphate, magnesium citrate or magnesium
sulphate. Sorbitol 70% or lactulose are also useful cathartics. Immediate attention to an adequate
airway, and artificial ventilation, may be indicated.
Naloxone, an opioid antagonist, is administered intravenously or intramuscularly
(preferably IV). The initial adult dose is 0.4-2 mg. If improvement does not occur immediately
with IV administration, it may be repeated at 2-3 minute intervals to a maximum of 10 mg.
The diagnosis should be reconsidered if 2-3 doses fail to produce a response. In children, the
initial dose is 0.01 mg/kg, followed if necessary by a dose of 0.1 mg/kg. Intramuscular
naloxone is an alternative in the event that IV access is not possible, or if the patient is
threatening to self-discharge.
Naloxone may precipitate a severe withdrawal syndrome in an addict that cannot be
readily suppressed during the period of action of the antagonist. The duration of action of
naloxone is shorter than that of most opioids. Patients should be observed carefully; repeated
doses may be required after initial improvement.
Opioid induced pulmonary oedema should be treated with positive- pressure ventilation
using positive end expiratory pressure (PEEP).
Intravenous infusions of naloxone may be useful where repeated doses are required. An
infusion of 60% of the initial dose per hour is a useful starting point (dose adjusted to clinical
response). Infusions are not a substitute for frequent review of the patient's clinical state.
3. Aspirin and other salicylates
Toxic doses disturb the acid/base balance and uncouple oxidative phosphorylation which
may result in metabolic acidosis or compensated respiratory alkalosis. In overdose, salicylates
may be retained in the stomach for 4-8 hours or longer. Ingestion of large amounts may form
concretions in the stomach which may delay absorption.
Clinical features
These may include restlessness, hyperventilation, tinnitus, deafness, tachycardia, nausea,
vomiting, sweating, hyperthermia, dehydration, pulmonary oedema, acute renal failure,
hypokalaemia, hypoglycemia and hypoprothrombinaemia. Stupor and coma indicate severe
poisoning.
Management
Therapeutic plasma salicylate level lies between 0.7 to 2.2 mmol/L or 100-300 mcg/mL.
Severity can be determined by measuring blood salicylate levels 6 or more hours after acute
ingestion, but may be misleading in severe acidosis. Emesis or lavage should be followed by
activated charcoal. Studies have indicated that repeated doses, 50-100 g every 4 hours, increase
clearance significantly by a process termed `gastrointestinal dialysis'.
Management of Some Common Poisonings  249
Dehydration, acidosis, hypoglycemia and electrolyte disturbances should be corrected.
Hyperthermia is managed by external cooling.
Alkalinisation of the urine (pH 7.5-8.5) by administering sodium bicarbonate orally or
by infusion is recommended to increase excretion of salicylates. Care must be taken to avoid
fluid overload and renal function closely monitored.
In severe poisoning with decreased urinary flow, pulmonary oedema or progressive
deterioration, charcoal haemoperfusion or haemodialysis should be considered. Antacids
may be administered to counteract gastric irritation and vitamin K to correct deranged
coagulation mechanisms.
4. Methanol
The potentially fatal human dose of methanol is 30 ml of a 40% solution, although fatalities
have been reported with 15 ml.
Clinical features
Initially symptoms include those of minor inebriation followed by a latent period of 12-30
hours when methanol is metabolised to the toxic products formaldehyde and formic acid.
Co-ingestion of alcohol delays the toxic effects. Severe acidosis is due to formic acid and
lactic acidosis and the severe retinal toxicity is caused by formaldehyde. Further symptoms
and signs include headache, confusion, vertigo, nausea, vomiting, abdominal pain, blurred
vision, blindness, Kussmaul's respiration, restlessness, delirium, convulsions and coma.
Management
Gastric lavage or emesis as early as possible. (Charcoal does not absorb methanol well
and is of little value.) Ethanol in all cases, while awaiting methanol determination. To maintain
a blood level of 100 mg/dl of ethanol begin with a loading dose of 0.6 g/kg, followed by an
ethanol infusion of 66 mg/kg/hour (for non-drinkers) to 154 mg/kg/hour (for chronic ethanol
drinkers).
Particular attention should be directed towards the correction of metabolic acidosis with
sodium bicarbonate. Haemodialysis, if the blood-methanol level is greater than 50 mg/dl,
continue until the level is in the range of 20 mg/dl.
The administration of folate, in the form of leucovorin, may have a therapeutic advantage
(1 mg/kg, up to 50 mg/dose, followed by the same dose 4 hourly for 6 doses).
Methanol, formic acid and formaldehyde are effectively removed by haemodialysis which
is about 8 times more effective than peritoneal dialysis.
Other indications for haemodialysis include any visual impairment, metabolic acidosis
not correctable with bicarbonate, and renal failure. Ethanol blood levels should be maintained
between 100 and 150 mg/dl. Note that ethanol prolongs the elimination half-life of methanol
to 24-30 hours so that several days may be required to reduce methanol levels to < 20 mg/dl
if haemodialysis is not used.
250  Practical Manual of Pharmacology
5. Tricyclic antidepressants (TCAs)
Cardiovascular toxicity is the principal cause of fatalities from TCA overdose. It is caused by
the blockade of noradrenalin uptake as well as the anticholinergic, membrane stabilising and
alpha-blocking effects of TCAs.
Clinical Features
Overdosage can produce central nervous system, anticholinergic and cardiovascular effects.
Nervous system toxic effects include drowsiness, agitation, hallucinations, hyperactive
reflexes, myoclonus, choreoathetosis, muscle twitching and rigidity, convulsions, respiratory
depression and coma. Anticholinergic effects include flushing, dry mouth, dilated pupils,
hyperpyrexia, and bladder and bowel paralysis.
Cardiovascular toxic effects include sinus tachycardia, hypotension, conduction
abnormalities and arrhythmias, e.g. PR and QRS prolongation, ST and T wave changes,
heart block, atypical and regular ventricular tachycardia, and ventricular fibrillation. Patients
may develop respiratory complications similar to those seen in barbiturate overdose, which
may include respiratory depression, aspiration pneumonia, adult respiratory distress
syndrome and pulmonary edema.
Management
Ensure a clear airway and adequate ventilation. Check arterial blood gases and correct any
hypoxia. If hypercapnia is present assisted ventilation is indicated. Gastric lavage is useful as
late as 8 hours after ingestion (gastric emptying is delayed by the TCAs).
Lavage should be followed by activated charcoal and further doses, given, e.g. every
4-6 hours, may effectively remove enterorecycling drug. Blood pH must be checked and
acidosis adequately corrected with bicarbonate to enhance protein binding and decrease the
concentration of free drug in the plasma.
Observe for 6 hours if asymptomatic. Patients who remain asymptomatic and have normal
ECG by 6 hours are unlikely to develop late complications. Perform 12 lead ECG and monitor
cardiac rhythm. Repeat ECG if symptomatic. Check urea and electrolytes and monitor urine
output.
Resist the temptation to treat arrhythmias with drugs. Arrhythmia is best treated by
correction of hypoxia and acidosis. Otherwise, phenytoin and lignocaine are the antiarrhythmic
drugs of choice. Seizures may be treated with diazepam (0.1-0.3 mg/kg body weight) or
lorazepam (4 mg).
Alkalinisation (with sodium bicarbonate) will usually benefit both convulsive activity
and cardiotoxicity 0.5-2 mEq/kg IV bolus followed by i.v. infusion to maintain blood pH of
7.5 has been suggested. Both sodium and potassium levels should be monitored closely.
Disopyramide, procainamide and quinidine are contraindicated because of their additive
cardiac depressant effect. Physostigmine has been used for delirium, coma, choreo-athetosis,
myoclonus and some resistant cardiotoxic effects, but must be used with caution because of
potentially serious cholinergic effects. It should always be administered under close ECG
monitoring.
Management of Some Common Poisonings  251
Prolonged monitoring is needed in severe poisoning as the half-lives of the TCAs vary
from 24 to 72 hours, and may be increased in overdose.
6. OPC poisoning
The organophosphates and carbamates are cholinesterase inhibitors, indirectly causing a
stimulation of muscarinic and nicotinic receptors. They can be absorbed by ingestion,
inhalation or via the skin. While the organophosphates form an irreversible complex with
cholinesterase, the carbamyl-enzyme complex is reversible, leading to a less severe intoxication
with a much shorter duration. The carbamates also penetrate the blood-brain barrier poorly,
producing fewer CNS effects.
Clinical Features
The onset of features may be delayed for 12-24 hours after skin exposure. Early features
include anxiety, restlessness, insomnia, tiredness, dizziness, headache, nausea, vomiting,
abdominal colic, diarrhoea, sweating, hypersalivation, chest tightness and miosis. Muscle
weakness and fasciculation may develop.
Severe poisoning causes widespread flaccid paralysis (including ocular and respiratory
muscles), convulsions, coma, pulmonary oedema with copious bronchial secretions,
bronchospasm and cardiac dysrhythmias. Hyperglycaemia and glycosuria occur without
ketonuria.
Plasma cholinesterase activity is usually reduced to < 50% with clinical poisoning and to
< 10% in severe cases.
Management
Supportive measures are vitally important to prevent further absorption according to route
of exposure. Remove soiled clothing and wash contaminated skin with soap and water (see
skin decontamination). Be sure that any cuts on your hands or face are protected. Pesticides
penetrate broken skin more readily than intact skin. Avoid contaminating yourself. Wear
protective clothing. In one report three emergency department staff suffered toxicity requiring
treatment after exposure to a contaminated patient!!
Consider gastric lavage if a substantial amount has been ingested within 1-2 hours. Care
should be taken to protect the airway, particularly if a hydrocarbon solvent is involved or if
consciousness is depressed.
If there is bronchorrhoea and/or bronchospasm give atropine. Very large doses are
occasionally required. An initial intravenous 'test dose' of 1 mg in adults and 0.01 mg/kg in
children provides a measure of severity. The dose of atropine in organophosphate poisoning
is 0.05 mg/kg (2-4 mg in adults) every 15 minutes until full atropinisation is reached. For
maintenance therapy, an intermittent or continuous intravenous infusion of 0.05 mg/kg/hr
may be given. High doses of atropine are sometimes required initially (4-5 mg every 15
minutes).
The criterion of adequate therapy is control of excessive bronchial and oral secretions. In
severe poisoning ensures a clear airway, adequate ventilation and removal of bronchial
secretions. Give high inspired oxygen concentration.
252  Practical Manual of Pharmacology
In moderate or severe poisoning give pralidoxime mesylate (P2S) to reactivate
cholinesterase. Dosage instructions follow. Intravenous diazepam (5-10 mg for an adult, 0.02
mg/kg body weight for a child) will control twitching and may reduce morbidity and
mortality.
In moderate or severe poisoning give pralidoxime 30 mg/kg by intravenous injection
(over 5-10 minutes) to reactivate cholinesterase—improvement should be apparent within
30 minutes. Repeat doses at 4-6 hourly intervals may be necessary or an intravenous infusion
of 8 mg/kg/hour can be given. Atropine administration should be initiated as soon as possible.
Close observation during this stage is essential, as rebound effects of organophosphate
toxicity (due to their lipid solubility) may occur.
Parameters to monitor
Presence of hypersecretion, ECG, pupil size, blood pressure and pulse, serial measurement
of vital capacity (preferred to peak flow measurements) to detect respiratory insufficiency,
and plasma cholinesterase. Normal levels of plasma cholinesterase are 3000-8500 U/L in
adults.
Although cholinesterase reactivators such as obidoxime are widely regarded as valuable
adjuvants in the early management of moderate to severe organophosphate poisoning (if
given within 24 hours of exposure), it is not clear if their use alters the outcome. Therapy
should be in conjunction with atropine and other supportive measures.
Cholinesterase reactivators, e.g. obidoxime, are contraindicated in carbamate poisoning.
Several complications may follow organophosphate poisoning:
• Since most of these substances have a petroleum base, aspiration may cause a chemical
aspiration pneumonitis.
• Potential toxicity of the vehicle should be taken into account.
• Ventricular arrhythmias (with a prolonged QT interval) may occur.
• Confusion and convulsions, due to the effects of the organophosphate or to excess
atropine, are best controlled with diazepam.
• Aminoglycosides and succinylcholine should be avoided in organophosphate poisoning
because of their blocking effect on the neuromuscular junction.
• Phenothiazines, reserpine and theophylline are also contraindicated.
OBJECTIVES
At the end of the session the student will be able to:
1. List the general supportive measures to be extended to a patient with poisoning.
2. Understand the principles of treatment of a patient with poisoning.
3. List the steps in the management of a patient with:
(a) Organophorous poisoning.
(b) Opioid poisoning.
CHAPTER
30
Objective Structured
Practical Examination (OSPE)
One of the most important aspects of training of a doctor is acquisition of practical skills.
Objective assessment of practical (psychomotor skills) is thus a challenge for examiners.
OSPE is a method of examination which evaluates student's wide range of skills uniformly
and objectively. An OSPE consists of a number of predetermined stations (spots) through
which each student rotates. An examiner (observer) may be present on each spot to score the
student's performance using a predetermined checklist or scoring is done after conduct of
OSPE.
OSPE fulfills all the requirements of a good evaluation method
1. Validity—it measures what it is supposed to measure.
2. Reliability—
Is the examination objective assessment?
Are results accurate and consistent?
There is same station and predetermined checklist, so interobserver variation is
decreased to minimum. The difference in marks obtained in OSPE is because of ability
of the student, rather than due to extraneous factors.
3. Feasibility
Is it feasible to put into practice? The requirements for the staff and accommodation can
be met. It can cope with sufficient no. of students. If 1 minute is given for each station,
in total 50 minutes you can objectively examine 50 students.
So, in nutshell OSPE is a form of practical examination which is objective and which owes
its objectivity to a structured marking scheme. The OSPE converts subjectivity into objectivity,
leading to fair and equal evaluation of students.
Approximately 20-50 spots can be chosen for OSPE. They can be from all branches of
pharmacology, for example:
Problem based therapeutics
Problem based drug interaction
Prescription correction
Correct use of inhaler
254  Practical Manual of Pharmacology
Filling injection from vial
Calculate pharmacokinetic parameter, e.g. Vd
Calculation of dose
Identify instrument/apparatus
Indication of a drug combination
New drug delivery system
Pharmacy preparation
Dosage forms, etc.
Hence, there is wide inexpensive variety of spots you can choose in your department.
The various spots can be put serial wise in a room. There can be a list of questions for that
spot on each serial number. You need to appoint observers and give them a check list for
observatory spots, e.g. correct use of inhaler.
The various spots can be:
1. Starling heart lever:
a. Identify.
b. Where it is used?
c. Write 1 advantage over simple lever.
2. Frontal writing lever
a. Identify.
b. Where it is used?
c. Write 1 advantage over simple lever.
3. Inhaler
a. Identify.
b. Write 2 indications.
c. Demonstrate how it is used.
4. Lignocaine 2%
a. Identify.
b. Write 2 indications.
c. Write 1 adverse effect.
5. Calculate Vd
a. Plasma conc. 20 mg/L.
b. Drug administered 1000 mg.
c. Write 1 clinical significance of Vd.
6. Advertisement of a drug
a. Write 2 good points of this advertisement.
b. Write 2 bad points of this advertisement.
Objective Structured Practical Examination (OSPE)  255
7. Combination of amoxycillin and clavulanic acid
a. Write 1 advantage of this combination.
b. Write 2 adverse effects of this combination.
8. Fill in the blanks from the sample given
a. Manufacturing date----------b. IP means----------------------9. Vial of heparin
a. Write 1 indication.
b. Write 2 adverse effects of this.
10. Skin patch of diclofenac
a. Write 1 advantage of this.
b. Write 1 adverse effect of this combination.
11. Combination of amoxycillin and clavulanic acid
a. Write 1 advantage of this combination.
b. Write 2 adverse effects of this combination.
12. Informed consent form
a. Write 1 reason why it is used in clinical studies in humans.
b. Informed consent in clinical trials is mandatory True/False.
13. IV set
a. Identify.
b. Write 2 drug given by this.
14. Rotahaler
a. Write 1 advantage of this.
b. Write 2 adverse effects of this.
c. How it is used?
15. Analgesiometer
a. Which drugs are screened by this instrument?
b. Which animals are used in this experiment?
16. Set up iv infusion on given model
a. Write name of 2 drugs given by this route.
17. Inject im in given model
a. Write name of 2 drugs given by this route.
18. Inject iv in given model
a. Write name of 2 drugs given by this route.
19. Aspirate drug from ampoule.
20. Reconstitute solution for injection.
256  Practical Manual of Pharmacology
21. Ciprofloxacin strip
a. Write 2 brand names of this drug.
b. Which is the cheapest brand?
22. OPC poisoning
a. Write antidote.
b. What is the dose?
23. A 40-year-old woman had a renal failure. She was not able to stick to a salt and
protein restricted diet. She developed an upper respiratory tract infection and comes
to the hospital breathless, coughing up with purulent sputum. She got edema and her
blood urea is raised. The intern on duty treated the infection with minocycline and
edema with furosemide. After a week patient complaint improved but now she
complained of deafness.
a. What is the reason of deafness?
b. Why was her blood urea raised?
c. What alternate would you choose?
Appendix I
PROPOSED REVISED CURRICULUM
Skills to be acquired in pharmacology practicals as per proposed revised curriculum:
Psychomotor skills
1. Dosage forms: Oral, Parenteral, Topical and Others
2. Routes of drug administration, setting up an intravenous drip—Administer the required
dose of different drug formulations using appropriate devices and techniques (e.g.
hypodermic syringes, inhalers, transdermal patches, etc.)
3. Calculation of drug dosage using appropriate formulae for an individual patient.
4. Sources of drug information—how to retrieve information
5. ADR monitoring—recognize and report adverse drug reactions to suitable authorities.
6. Therapeutic Drug Monitoring—advice and interpret the therapeutic monitoring reports
of important drugs
7. Critical appraisal of drug promotional literature—
a. Analyse critically, drug promotional literature for proprietary preparations, in
terms of the (a) pharmacological actions of their ingredients (b) claims of
pharmaceutical companies (c) economics of use (d) rational or irrational nature of
fixed dose drug combinations
b. Retrieve drug information from appropriate sources, especially electronic resources
8. Essentials of Clinical trials
9. Communicating to patients on the proper use of medication
10. Selection of P drug
11. Prescription writing, prescription auditing and standard treatment protocols—Write a
correct, complete and legible prescription for common ailments including the conditions
in the National Health Programmes
12. Essential drugs list
13. Use of drugs in pregnancy, lactation children and elderly
14. Use of drugs in liver disease and renal disease
258  Practical Manual of Pharmacology
15.
16.
17.
18.
19.
Ethics in clinical trials, therapy
Preparation of test dose for penicillin solution
Preparation and use of oral rehydration solution
Informed Consent Form
Computer assisted learning (CAL).
Attitudes and Communication skills
1. Communicate to patients regarding the optimal use of drug formulations, devices and
storage of medicines.
2. Follow the drug treatment guidelines laid down for diseases covered under the National
Health Programmes and be capable of initiating, monitoring treatment, recording
progress, and assessing outcomes.
3. Motivate patients with chronic diseases to adhere to the line of management outlined
by the health care provider.
4. Appreciate the relationship between cost of drugs and patient compliance.
5. Exercise caution in prescribing drugs likely to produce dependence and recommend
the line of management.
6. Understand the legal aspects of prescribing drugs.
7. Evaluate the ethics, scientific procedures and social implications involved in the
development and introduction of new drugs.
Appendix II
260  Practical Manual of Pharmacology
Appendix III
Schedule of practicals for MBBS 2nd Prof (18 months)
(Effective period 15 months)
Theory Lectures
Practicals
General pharmacology teaching
Clinical pharmacy simultaneously
Pharmacokinetics part of
general pharmacology
ANS
When about to finish ANS
CVS
Antihypertensives
CNS
Chemotherapy
GIT
Endocrinology
Respiratory
Miscellaneous
Pharmacokinetic parameters
in between clinical pharmacy
Continue clinical pharmacy
Introduction to experimental pharmacology
Experimental pharmacology
Effect of drugs on dog BP
Short experiments
Ethics
Introduction to prescription
writing, P drug concept
Prescription examples of ANS, CVS, CNS
ADR, TDM, Therapeutic follow-up,
dose calculation
Drug use in special population,
new drug development
Promotional literature, drug interactions,
rest of prescriptions and analysis
of prescriptions
Formulation evaluation, ethics
Revision
Appendix IV
ESSENTIAL DRUG LIST (INDIA) 2003
The names of drugs are followed by the following letters to indicate their need at various
levels of medical care:
P-Primary health care
S-Secondary health care
T-Tertiary health care
U-Universal.
The information is given as:
• Name of the Drug Category
• Medicine Category
• Route of Administration/ Strengths
• Dosage Form.
1. ANAESTHETICS
1.1 General anaesthetics and
Ether
Halothane
Isoflurane*
Ketamine HCl
Nitrous Oxide
Oxygen
Thiopentone Na
0.5%, 0.5% + 7.5% Glucose
1.2 Local Anaesthetics
Bupivacaine HCL
Ethyl Chloride
Lignocaine HCl
* Complementary
Oxygen
S, T
S, T
S, T
U
U
U
S, T
S, T
Inhalation
Inhalation
Inhalation
Injection 10 mg/ml 50 mg/ml
Inhalation
Inhalation
Injection 0.5 g, 1 g powder
Injection 0.25%
U
U
Spray 1%
Topical Forms 2-5%
Appendix IV  263
Injection 1-2%
Spinal 5% + 7.5% Glucose
Lignocaine HCl + Adrenaline U
Injection 1%, 2% +
adrenaline 1:200,000 in vial
1.3 Preoperative medication and sedation for short term procedures
Atropine Sulphate
U
Injection 0.6 mg/ml
Diazepam
U
Tablets 5 mg Injection 5 mg/ml
Midazolam
U
Injection 1 mg/ml 5 mg/ml
Morphine Sulphate
S, T
Injection 10 mg/ml
Promethazine
U
Syrup 5 mg/5 ml
1.4 Postoperative respiratory stimulant
Doxapram*
T
Injection 4 mg/ml
2. ANALGESICS, ANTIPYRETICS, NSAIDS, MEDICINES IN GOUT AND
RHEUMATOID DISORDERS
2.1 Non-opioid analgesics, antipyretics and nonsteroidal antiinflammatory medicines
Acetyl Salicylic Acid U Tablets 300-350 mg
Diclofenac
T
Tablets 50 mg, 100 mg
Injection 25 mg/ml
Ibuprofen
U
Tablets 200 mg, 400 mg
Paracetamol
U
Injection 150 mg/ml
Syrup 125 mg/5ml
Tablets 500 mg
2.2 Opioid Analgesics
Morphine Sulphate
S, T
Injection 10 mg/ml
Tablets 10 mg
Pentazocine
S, T
Tablets 25 mg,
Injection 30 mg/ml
Pethidine HCl
S, T
Injection 50 mg/ml
2.3 Medicines used to treat Gout
Allopurinol
S, T
Tablets 100 mg
Colchicine
S, T
Tablets 0.5 mg
2.4 Disease modifying agents used in rheumatoid disorders
Azathioprine
S, T
Tablets 50 mg
Chloroquine Phosphate
S, T
Tablets 150 mg
Methotrexate
S, T
Tablets 2.5 mg
Sulfasalazine
S, T
Tablets 500 mg
* Complementary
264  Practical Manual of Pharmacology
3. ANTIALLERGICS AND MEDICINES USED IN ANAPHYLAXIS
Adrenaline Bitartrate
U
Chlorpheniramine Maleate
U
Dexchlorpheniramine Maleate
Dexamethasone
U
Hydrocortisone Sodium Succinate
U
Pheniramine Maleate
U
Prednisolone
S
Promethazine
U
Injection 1 mg/ml
Tablets 4 mg
Syrup 0.5 mg/5 ml
Tablets 0.5 mg
Injection 4 mg/ml
Injection 100 mg
Injection 22.75 mg/ml
Tablets 5 mg
Tablets 10 mg, 25 mg
Syrup 5 mg/5 ml
4. ANTIDOTES AND OTHER SUBSTANCES USED IN POISONINGS
4.1 Nonspecific
Activated Charcoal
U
Atropine Sulphate
U
4.2 Specific
Antisnake Venom
U
solution/ Lyophilyzed Polyvalent serum
Calcium Gluconate
S,T
Desferrioxamine Mesylate
S, T
Dimercaprol
S, T
Flumazenil*
T
Methylthioninium Chloride (Methylene blue)
S, T
Naloxone
S, T
Penicillamine
S, T
Pralidoxime Chloride (2-PAM)
S, T
Sodium Nitrite
S, T
Sodium Thio
S, T
Powder
Injection 0.6 mg/ml
Injection Polyvalent
Injection 100 mg/ml
Injection 500 mg
Injection in oil 50 mg/ml
Injection 0.1 mg/ml
Injection 10 mg/ml
Injection 0.4 mg/ml
Tablets or Capsules 250 mg
Injection 25 mg/ml
Injection 30 mg/ml
Injection 250 mg/ml
5. ANTIEPILEPTICS
Carbamazepine
U
Diazepam
U
* Complementary
Tablets 100 mg, 200 mg
Syrup 20 mg/ml
Injection 5 mg/ml
Appendix IV  265
Magnesium Sulphate
Phenobarbitone
Phenytoin Sodium
T
U
ST
U
Sodium Valproate
U
Injection 500 mg /ml
Tablets 30 mg, 60 mg
Injection 200 mg/ml
Capsules or Tablets 50 mg, 100 mg,
Syrup 25 mg/ml,
Injection 50 mg/ml
Tablets 200 mg, 500 mg
Syrup 200 mg/5 ml
6. ANTIINFECTIVES
6.1 Anthelminthics
6.1.1 Intestinal Anthelminthics
Albendazole
U
Mebendazole
U
Niclosamide
Pyrantel Pamoate
U
U
6.1.2 Antifilarials
Diethylcarbamazine Citrate U
6.1.3 Antischistosomals and Antitrematode
Praziquantel
S, T
6.2 Antibacterials
6.2.1 Beta lactam medicines
Amoxicillin
U
Ampicillin
U
Benzathine Benzylpenicillin
Benzylpenicillin
Cefotaxime*
Ceftazidime*
Ceftriaxone*
Cefuroxime*
Cloxacillin
U
U
S, T
S, T
S, T
S, T
U
* Complementary
Tablets 400 mg
Suspension 200 mg/5 ml
Tablets 100 mg
Suspension 100 mg/5 ml
Chewable Tablets 500 mg
Tablets 250 mg
Suspension 250 mg/5 ml
Tablets 50 mg
Tablets 600 mg
Powder for suspension 125 mg/5 ml,
Capsules 250 mg, 500 mg
Capsules 250 mg, 500 mg
Powder for suspension 125 mg/5 ml
Injection 500 mg
Injection 6 lacs, 12 lacs, 24 lacs units
Injection 5 lacs,10 lacs units
Injection 125, 250, 500 mg
Injection 250 mg, 1g
Injection 250 mg, 1 g
Injection 250 mg, 750 mg
Capsules 250 mg, 500 mg
266  Practical Manual of Pharmacology
Procaine Benzylpenicillin
U
(1 lac units) +Procaine penicillin (3 lacs units)
6.2.2 Other antibacterials
Amikacin*
S, T
Azithromycin*
S, T
Injection 250 mg, Liquid 125 mg/5 ml
Injection Crystalline penicillin
Injection 250 mg/2 ml
Capsules or Tablets 100 mg,
250 mg, 500 mg
Suspension 100 mg/5 ml
Injection 500 mg
Cephalexin*
U
Syrup 125 mg/5 ml
Capsules 250 mg, 500 mg
Clarithromycin*
S, T
Capsules 500 mg
Chloramphenicol
S, T
Injection 1 g
S, T
Suspension 125 mg/5 ml
S, T
Capsules, Tablets 250 mg, 500 mg
Ciprofloxacin HCl
U
Injection 200 mg /100 ml
Tablets 250 mg, 500 mg
Co-Trimoxazole
U
Tablets 40 + 200 mg
(Trimethoprim 80 + 400 mgSulphamethoxazole) Suspension 40 +200 mg/5 ml
Doxycycline
U
Capsules 100 mg
Erythromycin Estolate
U
Syrup 125 mg/5 ml
Tablets 250 mg, 500 mg.
Gentamicin
U
Injection 10 mg/ml 40 mg/ml
Metronidazole
U
Tablets 200 mg, 400 mg
Injection 500 mg /100 ml
Nalidixic Acid
U
Tablets 250 mg, 500 mg
Nitrofurantoin
U
Tablets 100 mg
Norfloxacin
U
Tablets 400 mg
Roxithromycin*
S, T
Tablets 50 mg, 150 mg
Sulphadiazine*
S, T
Tablets 500 mg
Tetracycline
U
Tablets or Capsules 250 mg
Vancomycin HCL*
T
Injection 500 mg, 1 g
6.2.3 Antileprosy
Clofazimine
S, T
Capsules 50 mg, 100 mg
Dapsone
U
Tablets 50 mg, 100 mg
Rifampicin
U
Capsules or Tablets 150, 300 mg
* Complementary
Appendix IV  267
6.2.4 Antituberculosis medicines
Ethambutol
U
Isoniazid
U
Ofloxacin*
S, T
Pyrazinamide
U
Rifampicin
U
Streptomycin Sulphate
Thiacetazone + Isoniazid
6.3 Antifungal medicines
Amphotericin
Clotrimazole
Fluconazole
Flucytosine
Griseofulvin
Ketoconazole
Nystatin
U
S, T
B S, T
U
S, T
S, T
U
S, T
U
6.4 Antiviral medicines
6.4.1 Antiherpes medicines
Acyclovir*
S, T
Tablets 200 mg, 400 mg, 600 mg, 800 mg
Tablets 50 mg, 100 mg, 300 mg
Tablets 100 mg, 200 mg
Syrup 50 mg/5 ml
Tablets 500 mg, 750 mg, 1000 mg,
1500 mg
Capsules/Tablets 50 mg, 150 mg,
300 mg, 450 mg
Syrup 100 mg/5 ml
Injection 0.75 g, 1 g
Tablets 150 mg + 300 mg
Injection 50 mg
Pessaries 100 mg,200 mg Gel 2%
Capsules or Tablets 50 mg,
100 mg, 150 mg, 200 mg
Capsules 250 mg
Capsules or Tablets 125,250 mg
Tablets 200 mg
Tablets 500,000 IU
Pessaries 100,000 IU
Tablets 200 mg, 400 mg
Injection 250 mg, 500 mg
Suspension 400 mg/5 ml
6.4.2 Antiretroviral medicines*
6.4.2.1 Nucleoside reverse transcriptase inhibitors
Didanosine*
S, T
Tablets 250 mg, 400 mg
Lamivudine*
S, T
Tablets 150 mg
Lamivudine +Nevirapine + Stavudine*
S, T
Tablets 150 mg + 200 mg + 30 mg
Lamivudine + Zidovudine* S, T
Tablets 150 mg + 300 mg
Stavudine*
S, T
Capsules 15 mg, 30 mg, 40 mg
Zidovudine*
S, T
Tablets 100 mg, 300 mg
* Complementary
268  Practical Manual of Pharmacology
6.4.2.2 Non-nucleoside reverse transcriptase inhibitors
Efavirenz*
S, T
Capsules 200 mg, 600 mg
Nevirapine*
S, T
Capsules 200 mg
Suspension 50 mg/5 ml
6.4.2.3 Protease inhibitors
Indinavir*
S, T
Capsules 200 mg, 400 mg
Nelfinavir*
S, T
Capsules 250 mg
Ritonavir*
S, T
Capsules 100 mg
Syrup 400 mg/ml
Saquinavir*
S, T
Capsules 200 mg
6.5 Antiprotozoal
6.5.1 Antiamoebic and antigiardiasis
Diloxanide Furoate
U
Tablets 500 mg
Metronidazole
U
Tablets 200 mg, 400 mg
Injection 500 mg/100 ml
Tinidazole
U
Tablets 500 mg
6.5.2 Antileishmaniasis
Amphotericin
B S, T
Injection 50 mg
Pentamidine Isothionate
S, T
Injection 200 mg
Sodium Stibogluconate
S,T
Injection 100 mg/ml
6.5.3 Antimalarial medicines
6.5.3.1 For curative treatment
Artesunate
T
Injection 60 mg
Chloroquine Phosphate base U
Tablets 150 mg
Injection 40 mg/ml, Syrup 50 mg/5 ml
Primaquine
U
Tablets 2.5 mg, 7.5 mg
Pyrimethamine
U
Tablets 25 mg
Quinine Sulphate
U
Tablets 300 mg
S, T
Injection 300 mg/ml
Sulfadoxine + Pyrimethamine U
Tablets 500 mg + 25 mg
6.5.3.2 For Prophylaxis
Chloroquine Phosphate base U
Tablets 150 mg
Syrup 50 mg/5 ml
6.5.4 Antipneumocystosis and Antitoxoplasmosis
Co-Trimoxazole (Trimethoprim+ Sulphamethoxazole)
U
Tablets 40 + 200 mg, 80 mg + 400 mg
Suspension 40 + 200 mg/5 ml
* Complementary
Appendix IV  269
Pentamidine Isothionate
Trimethoprim
S, T
U
Injection 200 mg
Tablets 100 mg
7. ANTIMIGRAINE MEDICINES
7.1 For Treatment of acute attack
Acetyl Salicylic Acid
U
Dihydroergotamine
S, T
Paracetamol
U
7.2 For prophylaxis
Propranolol HCl
U
Tablets 300 - 350 mg
Tablets 1 mg
Tablets 500 mg
Tablets 10 mg, 40 mg
8. ANTINEOPLASTIC, IMMUNOSUPPRESSIVES AND MEDICINES
IN PALLIATIVE CARE
8.1 Immunosuppressive medicines
Azathioprine*
T
Cyclosporine
T
8.2 Cytotoxic medicines
Actinomycin D*
Alpha Interferon*
Bleomycin*
Busulphan*
Cisplatin*
Cyclophosphamide*
T
T
T
T
T
T
Cytosine Arabinoside*
T
Danazol*
Doxorubicin*
Etoposide*
T
T
T
Flutamide*
5-Fluorouracil*
Folinic Acid*
Gemcitabine HCl*
L- Asparaginase*
Melphalan*
T
T
T
T
T
T
* Complementary
Tablets 50 mg
Capsules 10 mg, 25 mg, 50 mg, 100 mg
Concentrate for Injection 100 mg/ml
Injection 0.5 mg
Injection 3 million IU
Injection 15 mg
Tablets 2 mg
Injection 10 mg/vial 50 mg/vial
Tablets 50 mg
Injection 200 mg, 500 mg
Injection 100 mg/vial
500 mg/vial, 1000 mg/vial
Capsules 50 mg,100 mg
Injection 10 mg, 50 mg
Capsules 100 mg
Injection 100 mg/5 ml
Tablet 250 mg
Injection 250 mg/5 ml
Injection 3 mg/ml
Injection 200 mg, 1 g
Injection 10000 KU
Tablets 2 mg, 5 mg
270  Practical Manual of Pharmacology
Mercaptopurine*
T
Methotrexate*
T
Mitomycin-C*
T
Paclitaxel*
T
Procarbazine*
T
Vinblastine Sulphate*
T
Vincristine
T
8.3 Hormones and antihormones
Prednisolone*
S, T
Raloxifene*
T
Tamoxifen Citrate*
T
8.4 Medicines used in palliative care
Morphine Sulphate*
T
Ondansetron*
S, T
Tablets 50 mg,
Injection 100 mg/ml
Tablets 2.5 mg
Injection 50 mg/ml
Injection 10 mg
Injection 30 mg/5 ml
Capsules 50 mg
Injection 10 mg
Injection 1 mg/ml
Tablets 5 mg
Injection 20 mg 25 mg (as sodium
phosphate or succinate)
Tablets 60 mg
Tablets 10 mg, 20 mg
Tablets 10 mg
Tablets 4 mg, 8 mg
Injection 2 mg/ml
Syrup 2 mg/5 ml
9. ANTIPARKINSONISM MEDICINES
Bromocriptine Mesylate
Levodopa+ Carbidopa
S, T
U
Trihexyphenidyl HCl
U
Tablets 1.25 mg, 2.5 mg
Tablets 100 mg + 10 mg,
250 mg + 25 mg, 100 mg + 25 mg
Tablets 2 mg
10. MEDICINES AFFECTING BLOOD
10.1 Antianemia medicines
Cyanocobalamin
Ferrous Salt
U
U
Oral solution 25 mg elemental
iron (as sulphate)/ml
Folic Acid
U
Iron Dextran
S, T
Pyridoxine
U
* Complementary
Injection 1 mg/ml
Tablets Equivalent to 60 mg elemental
iron
Tablets 1 mg, 5 mg
Injection 50 mg iron/ml
Tablets 5 mg
Appendix IV  271
10.2 Medicines affecting coagulation
Acenocoumarol 4 mg
Heparin Sodium
S, T
Menadione Sodium Sulphite S, T
Protamine Sulphate
S, T
Phytomenadione
S, T
Warfarin Sodium
S, T
Injection 1000 IU/ml 5000 IU/ml
Tablets 10 mg
Injection 10 mg/ml
Injection 10 mg/ml
Tablets 5 mg
11. BLOOD PRODUCTS AND PLASMA SUBSTITUTES
11.1 Plasma substitutes
Dextran-40
U
Injection 10%
Dextran-70
U
Injection 6%
Fresh Frozen Plasma*
T
Injection
Hydroxyethyl Starch (Hetastarch)
S, T
Injection 6%
Polygeline
S, T
Injection 3.5%
11.2 Plasma fractions for specific use
Albumin
S, T
Injection 5%, 20%
Cryoprecipitate
S, T
Injection
Factor VIII Concentrate*
S, T
Injection Dried
Factor IX Complex (Coagulation Factors II,VII, IX, X)
* S, T
Injection Dried
Platelet Rich Plasma
S, T
Injection
12. CARDIOVASCULAR MEDICINES
12.1 Antianginal medicines
Acetyl Salicylic Acid*
Diltiazem
Glyceryl Trinitrate
U
S, T
U
Isosorbide 5 Mononitrate/Dinitrate
U
Metoprolol*
U
Propranolol
* Complementary
U
Tablets 75 mg, 100 mg, 350 mg
Tablets 30 mg, 60 mg
Sublingual Tablets 0.5 mg,
Injection 5 mg/ml
Tablets 10 mg, 20 mg
Tablets 25 mg, 50 mg
Injection 1 mg/ ml
Tablets 10 mg, 40 mg
Injection 1 mg/ml
272  Practical Manual of Pharmacology
12.2 Antiarrhythmic medicines
Adenosine*
S, T
Amiodarone
S, T
Bretylium Tosylate*
Diltiazem
Diltiazem
Esmolol*
Isoprenaline HCl*
Lignocaine HCl
Mexiletine HCL
T
S, T
T
T
T
S, T
S, T
Procainamide HCl
T
Quinidine
Verapamil
T
S, T
12.3 Antihypertensive medicines
Amlodipine
U
Atenolol
U
Chlorthalidone*
U
Clonidine HCl*
S, T
Enalapril Maleate
U
Injection 3 mg/ml
Tablets 100 mg, 200 mg
Injection 150 mg
Injection 1 mg, 2 mg 4 mg/ml
Tablets 30 mg, 60 mg
Injection 5 mg/ml
Injection 10 mg/ml
Injection 2 mg/ml
Injection 1%, 2%
Capsules, 50 mg,150 mg
Injection 25 mg/ml
Tablets 250 mg
Injection 100 mg/ml*
Tablets 100 mg
Tablets 40 mg, 80 mg
Injection 2.5 mg/ml
Tablets 2.5 mg, 5 mg,10 mg
Tablets 50 mg, 100 mg
Tablets 25 mg, 50 mg
Tablets 100 mg, 150 mg
Tablets 2.5,5,10 mg
Injection 1.25 mg/ml
Losartan Potassium*
S, T
Tablets 25, 50 mg
Methyldopa
U
Tablets 250 mg
Nifedipine
S, T
Capsules 5, 10 mg
tablets 10 mg, 20 mg, Sustained release capsules 10 mg, or tablets 20 mg,
Propranolol
U
Tablets 10 mg, 40 mg
Sodium Nitroprusside*
T
Injection 50 mg/ 5 ml
Terazosin*
S, T
Tablets 1, 2, 5 mg
12.4 Medicines used in heart failure
Digoxin
S, T
Tablets 0.25 mg
Injection 0.25 mg/ml
Elixir 0.05 mg/ml
Dobutamine*
S,T
Injection 50 mg/ml
Dopamine HCl
S,T
Injection 40 mg/ml
* Complementary
Appendix IV  273
12.5 Antithrombotic medicines
Acetyl Salicylic Acid
U
Heparin Sodium*
S, T
StreptokinaseST Injection 750,000,15,00,000IU,
Urokinase
T
Tablets 75, 100 mg
Injection 1000, 5000 IU/ml
Injection 500,000 IU/ml
10,00,000 IU/ml
13. DERMATOLOGICAL MEDICINES (TOPICAL)
13.1 Antifungal medicines
Benzoic Acid + Salicylic Acid
Miconazole
13.2 Antiinfective medicines
Acyclovir
Framycetin Sulphate
Methylrosanilinium Chloride
U
U
Ointment or Cream 6% + 3%
Ointment or Cream 2%
S, T
Cream 5%
U
Cream 0.5%
(Gentian Violet)
U
Aqueous solution 0.5%
Neomycin+Bacitracin
U
Ointment 5 mg + 500 IU
Povidone Iodine
U
Solution or Ointment 5%
Silver Nitrate
U
Lotion 10%
Silver Sulphadiazine
U
Cream 1%
13.3 Antiinflammatory and antipruritic
Betamethasone Dipropionate U
Cream/Ointment 0.05%
Calamine
U
Lotion
13.4 Astringent medicines
Zinc Oxide
U
Dusting Powder
13.5 Medicines affecting skin differentiation and proliferation
Coal Tar
U
Solution 5%
Dithranol*
T
Ointment 0.1-2%
Glycerin
U
Solution
Salicylic Acid
U
Solution 5%
13.6 Scabicides and pediculicides
Benzyl Benzoate
U
Lotion 25%
Gamma Benzene Hexachloride
U
Lotion 1%
* Complementary
274  Practical Manual of Pharmacology
14. DIAGNOSTIC AGENTS
14.1 Ophthalmic medicines
Fluorescein
Lignocaine
Tropicamide
14.2 Radiocontrast media
Barium Sulphate
Calcium Ipodate
Iopanoic Acid
Meglumine Iothalamate
S, T
S, T
S, T
Eye drops 1%
Eye drops 4%
Eye drops 1%
S,
S,
S,
S,
Suspension 100% w/v 250% w/v
Injection 3 g
Tablets 500 mg
Injection 60% w/v
(iodine = 280 mg/ml)
Solution 5-8 g
iodine in 100-250 ml
Oily, suspension 500-600 mg/ml
Injection 70% w/v
(Iodine = 420 mg/ml)
T
T
T
T
Meglumine Iotroxate
S, T
Propyliodone
Sodium Iothalamate
S, T
S, T
Sodium Meglumine Diatrizoate
S, T
Injection 60% w/v(Iodine conc. = 292
mg/ml) 76% w/v
(Iodine conc. = 370 mg/ml)
15. DISINFECTANTS AND ANTISEPTICS
15.1 Antiseptics
Acriflavin+Glycerin
Benzoin Compound
Cetrimide
Chlorhexidine
Ethyl Alcohol 70%
Gentian Violet
Hydrogen Peroxide
Povidone Iodine
15.2 Disinfectants
Bleaching Powder
Formaldehyde IP
Glutaraldehyde
Potassium Permanganate
U
U
U
U
U
U
U
U
Solution
Tincture
Solution 20% (conc. for dilution)
Solution 5% (conc. for dilution)
Solution
Paint 0.5%, 1%
Solution 6%
Solution 5%, 10%
U
U
S,T
U
Powder
Solution
Solution 2%
Crystals for solution
Appendix IV  275
16. DIURETICS
Furosemide
U
Hydrochlorothiazide
Mannitol*
Spironolactone
U
U
U
Injection, 10 mg/ ml,
Tablets 40 mg
Tablets 25 mg, 50 mg
Injection 10%, 20%
Tablets 25 mg
17. GASTROINTESTINAL MEDICINES
17.1 Antacids and other antiulcer medicines
Aluminium Hydroxide + Magnesium Hydroxide
U
Tablet Suspension
Omeprazole
U
Capsules 10, 20, 40 mg
Ranitidine HCl
U
Tablets 150, 300 mg
Injection 25 mg/ml
17.2 Antiemetics
Domperidone
U
Tablets 10 mg
Syrup 1 mg/ml
Metoclopramide
U
Tablets 10 mg
Syrup 5 mg/ml
Injection 5 mg/ml
Prochlorperazine
U
Tablets 5, 25 mg
Promethazine
U
Tablets 10 mg, 25 mg
Elixir or Syrup 5 mg/5 ml
Injection 25 mg/ml
17.3 Antihaemorrhoidal medicines
Local Anaesthetic, Astringent and Antiinflammatory Medicines
U
Ointment/suppository
17.4 Antiinflammatory medicines
Sulfasalazine
T
Tablets 500 mg
17.5 Antispasmodic medicines
Dicyclomine HCl
U
Tablets 10 mg
Injection 10 mg/ml
Hyoscine Butyl Bromide
U
Tablets or 10 mg
Injection 20 mg/ml
17.6 Laxatives
Bisacodyl
U
Tablets/suppository 5 mg
Isphaghula
U
Granules
* Complementary
276  Practical Manual of Pharmacology
17.7 Medicines used in diarrhoea
17.7.1 Oral rehydration salts
U
17.7.2 Antidiarrhoeal medicines
Furazolidone
S, T
Loperamide*
S, T
(Contraindicated for paediatric use)
Powder for solution As per IP
Tablets 100 mg
Syrup 25 mg/5 ml
Capsules 2 mg
18. HORMONES, OTHER ENDOCRINE MEDICINES AND CONTRACEPTIVES
18.1 Adrenal hormones and synthetic substitutes
Dexamethasone
S, T
Tablets 0.5 mg
Injection 4 mg/ml
Hydrocortisone Sodium Succinate
U
Injection 100 mg/ml
Methylprednisolone
S, T
Injection 40 mg/ ml
Prednisolone
U
Tablets 5 mg, 10 mg
18.2 Androgens
Testosterone
T
Capsules 40 mg (as undecanoate)
T
Injection 25 mg/ml (as propionate)
18.3 Contraceptives
18.3.1 Hormonal contraceptives
Ethinylestradiol + Levonorgesterol
U
Tablets 0.03 mg + 0.15 mg
Ethinylestradiol + Norethisterone
U
Tablets 0.035 mg + 1.0 mg
Hormone Releasing IUD
T
Levonorgesterol Releasing IUD
18.3.2 Intrauterine devices
IUD containing Copper
U
18.3.3 Barrier mMethods
Condoms
U
18.3.4. Non hormonal contraceptives
Centchroman
U
Tablets 30 mg
18.4 Estrogens
Ethinylestradiol
U
Tablets 0.01, 0.05 mg
* Complementary
Appendix IV  277
18.5 Antidiabetics and hyperglycaemics
18.5.1 Insulins and other antidiabetic Agents
Glibenclamide
U
Tablets 2.5 mg, 5 mg
Insulin Injection (Soluble)
U
Injection 40 IU/ml
Intermediate Acting Insulin (Lente/NPHInsulin)
U
Injection 40 IU/ml
Metformin
U
Tablets 500 mg
18.5.2 Hyperglycaemics
Glucagon*
T
Injection 1 mg/ml
18.6 Ovulation inducers
Clomiphene Citrate*
T
Tablets 25, 50, 100 mg
18.7 Progestogens
Medroxy Progesterone Acetate
U
Tablets 5, 10 mg
Norethisterone
U
Tablets 5 mg
18.8 Thyroid and antithyroid medicines
Carbimazole
S, T
Tablets 5 mg, 10 mg
Levothyroxine
S, T
Tablets 0.1 mg
Iodine
S, T
Solution 8 mg/5 ml
19. IMMUNOLOGICALS
19.1 Diagnostic agents
Tuberculin, Purified Protein Derivative
U
19.2 Sera and Immunoglobulins
Anti-D S, Immunoglobulin(Human)
T
Antisnake Venom
U
Antitetanus Human Immunoglobin
U
Diphtheria Antitoxin
S, T
Rabies Immunoglobulin
U
19.3 Vaccines
19.3.1 For universal immunisation
BCG Vaccine
U
DPT Vaccine
U
Hepatitis B vaccine
U
* Complementary
Injection
Injection 250, 300 mg
Injection 10 ml
Injection 250 IU, 500 IU
Injection 10,000 IU
Injection 150 IU/ml
Injection
Injection
Injection
278  Practical Manual of Pharmacology
Measles Vaccine
U
Oral Poliomyelitis Vaccine (Live Attenuated)
U
19.3.2 For Specific group of individuals
Rabies Vaccine
U
Tetanus Toxoid
U
Injection
Solution
Injection
Injection
20. MUSCLE RELAXANTS (PERIPHERALLY ACTING) AND CHOLINESTERASE
INHIBITORS
Atracurium Besylate*
Neostigmine
S, T
S, T
Pancuronium Bromide
Pyridostigmine Bromide
S, T
S, T
Succinyl Choline Chloride
S,T
Injection 10 mg/ml
Tablets 15 mg
Injection 0.5 mg/ml
Injection 2 mg/ml
Tablet 60 mg
Injection 1 mg/ml
Injection 50 mg/ml
21. OPHTHALMOLOGICAL PREPARATIONS
21.1 Antiinfective Agents
Chloramphenicol
U
Ciprofloxacin HCl
U
Gentamicin
U
Miconazole
U
Povidone Iodine
S, T
Sulphacetamide Na
U
Tetracycline HCl
U
21.2 Antiinflammatory agents
Prednisolone Acetate
U
Prednisolone Sodium Phosphate
U
Xylometazoline
U
21.3 Local anaesthetics
Tetracaine HCl
U
21.4 Miotics and antiglaucoma medicines
Acetazolamide
S, T
Betaxolol HCl
S, T
Physostigmine Salicylate*
S, T
* Complementary
Drops/Ointment 0.4%, 1%
Drops/Ointment 0.3%
Drops 0.3%
Drops 1%
Drops 0.6%
Drops 10%, 20%, 30%
Ointment 1%
Drops 0.1%
Drops 1%
Drops 0.05%, 0.1%
Drops 0.5%
Tablets 250 mg
Drops 0.25%, 0.5%
Drops 0.25%
Appendix IV  279
Pilocarpine
S, T
Timolol Maleate
S, T
21.5 Mydriatics
Atropine Sulphate
U
Homatropine
U
Phenylephrine
U
21.6 Ophthalmic Surgical Aids
Methyl Cellulose*
T
Drops 2%, 4%
Drops 0.25%, 0.5%,
Drops/Ointment 1%
Drops 2%
Drops 5%
Injection 2%
22. OXYTOCICS AND ANTIOXYTOCICS
22.1 Oxytocics
Methyl Ergometrine
Mifepristone
Oxytocin
22.2 Antioxytocics
Isoxsuprine HCl
Terbutaline Sulphate
U
T
S, T
S, T
S, T
Tablets 0.125 mg
Injection 0.2 mg/ml
Tablets 200 mg
Injection 5, 10 IU/ml
Tablets 10 mg
Injection 5 mg/ml
Tablets 2.5 mg
Injection 0.5 mg/ml
23. PERITONEAL DIALYSIS SOLUTION
Intraperitoneal Dialysis Solution (of approximate composition)
24. PSYCHOTHERAPEUTIC MEDICINES
24.1 Medicines used in psychotic disorders
Chlorpromazine HCl
U
Haloperidol
S, T
Tablets 25, 50, 100 mg
Syrup 25 mg/5 ml
Injection 25 mg/ml
Tablets 1.5, 5, 10 mg
Injection 5 mg/ml
Tablet 5 mg, 10 mg
Trifluoperazine
S, T
24.2 Medicines used in mood disorders
24.2.1 Medicines used in depressive disorders
Amitriptyline
U
Tablets 25 mg
Fluoxetine HCl
U
Capsules 20 mg
Imipramine
U
Tablets 25 mg, 75 mg
* Complementary
280  Practical Manual of Pharmacology
24.2.2 Medicines used in bipolar disorders
Lithium Carbonate T Tablets 150 mg
24.3 Medicines used for generalized anxiety and sleep disorders
Alprazolam
U
Tablets 0.25, 0.5 mg
Diazepam
U
Tablets 2, 5, 10 mg
Nitrazepam
U
Tablets 5 mg, 10 mg
24.4 Medicines used for obsessive compulsive disorders and panics attacks
Clomipramine HCl
S, T
Tablets 10, 25 mg
25. MEDICINES ACTING ON THE RESPIRATORY TRACT
25.1 Antiasthmatic medicines
Aminophylline
U
Beclomethasone Dipropionate U
Hydrocortisone Sodium Succinate
U
Salbutamol Sulphate
U
Theophylline Compounds
25.2 Antitussives
Codeine Phosphate
Dextromethorphan
U
U
U
Injection 25 mg/ml
Inhalation 50 mg, 250 mg/dose
Injection 100, 200, 400 mg
Tablets 2 mg, 4 mg
Syrup 2 mg/5 ml
Inhalation 100 mg/dose
Tablets 100, 200 mg
Tablets 10 mg
Syrup 15 mg/5 ml
Tablets 30 mg
26. SOLUTIONS CORRECTING WATER, ELECTROLYTE AND ACID-BASE
DISTURBANCES
26.1 Oral
Oral Rehydration Salts
U
Powder for Solution
As per IP
26.2 Parenteral
Glucose
U
Injection 5% isotonic
50% hypertonic
Glucose with Sodium Chloride
U
Normal Saline
U
N/2 Saline
S, T
N/5 Saline
S, T
Potassium Chloride
U
Injection 5% + 0.9%
Injection 0.9%
Injection
Injection
Injection 11.2% Sol.
Appendix IV  281
Ringer Lactate
Sodium Bicarbonate
26.3 Miscellaneous
Water for Injection
U
U
Injection
Injection
U
Injection 2, 5, 10 ml
27. VITAMINS AND MINERALS
Ascorbic Acid
Calcium salts
Multivitamins
U
U
U
Tablets 100, 500 mg
Tablets 250, 500 mg
Tablets
(Having composition as per schedule v of drugs and cosmetics act, 1940)
Nicotinamide
Pyridoxine
Riboflavine
Thiamine
Vitamin A
U
U
U
U
U
Vitamin D 3 (Ergocalciferol)
S, T
Tablets 50 mg
Tablets 25 mg
Tablets 5 mg
Tablets 100 mg
Tablets 5000 IU,
Capsules 10,000 IU 50,000 IU
Injection 50,000 IU/ml
Capsules 0.25 mg, 1 mg
Terminologies Used in Pharmacology
PHARMACOLOGY
Pharmacology is the science that deals with study of drugs and their action on living
organisms. It consists of detailed study of drugs, including their actions on living animals,
organs or tissues. The actions may be beneficial or harmful.
Pharmacology is combination of two words:
Pharmacon = an active principle (drug)
Logos
= a discourse or treatise
DRUG
The name is derived from Drogue, a French word (means Dry herb). The name is derived
from the fact that most of the drugs earlier were obtained by drying plant or animal parts.
Definition of Drug
According to WHO “A drug is any substance/product that is used/ intended to be used to
modify/explore physiological systems/pathological states for benefit of the recipient.”
Drug is also defined as any chemical substance which is used for prevention, treatment
or diagnosis of a disease.
Examples:
• Antibiotics for treatment of infection
• Vaccines for prevention of disease
• Radioactive iodine for diagnosis of thyroid cancer.
Branches of Pharmacology: Pharmacology has expanded to much wider areas, so now it
has a number of branches or subdivisions.
PHARMACY
It is the art of preparing, compounding and dispensing drugs in such a way so as to make the
medication suitable for easy, effective and palatable administration in the treatment of a
disease.
284  Practical Manual of Pharmacology
Experimental Pharmacology
It is the study of drugs in animals. It usually involves research on animals using drugs.
Clinical Pharmacology
It is the scientific study of drugs in human being. It includes clinical trials/studies of new
drugs in human beings, identifying and reporting adverse drug reactions, rational drug use
and essential drug concept. This area of pharmacology is most demanding these days. With
the shift of a number of clinical trials of new drugs to India, the training, demand and
recruitment has increased tremendously in clinical pharmacology.
CLINICAL PHARMACY
It deals with patient care with particular emphasis on drug therapy. In practice it is patient
oriented and includes not only the dispensing of required drug but also giving advice to the
patient on the proper use of all drugs, both prescribed and over the counter drugs. It usually
utilizes the services of a pharmacist as an information source for members of the medical and
other health professions on all matters pertaining to drugs and their dosage forms. This
practice is quite common and also mandatory in developed countries. In India it has just
started in few metropolitan cities. A number of good pharmacy stores have come up in
major cities in India, which are following all aspects of clinical pharmacy.
Molecular Pharmacology
It deals with study of actions of drugs at molecular level.
Pharmacodynamics
It is the study of action of drugs on the body (what the drug does to the body).
Pharmacokinetics
It is the study of absorption, distribution, metabolism and excretion (ADME) of drugs (what
the body does to the drug).
Pharmacognosy
It is the study of identification of source and physical properties of natural medicinal
substances, i.e. drugs obtained from plants.
Pharmacotherapeutics
It is a branch of medicine concerned with the cure of disease or relief of symptoms using
drugs. (It deals with the use of drugs in clinical practice). It is also called Drug therapy or
pharmacotherapy.
Poison
A poison is a substance which when absorbed or ingested into the body may alter physiology
to a mild or a critical extent by damaging body tissues or cells.
Terminologies Used in Pharmacology  285
TOXICOLOGY
It is the science of poisons dealing with their detection, measurement and management of
poisons. (Poisons are substances that cause harmful, dangerous or fatal symptoms in animals
and human beings.)
Pharmaceutics
It is an adjective which means pertaining to pharmacy. It deals in technique of calculation,
preparation and dispensing required dosage forms.
Pharmaceutical chemistry
It is the application of organic and inorganic chemistry to pharmaceutics and relation of
these principles to drug use.
Pharmacoeconomics
It involves the cost of drug therapy, including those of purchasing, dispensing (e.g. salaries
of pharmacists, pharmacy technicians), storage, administration (e.g. salaries of nurses, costs
of supplies), laboratory, other tests used to monitor client responses and losses from
expiration. Length of illness or hospitalization is also considered.
Pharmacovigilance
It involves adverse drug event monitoring, detection, reporting and remedial measures.
Index
A
C
Acute abdomen 126
Acute asthma 120
Acute attack of migraine 128
Acute gouty arthritis 137
Acute severe asthma 121
Adverse drug reaction (ADR) 178
types 178
augmented 178
bizarre 178
continues use 178
delayed 179
end of dose 179
Adverse effects of drugs on mice
using rota rod apparatus 96
Allergic conjunctivitis 129
Analgesic effect of drugs on rats
using tail flick method 94
Anemia (microcytic hypochromic)
118
Angina pectoris 119
Animal toxicity studies 98
Antidepressant effect of drugs
on mice 95
Antipsychotics and tricyclic
antidepressants 197
Aphthous ulcer 154
Aspirate drug from ampoule
into syringe 41
requirements 41
technique 41
Aspirate drug from vial into
syringe 42
requirements 42
technique 42
AUC 106
Autonomic nervous
system pharmacology 74
Calculation of drug doses and
dilutions 223
Cerebral malaria 143
Chloroquine resistant malaria 142
Chloroquine sensitive malaria 141
Chronic simple glaucoma 153
Clark’s rule 195
Clearance 109
clinical significance 110
salient features 109
Commercial preparations of drugs 13
Common errors in prescription
writing 157
Conversion between systems 8
Creams 61
advantage 61
disadvantage 61
Cytochrome P450 isoenzymes 165
B
Bipolar disorder 148
D
Depression 147
Dilator pupillae 75
Dissolve dry medicine in vial aspirate
drug solution into syringe 43
requirements 43
technique 43
Domestic weights and measures 8
Dosage adjustment and plasma level
monitoring 200
Dosage forms for injections 40
Drug characteristics 36
Drug interaction 162
pharmaceutical 162
pharmacokinetic 163
Drug nomenclature 16
Drug schedules 18
Drugs and solutions used in dog BP
experiment 91
Drugs and solutions used in rabbit
intestine experiment 87
Drugs classified into various
categories 14
over-the counter (OTC)
drugs 14
prescription-only drugs 14
Drugs on the rabbit eye 75
drugs and solutions 76
procedure 76
corneal reflex 77
light reflex 77
size of pupil 76
requirements 76
Drugs schedules and acts 17
Dusting powder 59
advantages 60
disadvantages 60
Dysmenorrhoea 127
E
Ear drops 55
advantage 55
disadvantage 55
procedure 56
Effect of drugs on dog BP 92
Effect of drugs on frog heart 80
Effect of drugs on rabbit intestine 88
Effect of drugs on rats using hole
board test 97
Erectile dysfunction 152
Essential drug concept 234
implementation 234
purpose 234
selection criteria 234
Essential drug list (India) 2003 262
anaesthetics 262
general anaesthetics and
oxygen 262
local anaesthetics 262
288  Practical Manual of Pharmacology
analgesics, antipyretics, NSAIDs,
medicines in gout and
rheumatoid disorders
263
disease modifying agents
used in rheumatoid
disorders 263
medicines used to treat
gout 263
non-opioid analgesics,
antipyretics and
nonsteroidal antiinflammatory
medicines 263
opioid analgesics 263
antiallergics and medicines used
in anaphylaxis 264
antidotes and other substances
used in poisonings 264
antiepileptics 264
antiinfectives 264
antimigraine medicines 269
antineoplastic immunosuppressives and medicines
in palliative care 269
antiparkinsonism medicines 270
blood products and plasma
substitutes 271
cardiovascular medicines 271
dermatological medicines
(topical) 273
diagnostic agents 274
disinfectants and antiseptics 274
diuretics 275
gastrointestinal medicines 275
hormones, other endocrine
medicines and
contraceptives 276
immunologicals 277
medicines acting on the
respiratory tract 280
medicines affecting blood 270
muscle relaxants (peripherally
acting) and cholinesterase
inhibitors 278
ophthalmological preparations
278
oxytocics and antioxytocics 279
peritoneal dialysis solution 279
psychotherapeutic medicines
279
solutions correcting water,
electrolyteand acid-base
disturbances 280
vitamins and minerals 281
Ethical criteria for drug promotion
211
Ethics 238
principles 238
Ethics and humans 238
Evaluation of drug formulations 232
Eye drops 54
advantages 54
disadvantages 54
procedure 54
Eye ointment 55
advantage 55
disadvantage 55
procedure 55
F
Factors affecting drug disposition in
children 194
Factors affecting oral route of
administration 35
Facts about frog heart 81
FDA (USA) schedules 18
Food-drug interactions 167
Formulations 10
Fried’s rule 195
G
Generalized tonic clonic and partial
seizures 146
Genetic variations 204
Golden rules in treatment of
elderly 198
H
Half-life 108
clinical significance 109
salient features 108
Hepatic amoebiasis 133
Hepatic disease 201
first pass metabolism 201
hepatic blood supply 201
prodrugs 201
Herpes zoster 130
Hypertension (essential
hypertension with no
associated disease) 122
I
Imperial system 7
apothecary system (UK)/troy
system 8
avoirdupois system 7
Importance of ethics 100
Inject drugs subcutaneously 47
procedure 48
requirements 48
Injection by intramuscular route 46
procedure 46
requirements 46
Injections by intramuscular route in
an orange model 46
procedure 46
requirements 46
Injections by intravenous route 43
procedure 43
requirements 43
Inscription 113
Insomnia 151
Instruments in pharmacy 4
containers 5
dispensing balance 4
measuring cylinders and flask 4
mortar and pestle 4
pill tile 5
spatulas 5
wash bottle 5
weights 4
Intestinal amoebiasis 134
L
Label 19
primary label 19
secondary label 19
Liniments 60
advantage 60
disadvantage 60
procedure 60
Loading dose 110
maintenance dose 111
Local anaesthetics (Las) 79
Local-inhalation 62
advantages 63
care of for the rotahaler 64
Index  289
disadvantages 63
procedure (for rotahaler) 64
procedure for correct use
(for MDI) 63
Local-oral 64
gargles and mouthwashes 64
advantage 65
disadvantage 65
procedure 65
Lotions 60
advantage 60
disadvantage 60
procedure 60
M
Medical journals 210
Metabolism 164
Metric system 7
Miotics and mydriasis 78
classification 78
indications 78
Model for IV injections for students
in laboratory 44
general principles 44
requirements 44
Multibacillary leprosy 138
Myasthenia gravis 150
N
Naranjo algorithm 179
Nasal drops 56
advantage 56
disadvantages 56
procedure 56
Nasal sprays 56
advantages 56
disadvantage 56
procedure 57
NDDS-oral 66
advantages 66
prodrugs 66
New drug development 219
New techniques for drug delivery 65
NIDDM 125
O
Objective structured practical
examination (OSPE) 253
Ointments 60
advantages 61
disadvantages 61
procedure 61
Oral candidiasis (thrush) 131
Oral-capsules 32
advantages 33
disadvantages 33
type 32
hard gelatin type 32
soft gelatine type 32
Oral-liquids 34
advantages 34
disadvantages 34
Oral-pills 33
advantages 33
disadvantages 33
Oral-powder 33
advantages 33
disadvantages 33
Oral-special preparations 36
coated preparations 36
sustained release (SR)
preparations 37
advantages 37
disadvantages 37
Oral-tablets 31
disadvantages 32
Organization of ADR monitoring
system in India 183
P
Paints 61
advantage 62
disadvantage 62
Parameters of prescription audit 159
Parenteral 40
intravenous injections (IV)
advantages 41
disadvantages 41
Parenteral-IM 45
intramuscular injections 45
advantages 45
disadvantages 45
precautions 45
Parenteral-intradermal injection 48
epidural injections 48
intra-arterial injections 48
intra-articular injections 49
intra-thecal injections 48
Parenteral-SC 46
advantages 47
disadvantages 47
Parenteral-sublingual 49
advantages 49
disadvantages 49
Parenteral-transdermal 49
advantages 51
disadvantages 51
types 50
matrix controlled 50
membrane controlled 50
sandwich type 50
Parkinsonism 149
Patient consent document 240
Paucibacillary leprosy 139
Peptic ulcer 124
Pharmaceutical calculations 8
percent calculation 8
percent by volume (%v/v) 9
percent by weight (%w/w) 9
percent weight in volume
(%w/v) 8
proportion calculation 9
Pharmaceutical containers 6
Pharmacopoeia 16
Poisoning with drugs 246
aspirin and other salicylates 248
clinical features 248
management 248
methanol 249
clinical features 249
management 249
OPC poisoning 251
clinical features 251
management 251
opioid poisoning 247
clinical features 247
management 248
paracetamol poisoning 246
clinical features 246
management 246
tricyclic antidepressants (TCAs)
250
clinical features 250
management 250
Postmarketing methods 180
case control studies
(retrospective) 181
case reports 181
cohort studies 181
prescription event monitoring
181
spontaneous reporting-yellow
card system 181
Premarketing clinical trails 180
290  Practical Manual of Pharmacology
Prepare and dispense 1:5000 solution
of potassium permanganate 24
adverse effects 26
labeling 25
pharmacological actions 25
procedure 24
storage conditions 25
therapeutic uses 25
Prepare and dispense 25 ml of
Mandle’s throat paint 23
labeling 23
pharmacological actions 24
iodine 24
potassium iodide 24
precautions 24
procedure 23
therapeutic uses 24
Prepare and dispense 50 ml of
calamine lotion 21
labeling 22
pharmacological actions 22
bentonite 22
calamine 22
glycerine 22
liquefied phenol 22
sodium citrate 22
zinc oxide 22
precautions 23
procedure 21
therapeutic uses 23
Prepare and dispense one dose of oral
rehydration powder for 1000 ml
of oral rehydration
solution (ORS) 26
home made ORS 28
new WHO ORS 29
objective of ORS 26
pharmacological action of
salts 27
glucose 27
sodium chloride 27
pharmacological actions 27
precautions 29
procedure 26
reduced osmolarity ORS 29
super-ORS 28
therapeutic uses 28
WHO formula (for 1 litre ORS)
26
Prescription 112
Primary syphilis 135
Principles of ethics 100
Process of pharmacokinetics 104
absorption of drugs 104
distribution of drugs 104
elimination of drugs 104
bioavailability 104
clinical significance 105
salient features 105
metabolism of drugs 104
R
Rational drug 233
Rectal 37
advantages 37
disadvantages 38
Renal diseases 202
Routes of drug administration 11
S
Source of drug information 208
Sources of drugs 30
animals 30
biosynthetic 30
microorganisms 30
minerals 30
plants 30
semisynthetic 30
synthetic 30
Special need for ADR monitoring
in India 182
Special toxicity studies 99
Sphincter pupillae 75
Sprays 61
advantage 61
disadvantage 61
Starling heart lever 80
Status epilepticus 123
Subscription 113
Suppositories 57
advantages 57
disadvantages 57
procedure 58
Suspected adverse drug reaction
reporting form 260
Sustained vs. controlled release 66
Syme’s cannula 80
Symposia/conferences 210
T
Terminologies used in pharmacology
283
Therapeutic drug monitoring (TDM)
187
characteristics 187
cost-effective 192
indications 188
steps 188
dosage adjustment 190
drug estimation methods 189
interpretation of plasma
concentration data 189
time of sampling 188
TDM procedure 191
antiepileptic drugs
(AED) 191
carbamazepine 192
phenobarbitone 192
phenytoin 191
Therapeutic follow-up cases/
problems 215
Time of drug administration 10
Tips for writing a good prescription
159
Tuberculosis 140
Typhoid 136
U
Upper respiratory tract infection 144
V
Vaginal candidiasis (vulvovaginitis)
132
Vaginal pessaries 58
advantages 58
disadvantages 58
procedure 58
Volume of distribution (VD) 106
W
Written informed consent 240
Y
Young’s formula 195