General Pharmacology
Dr Nasim Ullah Siddiqui
What is Pharmacology?
• Pharmacology:
– Pharmacon (drugs) + Logos (studies)
– The study of drugs
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Drugs & Medicines
• Drugs:
– Any substance that, when absorbed into the
body of a living organism, alters (changes)
normal body function
– Examples:
•
•
•
•
•
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aspirin,
Antibiotics,
Nicotine,
alcohol,
Marijuana….
Drugs & Medicines
• Medicines:
– In pharmacology, a drug is a chemical
substance used in the:
• treatment, cure, prevention, or diagnosis of
disease
• Or used to enhance physical or mental wellbeing
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Drugs & Medicines
• Drug is called medicine when used in
proper dosage form for safe
administration
• All medicines are drugs but all drugs are
not medicines
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Clinical / Experimental
• Clinical Pharmacology
– deals with the study of drug effects in
humans beings, i.e. healthy volunteers and
patients
• Experimental Pharmacology
– deals with the study of drug effects in
laboratory animals
• In vitro – Isolated tissue
• In vivo – Intact organism
Definitions
• Toxicology:
– deals with adverse (undesired) reactions of
drugs & their treatment
• Pharmacogenetics:
– How genetics influence the mode of drug
actions (e.g.. Metabolism) and biological
variations of drug responses
Definitions
• Pharmacogenetics is generally regarded as the
study or clinical testing of genetic variation
that gives rise to differing response to drugs.
• Pharmacogenetics
refers
to
genetic
differences in metabolic pathways which can
affect individual responses to drugs, both in
terms of therapeutic effect as well as adverse
effects.
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Definitions
• Pharmacokinetics:
– How the body handles the drug
– Includes absorption, distribution ,
biotransformation, and elimination
• Pharmacodynamics:
– How drug handles the body
– Deals with the biochemical and
physiological effects of drugs on man
Definitions
Receptors
• Biochemical receptors are large protein
molecules that can be activated by the binding
of a ligand (such as a hormone or drug).
• Receptors can be membrane-bound, occurring
on the cell membrane of cells, or intracellular,
such as on the nucleus or mitochondrion.
Binding occurs as a result of noncovalent
/covalent interaction between the receptor and
its ligand, at locations called the binding site on
the receptor.
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Definitions
• Potency is a measure of drug activity
expressed in terms of the amount required to
produce an effect of given intensity.
• A highly potent drug (e.g., morphine) evokes
a larger response at low concentrations.
• while a drug of lower potency (acetylsalicylic
acid) evokes a small response at low
concentrations
• It is proportional to affinity and efficacy
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Definitions
• Affinity is the ability of the drug to bind to a
receptor.
• Efficacy is the relationship between receptor
occupancy and the ability to initiate a response
at the molecular, cellular, tissue or system level.
• The response is equal to the effect(E), and
depends on both the drug binding and the drugbound receptor then producing a response;
thus, potency depends on both affinity and
efficacy.
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Definitions
• The agonist (ligand, drug or hormone)
that binds to the receptor and initiates
the response.
• The less the concentration of a drug is
required to produce 50% of maximum
effect and the higher the potency.
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Definitions
• A receptor antagonist is a type of receptor ligand or
drug that does not provoke a biological response
itself upon binding to a receptor, but blocks or
dampens agonist-mediated responses.
• The majority of drug antagonists achieve their
potency by competing with endogenous ligands or
substrates at structurally-defined binding sites on
receptors.
• Antagonists have affinity but no efficacy for their
receptors, and binding will disrupt the interaction
and inhibit the function of an agonist at receptors.
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Antagonist
• Antagonist activity may be reversible or irreversible
depending on the longevity of the antagonist–receptor
complex, which, in turn, depends on the nature of antagonist
receptor binding.
• Physiological antagonists, substances that have opposing
physiological actions, but act at different receptors. For
example, histamine lowers arterial pressure through
vasodilation at the histamine H1 receptor, while adrenaline
raises arterial pressure through vasoconstriction mediated by
β-adrenergic receptor activation.
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Definitions
• Tachyphylaxis : Rapidly developed tolerance is
tachyphylaxis, is a medical term describing a
decrease in the response to a drug due to previous
exposure to that drug.
• Caused by depletion or marked reduction of the
amount of neurotransmitter responsible for creating
the drug's effect, or by the depletion of receptors
available for the drug or neurotransmitter to bind to.
Examples: Amphetamine, ephedrine (indirectly
acting drugs)
• Tachyphylaxis is characterized by the rate sensitivity
i.e, a high-intensity prolonged stimulus or oftenrepeated stimulus may bring about a diminished
response also known as desensitization.
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Definitions
• Physiological tolerance or drug tolerance is a
subject's reaction to a drug (such as an opiates
painkiller, benzodiazepine drug) is reduced at a later
time even though the dose or concentration at the
effect site is the same.
• This means that larger doses are required to achieve
the same effect.
• Drug tolerance can involve both psychological &
physiological drug tolerance factors.
• It is reversible
• Physiological tolerance occurs after repeated
exposure .
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Definitions
• Idiosyncrasy (idiosyncratic drug reaction)
denotes a non-immunological hypersensitivity
to a substance, without connection to
pharmacological toxicity.
• Is an individual based on a specific condition
of the one who suffers it. Most commonly, this
is caused by an enzymopathy, congenital or
acquired.
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Drugs actions
• Drug actions are mediated by 3 ways:
1. Acting on somatic or psychic processes or
functions
2. Correction of deficiencies
3. Toxic action on pathogenic microorganism
Ideal drug effects
• Drug effects should be:
– Selective
– Temporary
– Dose-related (controllable)
– Show close relationship with bioavailability
Drug Responses
• How are drug responses produced?
• By interaction with active binding sites
called RECEPTORS
– Drug may be agonist or antagonist for the
receptors
Nature of drugs
• Physical:
– Solid (aspirin)
– Liquid (nicotine, ethanol)
– Gas (nitrous oxide)
• Chemical structure:
– Protein, lipid, carbohydrate
– To be weak acid or weak base
– Amine (primary, secondary, tertiary, ..)
Sources of drugs
• Natural from:
– Plants
– Animals / Humans
– Micro-organisms
– Minerals
– Inorganic metals
• Semi-synthetic
• Synthetic
• Bio-synthetic
Sources of drugs
Natural from Plants:
• Active principles are found in roots, leaves
and seeds in 2 forms:
– Glycoside, e.g
• Cardiac glycoside Digoxin ( from the Foxglove plant)
– Alkaloid, e.g
• Morphine (from Poppy capsules),
• Atropine (from Belladonna leaves)
• Quinine (from bark of Cinchona tree)
– Castor oil (from castor seed)
Sources of drugs
Natural from animals / humans:
• Hormones:
– Heparin from Pig or Ox liver,
– Insulin from Pig or Ox pancreas
– Gonadotrophins from urine of pregnant
women
• Plasma or serum from blood
• Thyroxin from Pig or Ox thyroid gland
• Cod Liver Oil from Cod fish Liver
Sources of drugs
Natural from micro-organisms:
• Antibiotics:
– Penicillin from Penicillium notatum,
– Streptomycin from Streptomyces griseus,
– Bacitracin from Bacillus
Sources of drugs
Minerals:
• Calcium, Magnesium, Aluminium,
Sodium, Potassium & Iron salts,
• Liquid paraffin from petroleum.
Inorganic metals:
• Iodine,
• Lithium,
• Radioactive elements: I131
Sources of drugs
Semi synthetic drugs:
• Prepared by chemical modification of
natural drugs in labs.
– Ampicillin from Penicillin-G,
– Semisynthetic cephalosporin's from 7amino cephalosporinic acid
Sources of drugs
Synthetic Drugs:
• Prepared by chemical synthesis
pharmaceutical laboratories
– Sulphonamides
– Salicylates
– Barbiturates
– Benzodiazepines
in
Sources of drugs
Bio-Synthetic Drugs:
• Prepared by cloning of human DNA into
bacteria like E.Coli.
Sources of drugs
Bio-Synthetic Drugs:
• Technique is called Recombinant DNA
technology or Genetic Engineering
– Cells from animals or human that produce active
substance
– Isolation of DNA
– Transfer to bacteria (E-coli) by plasmids (Gene cloning)
– A new E-coli synthesizes the new substance
– Cloning of ‘new’ E-Coli means production of identical
subjects like parent
Sources of drugs
Bio-Synthetic Drugs:
• Examples: Human Insulin's, Human
Growth Hormones, Human BCG vaccine ,
Human Hepatitis B Vaccine
Criteria for drug classification
1. Chemical structure:
– Cholinesters,
– Organophosphates,
– Catecholamine's
2. Location of action:
– Cardiac glycosides,
– Autonomic drugs
Criteria for drug classification
3.
Purpose of medication:
–
–
–
–
4.
Antihypertensive
Diuretic
Antiemetic
Analgesic
Name of plant:
– Opium alkaloids
– Cardiac glycosides
– Belladonna alkaloids
Prescription / Over the counter
• Drugs fall into two distinct categories:
1)Those that require a physician’s prescription to
obtain (Rx)
2)Those that can be purchased over-the counter
(OTC)
• both are regulated by the regulatory
authorities
Pharmacotherapy
• Employment of drugs for the prevention and
treatment of diseases
• Its scope:
1.
2.
3.
Indications
Contraindications
Drug interactions
• Therapy:
– Radical (full healing)
– Symptomatic (treatment of symptoms only)
– Prophylactic (e.g. contraception, vaccine)
Therapeutic Index
• Therapeutic Index (TI):
– Toxic dose / Effective dose
• Indicates the relative safety of a drug
• Examples:
– Acetominophen : 27
– Valium: 3
– Methotrexate, vincristine: 1
• Narrow TI indicates the need for frequent
blood tests to monitor drug levels
Mechanism of Action
• Agonist:
– drug mimics an endogenous substance that
would normally stimulate a receptor
• Antagonist:
– drug which binds a receptor site, doesn't
stimulate it, but blocks other substances
from stimulating it
Drug Nomenclature
Most drugs have at least three names:
1. Chemical name
2. Generic name (Official, Approved)
3. Proprietary name (Trade name,
Company name)
Drug Nomenclature
1. Chemical name
– The chemical composition and structure
Drug Nomenclature
2. Generic name (Official, Approved)
– is usually the abbreviated form of the
chemical name
– this name is used and chosen by official
bodies
Drug Nomenclature
3. Proprietary name (Trade name,
Company name)
– the name given by the company which
markets the drug
– It is the commercial property of a
pharmaceutical company
– It indicates a particularly formulation of a
particular substance by a particularly
manufacturer
Drug Nomenclature
• Since several companies market the same
drug under different proprietary names,
unnecessary confusion may arise
• Whenever possible drugs should be
prescribed by their approved names
– Chemical name:
• Acetyl-p-aminophenol
– Official name:
• Paracetamol
– Proprietary name:
• Panadol, Calpol, Adol, Fevadol
Routes of Drug Administration
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Routes of Drug Administration
• Factors Deciding Choice of Route
1. Type of described effect, systemic or local
2. Physiochemical properties, solid or
insoluble
3. Rapidity of effect, oral, intramuscular (IM),
intravascular (IV)
4. Condition of patient, conscious or
unconscious, vomiting
Topical Application - Mucous Membrane
• Conjunctiva, nasopharynx , oropharynx,
vagina, urethra, urinary bladder, ear, nose,
anal canal for local / systemic effects
• Absorption rapid
• Local anesthetic for local effects rapidly
absorbed, produce systemic toxicity
• Types:
– ointment, cream, drops, jelly, powder, tablet,
suppository, pessary
Topical Application - Skin
• Absorption- depends on
– surface area, lipid solubility
• Few drugs readily penetrate skin
• Burned, denuded, abraded, inflamed skin
increase systemic absorption
• Toxicity by highly lipid soluble
insecticides
• Controlled- release by topical patches
Topical Application - Injection
• Intra articular (in joint)
– hydrocortisone
• Intra thecal into subarachnoid space of L2-3
or L3-4,
– Local anaesthetics
• Subcutaneous (under skin)
– Local anaesthetics
• Intra arterial
– anticancer drugs in limbs cancer
Systemic Routes
• Enteral through GIT
– Orally
– Buccal or sublingual
– Rectal
• Parental
– Intravenous (IV)
– Intramuscular (IM)
– Subcutaneous (SC)
– Transdermal Therapeutic system (TTS)
– Inhalation
Oral Ingestion /Swallowing
• Tablets, capsules, powder, syrup, mixture
suspension or emulsion
• Absorption variable
• Most conventional, economical, more safe
and acceptable to patient
• Absorption delayed, reduced after food
• Not good for some drugs:
– Gentamicin not absorbed
– Insulin destroyed in gut
Oral Ingestion /Swallowing
• Absorption from stomach
intestine is affected by:
and
upper
– Surface area,
– Blood flow to site of absorption,
– Physical state: (solid, solution, suspension),
– Water solubility,
– Concentration at the site of absorption,
– Rate of dissolution,
– Rate of disintegration,
– Particle size
Sublingual
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•
•
•
Good, readily available
Systemic effect
Quick
Example of a clinically useful drugs:
– Nitroglycerine
Rectal Administration
• Used when recurrent vomiting or
unconscious
• 50% absorbed drug bypass liver
• Absorption incomplete, irregular in lower
rectum by external haemorrhoidal veins
• Example:
– indomethcin, steroids, soap water & barium
sulphate as enema
• Inconvenient & embarrassing
• Rectal inflammation occurs
Intravenous
• Advantages:
– Rapid reach and response
– Life-saving in critical conditions (Blood, IV
fluids)
• Disadvantages / Precautions
– Careful of too quick infusion
– Anaphylactic shock
– Can not withdraw medication once given
• Example:
– Blood transfusion, Antibiotics for rapid effect
Intramuscular
• Advantages:
– Quick absorption and response
– Easy to learn
• Disadvantages / Precautions
– Possible infection, or injury to nerve
– Could not retrieve
– Painful
• Example:
– Pain killer (Pethidine)
Subdermal
• Advantages:
– Slow control release
– Easy accessibility
– Less painful
• Disadvantages / Precautions
– Not very effective
– Not good if circulation not effective
– Collapsed hypotensive patients
• Example:
– Insulin (bypasses digestion)
Inhalation Drug Administration
• Most common types:
– Volatile liquids, gaseous anaesthetics and
therapeutics gases
– Metered dose aerosol inhaler
• e.g. salbutamol
– Compressed air driven nebulised solution
inhaler
Inhalation Drug Administration
Pulmonary Absorption
• Important route for drugs abuse
• Access to circulation rapid
– large surface area of lungs
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•
•
•
Fine drug droplets in air (aerosol ) inhaled
Instantaneous absorption
Avoids hepatic first-pass loss
Local application at the desired site of action in
pulmonary disease
• Treatment of bronchial asthma Aerosol Delivery
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Inhalation Drug Administration
• Only 2-10 % dose deposited in lungs
• 90 % dose is swallowed
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Pharmacokinetics
• Pharmacokinetics
deal
quantitative study of:
– Absorption
– Distribution
– Biotransformation and
– Excretion of drugs
with
the
Pharmacokinetics
Absorption:
• is the process by which a drug is
transferred from its site of entry to the
volume of distribution
• The rate of absorption affects the
– Onset,
– Duration, and
– intensity of drug action
Factors affecting drug absorption
Drug-related factors:
• Physical state
• Particle size
• Concentration
• Dosage form (preparation)
• Solubility (lipid and water solubility)
• Degree of ionization
Factors affecting drug absorption
Host-related and other factors:
• Transport (absorption) of drug
– Passive transport (e.g. simple diffusion)
– Specialized transport (e.g. active transport)
• Circulation at the site of absorption
• Area of absorbing surface
• Presence of other agents
Drug Distribution
• The process by which a drug leaves the
blood stream and enters the extracellular
fluid and or cells of the tissues
• Depends on:
– Capillary permeability,
– Degree of drug to plasma and tissue
proteins,
– Relative hydrophobicity of the drug
Bioavailability
• Bioavailability of a drug = availability of
biologically active drug
• Is the proportion of the active drug that
reaches the systemic circulation (site of
action) after administration
– Helps in choosing “best drug” and “best
route” of administration
Bioavailability
• The bioavailability of a drug may vary from
one dosage form to another and for the same
dosage form it may vary according to the
pharmaceutical formulation.
• The bioavailability is of great importance in
therapeutics specially in the case of life saving
drugs, antibiotics and drugs with a narrow
margin of safety e.g. anticoagulants.
• Differences in the rate of absorption may
cause patients to be overmedicated or under
medicated.
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Factors Affecting Bioavailability
• Quality Control in Manufacturing and
formulation
• First pass metabolism
• Factors affecting absorption of drugs from
GIT
- These are pH of GIT fluids, area of absorbing
surface, functional integrity of GIT, presence of
food and other substances in stomach, blood
flow, physiochemical properties of the drug.
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Biotransformation
• Chemical alteration which a drug
undergoes within a living organism
• Most of the substance (taken
exogenously or produced endogenously)
need a change in their forms, which
changes their activity (increased,
decreased or become inactive) and make
them available for elimination from liver
and kidney
Biotransformation
Metabolism of drugs may may change
them from:
• Inactive to active
• Active to:
– Less active
– More active
– Inactive
Biotransformation
Metabolism of drugs takes place in various
organs:
• Liver (most important)
• Epithelial cells of GIT
• Lungs
• Kidneys
• skin
• brain
Drug metabolism
Extrahepatic microsomal enzymes
(oxidation, conjugation)
Hepatic microsomal enzymes
(oxidation, conjugation)
Hepatic non-microsomal enzymes
(acetylation, sulfation,GSH,
alcohol/aldehyde dehydrogenase,
hydrolysis, ox/red)
Drug metabolism
Factors affecting drug metabolism:
• Age
• Sex
• Genetic differences
• Nutrition
• Pathological conditions
• Route of administration
• Effect of drug on metabolism
Drug elimination
• The removal of drugs from the body
• may occur from
– Kidneys (most important),
– Bile,
– Intestine,
– Lung,
– Breast,
– Skin
M
A
J
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R
M
I
N
O
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Concept of “Half-Life”
• Time required to metabolize 1/2 of the
original dose of the drug
• Use of this terms helps in determining
how long a drug will remain in the body
Concept of Critical Threshold
• Defined as the minimum level of drug
concentration needed for the desired
therapeutic effect to be present.
Elimination
• Zero order:
– Constant rate of elimination irrespective of
plasma concentration.
• First order:
– Rate of elimination proportional to plasma
concentration. Constant Fraction of drug
eliminated per unit time.
– Rate of elimination ∝ Amount
– Rate of elimination = K x Amount
Plasma Concentration (mg/l)
Zero order elimination
1000
C
100
C/2
10
t1/2
1
0
1
2
3
4
5
6
Time (hr)
t½ is the time for the plasma concentration to reach
half the original, i.e., the half-life of elimination.
First Order Elimination
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12
Plasma concentration
10
C
8
t1/2
6
t1/2
C/2
4
C/4
2
0
0
5
10
TIME (hours)
15
20
Drug elimination
• Elimination of drugs from the body
usually follows first order kinetics with a
characteristic half-life (t1/2) and
fractional rate constant (Kel).
First Order Elimination
• Clearance: volume of plasma cleared of drug
per unit time.
• Clearance = Rate of elimination ÷ plasma
conc.
• Half-life of elimination: time for plasma conc.
to decrease by half.
• Useful in estimating:
– Time to reach steady state concentration
– Time for plasma concentration to fall after
dosing is stopped.
Plasma concentration
Concentration due to repeated
doses (infusion)
Concentration due to a single dose
The time to reach steady state is ~ 4 t1/2’s
Plasma concentration
• Drug concentration in plasma
– Should be maintained within the specific
drug therapeutic range
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Plasma concentration
• Drug concentration in plasma
– Should always be maintained above the
drug sub-therapeutic level
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Plasma concentration
• Drug concentration in plasma
– Should always be maintained below the
specific drug lethal dose level
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Plasma concentration
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Adverse Drug Reactions
• Unwanted or unexpected effects of drug
• Quite common but in most of the cases
they are not serious
• Occasionally they could be so serious as
to endanger life e.g.
– Acute anaphylactic shock with penicillin,
– Severe hypoglycemia after excessive insulin
administration
Adverse Drug Reactions
Adverse Drug Reactions
Adverse Drug Reactions
Adverse Drug Reactions
• Adverse drug effects can be divided into
two groups:
• Predictable Reactions
• Withdrawal symptoms or rebound
responses
Adverse Drug Reactions
Predictable Reactions:
a) Due to excessive pharmacological activity
of the drug
• They are liable to occur with CNS depressants
cardio-active drugs, hypotensive agents and
hypoglycemic drugs
• All patients are at risk of developing this type of
reaction if high doses are given
• Patients with renal disease, liver disease and
extreme of ages are particularly susceptible
Adverse Drug Reactions
Predictable Reactions:
b) Withdrawal symptoms or rebound responses
after discontinuation of treatment
• Crisis may be precipitated by sudden stoppage of
corticosteroid therapy
• Withdrawal symptoms occur after narcotic
analgesics, barbiturates and drugs liable to cause
addiction
• These drugs should be gradually withdrawn to
avoid such mishaps.
Adverse Drug Reactions
Unpredictable Reactions:
– They occur usually infrequently, and are not
dose dependent. They are of following
types:
• Drug allergy: (e.g. to Penicillin)
• Genetically determined: ( e.g. patients with
G6PD deficiency may develop acute hemolytic
anemia after anti-malarial drugs)
• Idiosyncrasy:
(unusual,
unexpected,
unexplained)
Summary: Concept no 1
• Almost ALL DRUGS ARE POISONS
• The only thing that determines if a drug
provides a benefit or kills a patient is
how we administer it
Concept II : Our Therapeutic Goal
• To achieve drug concentrations at the site of
action (target tissue)…that are sufficiently
high enough…to produce the intended effect
without producing adverse drug reactions (or
with minimal adverse reactions)
Summary
What happens after drug administration?
Drug at site of
administration
1. Absorption
Drug in plasma
Drug metabolites
in tissues
3. Metabolism
Drug metabolites
In urine, feces, bile
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