Charles University in Prague, Third Faculty of Medicine
Cycle II, Subject: General
Pharmacology
1st Teaching Unit ID9234
Introduction to pharmacology.
Basic terminology.
Prof. Kršiak
Department of Pharmacology, Third Faculty of Medicine,
Charles University in Prague
WHAT IS PHARMACOLOGY ?
Searches for new drugs
pharmacologists are drug hunters
PHARMACOLOGY
Investigates effects of known drugs
mechanism of action, evidence of effect, adverse reactions,,
fate in the body (absorption, distribution, elimination),
dosage, course of effect …
PHARMACOLOGY x PHARMACY
Pharmacology is the study of effects of drugs
(chemicals) on the functioning of the body
Pharmacy deals with the preparation
(compounding, manufacture), distribution
and supply of medicines
THE AIM OF TEACHING PHARMACOLOGY
1/ To UNDERSTAND how drugs act
(mechanism of action) and general
pharmacological principles
2/ To know how to prescribe a drug
Recommended textbook:
PHARMACOLOGY - Rang H. P., et al.
7th ed. Churchill Livingstone, 2011,
2012 or 6th ed 2007.
https://is.cuni.cz/studium/eng/predmety
Alternative Textbooks
Basic & clinical pharmacology -. Katzung BG 11th ed. - Lange Medi. Books - McGraw-Hill 2009 or
12th ed. 2012
Lippincott‘s Illustrated Reviews Pharmacology. 4th
ed. Howland RD, et al.: 2008 or 5th ed. Harvey R.D. et
al. 2012
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Additional texts for suplementary reading:
Medical Pharmacology at a Glance - M. J. Neal. 6th
ed. Wiley-Blackwell, 2009
Pharmacology Condensed Dale NN, Haylett DG,
2nd ed., Churchill Livingstone, 2009
British National Formulary No. 62 [or higher] - BMJ
Books, September 2011[or more recent editions].
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BASIC TERMS:
[non-proprietary]
(brand, proprietary)
generic names
x
trade names
paracetamol
x
PANADOL, PARALEN, etc
SPC = Summary of Product Characteristics
ATC = Anatomical Therapeutic Chemical (ATC)
Classification of drugs
BNF, AISLP, Micromedex = electronic drug databases
generic drug =copies when patent expires
compliance= adherence to a treatment plan
paracetamol
Proprietary Names Martindale
222 AF (Johnson & Johnson, Canad.) ,4-Way Cold Tablets (Bristol-Myers Products, USA) ,Abajos (Nufarindo, Indon.) ,Abatem (Wermar, Mex.) ,Abdine Cold Relief (Bell,
UK) ,Abenol (Pendopharm, Canad.) ,Abflex (Xeragen, S.Afr.) ,Abrol (Rekah, Israel) ,Abrolet (Rekah, Israel) ,Acamol (Teva, Israel) ,Acamol (Volta, Chile) ,Acamol
Compuesto (Volta, Chile) ,Acamoli (Teva, Israel) ,Acamoli Cold (Teva, Israel) ,Acamol Tsinun Day (Teva, Israel) ,Acamol Tsinun Night (Teva, Israel) ,Acecat (Tiedra,
Spain) ,Acenol (Galena, Pol.) ,Acephen (G & W, USA) ,Acertol (Lacer, Spain) ,Acet (Euro-Med, Philipp.) ,Acet (Pharmascience, Canad.) ,Acet (Pharmascience, Malaysia)
,Acet (Pharmascience, Singapore) ,Acet-2, Acet-3 (Pharmascience, Canad.) ,Aceta (Century, USA) ,Acetab (Romilo, Canad.) ,Acetaco (Legere, USA) ,Acetacol (PP Lab,
Thai.) ,Acetadol (Medi-Rx, Philipp.) ,Acetafen (Infinity, Venez.) ,Acetafen (Rayere, Mex.) ,Aceta-Gesic (Rugby, USA) ,Acetalgine (Streuli, Switz.) ,Acetalis (Proula,
Venez.) ,Acetamil (Ducto, Braz.) ,Acetaminophen, Aspirin, and Caffeine Tablets USP 32,Acetaminophen, Chlorpheniramine Maleate, and Dextromethorphan
Hydrobromide Tablets USP 32,Acetaminophen, Dextromethorphan Hydrobromide, Doxylamine Succinate, and Pseudoephedrine Hydrochloride Oral Solution USP
32,Acetaminophen, Diphenhydramine Hydrochloride, and Pseudoephedrine Hydrochloride Tablets USP 32,Acetaminophen and Aspirin Tablets USP 32,Acetaminophen
and Caffeine Tablets USP 32,Acetaminophen and Codeine Phosphate Capsules USP 32,Acetaminophen and Codeine Phosphate Oral Solution USP 32,Acetaminophen
and Codeine Phosphate Oral Suspension USP 32,Acetaminophen and Codeine Phosphate Tablets USP 32,Acetaminophen and Diphenhydramine Citrate Tablets USP
32,Acetaminophen and Pseudoephedrine Hydrochloride Tablets USP 32,Acetaminophen Capsules USP 32,Acetaminophen Extended-Release Tablets USP
32,Acetaminophen for Effervescent Oral Solution USP 32,Acetaminophen Oral Solution USP 32,Acetaminophen Oral Suspension USP 32,Acetaminophen Suppositories
USP 32,Acetaminophen Tablets USP 32,Acetaminophen with Codeine (Pharmascience, Canad.) ,Acetamol (Abiogen, Ital.) ,Acetamol (Bergamo, Braz.) ,Aceta-P (PP
Lab, Thai.) ,Acetapon (Pharmagen, S.Afr.) ,Acetapyrin-C (PP Lab, Thai.) ,Acetasil (Silom, Thai.) ,Aceta with Codeine (Century, USA) ,Acetazone Forte (Rougier, Canad.)
,Acetazone Forte C8 (Rougier, Canad.) ,Acet Codeine (Pharmascience, Canad.) ,Acetif (Novag, Mex.) ,Acetofen (Medley, Braz.) ,Acetolit (Mertens, Arg.) ,Aceval
(Valmor, Venez.) ,Ac-Fast (Hormona, Mex.) ,Acide acetylsalicylique comp. "Radix" (Streuli, Switz.) ,Acid-X (BDI, USA) ,Acifein (Herbacos, Cz.) ,Aclophen (Nutripharm,
USA) ,Actidue (Pfizer Consumer, Ital.) ,Actifed (Pfizer Sante, Fr.) ,Actifed-A (Wellcome, Canad.) ,Actifed Cold & Fever (GSK, S.Afr.) ,Actifed Cold & Sinus (WarnerLambert, USA) ,Actifed jour et nuit (Pfizer Sante, Fr.) ,Actifed Plus (GSK, India) ,Actifed Plus (Pfizer Consumer, Canad.) ,Actifed Plus (Wellcome, USA) ,Actifed Sinus
Daytime (Wellcome, USA) ,Actifed Sinus Nighttime (Wellcome, USA) ,Actiflu Plus (Cipla, India) ,Actigesic (GSK, Indon.) ,Actigrip (Pfizer Consumer, Ital.) ,Actimol
(Pharmed, India) ,Actron (Bayer, Fr.) ,Actron (Bayer, Spain) ,Actron (Bayer, UK) ,Actron Compuesto (Bayer, Spain) ,Acuflu P (Apotex, S.Afr.) ,Acugesil (Apotex, S.Afr.)
,Acurate (Apotex, S.Afr.) ,Acustop (Apotex, S.Afr.) ,Acuten (Farma, Venez.) ,Acxen (Loren, Mex.) ,Adafen (Akdeniz, Turk.) ,Adalgen (Andromaco, Chile) ,Adalgur
(Teofarma, Spain) ,Adalgur N (Angelini, Port.) ,Adco-Dol (Adcock Ingram, S.Afr.) ,Adco-Flupain (Adcock Ingram, S.Afr.) ,Adco-Kiddipayne (Adcock Ingram, S.Afr.) ,AdcoPayne (Adcock Ingram, S.Afr.) ,Adco-Sinal Co (Adcock Ingram, S.Afr.) ,Ado C (Kwizda, Austria) ,Adol (Julphar, UAE) ,Adol Allergy Sinus (Julphar, UAE) ,Adol Cold
(Julphar, UAE) ,Adol Compound (Julphar, UAE) ,Adolef (Biomed, Ital.) ,Adolen (Konsuma, Venez.) ,Adol Extra (Julphar, UAE) ,Adolorin (Kwizda, Austria) ,Adol PM
(Julphar, UAE) ,Adol Sinus (Julphar, UAE) ,Adoluron CC (Kwizda, Austria) ,Adona (Silesia, Chile) ,Aeknil (Therapeutic, Philipp.) ,AF Anacin (Whitehall-Robins, Canad.)
,Afebrin (Konimex, Indon.) ,Afebrin (Westmont, Hong Kong) ,Afebryl (Azevedos, Port.) ,Afebryl (Galephar, Fr.) ,Afebryl (Galepharma, Turk.) ,Afebryl (SMB, Belg.)
,Aferadol (Oberlin, Fr.) ,A-ferin (Bilim, Turk.) ,A-ferin (Bilim, Turk.) ,A-ferin (Bilim, Turk.) ,A-ferin (Bilim, Turk.) ,Afluvit (IPS, Neth.) ,Agrip (Plata, Arg.) ,Agrippin (Bernofarm,
Indon.) ,Agurin (Nolver, Venez.) ,Akindol (Fournier, Fr.) ,Akindol (Fournier, Spain) ,Aknil (Sunthi Sepuri, Indon.) ,Alacetan (Asconex, Ger.) ,Alaxan (United Laboratories,
Philipp.) ,Alaxan PI (Great Eastern, Thai.; Therapharma, Thai.) ,AlbaTemp (Alba, USA) ,Alcinal Plus (Rekah, Israel) ,Aldolor (CTI, Israel) ,Alergical Expect (Juventus,
Spain) ,Alerid Cold (Cipla, India) ,Alex (Glenmark, India) ,Alex-P (Glenmark, India) ,Algafan (Darrow, Braz.) ,Algi-Butazolon (Dovalle, Braz.) ,Algi-Butazolon (Dovalle,
Braz.) ,Algicler (Monserrat, Arg.) ,Algi-Danilon (Allergan-Frumtost, Braz.) ,Algidol (Almirall, Spain) ,Algidol (Sintesa, Belg.) ,Algifen (Sintofarma, Braz.) ,Algifene (Ferraz,
Lynce, Port.) ,Algiflamanil (Neo Quimica, Braz.) ,Algi-Itamanil (Neo Quimica, Braz.) ,Algik (Azevedos, Port.) ,Algine (Adelco, Gr.) ,Alginflan (Teuto, Braz.) ,Alginina
(Upsamedica, Spain) ,Algion (Saval, Chile) ,Algio-Truxa (Raffo, Arg.) ,Algi Peralgin (Infabra, Braz.) ,Algi-Reumac (Windson, Braz.) ,Algi-Reumatril (Hertz, Braz.) ,Algiseda
(Sanitas, Arg.) ,Algisedal (Viatris, Fr.) ,Algisin (Ram, USA) ,Algist (Hoechst Marion Roussel, S.Afr.) ,Algi-Tanderil (Klinger, Braz.) ,Algitrin (Schering-Plough, Mex.)
,Algizolin (Luper, Braz.) ,Algoced (Pharmascience, Fr.) ,Algocod (SMB, Belg.) ,Algofina (Sanamed, Austria) ,Algogen (Nakornpatana, Thai.) ,Algolysin (Teva, Israel)
,Algomen (Menarini, Spain) ,Algon (Lavipharm, Gr.) ,Algophene (SMB, Belg.) ,Algopirina (Medisint, Ital.) ,Algostadol N (Stada, Ger.) ,Algostase (SMB, Belg.) ,Algostase
Mono (SMB, Belg.) ,Algotropyl (Alpharma, Fr.) ,Alikal Dolor (GSK, Arg.) ,Alipal Forte (Arex, Venez.) ,Alivax (Vivax, Venez.) ,Alivet (Leti, Venez.) ,Alivet Dia (Leti, Venez.)
,Alivetforte (Leti, Venez.) ,Alivetnoc (Leti, Venez.) ,Aljil (Yeni, Turk.) ,Alka-Seltzer Advanced Formula (Miles Consumer Healthcare, USA) ,Alka-Seltzer Plus Cold (Miles
Consumer Healthcare, USA) ,Alka-Seltzer Plus Cold & Cough (Bayer Consumer, USA) ,Alka-Seltzer Plus Cold & Cough (Miles Consumer Healthcare, USA) ,Alka-Seltzer
Plus Day & Night Cold (Bayer Consumer, USA) ,Alka-Seltzer Plus Day & Night Cold (Bayer Consumer, USA) ,Alka-Seltzer Plus Day Cold (Bayer, USA) ,Alka-Seltzer Plus
Day Non-Drowsy Cold (Bayer Consumer, USA) ,Alka-Seltzer Plus Night Cold (Bayer Consumer, USA) ,Alka-Seltzer Plus Night-Time Cold (Miles Consumer Healthcare,
USA) ,Alka-Seltzer Plus Nose & Throat (Bayer, USA) ,Alka-Seltzer Plus Original Cold Formula (Bayer Consumer, USA) ,Alka-Seltzer Plus Regular Seltzer Multi-Symptom
Cold Relief (Bayer, USA) ,Alka-Seltzer Plus Sinus (Bayer Consumer, USA) ,Alka-Seltzer XS (Bayer Consumer, UK) ,Alkasol-P (Stadmed, India) ,Alka XS Go (Bayer
Consumer, UK) ,Allerest Allergy & Sinus Relief (Heritage Consumer, USA) ,Allerest Headache Strength (Ciba, USA) ,Allerest Sinus Pain Formula (Ciba, USA) ,Allergy
Sinus (Vita Health, Canad.) ,All-Nite Cold Formula (Major, USA) ,Almigripe (Jaba, Port.) ,Alpara (Molex Ayus, Indon.) ,Alphamol (Molex Ayus, Indon.) ,Alpirex (Berman,
Mex.) ,Alres (Elmor, Venez.) ,Alsiphene (Alsi, Canad.) ,Alsogil (Also, Ital.) ,Alsogil (Also, Ital.) ,Alumadrine (Fleming, USA) ,Alvedon (Astra, Norw.) ,Alvedon (AstraZeneca,
GENERAL PHARMACOLOGY Syllabus 2013/2014
week
Teach.
Unit
No.
1.
1.
ID92
34
2.
3.
3.
ID92
31
5.
ID92
45
LECTURES
Teach.Unit
No.
Introduction to pharmacology.
Principles of
pharmacokinetics
2.
ID9238
PRACTICALS
Basic terminology in pharmacology. Organization of teaching and
testing. Basics of drug prescription
M. Šustková
M. Kršiak
Autonomic pharmacology
– sympathetic system.
M. Šustková
Autonomic pharmacology –
parasympathetic system.
P.Potměšil
QUIZ - Basics of pharmacokinetics
4.
ID9252
Pharmacokinetics, single and repeated dose administration, changes
in disease states - computer simulations
P. Potměšil
QUIZ - Autonomic pharmacology – sympathetic systém
6.
ID9246
Alfa/beta agonists , antagonists , catecholamines.
Case study, drug prescription.
T. Celtová
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Conditions for credits & examination in General Pharmacology
(in 2013-2014)
credit > at least 80% attendance of practicals and
success in 4 interim tests during semester :
1st TEST for credit - PHARMACODYNAMICS I (Pharmacology of
autonomic nervous systém) - Teaching Unit (TU) 3, 5,6,8)- 5th week
of the semester
2nd TEST for credit - PHARMACOKINETICS (basic principles,
biotransformation and elimination of DRUGS, TU drugs TU
1,4,7,10) - 7th week of the semester
3rd TEST for credit PHARMACODYNAMICS II ( pharmacology of
selected receptors, ion channels, enzymes and
regulatory
systems - TU 9, 11-16, 18)- 10th week of the semester
4th TEST fro credit - DRUG PRESCRIPTION - 13th week of the
semester
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Examination: final test (general pharmacology)
Examination will be in a form of final multiple-choice
test
Terms of exam (Final tests):
Jan 23, 2014 - 15:30
Jan 30, 2014 - 10:00
Feb 6, 2014 - 10:00
Feb 13, 2014 - 10:00
In case of failure, a student will have a possibility of
another test (2nd test). In case of failure in the 2nd test,
a 3rd test will be possible as the last chance.
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The questions (in a multiple choice form) of the final test will be
stemming from the following topics:
Basic terminology in pharmacology
Principles of pharmacokinetics
Autonomic pharmacology - sympathetic system.
Autonomic pharmacology - parasympathetic system.
Biotransformation and elimination of drugs, drug interactions.
Drugs acting by inhibition of enzymes
Drugs acting via ion channels and transporters
Principles of pharmacologic blood pressure control
Drug and remedy addiction
Biological therapy, gene therapy, pharmacogenetics
Drug discovery and development. Preclinical and clinical
trials. EBM. Placebo.
Adverse drug reactions. Regulatory agencies (EMA etc).
Pharmacovigilance. Pharmacoeconomics.
Complementary and Alternative Medicine (CAM), homeopathy
Principles of toxikology - intoxications, termination of drug effect.
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Charles University in Prague, Third Faculty of Medicine
Cycle II, Subject: General
pharmacology
1st Teaching Unit ID9234
Principles of pharmacokinetics
Prof. Kršiak
Department of Pharmacology, Third Faculty of Medicine, Charles University
in Prague
M. Kršiak Department of Pharmacology, Third Faculty of Medicine,
Charles University in Prague, 2008
1. Fate of drugs in the body
1.1 absorption
1.2 distribution - volume of distribution
1.3 elimination - clearance
2. The half-life and its uses
3. The uses of the half-life
4. Plasma concentration-effect relationship
FATE OF DRUGS IN THE BODY
WHAT HAPPENS TO DRUGS INSIDE THE BODY
ADMINISTERED
ABSORPTION
ABSORBED
DISTRIBUTION
„HIDDEN“
ELIMINATED
ACTING
ELIMINATION
1.1 ABSORPTION
Depends on:
• lipid solubility
• ionization (depends on pH)
non-ionized (non-polar), local changes in the pH
• routes of administration
- per os
- presystemic elimination
FIRST-PASS EFFECT
- pharmaceutical technology
BIOAVAILABILITY, bioequivalence
- parenteral
FIRST-PASS EFFECT:
loss of a drug by a metabolism mostly in the liver that
occurs en route from the gut lumen to the systemic
circulation
e.g. in nitroglycerin, morphine
Clinical consequence of the first-pass effect:
• limited effect after oral administration
• great interindividual differences in dosage
BIOAVAILABILITY:
the proportion of drug that reaches the systemic circulation
It is usually calculated from the AUC
(Area Under the Curve)
FATE OF DRUGS IN THE BODY
WHAT HAPPENS TO DRUGS INSIDE THE BODY
ADMINISTERED
ABSORPTION
ABSORBED
DISTRIBUTION
„HIDDEN“
ELIMINATED
ACTING
ELIMINATION
1.2 DISTRIBUTION
Depends on:
- membrane penetration
- protein binding
-plasma proteins
-tissue proteins
ONLY A FREE DRUG ACTS!
The bound drug is inactive.
Free and bound drug are in equilibrium.
Displacement: drug-drug interactions
FATE OF DRUGS IN THE BODY
WHAT HAPPENS TO DRUGS INSIDE THE BODY
ADMINISTERED
ABSORPTION
ABSORBED
DISTRIBUTION
„HIDDEN“
ELIMINATED
ELIMINATION
ACTING
1.3 ELIMINATION:
METABOLIC (biotransformation)
mostly in the liver
ENZYME INDUCTION/ INHIBITION
oxidase enzymes - cytochrom P450
(CYP2D6 etc)
GENETIC POLYMORPHISM
EXCRETION
kidneys metabolites or unchanged
(almost completely unchanged e.g. digoxin, gentamycin)
GIT... enterohepatic circulation
e.g. tetracyclines
FATE OF DRUGS IN THE BODY
WHAT HAPPENS TO DRUGS INSIDE THE BODY
ADMINISTERED
ABSORPTION depends on
- membrane penetration which depends on
ABSORBED
-lipid solubility
DISTRIBUTION depends
on:
- ionization (depends on pH)
„HIDDEN“
- routes of administration
FIRST-PASS EFFECT BIOAVAILABILITY
- membrane penetration
- protein binding
ELIMINATED
ONLY A FREE DRUG ACTS!
ELIMINATION
ACTING
- metabolic
- excretion
VOLUME OF DISTRIBUTION
Depends on:
protein binding
-plasma proteins
-tissue proteins
ONLY A FREE DRUG ACTS!
The bound drug is inactive.
Free and bound drug are in equilibrium.
Displacement: drug-drug interactions
VOLUME OF DISTRIBUTION
Vd = Amount of drug in body / Concentration of drug in plasma
Because the result of the calculation may be a volume greater than that of
the body, it is an APPARENT (imaginary, not actual) volume
For example, Vd of digoxin is about 645 liters for a 70 kg man (i.e. about 9
times bigger than his actual volume)
Clinical importance of volume of distribution:
• When Vd of a drug is big it takes long time to
achieve effective plasma concentration of the drug.
In such cases a loading dose may be given to boost
the amount of drug in the body to the required level.
This is followed by administration of lower
maintenance dose.
METABOLIC (biotransformation)
mostly in the liver
the drug is made more hydrophilic – this increases its
excretion in the urine
EXCRETION
mostly by the kidneys
metabolites or unchanged
GIT... enterohepatic circulation e.g. tetracyclines
CLEARANCE
Clearance (CL) is the volume of plasma totally cleared of
drug in unit of time (ml/min/kg)
CLtot total
CLR renal
CLH hepatic
CLNR nonrenal (= Cltot - CLR)
Example – analogy
for utilization of information on volume of distribution (Vd) and clearance (CL):
Bathtube in a hotel
with two holes, no plugs,
and a plate indicating Vd= 1000 L, CL = 100 mL/min
How would you regulate supply of water (water tap) to fill the bath in order to
take a bath soon and for a longer time?
the half-life is the time taken for the
plasma concentration to fall by half
[plasmatic half-life]
t½
= 0,69 .
Volume of distribution
Clearance
In most drugs after therapeutic doses:
plasma concentration falls exponentially
Linear kinetics (First order)
The rate of elimination is
proportional to the concentration
[t 1/2 is stable]
In most drugs after therapeutic doses:
plasma concentration falls exponentially because elimination processes
are not saturated
Linear kinetics (First order)
Cmax
[some robustness to
dose increase]
Cmin
Elimination is the bigger the higher is
the level
The rate of elimination is
proportional to the concentration
Elimination processes are saturated e.g. in alcohol, after higher doses of
phenytoin, theophyllin
Non-linear (Zero-order, saturation)
kinetics
The rate of elimination is constant
[unstable t 1/2 ]
For example, in alcohol the
rate of metabolism remains
the same at about 1 g of
alcohol for 10 kg of body
weight per hour
In a few drugs at therapeutic doses or in poisoning, elimination
processes are saturated
Cmax
[low robustness to
dose increase]
Cmin
elimination is constant,
limited
Non-linear (Zero-order, saturation) kinetics
Kinetics
Linear
(First-order)
Non-linear
(saturation,
zero-order)
Half-life
Robustness Predictability
(plasmatic)
to dose
for any
increase
therapeutic
dose
stable
good
good
unstable
poor
poor
T1/2 as a guide to asses:
1/ At a single-dose: duration of drug action
2/ During multiple dosing:
•to asses whether a drug is accumulated in the
body (it is - if the drug is given at intervals shorter
than 1,4 half-lifes) and
•when a steady state is attained (in 4-5 half-lifes)
3/ After cessation of treatment: to asses the time
taken for drug to be eliminated from the body (in 4-5
half-lifes)
[t1/2 = 1 - 2 h]
Ampicillin - single dose
THE USES OF THE HALF-LIFE
T1/2 as a guide to asses:
1/ At a single-dose: duration of drug action
2/ During multiple dosing:
• to asses whether a drug is accumulated in the
body (it is accumulated if the drug is given at
intervals shorter than 1,4 half-lifes) and
• when a steady state is attained (in 4-5 halflifes)
3/ After cessation of treatment: to asses the time
taken for drug to be eliminated from the body (in 4-5
half-lifes)
„PRINCIPLE OF 4-5 HALF-LIFES“:
If a drug is administered in intervals shorter than 1.4 half-life, then a
steady state is attained after approximately 4-5 half-lifes
The time to attain the steady state is independent of dose.
Steady state
t1/2
Why SS is attained after 4-5 half-lifes?
Attainment of steady state (SS) during multiple dosing of drug at intervals of 1
half-life
Interval
Administered
Initial plasma
concentration at
the beginning of
interval
microg/ml
Remains at
the end of
interval
microg/ml
[Eliminated
during
interval
microg/ml]
1.
100 mg
100
50
50
2.
100 mg
150
75
75
3.
100 mg
175
88
88
4.
100 mg
188
94
94
5.
100 mg
194
97
97
THE USES OF THE HALF-LIFE
T1/2 as a guide to asses:
1/ At a single-dose: duration of drug action
2/ During multiple dosing:
•to asses whether a drug is accumulated in the
body (it is - if the drug is given at intervals shorter
than 1,4 half-lifes) and
•when a steady state is attained (in 4-5 half-lifes)
3/ After cessation of treatment: to asses the time
taken for drug to be eliminated from the body (in 4-5
half-lifes)
Elimination of a drug during 5 half-lifes
of initial level
% of total elimination
REPEATED ADMINISTRATION OF DRUGS
TIME TO STEADY STATE (attained after 4-5 half-lifes)
independen of dose
FLUCTUATIONS
• proportional to dose intervals
• blunted by slow absorption
STEADY-STATE LEVELS (CONCENTRATIONS)
proportional to dose
t1/2
Steady-state concentrations are proportional to dose
Linear kinetics - diazepam
toxic
plasma concentrations
daily
therapeutic
daily
daily
Time (days)
Non-linear, saturation kinetics - phenytoin
plasma concentrations
toxic
daily
daily
therapeutic
daily
Time (days)
REPEATED ADMINISTRATION OF DRUGS
TIME TO STEADY STATE (attained after 4-5 half-lifes)
independen of dose
FLUCTUATIONS
• proportional to dose intervals
• blunted by slow absorption
STEADY-STATE LEVELS (CONCENTRATIONS)
proportional to dose
t1/2
How to reduce fluctuations in drug
concentrations?
by administering drugs slowly, continually, e.g.:
slow i.v. injection,
infusion,
sustained–release (SR) tablets,
slow release from depots
(e.g. from patches transdermally, depot antipsychotics injected i.m.)
or
by administering a total dose (e.g. a daily dose) in parts at shorter intervals
(mostly inconvenient)
Effects of drug
• correlate with plasma concentrations
Therapeutic Drug Monitoring (TDM) (eg. gentamicin, lithium, some
antiepileptics)
• do not correlate with plasma concentrations
- „hit and run“
- tolerance or sensitisation
- active metabolites
The *.ppt set of this lecture will appear at:
http://vyuka.lf3.cuni.cz
1st Teaching Unit (ID9234)