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Objectives
1. Drug-Response Relationship
2. Why we need to study pharmacokinetics?
3. Absorption
4. Sites of Drug Administration
5. Bioavailability and factors affecting bioavailability
6. Absorption in children and elderly
7. Distribution
8. Distribution in children and elderly
9. Metabolism
10. Metabolism in children and elderly
11. Excretion
12. Excretion in children and elderly
Pharmacokinetics
Study of the movement of drugs through
the body.
Pharmacokinetics determine the time
course of drug concentrations in serum
or plasma as well as in tissues and body
fluids
Pharmacokinetics
Absorption
Distribution
Metabolism
Excretion
Dosage
Plasma Site of
Concen. Action
Pharmacokinetics
Effects
Pharmacodynamics
Drug-Response Relationship
Relationship between dose of a drug
and response produced by that drug
Generally if there is more dose, then
there will be more drug-receptor
complex and more response
But when the maximum response is
produced by the drug, then there will
be no more increase of response even
after administration of more dose.
Drug Concentration
Therapeutic Window
Therapeutic Response
Adverse Effects
Dose-Response Relationship
Potency of A is more than B (less dose is needed
to produce same response)
Efficacy of both same (max response same).
Pharmacokinetics
GI tract
Artery
Peripheral vein
Muscle
Subcutaneous tissue
Lung
Bioavailability
Percentage or fraction of
administered dose that
reaches systemic
circulation of patient.
Bioavailability
1. Dissolution
2. Absorption
3. Chemical form (e.g. salt)
4. Dosage form (tablet, solution)
5. Route of administration
6. Stability of active ingredient in GI tract
7. Extent of drug metabolism
Oral Bioavailability
Destroyed
in gut
Dose
Not
absorbed
Destroyed
by gut wall
Destroyed
by liver
to
systemic
circulation
Oral bioavailability
Drug
Gentamicin
Verapamil
Lignocaine
Propranolol
Digoxin
Phenytoin
Valproate
Foral (%)
<5
22
35
36
75
98
100
Plasma concentration-time
relationship after a single oral dose
verapamil - 36%
Carbamazepine
Antidepressants
Sertaline, buspirone,
clomipramine
Benzodiazepines
Diazepam
Felodipine, nifedipine,
nimodipine, verapamil
Antiretroviral agents
Saquinavir, indinavir
Statins
Simvastatin, lovastatin,
atorvastatin
Cytotoxic drugs
Cyclosporin, tacrolimus,
Antiarrhythmics
Amiodarone
Miscellaneous
Methadone, sildenafil
Pillai et al, South Med J. 2009
Absorption in Children
Infant- slower compared to older children
and adults:
Absorption in Children
Gastric pH values:
1 to 3 within 24 hours after birth
neutral by 1 week of age
slowly decline over 2 to 3 years to adult values.
Cmax
Distribution
Refers to transport of drugs to body
compartment and the time required
for the drug to reach those locations.
Vd : Volume of distribution
(liters or L/kg).
Distribution
Factors affecting drug transport:
Protein binding
Body fluids
Membrane transport/permeability
Blood and tissue hemodynamics
Distribution
Determinants of drug movement to
maintain equilibrium:
Disease states
Drug lipid solubility
Characteristics of body tissues
Regional pH differences
Protein binding
Volume of Distribution
A measure of the tendency of
a drug to move out of the
blood plasma to some other
site.
Volume of Distribution
C = D/V
D
V
V = D/C
Total amount of
the drug in the
body
Concentration of
a drug in the
plasma
Volume of Distribution
Vd (L/Kg) =Amount of drug (mg)
Css (mg/L)
D
V
Volume of Distribution
Vd (L/Kg) =Amount of drug (mg)
Css (mg/L)
D = 50 mg
C = 2.5 mg/L
V = D/C
= 50mg /
2.5mg/L
= 20 Litres
Loading Dose
As with infusions, a loading dose may be required to produce
therapeutically effective blood levels without delay.
Divided doses
Volumes of distribution
(In litres for average 70 Kg adult)
Warfarin
7
Gentamicin
16
Theophylline 35
Cimetidine
140
Digoxin
510
Mianserin
910
Quinacrine
50,000
Medium volume.
Similar concent in
plasma and tissues
Large volume.
Mainly in tissues,
little in plasma.
Steady state
Amount
eliminated = 1
dose
Amount
eliminated << 1
dose
Amount
eliminated < 1
dose
36
Concentrations at
Steady State
Css,max = Peak
Css (Average)
Css,min = Trough
hypoalbuminemia
Protein Binding
(%)
Protein Type
Amikacin
<5
No
Kanamycin
<5
No
Ethosuximide
No
Procainamide
1015
Albumin
Theophylline
40
Albumin
Phenobarb
40
Albumin
Phenytoin
90
Albumin
Carbamazepine
80
Albumin
9095
Albumin
Primidone
15
Albumin
Digoxin
25
Albumin
Quinidine
80
1-acid glycoprotein
Lidocaine
6080
1-acid glycoprotein
98
Lipoproteins
Valproic acid
Cyclosporine
Distribution in Elderly
Fat soluble (lipophilic)
Increased Vd in older persons because they have
greater fat stores.
Longer time to reach a steady-state
Longer elimination from the body.
Distribution in Elderly
Vd also influenced by protein binding.
Albumin is often decreased in older patients
Distribution in Children
Total Body Water and Extracellular Fluid Volume
Metabolism
Defined as chemical modification
of a drug in a biologic environment.
Also referred as drug
biotransformation or drug
detoxification.
Metabolism
Liver - most common
site of drug
metabolism
Metabolic
conversion also can
take place in:
intestinal wall
lungs
skin
kidneys
other organs
Metabolism
Most drugs undergo
metabolism.
Only few excreted
unchanged in urine.
e.g. Acetazolamide
Penicillin G
First-Pass Effect
Some drugs may be extensively
metabolised by the liver before
reaching systemic circulation
First pass refers to metabolism by the
liver as a drug passes through the liver
via portal vein following absorption
Metabolism in Children
Both Phase I and II reactions mature over time.
Phase I reactions generally mature by 1 year of
age.
Metabolism in Elderly
Aging affects the liver by
decreasing liver blood flow,
liver size & mass.
Consequently, in the older
patient the metabolic
clearance of drugs by the liver
may be reduced.
Excretion
Excretion refers to a drugs final route(s) of exit
from the body.
For most drugs, this involves elimination by the
kidney as either the parent compound or as a
metabolite or metabolites.
Half-Life
A drugs half-life is the time it takes for its plasma or
serum concentration to decline by 50%,
e.g. from 20 g/mL to 10 g/mL.
Expressed in hours.
Steady state is reached when the amount of drug
entering the systemic circulation is equal to the amount
being eliminated.
For a drug administered on a regular basis, 95% of
steady state in the body is achieved after five half-lives
of the drug.
Half-Life
Linear vs non-linear pk
First order kinetics = linear
Rate of change in drug concentration is
proportional to drug concentration
Elimination
rate
Graph would start to curve if
we went to much higher
concentrations and began to
saturate the enzyme.
Drug concentration
Linear kinetics
(most drugs)
Non-linear
kinetics
(e.g. phenytoin)
Rate of
eliminatn
Rate of
eliminatn
NON-LINEAR KINETICS
There are a small number of drugs where
concentrations seen in real life use are high
enough to saturate the eliminating enzymes.
Excretion in Children
Creatinine in Elderly
Serum creatinine - not accurate
reflection of creatinine clearance in
elderly patients.
Decline in lean muscle mass cause
reduced production of creatinine.
Acknowledgements
Dr. Mohd Suhaimi Ab Wahab
Dr. Ruzilawati Abu Bakar
Suggested Readings
Michael E. Winter, Basic Clinical Pharmacokinetics,
4th ed. Lippincott Williams & Wilkins, Philadelphia
Thomas N. Tozer & Malcolm Rowland, Introduction to
Pharmacokinetics and pharmacodynamics:
The quantitative basis of drug therapy.
Lippincott Williams & Wilkins, Philadelphia