INTRODUCTION,

Pharmacokinetics
What the body does to the drug
Dr Baba Sule Mahamma
 Objectives
Define Pharmacology and its branches
Define what a drug is
State the different types of drug names
Define Pharmacokinetics (PK)
Explain
Absorption
Distribution

Elimination (metabolism & excretion)

 Pharmacology and its
Scope?
(Greek: pharmacon- drug; logos study)
deals with interaction of exogenously
administered chemical molecules (drugs)
with the living system
Science that deals with the study of drugs
and their interaction with the living system.
Scope
The properties of drugs
Their design
Sources
Genetic screens
Protein engineering
Novel drug delivery vehicles (viruses)
 Branches of pharmacolgy
2 main subdivisions
1. Pharmacokinetics
2. Pharmacodynamics
Other subdivisions are
- Pharmacotherapeutics
- Pharmacogenetics
- Pharmacogenomics (applied
pharmcogenetics)
- Pharmacoepidemeology
- Pharmacoeconomics
 Drugs
These are any chemical/biological substances used
in the treatment, cure, prevention and diagnosis of
a disease
An Ideal Drug is what is desired
An Ideal drug should be:
Effective (elicit the intended response)
Safe (even at high concentration, less adverse
effects)
Selective in action (less side/ adverse effects)
Reversible in its effect (termination of effect at a
point)
Predictable in its effect (known outcome of
patient)
Easy to administer
 Sources of drugs

Natural
Plant (digitalis, belladonna, cinchona)
Animal (dry skin of toad adrenaline; insulin,
Cod liver oil -Vitamin A)
Mineral (Kaolin, Iron, Aluminium hydroxide)

Synthetic (prednisolone, phalcodine

Semisynthetic (sulphonamides, thiazide
diuretics)
Recombinant DNA technology
 Naming Drugs
Three categories of names exists:
1. Chemical name: describes the chemical
composition of the substance.
E.g. 1-(Isopropylamino)-3-(1-
naphthyloxy)propan-2-ol for propranolol, 3-
azido-3-deoxythimydine for Zidovudine
- Chemical names are not used in prescribing
2. Non-proprietary/generic name: name adopted for
the purposes of harmonization, by a competent
scientific body. Two notable bodies are United State
Adopted Name (USAN) council and British Adopted
Name(BAN) council.
- Examples of non-proprietary names Aspirin,
Diazepam, Codeine, Paracetamol /
Acetaminophen , Pethidine/ Meperidne
 Drug names contd.
Generic name and non-proprietary names
are interchanged; however generic names
apply to the chemical or pharmacological
group of the compound. E.g. analgesics,
antibiotics, TCAs etc.
3. Proprietary/ Brand/trade name: name
assigned by the manufacturer and bears
the trade mark. E.g. Timoptic or Glucomol
for Timolol, Viagra for Sildenafil, Clomid or
Fertomid for Clomiphene
 Pharmacokinetics:
Definition
Time course of drug absorption,
distribution, metabolism,
excretion (ADME)

How the drug

comes and goes.
 Pharmacokinetics (PK)

The study of the disposition of a drug

The disposition of a drug includes
the processes of ADME
Absorption

Distribution
Metabolism
Elimination
Excretion
Toxicity
 Absorption
Absorption is defined as the process
by which a drug proceeds from the
site of administration to the site of
measurement (?) (usually blood,
plasma or serum).
Parameters
Rate of absorption
Area under the concentration curve
(AUC)
 Membranes and
Absorption
Hydrophilic
Lipid Bilayer
Heads Hydrophobic
Tails
Small, H2O, urea,
uncharged Swoosh!
CO2, O2, N2

Large, Glucose DENIED!

uncharged Sucrose
Small
charged H+, Na+, K+,
ions Ca2+, Cl-, DENIED!
HCO3-
 First Pass Metabolism

Destroyed Not Destroyed Destroyed

in gut absorbed by gut wall by liver

to
Dose systemic
circulation

Bioavailability: the fraction of the administered dose

reaching the systemic circulation
 Determination of
bioavailability
A drug given by the
intravenous route will have
an absolute bioavailability
of 1 (F=1 or 100%
bioavavailable)

While drugs given by other

routes usually have an
absolute bioavailability of
less than one.

.
The absolute bioavailability
is the area under curve (AUC)
non-intravenous divided by
AUC intravenous
 Distribution
The movement of drug from the blood
to and from the tissues
 Distribution
The process of reversible transfer of
drug to and from the site of
measurement (usually blood or
plasma).
Rate and Extent of drug distribution is
determined by:
1. how well the tissues and/or organs are
perfused with blood
2. the binding of drug to plasma proteins
and tissue components
3. the permeability of tissue membranes
to the drug molecule (BBB, placenta).
Physicochemical properties of the drug
Characterised by volume of
distribution (Vd)
 Volume of distribution (Vd)
Volume within which drug appears to be distributed
(Apparent Vd), if the concentration throughout the
body were equal to that in plasma (assuming single
compartment)

Relates drug concentration in plasma to the total

amount in the body (Vd = A/Cp)

Determinants
Plasma protein binding (bounded and unbounded
drugs)
Albumin, lipoprotein, 1-acid glycoprotein,
globulins
Result in small Vd
Tissue binding
Protein
Fat
Result in large Vd
 Protein Binding

Reversible and rapid

Depends on [free drug], affinity for binding
sites, [protein]
 Protein binding

Many drugs bind to plasma proteins

Albumin (acidic drugs, eg warfarin,
NSAIDs)
Alpha-1 acid glycoprotein (basic drugs,
eg quinine)
Lipoproteins (basic drugs)
Globulins (hormones)
Only free drug can bind to receptors
 Plasma Protein Binding

warfarin (Coumarin) is highly protein

bound (99%). Aspirin binds to the same
site on serum proteins as does
Coumarin. If a patient on Coumarin
also takes aspirin, what will happen?

The available Coumadin will

1) Why?
increase.
2) Why do we care?
Blood-Brain Barrier

The blood brain barrier consists

of cell tightly packed around the
capillaries of the CNS. What
characteristics must a drug
possess to easily cross this
barrier?

Non-protein bound, non-ionized,

Why?
and highly lipid soluble
 Elimination

Elimination is the irreversible loss

of drug from the site of
measurement (blood, serum,
plasma).
occurs by one or both of:
Metabolism
Excretion
Characterised by:
Clearance (CL) (Vol of blood cleared
of drug per unit time ( l/h, ml/min)
Half-life of elimination (t1/2) ( time for
initial conc to fall by half)
 Metabolism

process of a conversion of one

chemical species to another chemical
species
Resulting metabolites (usually)
possess little or none of the activity of
parent drug
active metabolites may result:
propranolol HCl a non-selective b-
antagonist: active metabolite - 4-
hydroxypropranolol
diazepam (Valium) tension and anxiety:
active metabolite desmethyldiazepam
 The process of
metabolism
Main site Liver (rich in enzymes)
Other sites kidney, lungs, gut mucosa
Phases
1. Phase I change by oxidation,
reduction and hydroxylation
Chemical active site often
introduced
Mixed function oxidases
(cytochrome P450 enzymes)
most important reaction
Eg paracetamol, midazolam,
diazepam..
 The process contd.
Phase II changes involving
union/synthesis of drug with
endogenous molecules from
intermediary metabolism (Phase I)
Result - water-soluble conjugates (
readily removed by the kidney
Eg.
morphine, paracetamol, salicylates (
glucuronic acid)
oral contraceptives, paracetamol
(sulphates)
Isoniazid, phenelzine (acetyl group)
 CYP family of enzymes

Found in liver, small intestine, lungs, kidneys,

placenta

Consists of > 50 isoforms

Major source of catalytic activity for drug oxidation

Its been estimated that 90% or more of human drug

oxidation can be attributed to 6 main enzymes:
CYP1A2 CYP2D6
CYP2C9 CYP2E1
CYP2C19 CYP3A4

Indifferent people and different populations,

activity of CYP oxidases differs.
 Inhibitors and inducers of
microsomal enzymes

Inhibitors:cimetidine, fluconazole, prolong

action of drugs or inhibits action of those
biotransformed to active agents (pro-drugs)

Inducers: barbiturates, carbamazepine,

phenytoin, rifampicin, alcohol, shorten
action of drugs or increase effects of those
biotransformed to active agents
 Phase II

Main function of phase I reactions is to

prepare chemicals for phase II
metabolism and subsequent excretion

Phase II is the true detoxification

step in the metabolism process.
 Phase II reactions

Conjugation reactions

Glucuronidation (on -OH, -COOH, -NH2, -SH groups)

Sulfation (on -NH2, -SO2NH2, -OH groups)

Acetylation (on -NH2, -SO2NH2, -OH groups)

Amino acid conjugation (on -COOH groups)

Glutathione conjugation (to epoxides or organic

halides)

Fatty acid conjugation (on -OH groups)

Condensation reactions
 Metabolism contd.

Liver disease
Slows metabolism
Prolongs effects

Dose
adjustment/contraindications
 Excretion
Defined as the irreversible loss of a
drug in a chemically unchanged or
unaltered form
Primary site kidney (liver important,
lungs, milk, faecal matter)
Renal excretion
Glomerular filtration (MW less than 10,
000, ie almost all drugs)
Renal tubular excretion cells of
proximal tubule actively transport (eg
OATs and OCTs)
Renal tubular reabsorption
 Excretion contd.

Renal disease
Slows excretion
Prolongs effects

Dose adjustment in disease

conditions
Active Tubular Transport

Probenecid is moved into the urine by

the same transport pump that moves
many antibiotics. Why is probenecid
sometimes given as an adjunct to
antibiotic therapy?

It competes with the

antibiotic at the pump and
slows its excretion.
 Biological Half-life (t 1/2)

Amount of time to eliminate 1/2

of total drug amount
Shorter t 1/2 may need more
frequent doses
Hepatic disease may increase t1/2
A drug has a half life of 10 seconds. You give a
patient a dose of 6mg. After 30 seconds how much
of the drug would be left?

Time Amount

0 sec 6 mg
10 sec 3 mg
20 sec 1.5 mg
30 sec 0.75 mg