Pharmacokinetics

Dr. Jahid
MBBS, M.phil (Pharmacology)
Head of Pharmacology (MD-AUCMS)
Learning objectives

 Learning objectives
 Drug absorption and clinical implications (1 hour)
 Drug transport processes
 Discuss factors affecting drug absorption
 Define and describe the following pharmacokinetic
parameters: bioavailability (absolute and relative), area
under the curve
 Define and describe bioequivalence studies
 Describe the principle of first-pass effect
 Explain the physicochemical factors influencing the
absorption of drugs across biological membranes
 Pharmacokinetics:
 It is a branch of pharmacology
which deals with- body
absorption

distribution

metabolism

and excretion
drug
Drug absorption
•
•
Drug absorption

 It is the process of drug transport from site of

administration to systemic circulation by crossing
biological membrane.

 Why drugs should be transported?

In order to reach its receptor and produces biological
functions.
 ABSORPTION OCCURS FOR THE FOLLOWING DRUG
ADMINISTRATION SITE

1. oral

1. sublingual (will avoid 1st pass metabolism, breakdown in

stomach and liver)
2. transdermal (e.g. contraceptive) (very slow absorption)
3. rectal (use when patient is vomiting)

4. intramuscular injection
5. subcutaneous injection (Slow absorption)
6. miscellaneous - inhalation, intranasal, eye, nose, ear
drops
 Drug absorption

 If oral……from Stomach & Intestine to portal circulation

 If Per-rectal……from Rectum to systemic circulation
 If Intramuscular…..from muscles to systemic circulation…

 No absorption is needed if given

Intravenously.
 Drug absorption

So, for absorption, drug needs crossing of the cell

membrane.
Drug absorption
Drug absorption

 Cell membrane consists of-

Lipid bilayer with
Interspersed protein (islands of protein)
 Drug absorption

• Lipid layers are mostly “tight junction”

 Only lipid soluble substances can diffuse through it…..

 Water soluble substances can’t cross through tight lipid

layer…..
Drug absorption
Drug transport processes

 Specialized transport
 Passive Transport • Active transport
Simple diffusion (99%) • Facilited diffusion
• Endocytosis
• Exocytosis

 Almostall drugs are absorbed by simple diffusion

with exception of a few.
Drug transport processes

 Simple diffusion-

 Movement of solute from

high to low conc.
 No carrier protein
 No energy required.

 Almost all drug follow this

Process.
Drug transport processes

 Simple diffusion occur by-

 Here the ink is spreading by

moving to lower ink solute
concentration.

 Eventually all the water will

be evenly colored.
Practice:

1. Release of Adrenaline into

synapse

2. Responsible for absorption of

glucose from intestine

3. This process don’t require

energy and carrier protein.

4. Vitamin B12 absorbed by this

process.
Drug absorption

Simple diffusion occurs

in-

 Passive aqueous diffusion

Through aqueous channel
For small molecules (150-200
MW)

 Passive lipid diffusion

 Only lipid soluble drugs can
cross by this process.
 Passive acqueous diffusion by-

 Fick’s Law:
 Rate = (C1 - C2) x (A x Permeability Coefficient)
T
 So this equation quantify-
 Moves from high to low conc.
C1: higher concentration area.
C2: lower concentration.  Drug absorption is faster from
A: diffusion surface area. organ with large surface area.
PC: Permeability Coefficient  Moreover drug absorption
better from organ with thin
T: Thickness of the membrane
membrane barrier (Lungs)
 Lipid Diffusion

• In the case of weak acids and weak bases the ability to move
from aqueous to lipid or vice versa varies with the pH of the
medium.

• Henderson-Hasselbalch equation (can be use to predict

the effect of pH change on ABSORPTION):

Acid: pH = pKa + log [A-]/[HA]

Base: pH = pKa + log [B]/ [HB+]

Drug absorption

 Factors influencing drug absorption (Drug factors) or

Physiochemical factors:
 Lipid solubility of drug
 Nature of the drug
 pH of the media (Stomach & Intestine)
 pKa of the drug

 Molecular size of drug

 Disintegration & dissolution of drug
Lipid solubility of drug

 Drugs which are lipophilic easily cross membrane

 Drugs which are lipophobic/hydrophilic have problem

crossing membrane

 This is a major source of variation in drug diffusion or

absorption.
 DEGREE OF IONIZATION (POLARITY)

 Only a non-ionized (non polar) drugs diffuses across

the membrane, hence this is an important factor .

 Non polar drugs are lipid soluble.

 Polar drugs are water soluble, they can’t absorb from

biological membrane.
DEGREE OF IONIZATION (POLARITY)

 Lipid soluble = Non-ionized molecules (NaCl)

 Hydrophilic = Ionized molecules. (Na+, Cl- ).

So,

The more Lipid Soluble of drug------more absorption

The more Water Soluble of drug-----less absorption
Drug absorption

CELL
Non-Ionized Molecule
(lipid soluble)

Ionized Molecule MEMBRANE

(water soluble)
 Effect of pH on Drug Absorption

 Acidic drug better absorbed in acidic media.

 Basic drug better absorbed in basic media.

Acidic drugs (Aspirin) are better absorbed in stomach

(in acidic media)
and

Basic drugs (Diazepum) are better absorbed in

intestine (in alkaline media)
Continue……….

Acidic drug better excreted in basic media.

Basic drug better excreted in acidic media

 Incase of acidic drug poisoning alkalization done to

promote excretion of that drug.
and
 Incase of basic drug poisoning acidification done to
promote excretion of that drug.
A. Diffusion of non-ionized form of a weak acid through lipid membrane
Continue……….

B. Diffusion of non-ionized form of a weak base through lipid membrane.

 Importance of environment pH &
drug pKa

 Degree of ionization (polarity) depends on the pKa of

drug (and pH of body fluid).

 pKa: value of drug pH when the concentration of

ionized and non-ionized drug form is equal.

 If pKa of a drug is equal to pH of the media, then…

“50% of the drug are ionized & 50% are non-ionized”
 Acidic Drug

Acidic drugs – more NON ionized in acidic pH

N I N I N I I

pH 2 pH 6 pH 8 pH 9
What’s the pKa for this drug?

= Non ionized molecules

= Ionized molecules
 TRY THIS OUT

Let’s consider the influence of pH on absorption of a

weak acid (pKa = 3.4) between gastric juice (pH1.4)
and plasma (pH7.4).

The mucosa can be considered a simple lipid barrier.

 Where more
Drug absorption drug???

Acid: pH = pKa + log [A-]/[HA]

Log [A-]/[HA] = (pH – pKa)

[A-]/[HA] = 10 (pH –pKa)

In plasma:
[A-]/[HA] = 10 (7.4-3.4) = 104 =10,000
In gastric juice:
[A-]/[HA] = 10 (1.4-3.4) = 10-2 = 0.01
 MOLECULAR
Drug absorption WEIGHT
 Molecular weight: this is relatively constant for most
drugs because molecular weights usually vary between
about 100 and 500.

Molecular size: The smaller in size-----more absorption

 Drug absorption

Disintegration & dissolution of drug

Drug orally given

GIT

Disintegration (to form granules ) into small molecules

Dissolution into the aqueous media

Absorption
 Drug absorption

 Host factors or Biological factors)

 Surface area
 Motility of GIT
 Presence of food (Drug binding)
 Blood supply at the absorptive area
 Destruction of drug in GIT
 Drug absorption

Surface area

The more absorptive surface area, the more

absorption

Surface area of intestine is far greater than the SA of

stomach, so more drug absorption takes place in
Intestine

Relative SA:
Stomach 0.1 - 0.2
Small Intestine 100
 Drug absorption

Motility of GIT
- Drugs are better absorbed in normal GIT movement

Blood supply at the absorptive area

- The more circulation
- the more maintenance of concentration gradient
- The more absorption
 DRUG BINDING

 Binding on Food
 Increased
hydrochlorothiazide, propranolol

 Reduced
Ampicillin, isoniazid, rifampicin, erythromycin, thyroxine

Binding with other drug or compounds

Tetracycline with Ca2+
Chloroquine with retina
Drug absorption

 Destruction of drug in GIT

In GIT, there are gastric HCl, enzymes etc.
So, drugs may be destroyed in GIT before absorption

Example:
Benzyl penicillin is destroyed by gastric HCL
Insulin is destroyed by proteolytic enzymes
Drug Bio-availability

Bio: Blood ( Systemic

circulation)

Availability : How much

available?
Drug absorption

Simply….
 Bioavailability is the percentage of administered drug
available in the systemic circulation in respect of route
of administration.

If 100 mg of drug A is administered orally & 60 mg

reaches in systemic circulation-
then the oral bioavailability of drug A is 60%
Drug absorption

Measurement of AUC
 Drug absorption

 Factors influencing oral bioavailability of drug:

 Any route other than iv route

 Incomplete absorption of drug
Destruction of drug in GIT
 1st pass hepatic metabolism
Distribution of drug to other tissue.
 Drug absorption

 Formula for bioavailability of drug:

 The systemic bioavailability of the drug F= f- (1-ER)

 Here: f = extent of absorption

Extraction Ratio (ER)= CLliver / Q
Q=where Q is hepatic blood flow, normally about 90 L/h.
 Bioequivalence (BE): Definition
 Two preparations of a drugs are consider Bioequivalence
when- there is absence of a significant difference in the rate
and extent of bioavailability at the same molar dose under
similar conditions in an appropriately designed study

 Importances:
 Oral formulation of a drug from different company
 Or different batches from same company may contain same
amount of drugs.
 90
80
Concentration (ng/mL)

70
60
Test/G eneric
50
Reference/B rand
40
30
20
10
0
0 5 10 15 20 25 30
Time (hours)
 1st pass hepatic metabolism

 After oral administration…..

Absorption from GIT

Portal circulation

Liver

Systemic circulation
1st pass hepatic metabolism

Metabolism of drugs after absorption in the liver

while passing through it before reaching systemic
circulation….

This is known as 1st pass hepatic metabolism.

1st pass hepatic metabolism

Usually most drugs undergo to some extent of 1st pass hepatic

metabolism

 But if this 1st pass hepatic metabolism happens extensively

for any drug, then the effect of that drug is not found by oral
administration

Example :
Nitroglycerine (GTN)