Pharmacokinetics I

MBBS-Y1, Sem2, 2020

Prof. Dr Abdelbaset Taher 1

• Learning Objectives
- Define pharmacokinetics and show its aspects
- Classify and discuss factors which affect
absorption of drugs
- Define distribution of drugs and describe its 4
basic patterns
- Discuss factors which affect drug distribution

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 Fate of drugs (pharmacokinetics)
Definition:
• it means all the processes to which a drug
is subjected after its administration;
absorption, distribution, biotransformation
and excretion.
Clearance:
• Means the processes which terminate
drug's actions e.g. metabolic inactivation,
tissue binding and excretion.
Prof. Dr Abdelbaset Taher 3
Cont…
N.B. : The main goal of a physician is to
give to the patient adequate drug dosage so
that therapeutic levels are obtained to
produce the desired effect with minimal
adverse effects.
Therefore the study of pharmacokinetics is
important to design a proper dosage
schedule including dose, route and
frequency of administration, and to
determine the drug's bioavailability.
Prof. Dr Abdelbaset Taher 4
 I. Absorption
Definition:
it's the passage of a drug from its site of
administration into the blood stream.

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Factors that modify absorption:
Cont…
A. Factors related to the drug:

(1) physicochemical properties of the drug:

a) lipid-water partition coefficient:
Absorption is proportional to the concentration of drug in the aqueous phase
and its lipid water partition coefficient. Insoluble drugs e.g. barium sulphate is
not absorbed
b) Degree of ionization:
The greater the degree of ionization, the lesser the absorption because of the
lesser the lipophilic properties of drug ions, unless the ionized molecule is
highly lipid soluble.
c) Chemical nature of the molecule:
Whether organic or inorganic e.g. inorganic iron preparation is better
absorbed from GIT than organic one.
d) Valency: ferrous salts are better absorbed from GIT than ferric salts.

(2) pharmaceutical form:

Drugs in aqueous solutions are better absorbed than those given in oily solutions
or suspensions, and the smaller the particle size of powders, the more efficient is
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their absorption.
B. Factors related to the patient:
a) Route of administration:
* absorption from intact skin is generally very poor
* absorption from mucous membranes:
- excellent from pulmonary alveoli
- very good from small intestine and rectum
- very good from sublingual mucosa
- poor from gastric mucosa.
* absorption from parenteral sites:
- absorption from SC tissues is more rapid than from mucous
membranes (other than pulmonary alveoli)
- absorption from skeletal muscle is more rapid than SC sites.
b) Area and vascularity of absorbing surface:
absorption is directly proportional to both area and vascularity.
c) State of health of absorbing surface
d) Rate of general circulation.
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e) Specific factors e.g. intrinsic factor for absorption of vitamin B12
 II. Distribution

• Definition:
after absorption from whatever route of administration a
drug reversibly leaves the blood stream and enters the
interstitium and or the cells of the tissues according to
the compartmental models. These compartments are
the extracellular (the intravascular and the interstitial)
and the intracellular compartments.

Prof. Dr Abdelbaset Taher 8

 There are 4 basic patterns of drug distribution (Fig. 4):
Cont…
1. One compartment model (intravascular):
– Drugs having too large MW to move out through endothelial slit junctions
of the capillaries
– E.g. High MW Heparin& Dextran or drugs highly bound to plasma
proteins
2. Two compartments model (extracellular):
– These compartments are intravascular and interstitial fluid. Drugs have
low MW, are hydrophilic and are distributed in these compartments
– E.g. Quaternary ammonium compounds (neostigmine) & Mannitol
3. Multicompartment model (extra and intracellular):
– Drugs are distributed to total body fluids. They have low MW and are
hydrophobic (lipid soluble)
– E.g. Tertiary amine (physostigmine) & ethanol
4. Other sites:
– Some drugs are concentrated specifically in one or more tissues of the
body
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– e.g. iodide is concentrated by thyroid gland, calcium by bone.
Prof. Dr Abel Baset Taher 10
Prof. Dr Abel Baset Taher 11
 Factors affecting drug distribution:

1- A drug lipophilicity:
− Lipid soluble drugs tend to distribute more widely in the
body compared to lipid insoluble drugs.
2- Blood flow:
− Highly perfused organs like the brain> liver >kidney
>skeletal muscles receive the largest amount of drug.
3- Capillary permeability:
− Capillary wall consists of endothelial cells lined from the
outside by basement membrane.
− In the liver there are wide pores between endothelial
cells which allow larger molecules to pass through.

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 Passage of drugs to CNS (BBB)
− The pores between the endothelial cells are absent and cells are
tightly joined to each other's. In addition the brain capillary cells
are surrounded by less permeable cells known as glial cells.
− Thus the drug molecules have not only to diffuse across tightly
packed endothelial cells but also must cross the poorly
permeable glial cells to enter CNS.
EXAMPLES
=Lipid soluble drugs pass freely through BBB e.g. general anesthetics
=Secondary and tertiary amines can pass while quaternary cannot.→
ANS drugs
=Dopamine cannot penetrate CNS while levodopa can pass. →
parkinsonism
=Penicillins pass slightly but they penetrate readily in acute bacterial
meningitis. → Antimicrobial drugs
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 Passage of drugs through breast milk:
• Most drugs administered to lactating women are
detected in breast milk in very small amounts.
• PH of milk is more acidic than that of plasma. So,
basic drugs ionize and accumulate in milk. Milk
also contains more fat than plasma, which favors
retention of lipid soluble drugs.

Prof. Dr Abdelbaset Taher 14

 N.B. Drugs contraindicated during breast feeding:

1. Antibiotics: chloramphenicol, tetracycline,

sulphonamides
2. CNS: narcotics, benzodiazepines, alcohol, nicotine
3. Laxatives as senna and cascara
4. Corticosteroids (suppress growth)
5. Bromocriptine and sex hormones (suppress lactation)

Prof. Dr Abdelbaset Taher 15

 Placental barrier:
• Placental membrane is lipid in nature and readily allows
the transfer of non-ionized, lipid soluble drugs by passive
diffusion according to concentration gradient. Thus most
drugs that are well absorbed orally can easily enter fetal
circulation and harm the fetus:
• -Drug administered in 3rd -10th week of pregnancy may
cause teratogenicity
• -Morphine respiratory depression
• -Oral anticoagulants  fetal hemorrhage in newborn
• -Antithyroid drugs  neonatal goiter
• -Aminoglycosides  8th cranial nerve damage
• -Oral hypoglycemic (sulphonylureas)  prolonged
neonatal hypoglycemia 16
 Cont…
Binding to plasma proteins
• Upon entering the blood, a drug may be bound to
plasma proteins (chiefly albumin) to varying extents e.g.
salicylates and sulphonamides are highly bound to
plasma protein.
• The protein bound fraction is inactive pharmacologically,
but there's usually just sufficient free drug which gives
the desired effect.
• The protein-bound fraction forms a sort of depot from
which a small proportion of active drug is constantly
released.
• Only the unbound drug is liable to degradation by liver
microsomal enzymes or to excretion by the kidney.
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 N.B. The amount of drug bound to plasma protein
Cont… will change according to:
• Affinity for binding sites:
– Competition between drugs for binding sites as a drug may
displace another one from its binding site e.g. salicylate
may displace warfarin causing hemorrhage.
• Hypoalbuminemia:
– As occurs during starvation,
– malnutrition  free drug change of therapeutic dose to
toxic dose e.g. phenytoin

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 Body fluid compartments Fig. (4)

Extracellular

Intravascular Interstatial

10 L
4L
Intravascular
Interstitial 28 L
Intracellular

Prof. Dr Abdelbaset Taher 19

Thank you

Prof. Dr Abdelbaset Taher 20