Pharmacokinetics l
Prepared by
Staff members of
Clinical pharmacology department
Faculty of medicine - Zagazig
University
ILOs
Absorption
Explain the mechanisms by which drugs cross biological membranes and
describe the factors influencing drug absorption
Explain the effect of pH on drug absorption
Distribution
Define bioavailability & Explain factors affecting it
Define the process of drug distribution & the transfer of drugs through
blood barriers.
Explain factors affecting drug distribution & Define the volume of
distribution and its clinical importance.
Explain importance of binding of drug to plasma protein and tissue
Drugs
Pharmacokinetics
Pharmacodynamics
what the what the
body does drug does
to the in the
drug? body?
Pharmacokinetics
what the body does to the drug?
Absorption
Distribution
Metabolism
Excretion.
Absorption
Passage of drug from
site of administration
to systemic
circulation.
Mechanisms of drug absorption
(how drugs cross biological
membranes)
1. Passive diffusion:
Rapid movement of lipid soluble drugs
across the cell membrane.
Movement of the water soluble drugs
across the aqueous channels(water
pores).
2. Facilitated diffusion
The drugs are carried into inside the cell
according to the concentration gradient by
carrier or transporter.
No energy is required
3. Active transport
The drug movement may be against the
concentration gradient by drug carrier or
transporter.
Energy is required
4. Endocytosis
Drugs of high molecular weight, the drug
binds to the cell membrane, dips in and
enveloped by the cell membrane.
:Factors affecting absorption
Factors related to the Factors related to the
patient. drug.
• Route of administration • Water & lipid solubility
• Absorbing surface • Pharmaceutical preparation
• Systemic circulation • Ionization of the drugs
• Specific factors
• Co administration of food or
drugs
A. Factors related to
the patient
Route of
administration
I.V. and inhalation > I.M. > S.C. > Oral
>Topical
Absorbing surface
• Vascularity: (Alveoli > S.C. tissue).
• Surface area: (Alveoli > Intestine >
Stomach).
• Pathological conditions: Diarrhea
decrease oral absorption
Systemic
circulation
Shock decrease absorption; oral and
subcutaneous routes are not suitable.
N.B.
Shock is a reduction of tissue perfusion by
O2 and nutrients due to failure of
microcirculation.
Specific factors
Intrinsic factor is essential for vitamin B12
absorption.
Co administration of other drugs&
food
S.C. adrenaline (added to local anesthetics) V.C.
↓absorption of local anesthetics longer duration of
action of local anesthetics.
Ca+2 (e.g. in milk) →↓oral absorption of tetracyclines
(antibiotics).
B. Factors related to
the drug
1- Water and lipid solubility:
Increase lipid solubility lead to increase
absorption (lipid/water partition coefficient).
Pharmaceutical preparation -2
• Dosage form: Solution > Suspension > tablet.
• Shape, size of particles and rate of dissolution
of tablets.
• Excepient containing Ca+2 decreases oral
absorption of tetracyclines.
3- Ionization of the drug:
Ionization decreases lipid solubility and absorption of drugs
The effect of pH on drug absorption
When drugs bind hydrogen,
•weak acids become unionized
(A-+H↔HA)
•while weak base are ionized (B+H↔BH+)
At low pH weak acids become unionized while the
weak bases become ionized.
At high pH weak base drugs become unionized
while weak acids become ionized.
- Accordingly, weak acid are more absorbed in
acidic media while weak bases are more absorbed
in alkaline media.
The pH at which the concentrations of
the ionized and unionized forms of the
drug are equal is termed pKa.
Each drug has its own pKa.
Clinical importance of pKa:
Drug molecules become
unionized in the empty
stomach (low pH) and can
1- GIT: Aspirin (acidic enter gastric mucosal cells. In
drug) has low pKa. gastric mucosal cells (high
pH) aspirin becomes ionized
and trapped in gastric
mucosal cell “peptic
ulceration”
renal elimination
could be enhanced
2- Kidney: In drug by changing urinary
poisoning, pH to increase
ionization of drug and
inhibit tubular
reabsorption of the
drug.
• Alkalinization of urine by sodium
bicarbonate (to increase urine pH above
drug pKa) is useful in acidic drug
poisoning e.g. Aspirin and phenobarbital.
• Acidification of urine by ascorbic acid
(to decrease urine pH below drug pKa) is
used in basic drug poisoning e.g.
amphetamine.
Distribution
It involves
the distribution of
the substance
throughout the body
compartment
Bioavailability
It is the percentage of drug that reaches the
systemic circulation and becomes available
for biological effect.
Factors affecting
:bioavailability
1- The extent of drug absorption.
2- 1st pass effect (1st pass metabolism):
It is the metabolism of some drugs in a single
passage through gut wall, liver or lungs
before reaching systemic circulation.
Hepatic 1st pass effect:
Nitroglycerin and propranolol pass from
GIT to liver where they are extensively
metabolized in their 1st pass through liver
before reaching systemic circulation.
Intestinal 1st pass effect:
Estrogens are extensively metabolized in
their 1st pass through intestinal wall.
Pulmonary:
Nicotine is partially metabolized in the
lung.
Distribution
After absorption the drug is distributed
through 3 body compartments:
• Vascular
1
• Vascular & interstitial
2
• Vascular, interstitial and intracellular
1. Vascular compartment:
Small volume of distribution
(4 Litres in 70 kg person)
Drugs distributed in this compartment are
hydrophilic, and most drugs are ionized at the
plasma pH (e.g. Heparin).
2. Vascular and Interstitial compartments:
Moderate volume of distribution (14 Litres in 70
kg person)
Drugs distributed in these compartments are
hydrophilic , with small molecular weight and
lesser degree of ionization at plasma pH
([Link]).
3. Vascular, interstitial and intracellular
compartments:
Large volume of distribution (40-42 litres in 70
kg person)
Drugs distributed in these compartments are
non-Ionized and lipophilic .e.g. barbiturates
VOLUME OF DISTRIBUTION (Vd)
It is a theoretical expression, relates the entire
amount of the drug in the body to its
concentration in plasma.
Importance of Vd:
1. Calculation of the loading dose of
a drug:
Loading dose = target plasma concentration
(Tc) x Vd
2. Treatment of drug toxicity:
Hemodialysis is not useful for drugs with
high Vd (most of the drug is in the
tissues).
Hemodialysis is useful for drugs with low
Vd (most of the drug is in the blood).
Factors affecting drug distribution.
1. Lipophilicity (Diffusion): The ability of the drug to diffuse
across cell membranes depends on its lipophilicity.
2. Binding to tissue constituents (Tissue affinity):
It is due to affinity of drugs to some cellular constituent.
Chloroquine is concentrated in the liver
Iodides are concentrated in the thyroid.
3- Plasma protein binding (PPB):
Drug in blood exists in two forms:
PP bound form: inactive, non diffusible and cannot be
metabolized or excreted.
Free Form: active, diffusible and can be metabolized or
excreted.
N.B The two forms exist in equilibrium, when fraction of the free
form is metabolized or excreted similar fraction is released from
plasma protein binding sites.
Characteristics of drug with high PP
binding:
PP bound fraction cannot be eliminated and
acts as reservoir.
Because the plasma protein binding sites are
limited, drugs can displace each other
clinically significant interactions.
Displacement from PP is clinically important
when the drug has high PPB capacity &
small Vd (most of the drug is present in the
circulation). So, minimal displacement
large increase in the free part toxicity.
Example: aspirin displaces warfarin (PPB:
99%) bleeding
:References
Lectures in pharmacology part (1) by staff members of clinical
pharmacology dep. Faculty of medicine, zagazig university.
Kadzung B.G., Masters S.B, and Trevor A.J. Basic & Clinical
pharmacology 12th edition.
Wilkins R,Cross S, Megson L and Meredith D (2011):Oxford
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Tao Le, Vikas Bhushan Matthew Sochat, Yash Chavda, Kimberly
Kallianos, Jordan Abrams, Mehboob Kalani and Vaishnavi
Vaidyanathan (2019): FIRST AID for the USMLE Step 1.
Sandra K. Leeper-Woodford and Linda R. Adkison, (2016):
Lippincott Illustrated Reviews: Integrated Systems. Page 173.
Duncan Richards, Jeffrey Aronson, D. John Reynolds, and Jamie Coleman
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