DRUG DISTRIBUTION PART I

1. DRUG DISTRIBUTION
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Dr. Nilesh S. Kulkarni
Department of Pharmaceutics,
PES Modern college of Pharmacy ( For
Ladies), Moshi, Pune 412105

2. Contents
➢ Factors affecting on drug distribution
➢ Volume of distribution
➢ Factors affecting on protein Binding
➢ Kinetics of protein binding
➢ Significance of protein binding
➢ Reference
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3. Introduction
Once a drug has gained excess to the blood stream, the
drug is subjected to a number of processes called as
Disposition Processes that tend to lower the plasma
concentration.
1. Distribution which involves reversible transfer of a
drug between compartments.
2. Elimination which causes irreversible loss of drug
from the body.
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4. Drug DistributionIt is the Reversible
Transfer of a Drug between the Blood and the
Extra Vascular Fluids and Tissues of the body
(for example, fat, muscle, and brain tissue).
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5. • The Process
occurs by the
Diffusionof Free
Drug until
equilibriumis
achieved.
Distributionis a
Passive Process,
for which the
driving force is the
Concentration
Gradient between
the blood and
Extravascular Tissues.
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6. As the Pharmacological action of a drug depends
upon its concentration at the site of action .
Distribution plays a significant role in the Onset,
Intensity, and Duration of Action.
Distribution of a drug is not Uniform throughout
the body because different tissues receive the
drug from plasma at different rates and to
different extents.
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7. Steps in drug distribution
Distribution of drug present in systemic circulation to extra vascular
tissues involves.
following steps
1)Permeation of free or unbound drug present in the blood through
the capillary wall(occurs rapidly)and entry in to the interstitial
/extracellular fluid(ECF)
2)Permeation of drug present in the ECF through the membrane of
tissues cells and in to the intracellular fluid. This step is rate
limiting and depends upon two major factors:
a.) Rate of perfusion to the extracellular tissue.
b.) Membrane permeability of the drug.
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8. 1) Tissue Permeability of the Drug
a. Physiochemical Properties of the drug like Molecular
size, pKa and o/w Partition coefficient.
b. Physiological Barriers to Diffusion of Drugs.
2)Organ / Tissue Size and Perfusion Rate
3)Binding of Drugs to Tissue Components
a)Binding of drug to Blood components.
b)Extravascular Tissue Proteins.
4)Miscellaneous Factors
Age, Pregnancy, Obesity, Diet, Disease states,Drug Interactions…
Factor affecting drug distribution:
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9. Tissue Permeability of the Drugs depend upon:
1. Rate of Tissue Permeability.
2. Rate of Blood Perfusion.
The Rate of Tissue Permeability, depends upon Physicochemical
Properties of the drug as well as Physiological Barriers that
restrict the diffusion of drug into tissues.
PhysicochemicalProperties that influence drug distribution are:
i. Molecular size,
ii. pKa and
iii. o/w Partition coefficient.
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10. ➢ Drugs having molecular wt. less than 500 to 600 daltons
easily cross the Capillary Membrane to diffuse into the
Extracellular Interstitial Fluids.
➢ However, penetration of drug from the Extracellular fluid
(ECF) is a function of :-
➢ Molecular Size:
Small ions of size below 50 Daltons enter the cell through Aq.
filled channels where as larger size ions are restricted unless a
specialized transport system exists for them.
➢ Ionisation:
❑ A drug that remains unionized at pH values of blood and ECF
can permeate the cells more rapidly.
❑ Blood and ECF pH normally remains constant at 7.4, unless
altered in conditions like Systemic alkalosis or acidosis.
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11. ➢ Lipophilicity:
❖ Only unionized drugs that are lipophilic rapidly cross the
cell membrane.
e.g. Thiopental, a lipophilic drug, largely unionized at Blood
and plasma pH readily diffuses the brain where as
Penicillin's which are polar and ionized at plasma pH do not
cross BBB.
❖In case of polar drug where permeability is the rate-limiting
step in the distribution ,the driving force is the Effective
Partition Coefficient for a drug is given by:
Effective K o/w = X
Fraction
unionizedat pH
7.4
K o/w unionized
drug
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12. Distribution of acid drug in CSF
Drug Relatively acidity Effective K o/w at
pH 7.4
Relative rate of
distribution
Thiopental Weaker acid 2.0 80
Salicylicacid Stronger acid 0.0005 1
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Thiopental distributes in CFS at a rate 80 time fasterthan Salicylic acid