DRUG DISTRIBUTION

FACTORS AFFECTING DRUG DISTRIBUTION

Dr. Sarwat Ali Raja

PhD Pharmacology & Toxicology
 Drug Distribution
2

Drugs are distributed to organs and

tissues through the circulation (via blood)
, from which they diffuse into interestitial
fluid and cells.

Dr. Sarwat Ali Raja (PhD)

 Different Possibilities of Drug
3
Distribution in the Body

Most drugs are not uniformly distributed

throughout the total body water;

 Some drugs are restricted to the extracellular fluid or

plasma compartment.

 Drugs with sufficient lipid solubility can diffuse into

cells.
Dr. Sarwat Ali Raja (PhD)
 Continued…..
4

 Some drugs are concentrated in cells by the

phenomenon of Ion-trapping e.g. with many weak
bases such as fluoxetine.

 Drugs can also be actively transported into cells by the

carrier e.g. some drugs are actively transported into
hepatic cells, where they undergo enzymatic
biotransformation.

Dr. Sarwat Ali Raja (PhD)

 Continued….
5

 Drugs are also transported by a carrier mediated transport

system that operates along the concentration
gradient(facilitated transport).
For Example , Intestinal absorption of vitamins
B1and B2 and vitamin B12 along with intrinsic factor.
 Volume of Distribution
 The volume of distribution can be defined as ;

“ The volume of fluid in which a drug would need to be

dissolved to have the same concentration in that volume as it does
in plasma”.

Dr. Sarwat Ali Raja (PhD)

 Vd Continued……
6

 The Vd does not represent the volume in a particular

physiologic body compartment instead “it is an
apparent volume that represents the relationship
between the dose of a drug and the resulting
plasma concentration of the drug”.

Dr. Sarwat Ali Raja (PhD)

 Calculation of Vd
7

 Vd is calculated generally by dividing the dose of a

drug (usually when given intravenously) by the
plasma drug concentration immediately after
distribution (Cpo).
Vd = Dose/Cpo
This equation can be rearranged to determine the
dose of a drug that is required to establish a
specified plasma drug concentration.

Dr. Sarwat Ali Raja (PhD)

 Interpretation of Vd
8

Vd does not correspond to a physiologic body fluid

compartment (e.g blood) , rather it provide an
indication of the physiologic distribution of a drug.

Dr. Sarwat Ali Raja (PhD)

 Continued….
9

I. A low Vd ( that approximates plasma volume or

extracellular fluid volume) usually indicates that the
drug’s distribution is restricted to a particular
compartment i.e plasma or extra-
cellular fluid.

Dr. Sarwat Ali Raja (PhD)

 Continued….
10

II . When the Vd of a drug is equivalent to total body

water this usually indicates that the drug has
reached the intracellular fluid as well .e.g with
ethanol ingestion.

Dr. Sarwat Ali Raja (PhD)

 Continued…..
11

III . Many drugs have a Vd that is much larger than

total body water. A large Vd usually indicates that
the drug is concentrated intracellularly with a
resulting low concentration in the plasma .

Dr. Sarwat Ali Raja (PhD)

 Factors Affecting Drug
12
Distribution
Most Important factors affecting Distribution are ;
1- ORGAN BLOOD FLOW:-
 The rate at which a drug is distributed to various
organs after a drug dose is administered depends
largely on the proportion of cardiac output
received by the organs.

Dr. Sarwat Ali Raja (PhD)

 Organ blood flow Continued…
13

Interpretation:-
 Drugs are rapidly distributed to highly
perfused tissues e.g brain,heart,liver and
kidney and this enables a rapid onset of
action of drugs affecting these tissues.

Dr. Sarwat Ali Raja (PhD)

 Interpretation Continued….
14

 Drugs are distributed more slowly to less highly

perfused tissues e.g skeletal muscles.

 Drugs are distributed even more slowly to those

with the lowest blood flow e.g skin and adipose
tissue.

Dr. Sarwat Ali Raja (PhD)

 Organ blood Flow Continued….
15

Inference:-
 Intially heart, liver, kidney, brain and other highly

perfused organs receive most of the drug during first

few minutes after absorption.

 There is redistribution of drug upon its release from

those sites as the drug re-enters the circulation and is
delivered to muscles , most viscera, skin and fat.

Dr. Sarwat Ali Raja (PhD)

 2-Plasma Protein Binding
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 Almost all drugs are reversibly bound to plasma

proteins , primarily albumin.

 The extent of binding depends on the affinity of a

particular drug for protein-binding sites and ranges
from less than 10% to as high as 99% of the
plasma concentration.

Dr. Sarwat Ali Raja (PhD)

 Plasma Protein Binding Continued…
17

 As the free(un-bound) drug diffuses into the interstitial

fluid and cells, drug molecules dissociate from albumin
to maintain the equilibrium between free drug and
bound drug.

 Plasma protein binding is saturable.

Dr. Sarwat Ali Raja (PhD)

 Plasma protein Binding
18
Continued…

 Protein binding becomes clinically important when it

involves a high proportion i.e more than 90% of drug
in the blood.

 Examples of highly protein bound drugs are;

Phenytoin, Propranolol, Prazosin, Warfarin, Tricyclic
antidepressants etc.

Dr. Sarwat Ali Raja (PhD)

 Clinical Significance of Plasma
19
protein Binding

 Protein-bound drugs donot undergo metabolism

and excretion through glomerular filtration.
Therefore heavily protein-bound drugs generally
have long plasma half-lives.

Dr. Sarwat Ali Raja (PhD)

 Clinical Significance continued….
20

 Protein-bound drugs may show drug displacement

interactions. Therefore, if such a drug that has a
narrow therapeutic index and has small volume of
distribution is heavily protein-bound, the
displacement may significantly increase the biological
activity and possible toxicity of the drug.

Dr. Sarwat Ali Raja (PhD)

 Clinical Significance Continued….
21

 Plasma Proteins are altered both in quantity and

chemical characteristics in renal and hepatic
diseases. There is decrease in drug binding and
the concentration of free drug increases resulting in
increased drug effects.

Dr. Sarwat Ali Raja (PhD)

 3-Molecular Size
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 Molecular size is a factor affecting the distribution

of extremely large molecules, such as those in
Heparin.

Dr. Sarwat Ali Raja (PhD)

 4-Lipid Solubility
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 Lipid solubility is a major factor affecting the extent

of drug distribution , particularly to the areas of the
body having anatomic barriers particularly to the
brain where the blood brain barrier restricts the
penetration of polar and ionized molecules.

Dr. Sarwat Ali Raja (PhD)

 Lipid Solubility Continued…
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Examples:-
 Thiopentone, Physostigmine, Levodopa readily
crosses blood brain barrier being highly lipid
soluble but Neostigmine , dopamine & penicillin
cannot enter the brain being highly ionized and of
low solubility and are not effective.

Dr. Sarwat Ali Raja (PhD)

 5-Storage of Drugs in Tissues
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Apart from above factors , some drugs have selective

preference for certain tissues and they are
concentrated in these tissues e.g
 Mepacrine is stored in liver.

 Chloroquine in liver and retina.

 Arsenic in keratinous tissue

 Calcium in bones

 Lipid soluble substances in the body fat depot.

Dr. Sarwat Ali Raja (PhD)

 Reference Books
26

 Essentials of Medical Pharmacology by K.D. Tripathi, Edition 7th.

 Lippincott’s illustrated review, Pharmacology, Edition 6th.
 Pharmacology by George M Brenner, Edition 4th.
 Katzung B G, Basic and Clinical Pharmacology, McGraw-Hill Medical Publishers, New York,
12th Edition.
 Katzung & Trevor, Edition 11th.
 Goodman Gillman, Pharmacological basis of therapeutics. McGraw-Hill Book Company, New
York, 12th Edition
 Color Atlas of Pharmacology 3rd edition, revised and expanded by Heinz Lüllmann, M.D.,
Klaus Mohr, M.D., Lutz Hein, M.D. & Detlef Bieger, M.D.
 Rang and Dale’s Pharmacology7th Edition.
 Pharmacology for Medical Graduates by Tara V Shanbhag & Smita Shenoy, 3rd Edition.
 Textbook of Comprehensive Pharmacy Review for Naplex by Leon Shargel, 8th edition.

Dr. Sarwat Ali Raja (PhD)