Pharmacology: Pharmacokinetic

1. Distribution of drugs
Mr. Dipak B. Bari,
KES’S Late Shri P C Bhandarkar College of D. Pharmacy,
Amalner

2. overview
Introduction
Factors affecting distribution
Barriers to distribution
Special compartments for drug
distribution
Plasma protein binding
Volume of distribution

3. Distribution
Reversible transfer of drugs
between one compartment and
another ( between blood &
extravascular fluids & tissues)

4.  Distribution is predominantly a passive process -
The driving force is the concentration gradient
between the blood and extravascular tissues
 Process occurs by the diffusion of free drug
until equilibrium is established.

5.  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.

6. Steps in drug distribution
 Permeation of free or unbound drug into interstitial
/ extracellular fluid
 Permeation of drug present in extracellular fluid into
intracellular fluid { rate limiting step}

7. Compartment through which drugs
equilibrates:
Central Compartment: The central compartment
includes the well-perfused organs and tissues (heart,
blood, liver, brain and kidney) with which drug
equilibrates rapidly.
Peripheral Compartment(s): The peripheral
compartment(s) include(s) those organs (e.g., adipose
and skeletal muscle) which are less well-perfused, and
with which drug therefore equilibrates more slowly.
Redistribution from one compartment to another
often alters the duration of effect at the target
tissue

8. Special Compartments:
Entry of drug into the cerebrospinal fluid (CSF) and
central nervous system (CNS) is restricted by the
structure of the capillaries and pericapillary glial
cells.
Drugs also have relatively poor access to pericardial
fluid, bronchial secretions and fluid in the middle
ear, thus making the treatment of infections in these
regions difficult

9. Plasma protein binding
After absorption of drug from GIT into blood, it is
distributed by binding to plasma proteins.
The phenomenon of complex formation between
drug & plasma protein is called plasma protein
binding.

10. DRUGS BINDING PROTEIN
WEAK ACIDS AND
NEUTRAL DRUGS
ALBUMIN
BASIC DRUGS ALPHA-1-ACID
GLYCOPROTEIN
SOME DRUGS SURFACE PROTEINS

11. Effect of protein binding on
distribution:
Only that fraction of the plasma drug concentration
which is freely circulating (i.e., unbound) can penetrate
cell membranes.
Protein binding thus decreases the net transfer of
drug across membranes.
Drug binding to plasma proteins is generally weak and
rapidly reversible, however, so that protein-bound drug
can be considered to be in a temporary storage
compartment.
Drug having higher affinity for protein binding
increases the duration of action of drug

12. Lipid: water partition coefficient of drug:
Drug with higher affinity to lipid shows lower
distribution.
Pka value of drug: If drug administered orally,
if it is weak acid absorbed on intestine or colon &
weak bases absorbed from stomach which
influences distribution.
Factor affecting Drug Distribution:

13. pKa - pH of blood & ECF (7.4) play a role in
degree of ionization, unionized drug diffuse
rapidly.
eg. Acidosis →↓ ionization of acidic drugs → ↑
concentration and duration of action
Alkalosis (sodium bicarbonate)→↑ ionization of
acidic drug like barbiturate → prevents further
entry into CNS and promote urinary excretion

14. Rout of drug administration: IV routs have greater
distribution than any other rout.
Degree of plasma protein binding: Drug having higher
protein binding shows lower distribution.
Regional blood flow: Certain body organ like ear has
lower blood flow which affect distribution.
Disease like uremia (impairment of kidney) & cirrhosis
(impairment of liver) affect distribution.
Fat lean body mass ratio: Which can vary with age,
sex & obesity, fatty person has greater adipose tissue
& higher will be storage of drug in adipose tissue
decreases distribution of drug.

15. Apparent volume of distribution:
The volume of distribution, or more properly the
apparent volume of distribution, is calculated from
measurements of the total concentration of drug in
the blood compartment after a single IV injection.
Suppose that we injected someone IV with 100 mg of a
drug, and measured the blood concentration of the
drug repeatedly during the next several hours & it is
calculated by

16. Apparent volume of
distribution
aVd = Total amount of drug (mg/kg)
Concentration of drug in plasma
(mg/l)

17. •Drug concentrations in body compartments will
vary according to the physicochemical properties of
the drug.
•Thus, Vd is a characteristic property of the drug
rather than the patient, although disease states
may influence Vd.
•If binding to plasma proteins is marked, most of
the drug will be maintained within the intravascular
compartment and Vd will be small.
•If there is extravascular binding, or storage in fat
or other tissues, Vd will be large.