Transcript Pharmacology 242 GBC - INAYA Medical College

Pharmacology I
BMS 242
Lecture 3
Pharmacokienetic Principles (2):
Distribution of Drugs
Dr. Aya M. Serry
2016
Pharmacokinetics
What body does
to the Drug
Drug
At the site of
administration
Blood
Stream
Site of
Action
Distribution is : the process by which the drug reaches the
site of its action
Another Definition: Drug distribution is the process by
which a drug reversibly leaves the bloodstream and enters
the extracellular fluid and/or the cells of the tissues
The delivery of a drug from the plasma to the extracellular
fluid primarily depends on :
• Blood flow
• Capillary permeability
• The degree of binding of the drug to plasma and tissue proteins
• the relative hydrophobicity of the drug
A) Blood Flow

The rate of blood flow to the tissue capillaries varies widely as a result
of the unequal distribution of cardiac output to the various organs
•
Blood flow to the brain, liver, and kidney is greater than that to the
skeletal muscles and adipose tissue
B) Capillary Permeability
•
Capillary Permeability is determined by two factors
Capillary Structure of
the Organ
Chemical nature of the
Drug
B) Capillary Permeability:
Capillary Structure of
the Organ
B) Capillary Permeability:
Capillary Structure of
the Organ
• In the brain, the capillary structure is continuous, and there are no slit
junctions
• This contrasts with the liver and spleen, where a large part of the
basement membrane is exposed due to large, discontinuous capillaries
through which large plasma proteins can pass
Blood Brain Barrier (BBB) :
A physiological mechanism that alters the permeability
of brain capillaries so that some substances (as
certain drugs and toxins) are prevented from entering
brain tissue, while other substances (as nutrients) are
allowed to enter freely
B) Capillary Permeability:
Chemical Nature of the
Drug
•The chemical nature of a drug strongly influences its ability to
cross cell membranes
• Hydrophobic drugs, which are not charged, readily move across
most biologic membranes (dissolve in the lipid membrane Bi-layer)
• The opposite for hydrophilic drugs, which have either a positive or
negative charge, do not readily penetrate cell membranes, and must
go through the slit junctions (Pores within cell membrane)
C) Binding of the drugs to Plasma Proteins and tissues
• Reversible binding to plasma proteins traps a drug in a non-diffusible
form and slows their transfer out of the vascular compartment
• PLASMA ALBUMIN is the major drug-binding protein and may act as a
drug reservoir;. i.e.: when the concentration of the free drug decreases
due to metabolism or excretion, the bound drug dissociates from the
protein. This maintains the free-drug concentration constant (Equilibrium)
C) Binding of the drugs to Plasma Proteins and tissues
• Drug may also bind to tissue proteins; accumulate in tissues (Reservoir),
leading to higher concentrations of the drug in tissues than in the
extracellular fluids and blood
• These tissue reservoirs may serve as a major source of the drug and
prolong its actions or, on the other hand, can cause local drug toxicity.
[Example: ACROLEIN, the metabolite of cyclo-phosphamide is toxic to the
KIDNEY because of its accumulation in renal cells.]
D) The Volume of Distribution (Vd)
• The volume in which the amount of drug is uniformly distributed in,
in order to produce the observed blood concentration
• Although Vd has no physiologic or physical basis, it can be useful to
compare the distribution of a drug with the volumes of the water
compartments in the body
amount of drug in body
Vd 
plasma drug concentrat ion
Drug distribution and Body water
Total body water
plasma
plasma volume
extracellular
interstitial
volume
4 liters
6%
17 liters
26%
intracellular
volume
intracellular
49 liters
70%
Water composition in
70 Kg Body Weight
31 liters 44%
interstitial volume
14 liters
20%
Distribution into the water compartments in the body:
Once a drug is administered to the body, it has the ability to distribute
into any one of three functionally distinct compartments of body water
or to become trapped in a cellular site
a- Plasma Compartment
6%
• If a drug has a very large molecular weight or binds extensively to plasma
proteins, it is too large to move out through the endothelial slit junctions of the
capillaries and, thus, is effectively trapped within the plasma (vascular)
compartment
Distribution into the water compartments in the body:
b- Extracellular Fluid (Plasma + Interstitial Fluid)
• If a drug has a low molecular weight but is hydrophilic, it can move
through the endothelial slit junctions of the capillaries into the
interstitial fluid. However, it cannot move across the lipid
membranes of cells to enter the water phase inside the cell
C- Total Body water (Extra cellular + Intracellular)
• If a drug has a low molecular weight and is hydrophobic, not only
can it move into the interstitial fluid, but it can also move through
the cell membranes into the intracellular fluid
6%
20%
6%
20%
44%