Pharmacokienetic Principles (2): Distribution of Drugs Pharmacology I BMS 242 Lecture 3 Pharmacokienetic Principles (2): Distribution of Drugs Dr. Aya M. Serry 2016

What body does to the Drug Pharmacokinetics Absorption Metabolism What body does to the Drug Distribution Excretion

At the site of administration II. Distribution of Drugs Absorption Distribution Drug Blood Stream At the site of administration 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

Factors affecting drug Distribution 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

Factors affecting drug Distribution 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

Factors affecting drug Distribution B) Capillary Permeability Capillary Permeability is determined by two factors Capillary Structure of the Organ Chemical nature of the Drug

Capillary Structure of the Organ Factors affecting drug Distribution B) Capillary Permeability: Capillary Structure of the Organ

Capillary Structure of the Organ Factors affecting drug Distribution 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

Chemical Nature of the Drug Factors affecting drug Distribution 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)

Factors affecting drug Distribution 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)

Factors affecting drug Distribution 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.]

Factors affecting drug Distribution 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

Drug distribution and Body water Total body water plasma volume plasma extracellular interstitial volume 4 liters 6% interstitial volume 17 liters 26% intracellular volume intracellular 14 liters 20% 49 liters 70% Water composition in 70 Kg Body Weight 31 liters 44%

Factors affecting drug Distribution 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 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 6%

Factors affecting drug Distribution 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 6% 20% 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% 44%