Pharmacokinetics

Definition: Pharmacokinetics is the quantitative study of the absorption, distribution, metabolism and excretion of drugs and their metabolites. In simple terms, pharmacokinetics (often simply called “kinetics”) is what the body does to the drug.

Plasma membranes and factors affecting passage

1. Drug factors that influence the ability of a drug to cross plasma membranes include molecular size and shape, solubility at the site of absorption, the degree of differences in pH across the membrane, the electrochemical gradient for the lipid form of the drug, degree of ionization, vascularity of the tissue, and relative solubility of ionized and nonionized forms.

2. The plasma membrane

3. The three most important ways by which drugs cross cell membranes are through channels, active transport, or direct penetration. The primary method of passage of drugs across plasma membrane is by passive diffusion and is directly proportional to magnitude of concentration gradient of the drug across the membrane & lipid solubility of the drug. Polar molecules (e.g., soluble in water) and ions cannot penetrate membranes.

Example: propranolol and nadolol are both non-selective beta-blockers. Propranolol is lipid soluble and nadolol is water soluble. Propranolol is rapidly & completely absorbed from the gut, has a large first pass effect (70%), is primarily metabolized by hepatic metabolism, and can cross the blood brain barrier to produce CNS side effects. Nadolol is poorly absorbed (30%), has no first pass effect, is primarily eliminated as such by renal filtration, and does not cross the blood brain barrier.

c. For nonpolar or lipid soluble drugs, the concentration of free drug is same on both sides of a membrane at steady state.

d. Many drugs are weak acids or weak bases and are present in solution as both ionized and nonionized. The nonionized is usually lipid soluble and able to penetrate the lipid membrane while the ionized form cannot penetrate the membrane and hence is not absorbed.

Thus, a weak acid (such as salicylic acid, the active metabolite of aspirin), in an acid medium (such as the stomach or acid urine,) is predominantly in the nonionized state (hence lipid soluble and can be absorbed). A weak base (e.g., morphine) in an acid medium is predominantly in the ionized state.

Clinical examples:

1. Treating salicylate toxicity by using sodium bicarbonate which is basic, alkalinizes the urine and hence increase the ionized form of salicylate that cannot be reabsorbed though the kidney tubules and hence excreted.

2. Phenobarbital (sodium - weak acid) is the only barbiturate with an ionization constant (7.4) close enough to blood and urine to be markedly affected by physiologically feasible pH changes. Treat phenobarbital toxicity with forced alkaline diuresis.

Carrier mediated membrane transport

(1) Active transport of some drugs (e.g., levodopa) occurs across neuronal membranes, the choroid plexus, renal tubular cells, and hepatocytes. Active transport is characterized by selectivity, competitive inhibition by congeners (similar drugs or metabolites), a requirement for energy, saturability, and movement against an electrochemical gradient

(2) Facilitated diffusion is a carrier-mediated transport process but there is no input of energy. The substance moves according to electrochemical gradient (some amino acids).

Category: Pharmacology Notes