Pharmacokinetics: Distribution & Elimination

1. The body handles most drugs by 1^st order reactions, e.g., rate is of absorption and elimination is proportional to concentration. The higher the blood concentration, the faster it is eliminated.
2. Few drugs (Eg- alcohol, phenytoin etc) follow zero order kinetics, where rate is independent of concentration (sometimes called "saturation kinetics", capacity-limited elimination, or Michaelis Menten kinetics). These drugs, at therapeutic concentrations, are the best known drugs with zero order elimination.

1. Plasma proteins

1. Many drugs bind to plasma proteins (generally, albumin for acid drugs or alpha₁-acid glycoprotein [AAG] for basic drugs although many basic drugs also bind to albumin). Binding is usually reversible and is very complex.
2. The binding of a drug to plasma proteins limits its concentrations in tissues and at the locus of action because only unbound drug is in equilibrium across membranes (bound drug acts as a depot.
3. Binding may be relatively nonselective for drugs with similar physicochemical characteristics. Such drugs may compete with each other as well as with endogenous substances for binding sites
4. Alcoholism, pregnancy, aging, congestive heart failure, malnutrition, burns, trauma, kidney and liver disease and many other conditions may lower plasma albumin. Renal disease may also change albumin configuration resulting in decreased binding. “Usual doses of a highly bound drug to persons with diminished plasma albumin may result in drug toxicity because of the increase in free drug.

2. Half Life:

1. Half-life is the time it takes the total amount of the drug in the body to be 50% eliminated from the body. However, when we measure "half-life" we determine the time it takes plasma concentration to be reduced by 50%. This is more correctly termed the plasma elimination half-life (symbolized as t½). A drug’s half-life can vary greatly from patient to patient (usually associated with impairment of the liver or kidneys).
2. The half-life can be determined from a plasma elimination curve or can be calculated. Half-life changes inversely with clearance and directly with volume of distribution, hence:t½ = 0.693 x V/Cl

The half-life is not always a good indicator of drug elimination or even of duration of action of a drug. However, it does provide a good indication of the time required to reach steady state after a dosage regimen is initiated or to decay by 50% from steady state after stopping a drug.

With repeated drug administration it takes about five (texts vary from 4 to 7) doses of drug administered on the half-life for the drug to reach a plateau in plasma concentration (steady state)

3. Clearance is the measure of the body's ability to eliminate a drug. It can be calculated.

The organs can only clear drugs from the blood with which they are in direct contact. As clearance is decreased (due to disease, for example), half-life would be expected to increase provided there is no change in Vd. Similarly, diseases that change protein binding of drugs may affect clearance as well as Vd. Generally, lipid soluble drugs are cleared through the liver; water soluble drugs through the kidneys. The balance of hepatic and renal clearance of both the parent drug and any active metabolites must be understood to prescribe wisely.

Category: Pharmacology Notes