Drug Elimination Metabolism Biotransformation and Excretion

Some effects of psychoactive drugs persist longer than the molecules that brought them about—such as the long-term effects of hallucinogens. Obviously, changes elicited in normal neurochemical balances can continue without the immediate influence of a drug. Nevertheless, as a rule, drugs cease to cause their specific physiological effects when they are structurally altered so that this renders them inactive or when they have been excreted from the body. Together these processes are called elimination, and the main elimination pathway for many drugs is their metabolic biotransformation in the liver and renal excretion of the water-soluble metabolites so produced. Nevertheless, there are exceptions to this rule. For example, active metabolites are sometimes formed in the liver.

The liver is mainly responsible for transforming biologically active molecules into harmless substances. Biotransformation is exerted through a host of chemical reactions catalyzed by enzyme systems in the liver cells, which are specialized for the efficient modification of substances belonging to various classes of chemicals. Thus an important concept in pharmacokinetics is the hepatic first-pass. When the major portion of a drug dose passes through the liver without first being distributed throughout the body, much of it can be metabolized before ever having the chance to reach its site of action. This occurs when the drug is administered orally, because drugs absorbed from the small intestine enter the hepatic portal circulation, and the inacti-vation of some drugs is of such proportion that an alternative route of administration is required.

Certain drugs have active metabolites. For example, oxazepam is itself an active metabolite of diazepam, and thus has a shorter duration of action. The possibility of active metabolites should always be considered with new drugs in the experimental phase.

Drugs and their metabolites can leave the body through the kidneys in urine, by exhalation via the lungs, excretion in bile into the intestine, or in sweat or saliva. For psychoactive drugs, the first route is the one to consider. In addition, one should acknowledge that in breastfeeding women, psychoactive drugs are present in milk, and this can have an deleterious effect on the infant.

Three processes that occur in the kidneys are important for drug excretion. The first of these is glomerular filtration, which refers to the formation of ultrafiltrate of blood plasma in the kidney subunits. This primary urine is free of plasma proteins, and thus protein-bound drugs remain in the blood. Most of this fluid and its ingredients are reabsorbed. Thus, reabsorption is the second important step. As in other diffusion processes involving cell membranes, substances that are lipid soluble can pass these semipermeable barriers easily. Psychoactive drugs, as emphasized above, are lipid soluble, and thus prone to be reabsorbed. The biotransforming action of the liver, which leads to the formation of more water-soluble molecules, is thus important for the excretion of these substances. The third process in urine formation, active excretion of certain substances, has less significance in psychopharmacology.

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