Pharmacokinetics Implications For Abusable Substances

Pharmacokinetics is the study of the movements and rates of movement of drugs within the body, as the drugs are affected by uptake, distribution, binding, elimination, and biotransformation. An understanding of the biological basis of the clinical actions of abused drugs depends, in part, on knowledge of their neurochemical and neurorecptor actions that reinforce and sustain drug use (Hall, Talbert, & Ereshefsk, 1990). The pharmacokinetic properties of abusable substances represent a second important component of the database. The discipline of pharmacokinetics applies mathematical models to understand and predict the time course of drug amounts (doses) and their concentrations in various body fluids (Greenblatt, 1991, 1992; Greenblatt & Shader, 1985). Pharmacokinetic principles can be used to provide quantitative answers to questions involving the relationship of drug dosage and route of administration to the amount and time course of the drug present in systemic blood and at the receptor site of action.

Before an orally administered PSYCHOACTIVE DRUG can exert a pharmacological effect through its molecular recognition site in the brain, a number of events must take place (see Figure 1). The drug must reach the stomach and dissolve in gastric fluid. The stomach empties this solution into the proximal small bowel, which is the site of absorption of most medications. The drug must diffuse across the gastrointestinal mucosal barrier, reach the portal circulation, and be delivered to the hepatic (liver) circulation. (The liver detoxifies chemicals, including drugs.) Before reaching the systemic circulation, then, the absorbed drug must "survive" this initial exposure to the hepatic circu lation—sometimes termed the ''first-pass'' through the liver (Greenblatt, 1993). After reaching the systemic blood, the drug is transported to the cerebral (brain) capillary circulation as well as to all other sites in the body that receive blood directly from the heart (cardiac output). The drug diffuses out of the

Figure 1

Schematic Representation of Physiological and Pharmacokinetic Events. These occur between administration of a centrally acting compound and the production of a pharmacological effect. If the medication is given orally, it must pass from the gastrointestinal (GI) tract to the portal circulation and to the liver before reaching the systemic circulation. Intravenous administration, however, yields direct access to the systemic circulation. Drugs of abuse may be taken by the intravenous route but are also taken by intranasal, intrabuccal, or inhalational routes, all of which will avoid the initial gastrointestinal-portal-hepatic exposure.

Receptor

Figure 1

Schematic Representation of Physiological and Pharmacokinetic Events. These occur between administration of a centrally acting compound and the production of a pharmacological effect. If the medication is given orally, it must pass from the gastrointestinal (GI) tract to the portal circulation and to the liver before reaching the systemic circulation. Intravenous administration, however, yields direct access to the systemic circulation. Drugs of abuse may be taken by the intravenous route but are also taken by intranasal, intrabuccal, or inhalational routes, all of which will avoid the initial gastrointestinal-portal-hepatic exposure.

cerebral capillary circulation, crosses the lipoidal (fatty) blood-brain barrier, and reaches the extracellular water surrounding the neuroreceptor site of action. Only then is the drug available to interact with its specific molecular recognition site.

All of these processes take time, and some may serve as obstacles that delay or prevent the drug from reaching its site of action. Pharmacokinetic models incorporate the physiology of these processes, and can allow rational prediction of important clinical questions: How much drug reaches the brain? How fast does it get there? How long does it stay there?

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