Pharmacological Phenomena

Tolerance While abuse and addiction are complex conditions combining the many variables outlined earlier, there are a number of relevant pharmacological phenomena that occur independently of social and psychological dimensions. First are the changes in the way the body responds to a drug with repeated use. Tolerance, the most common response to repetitive use of the same drug, can be defined as the reduction in response to the drug after repeated administrations. Figure 23-1 shows an idealized dose-response curve for an administered drug. As the dose of the drug increases, the observed effect of the drug increases. With repeated use of the drug, however, the curve shifts to the right (tolerance). Thus, a higher dose is required to produce the same effect that once was obtained at a lower dose. As outlined in Table 23-3, there are many forms of tolerance, likely arising via multiple mechanisms.

Tolerance develops to some drug effects much more rapidly than to other effects of the same drug. For example, tolerance develops rapidly to the euphoria produced by opioids such as heroin, and addicts tend to increase their dose in order to reexperience that elusive "high." In contrast, tolerance to the gastrointestinal (GI) effects of opiates develops more slowly. The discrepancy between tolerance to euphorigenic effects (rapid) and tolerance to effects on vital functions (slow), such as respiration and blood pressure, can lead to potentially fatal accidents in sedative abusers.

Innate tolerance refers to genetically determined sensitivity (or lack of sensitivity) to a drug that is observed the first time that the drug is administered.

Acquired tolerance can be divided into three major types: pharmacokinetic, pharmacody-namic, and learned tolerance, and includes acute, reverse, and cross-tolerance.

Pharmacokinetic, or dispositional, tolerance refers to changes in the distribution or metabolism of a drug after repeated administrations such that a given dose produces a lower blood concentration than the same dose did on initial exposure (see Chapter 1).

FIGURE 23-1 Shifts in a dose—response curve with tolerance and sensitization. With tolerance, there is a shift of the curve to the right such that doses higher than initial doses are required to achieve the same effects. With sensitization, there is a leftward shift of the dose-response curve such that for a given dose, there is a greater effect than seen after the initial dose.

FIGURE 23-1 Shifts in a dose—response curve with tolerance and sensitization. With tolerance, there is a shift of the curve to the right such that doses higher than initial doses are required to achieve the same effects. With sensitization, there is a leftward shift of the dose-response curve such that for a given dose, there is a greater effect than seen after the initial dose.

Dose

Table 23-3

Types of Tolerance

Innate (pre-existing sensitivity or insensitivity) Acquired

Pharmacokinetic (dispositional or metabolic) Pharmacodynamic Learned tolerance Behavioral Conditioned Acute tolerance

Reverse tolerance (sensitization) Cross-tolerance

Pharmacodynamic tolerance refers to adaptive changes that have taken place within systems affected by the drug so that response to a given concentration of the drug is reduced (see Chapters 1 and 12).

Learned tolerance refers to a reduction in the effects of a drug owing to compensatory mechanisms that are acquired by past experiences. One type of learned tolerance is called behavioral tolerance. This simply describes the skills that can be developed through repeated experiences with attempting to function despite a state of mild-to-moderate intoxication.

Conditioned tolerance (situation-specific tolerance) develops when environmental cues such as sights, smells, or situations consistently are paired with the administration of a drug. When a drug affects homeostatic balance by producing sedation and changes in blood pressure, pulse rate, gut activity, etc., there is usually a reflexive counteraction or adaptation in the direction of maintaining the status quo. If a drug always is taken in the presence of specific environmental cues (e.g., smell of drug preparation and sight of syringe), these cues begin to predict the effects of the drug, and the adaptations begin to occur even before the drug reaches its sites of action. If the drug always is preceded by the same cues, the adaptive response to the drug will be learned, and this will prevent the full manifestation of the drug's effects (tolerance).

The term acute tolerance refers to rapid tolerance developing with repeated use on a single occasion.

Sensitization

With stimulants such as cocaine or amphetamine, reverse tolerance, or sensitization, can occur. This refers to an increase in response with repetition of the same dose of the drug (learned drug effect). Sensitization results in a shift to the left of the dose—response curve (Figure 23-1). Sensitization, in contrast to acute tolerance during a binge, requires a longer interval between doses, usually ~1 day. It has been postulated that stimulant psychosis results from a sensitized response after long periods of use.

Cross-tolerance occurs when repeated use of a drug in a given category confers tolerance not only to that drug but also to other drugs in the same structural and mechanistic category. Understanding cross-tolerance is important in the medical management of persons dependent on any drug. Detoxification is a form of treatment for drug dependence that involves giving gradually decreasing doses of the drug to prevent withdrawal symptoms, thereby weaning the patient from the drug of dependence (see below).

Physical Dependence

Physical dependence is a state that develops as a result of the adaptation (tolerance) produced by a resetting of homeostatic mechanisms in response to repeated drug use. Drugs can affect numerous systems that previously were in equilibrium; these systems find a new balance in the presence of inhibition or stimulation by a specific drug. A person in this adapted or physically dependent state requires continued administration of the drug to maintain normal function. If administration of the drug is stopped abruptly, there is another imbalance, and the affected systems again must go through a process of readjusting to a new equilibrium without the drug.

WITHDRAWAL SYNDROME The appearance of a withdrawal syndrome when administration of the drug is terminated is the only actual evidence of physical dependence. Withdrawal signs and symptoms occur when drug administration in a physically dependent person is terminated abruptly. Withdrawal symptoms have at least two origins: (1) removal of the drug of dependence and (2) CNS hyperarousal owing to readaptation to the absence of the drug of dependence. Pharmacokinetic variables are of considerable importance in the amplitude and duration of the withdrawal syndrome. Withdrawal symptoms are characteristic for a given category of drugs and tend to be opposite to the original effects produced by the drug before tolerance developed. Tolerance, physical dependence, and withdrawal are all biological phenomena. They are the natural consequences of drug use and can be produced in experimental animals and in any human being who takes certain medications repeatedly. These symptoms in themselves do not imply that the individual is involved in abuse or addiction. Patients who take medicine for appropriate medical indications and in correct dosages still may show tolerance, physical dependence, and withdrawal symptoms if the drug is stopped abruptly rather than gradually.

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