Tolerance, Withdrawal and Sensitization PDF

104 Chapter 4 Dose-response curve for the analgesic effect of morphine Effect of drug high Margin of safety Dose-response curve for the depressive effect of morphine on respiration low low FIGURE Psychopharmacology Dose of drug high 4.3 Dose-Response Curves for Morphine Carlson/ POB,11e/...

104 Chapter 4 Dose-response curve for the analgesic effect of morphine Effect of drug high Margin of safety Dose-response curve for the depressive effect of morphine on respiration low low FIGURE Psychopharmacology Dose of drug high 4.3 Dose-Response Curves for Morphine Carlson/ POB,11e/C11B04F03.eps The dose-response curve on the left shows the analgesic 16.6 x 14.6 effect of morphine, and the curve on the right shows one of the drug’s adverse side effects: its depressant effect on respiration. A drug’s margin of safety is reflected by the difference between the dose-response curve for its therapeutic effects and that for its adverse side effects. respiration. A physician who prescribes an opiate to relieve a patient’s pain wants to administer a dose that is large enough to produce analgesia but not large enough to depress heart rate and respiration—effects that could be fatal. Figure 4.3 shows two dose-response curves, one for the analgesic effects of a painkiller and one for the drug’s depressant effects on respiration. The difference between these curves indicates the drug’s margin of safety. Obviously, the most desirable drugs have a large margin of safety. (See Figure 4.3.) One measure of a drug’s margin of safety is its therapeutic index. This measure is obtained by administering varying doses of the drug to a group of laboratory animals such as mice. Two numbers are obtained: the dose that produces the desired effects in 50 percent of the animals and the dose that produces toxic effects in 50 percent of the animals. The therapeutic index is the ratio of these two numbers. For example, if the toxic dose is five times higher than the effective dose, then the therapeutic index is 5.0. The lower the therapeutic index, the more care must be taken in prescribing the drug. For example, barbiturates have relatively low therapeutic indexes— as low as 2 or 3. In contrast, tranquilizers such as Valium have therapeutic indexes of well over 100. As a consequence, an accidental overdose of a barbiturate is much more likely to have tragic effects than a similar overdose of Valium. Why do drugs vary in their effectiveness? There are two reasons. First, different drugs—even those with the same behavioral effects—may have different sites of action. For example, both morphine and aspirin have analgesic effects, but morphine suppresses the activity of neurons in the spinal cord and brain that are involved in pain perception, whereas aspirin reduces the production of a chemical involved in transmitting information from damaged tissue to pain-sensitive neurons. Because the drugs act very differently, a given dose of morphine (expressed in terms of milligrams of drug per kilogram of body weight) produces much more pain reduction than the same dose of aspirin does. The second reason that drugs vary in their effectiveness has to do with the affinity of the drug with its site of action. As we will see in the next major section of this chapter, most drugs of interest to psychopharmacologists exert their effects by binding with other molecules located in the central nervous system—with presynaptic or postsynaptic receptors, with transporter molecules, or with enzymes involved in the production or deactivation of neurotransmitters. Drugs vary widely in their affinity for the molecules to which they attach—the readiness with which the two molecules join together. A drug with a high affinity will produce effects at a relatively low concentration, whereas a drug with a low affinity must be administered in higher doses. Thus, even two drugs with identical sites of action can vary widely in their effectiveness if they have different affinities for their binding sites. In addition, because most drugs have multiple effects, a drug can have high affinities for some of its sites of action and low affinities for others. The most desirable drug has a high affinity for sites of action that produce therapeutic effects and a low affinity for sites of action that produce toxic side effects. One of the goals of research by drug companies is to find chemicals with just this pattern of effects. Effects of Repeated Administration Often, when a drug is administered repeatedly, its effects will not remain constant. In most cases its effects will diminish—a phenomenon known as tolerance. In other cases a drug becomes more and more effective—a phenomenon known as sensitization. Let’s consider tolerance first. Tolerance is seen in many drugs that are commonly abused. For example, a x therapeutic index The ratio between the dose that produces the desired effect in 50 percent of the animals and the dose that produces toxic effects in 50 percent of the animals. x affinity The readiness with which two molecules join together. x tolerance A decrease in the effectiveness of a drug that is administered repeatedly. x sensitization An increase in the effectiveness of a drug that is administered repeatedly. Principles of Psychopharmacology regular user of heroin must take larger and larger amounts of the drug for it to be effective. And once a person has taken heroin regularly enough to develop tolerance, that individual will suffer withdrawal symptoms if he or she suddenly stops taking the drug. Withdrawal symptoms are primarily the opposite of the effects of the drug itself. For example, heroin produces euphoria; withdrawal from it produces dysphoria—a feeling of anxious misery. (Euphoria and dysphoria mean “easy to bear” and “hard to bear,” respectively.) Heroin produces constipation; withdrawal from it produces nausea and cramping. Heroin produces relaxation; withdrawal from it produces agitation. Withdrawal symptoms are caused by the same mechanisms that are responsible for tolerance. Tolerance is the result of the body’s attempt to compensate for the effects of the drug. That is, most systems of the body, including those controlled by the brain, are regulated so that they stay at an optimal value. When the effects of a drug alter these systems for a prolonged time, compensatory mechanisms begin to produce the opposite reaction, at least partially compensating for the disturbance from the optimal value. These mechanisms account for the fact that more and more of the drug must be taken to achieve a given level of effects. Then, when the person stops taking the drug, the compensatory mechanisms make themselves felt, unopposed by the action of the drug. Research suggests that there are several types of compensatory mechanisms. As we will see, many drugs that affect the brain do so by binding with receptors and activating them. The first compensatory mechanism involves a decrease in the effectiveness of such binding. Either the receptors become less sensitive to the drug (that is, their affinity for the drug decreases), or the receptors decrease in number. The second compensatory mechanism involves the process that couples the receptors to ion channels in the membrane or to the production of second messengers. After prolonged stimulation of the receptors, one or more steps in the coupling process become less effective. (Of course, both effects can occur.) The details of these compensatory mechanisms are described in Chapter 18, which discusses the causes and effects of drug abuse. As we saw, many drugs have several different sites of action and thus produce several different effects. This means that some of the effects of a drug may show tolerance but others may not. For example, barbiturates cause sedation and also depress neurons that control respiration. The sedative effects show tolerance, but the respiratory depression does not. This means that if larger and larger doses of a barbiturate are taken to achieve the same level of sedation, the person begins to run the risk of taking a dangerously large dose of the drug. Sensitization is, of course, the exact opposite of tolerance: Repeated doses of a drug produce larger and 105 larger effects. Because compensatory mechanisms tend to correct for deviations away from the optimal values of physiological processes, sensitization is less common than tolerance. And some of the effects of a drug may show sensitization while others show tolerance. For example, repeated injections of cocaine become more and more likely to produce movement disorders and convulsions, whereas the euphoric effects of the drug do not show sensitization—and may even show tolerance. Placebo Effects A placebo is an innocuous substance that has no specific physiological effect. The word comes from the Latin placere, “to please.” A physician may sometimes give a placebo to anxious patients to placate them. (You can see that the word placate also has the same root.) But although placebos have no specific physiological effect, it is incorrect to say that they have no effect. If a person thinks that a placebo has a physiological effect, then administration of the placebo may actually produce that effect. When experimenters want to investigate the behavioral effects of drugs in humans, they must use control groups whose members receive placebos, or they cannot be sure that the behavioral effects they observe were caused by specific effects of the drug. Studies with laboratory animals must also use placebos, even though we need not worry about the animals’ “beliefs” about the effects of the drugs we give them. Consider what you must do to give a rat an intraperitoneal injection of a drug. You reach into the animal’s cage, pick the animal up, hold it in such a way that its abdomen is exposed and its head is positioned to prevent it from biting you, insert a hypodermic needle through its abdominal wall, press the plunger of the syringe, and replace the animal in its cage, being sure to let go of it quickly so that it cannot turn and bite you. Even if the substance you inject is innocuous, the experience of receiving the injection would activate the animal’s autonomic nervous system, cause the secretion of stress hormones, and have other physiological effects. If we want to know what the behavioral effects of a drug are, we must compare the drug-treated animals with other animals who receive a placebo, administered in exactly the same way as the drug. (By the way, a skilled and experienced researcher can handle a rat so gently that it shows very little reaction to a hypodermic injection.) x withdrawal symptom The appearance of symptoms opposite to those produced by a drug when the drug is administered repeatedly and then suddenly no longer taken. x placebo (pla see boh) An inert substance that is given to an organism in lieu of a physiologically active drug; used experimentally to control for the effects of mere administration of a drug.