Therapeutic Index.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.