Dose Response Curve.pdf

103 primarily by the kidneys. The liver plays an especially active role in enzymatic deactivation of drugs, but some deactivating enzymes are also found in the blood. The brain also contains enzymes that destroy some drugs. In some cases, enzymes transform molecules of a drug into other forms that...

103 primarily by the kidneys. The liver plays an especially active role in enzymatic deactivation of drugs, but some deactivating enzymes are also found in the blood. The brain also contains enzymes that destroy some drugs. In some cases, enzymes transform molecules of a drug into other forms that themselves are biologically active. Occasionally, the transformed molecule is even more active than the one that is administered. In such cases the effects of a drug can have a very long duration. 600 500 Intravenous (0.6 mg/kg) 400 Smoked (100 mg base) 300 Oral (2 mg/kg) 200 Intranasal (2 mg/kg) 100 Drug Effectiveness 0 0 60 120 180 240 300 360 420 480 Time (min) FIGURE 4.1 Cocaine in Blood Plasma Carlson/ POB,11e/C11B04F01.eps The graph shows the concentration of cocaine in blood 20.0 x 14.8 plasma after intravenous injection, inhalation, oral administration, and sniffing. (Adapted from Feldman, R. S., Meyer, J. S., and Quenzer, L. F. Principles of Neuropsychopharmacology. Sunderland, MA: Sinauer Associates, 1997; after Jones, R. T. NIDA Research Monographs, 1990, 99, 30–41.) ENTRY OF DRUGS INTO THE BRAIN As we saw, drugs exert their effects only when they reach their sites of action. In the case of drugs that affect behavior, most of these sites are located on or in particular cells in the central nervous system. The previous section described the routes by which drugs can be introduced into the body. With the exception of intracerebral or intracerebroventricular administration, the routes of drug administration vary only in the rate at which a drug reaches the blood plasma (that is, the liquid part of the blood). But what happens next? All the sites of action of drugs of interest to psychopharmacologists lie outside the blood vessels. The most important factor that determines the rate at which a drug in the bloodstream reaches sites of action within the brain is lipid solubility. The blood–brain barrier is a barrier only for water-soluble molecules. Molecules that are soluble in lipids pass through the cells that line the capillaries in the central nervous system, and they rapidly distribute themselves throughout the brain. For example, diacetylmorphine (more commonly known as heroin) is more lipid soluble than morphine is. Thus, an intravenous injection of heroin produces more rapid effects than does one of morphine. Even though the molecules of the two drugs are equally effective when they reach their sites of action in the brain, the fact that heroin molecules get there faster means that they produce a more intense “rush,” and this explains why drug addicts prefer heroin to morphine. INACTIVATION AND EXCRETION Drugs do not remain in the body indefinitely. Many are deactivated by enzymes, and all are eventually excreted, Drugs vary widely in their effectiveness. The effects of a small dose of a relatively effective drug can equal or exceed the effects of larger amounts of a relatively ineffective drug. The best way to measure the effectiveness of a drug is to plot a dose-response curve. To do this, subjects are given various doses of a drug, usually defined as milligrams of drug per kilogram of a subject’s body weight, and the effects of the drug are plotted. Because the molecules of most drugs distribute themselves throughout the blood and then throughout the rest of the body, a heavier subject (human or laboratory animal) will require a larger quantity of a drug to achieve the same concentration as a smaller quantity will produce in a smaller subject. As Figure 4.2 shows, increasingly stronger doses of a drug cause increasingly larger effects until the point of maximum effect is reached. At this point, increasing the dose of the drug does not produce any more effect. (See Figure 4.2.) Most drugs have more than one effect. Opiates such as morphine and codeine produce analgesia (reduced sensitivity to pain), but they also depress the activity of neurons in the medulla that control heart rate and high After this point, increasing the dose does not produce a stronger effect Effect of drug Plasma cocaine concentration (ng/ml) Principles of Psychopharmacology low low FIGURE Dose of drug 4.2 A Dose-Response Curve high Carlson/ POB,11e/C11B04F02.eps Increasingly stronger doses of the drug produce 16.7 x 14.2 increasingly larger effects until the maximum effect is reached. After that point, increments in the dose do not produce any increments in the drug’s effect. However, the risk of adverse side effects increases.