Mechanisms of Drug Action PDF

106 Chapter 4 Psychopharmacology SECTION SUMMARY Principles of Psychopharmacology Psychopharmacology is the study of the effects of drugs on the nervous system and behavior. Drugs are exogenous chemicals that are not necessary for normal cellular functioning that significantly alter the functions...

106 Chapter 4 Psychopharmacology SECTION SUMMARY Principles of Psychopharmacology Psychopharmacology is the study of the effects of drugs on the nervous system and behavior. Drugs are exogenous chemicals that are not necessary for normal cellular functioning that significantly alter the functions of certain cells of the body when taken in relatively low doses. Drugs have effects, physiological and behavioral, and they have sites of action—molecules located somewhere in that body with which they interact to produce these effects. Pharmacokinetics is the fate of a drug as it is absorbed into the body, circulates throughout the body, and reaches its sites of action. Drugs may be administered by intravenous, intraperitoneal, intramuscular, and subcutaneous injection; they may be administered orally, sublingually, intrarectally, by inhalation, and topically (on skin or mucous membrane); and they may be injected intracerebrally or intracerebroventricularly. Lipid-soluble drugs easily pass through the blood–brain barrier, whereas others pass this barrier slowly or not at all. The time courses of various routes of drug administration are different. Eventually, drugs disappear from the body. Some are deactivated by enzymes, especially in the liver, and others are simply excreted. The dose-response curve represents a drug’s effectiveness; it relates the amount administered Sites of Drug Action Throughout the history of our species, people have discovered that plants—and some animals—produce chemicals that act on the nervous system. (Of course, the people who discovered these chemicals knew nothing about neurons and synapses.) Some of these chemicals have been used for their pleasurable effects; others have been used to treat illness, reduce pain, or poison other animals (or enemies). More recently, scientists have learned to produce completely artificial drugs, some with potencies far greater than those of the naturally occurring drugs. The traditional uses of drugs remain, but in addition they can be used in research (usually in milligrams per kilogram of the subject’s body weight) to the resulting effect. Most drugs have more than one site of action and thus more than one effect. The safety of a drug is measured by the difference between doses that produce desirable effects and those that produce toxic side effects. Drugs vary in their effectiveness because of the nature of their sites of actions and the affinity between molecules of the drug and these sites of action. Repeated administration of a drug can cause either tolerance, often resulting in withdrawal symptoms, or sensitization. Tolerance can be caused by decreased affinity of a drug with its receptors, by decreased numbers of receptors, or by decreased coupling of receptors with the biochemical steps it controls. Some of the effects of a drug may show tolerance, while others may not—or may even show sensitization. THOUGHT QUESTIONS 1. Choose a drug whose effects you are familiar with and suggest where in the body the sites of action of that drug might be. 2. Some drugs can cause liver damage if large doses are taken for an extended period of time. What aspect of the pharmacokinetics of these drugs might cause the liver damage? j laboratories to investigate the operations of the nervous system. Most drugs that affect behavior do so by affecting synaptic transmission. Drugs that affect synaptic transmission are classified into two general categories. Those that block or inhibit the postsynaptic effects are called antagonists. Those that facilitate them are called agonists. (The Greek word agon means “contest.” Thus, an agonist is one who takes part in the contest.) x antagonist A drug that opposes or inhibits the effects of a particular neurotransmitter on the postsynaptic cell. x agonist A drug that facilitates the effects of a particular neurotransmitter on the postsynaptic cell. Sites of Drug Action This section will describe the basic effects of drugs on synaptic activity. Recall from Chapter 2 that the sequence of synaptic activity goes like this: Neurotransmitters are synthesized and stored in synaptic vesicles. The synaptic vesicles travel to the presynaptic membrane, where they become docked. When an axon fires, voltage-dependent calcium channels in the presynaptic membrane open, permitting the entry of calcium ions. The calcium ions interact with the docking proteins and initiate the release of the neurotransmitters into the synaptic cleft. Molecules of the neurotransmitter bind with postsynaptic receptors, causing particular ion channels to open, which produces excitatory or inhibitory postsynaptic potentials. The effects of the neurotransmitter are kept relatively brief by their reuptake by transporter molecules in the presynaptic membrane or by their destruction by enzymes. In addition, the stimulation of presynaptic autoreceptors on the terminal buttons regulates the synthesis and release of the neurotransmitter. The discussion of the effects of drugs in this section follows the same basic sequence. All of the 107 effects I will describe are summarized in Figure 4.4, with some details shown in additional figures. I should warn you that some of the effects are complex, so the discussion that follows bears careful reading. I recommend that you Simulate actions of drugs on MyPsychLab, which reviews this material. Effects on Production of Neurotransmitters The first step is the synthesis of the neurotransmitter from its precursors. In some cases the rate of synthesis and release of a neurotransmitter is increased when a View precursor is administered; in these cases the precursor itself serves as an agonist. (See step 1 in Figure 4.4.) Watch The steps in the synthesis of neurotransmitters are controlled by enzymes. Therefore, if a drug inactivates Listen one of these enzymes, it will prevent the neurotransmitter from being produced. Such a drug serves as an Explore antagonist. (See step 2 in Figure 4.4.) Simulate Study and Review Drug serves as precursor AGO (e.g., L-DOPA—dopamine) 1 2 Read Precursor Map 3 4 Drug prevents storage of NT in vesicles ANT (e.g., reserpine—monoamines) Drug inactivates synthetic enzyme; inhibits synthesis of NT ANT (e.g., PCPA—serotonin) Enzyme 8 Drug stimulates autoreceptors; inhibits synthesis/release of NT ANT (e.g., apomorphine—dopamine) Neurotransmitter Drug stimulates release of NT AGO (e.g., black widow spider venom—ACh) 9 5 6 Inhibition Drug inhibits release of NT ANT (e.g., botulinum toxin—ACh) 10 Drug stimulates postsynaptic receptors AGO (e.g., nicotine, muscarine—ACh) Choline + acetate ACh 7 Drug blocks postsynaptic receptors ANT (e.g., curare, atropine—ACh) FIGURE Drug blocks autoreceptors; increases synthesis/release of NT AGO (e.g., idazoxan—norepinephrine) Molecules of drugs AChE 11 Drug blocks reuptake AGO (e.g., cocaine—dopamine) Drug inactivates acetylcholinesterase AGO (e.g., physostigmine—ACh) 4.4 Drug Effects on Synaptic Transmission The figure summarizes the ways in which drugs can affect the synaptic transmission (AGO = agonist; ANT = antagonist; NT = neurotransmitter). Drugs that act as agonists POB,11e/C11B04F04.eps Carlson/ are marked in blue; drugs that act as antagonists are marked in red. 42.0 x 24.8