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Basic and Clinical Pharmacology 12/E

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Basic and Clinical Pharmacology 12/E Dr. Murtadha Alshareifi e-Library SECTION V DRUGS THAT ACT IN THE CENTRAL NERVOUS SYSTEM CHAPTER Introduction to the 21 Pharmacology of CNS Drugs Roger A. Nicoll, MD Drugs acting in the central nervous system (CNS) were among the are extremely useful in such studies. The Box, Natural Toxins: first to be discovered by primitive humans and are still the most Tools for Characterizing Ion Channels, describes a few of these widely used group of pharmacologic agents. In addition to their substances. use in therapy, many drugs acting on the CNS are used without Third, unraveling the actions of drugs with known clinical prescription to increase the sense of well-being. efficacy has led to some of the most fruitful hypotheses regarding The mechanisms by which various drugs act in the CNS have the mechanisms of disease. For example, information about the not always been clearly understood. In recent decades, however, action of antipsychotic drugs on dopamine receptors has provided dramatic advances have been made in the methodology of CNS the basis for important hypotheses regarding the pathophysiology pharmacology. It is now possible to study the action of a drug on of schizophrenia. Studies of the effects of a variety of agonists and individual cells and even single ion channels within synapses. The antagonists on γ-aminobutyric acid (GABA) receptors have information obtained from such studies is the basis for several resulted in new concepts pertaining to the pathophysiology of major developments in studies of the CNS. several diseases, including anxiety and epilepsy. First, it is clear that nearly all drugs with CNS effects act on This chapter provides an introduction to the functional orga- specific receptors that modulate synaptic transmission. A very few nization of the CNS and its synaptic transmitters as a basis for agents such as general anesthetics and alcohol may have nonspe- understanding the actions of the drugs described in the following cific actions on membranes (although these exceptions are not chapters. fully accepted), but even these non–receptor-mediated actions result in demonstrable alterations in synaptic transmission. Methods for the Study of CNS Second, drugs are among the most important tools for study- ing all aspects of CNS physiology, from the mechanism of convul- Pharmacology sions to the laying down of long-term memory. As described Like many areas of science, major progress in the study of CNS below, agonists that mimic natural transmitters (and in many cases drugs has depended on the development of new experimental are more selective than the endogenous substances) and antagonists techniques. The first detailed description of synaptic transmission 359 021-Katzung_Ch021_p359-372.indd 359 9/21/11 12:01:10 PM Dr. Murtadha Alshareifi e-Library 360 SECTION V Drugs That Act in the Central Nervous System TABLE 21–1 Some toxins used to characterize Natural Toxins: Tools For Characterizing ion channels. Ion Channels Channel Types Mode of Toxin Action Source Evolution is tireless in the development of natural toxins. A Voltage-gated vast number of variations are possible with even a small num- Sodium channels ber of amino acids in peptides, and peptides make up only Tetrodotoxin (TTX) Blocks channel from Puffer fish one of a broad array of toxic compounds. For example, the outside predatory marine snail genus Conus is estimated to include at Batrachotoxin (BTX) Slows inactivation, Colombian least 500 different species. Each species kills or paralyzes its shifts activation frog prey with a venom that contains 50–200 different peptides or Potassium channels proteins. Furthermore, there is little duplication of peptides Apamin Blocks “small Honeybee among Conus species. Other animals with useful toxins Ca-activated” K channel include snakes, frogs, spiders, bees, wasps, and scorpions. Charybdotoxin Blocks “big Scorpion Plant species with toxic (or therapeutic) substances are too Ca-activated” K channel numerous to mention here; they are referred to in many chap- Calcium channels ters of this book. Omega conotoxin Blocks N-type channel Pacific cone Since many toxins act on ion channels, they provide a wealth (ω-CTX-GVIA) snail of chemical tools for studying the function of these channels. Agatoxin (ω-AGAIVA) Blocks P-type channel Funnel web In fact, much of our current understanding of the properties of spider ion channels comes from studies utilizing only a small per- Ligand-gated centage of the highly potent and selective toxins that are now available. The toxins typically target voltage-sensitive ion Nicotinic ACh receptor channels, but a number of very useful toxins block ionotropic α-Bungarotoxin Irreversible antagonist Marine neurotransmitter receptors. Table 21–1 lists some of the toxins snake most commonly used in research, their mode of action, and GABAA receptor their source. Picrotoxin Blocks channel South Pacific plant Glycine receptor Strychnine Competitive antagonist Indian plant was made possible by the invention of glass microelectrodes, which permit intracellular recording. The development of the brain slice AMPA receptor technique permitted an analysis of the physiology and pharmacol- Philanthotoxin Blocks channel Wasp ogy of synapses. Detailed electrophysiologic studies of the action of drugs on both voltage- and transmitter-operated channels were further facilitated by the introduction of the patch clamp tech- nique, which permits the recording of current through single chan- ( Figure 21–2 A and B). Voltage-gated channels respond to changes nels. Channels can be expressed in cultured cells and the currents in the membrane potential of the cell. The voltage-gated sodium evoked by their activation recorded ( Figure 21–1 ). Histochemical, channel described in Chapter 14 for the heart is an example of the immunologic, and radioisotopic methods have made it possible to first type of channel. In nerve cells, these channels are concen- map the distribution of specific transmitters, their associated trated on the initial segment and the axon and are responsible for enzyme systems, and their receptors. Molecular cloning has had a the fast action potential, which transmits the signal from cell body major impact on our understanding of CNS receptors. These tech- to nerve terminal. There are many types of voltage-sensitive niques make it possible to determine the precise molecular struc- calcium and potassium channels on the cell body, dendrites, and ture of the receptors and their associated channels. Finally, mice initial segment, which act on a much slower time scale and modu- with mutated genes for specific receptors or enzymes (knockout late the rate at which the neuron discharges. For example, some mice) can provide important information regarding the physio- types of potassium channels opened by depolarization of the cell logic and pharmacologic roles of these components. result in slowing of further depolarization and act as a brake to limit further action potential discharge. Neurotransmitters exert their effects on neurons by binding to ION CHANNELS & NEUROTRANSMITTER two distinct classes of receptor. The first class is referred to as RECEPTORS ligand-gated channels , or ionotropic receptors. The receptor consists of subunits, and binding of ligand directly opens the The membranes of nerve cells contain two types of channels channel, which is an integral parts of the receptor complex (see defined on the basis of the mechanisms controlling their gating Figure 22–6 ). These channels are insensitive or only weakly sensi- (opening and closing): voltage-gated and ligand-gated channels tive to membrane potential. Activation of these channels typically 021-Katzung_Ch021_p359-372.indd 360 9/21/11 12:01:11 PM Dr. Murtadha Alshareifi e-Library CHAPTER 21 Introduction to the Pharmacology of CNS Drugs 361 ABCD Glutamate Glutamate + STGGlutamate Glutamate + STG τ τ = 2.9 ms fast = 5.9 ms τ slow = 26 ms (22%) 10 pA 20 pA 50 ms 50 ms 4 pA 50 ms FIGURE 21–1 Whole-cell and single-channel currents. Modern techniques permit the recording of neuronal currents in response to the application of transmitters and modulators of transmission. A: Averaged and summed whole-cell currents evoked by the application of glutamate (inward currents are downward). B: Currents evoked by glutamate in the presence of a modulator (stargazin, STG). C: Single-channel currents evoked by glutamate alone. D: Single-channel currents evoked by glutamate plus stargazin. Note the prolonged channel openings in the presence of stargazin. (Reproduced, with permission, from Tomita et al: Stargazin modulates AMPA receptor gating and trafficking by distinct domains. Nature 2005;435:1052.) results in a brief (a few milliseconds to tens of milliseconds) open- is that, in contrast to the brief effect of ionotropic receptors, the ing of the channel. Ligand-gated channels are responsible for fast effects of metabotropic receptor activation can last tens of seconds synaptic transmission typical of hierarchical pathways in the CNS to minutes. Metabotropic receptors predominate in the diffuse neu- (see following text). ronal systems in the CNS (see below). The second class of neurotransmitter receptor is referred to as metabotropic receptors. These are seven-transmembrane G protein-coupled receptors of the type described in Chapter 2 . The THE SYNAPSE & SYNAPTIC POTENTIALS binding of neurotransmitter to this type of receptor does not result in the direct gating of a channel. Rather, binding to the receptor The communication between neurons in the CNS occurs through engages a G protein, which results in the production of second mes- chemical synapses in the majority of cases. (A few instances of sengers that modulate voltage-gated channels. These interactions electrical coupling between neurons have been documented, and can occur entirely with the plane of the membrane and are referred such coupling may play a role in synchronizing neuronal dis- to as membrane-delimited pathways ( Figure 21–2 C). In this case, charge. However, it is unlikely that these electrical synapses are an the G protein (often the βγ subunit) interacts directly with the important site of drug action.) The events involved in synaptic voltage-gated ion channel.
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