Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 21. Introduction to CNS Pharmacology

Targets of CNS Drug Action

Most drugs that act on the central nervous system (CNS) appear to do so by changing ion flow through transmembrane channels of nerve cells.

Types of Ion Channels

Ion channels of neuronal membranes are of 2 major types: voltage gated and ligand gated (Figure 21-1). Voltage-gated ion channels respond to changes in membrane potential. They are concentrated on the axons of nerve cells and include the sodium channels responsible for action potential propagation. Cell bodies and dendrites also have voltage-sensitive ion channels for potassium and calcium. Ligand-gated ion channels, also called ionotropic receptors, respond to chemical neurotransmitters that bind to receptor subunits present in their macromolecular structure. Neurotransmitters also bind to G-protein-coupled receptors (metabotropic receptors) that can modulate voltage-gated ion channels. Neurotransmitter-coupled ion channels are found on cell bodies and on both the presynaptic and postsynaptic sides of synapses.

FIGURE 21-1

Types of ion channels and neurotransmitter receptors in the CNS: A shows a voltage-gated ion channel in which the voltage sensor controls the gating (broken arrow). B shows a ligand-gated ion channel in which binding of the neurotransmitter to the ionotropic channel receptor controls the gating. C shows a metabotropic receptor coupled to a G protein that can interact directly with an ion channel. D shows a receptor coupled to a G protein that activates an enzyme; the activated enzyme generates a diffusible second messenger, for example, cAMP, which interacts to modulatean ion channel.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 21-2.)

Types of Receptor-Channel Coupling

In the case of ligand-gated ion channels, activation (or inactivation) is initiated by the interaction between chemical neurotransmitters and their receptors (Figure 21-1). Coupling may be (1) through a receptor that acts directly on the channel protein (B), (2) through a receptor that is coupled to the ion channel through a G protein (C), or (3) through a receptor coupled to a G protein that modulates the formation of diffusible second messengers, including cyclic adenosine monophosphate (cAMP), inositol trisphosphate (IP 3), and diacylglycerol (DAG), which secondarily modulate ion channels (D).

Role of the Ion Current Carried by the Channel

Excitatory postsynaptic potentials (EPSPs) are usually generated by the opening of sodium or calcium channels. In some synapses, similar depolarizing potentials result from the closing of potassium channels. Inhibitory postsynaptic potentials (IPSPs) are usually generated by the opening of potassium or chloride channels. For example, activation of postsynaptic metabotropic receptors increases the efflux of potassium. Presynaptic inhibition can occur via a decrease in calcium influx elicited by activation of metabotropic receptors.

High-Yield Terms to Learn

Voltage-gated ion channels Transmembrane ion channels regulated by changes in membrane potential Ligand-gated ion channels Transmembrane ion channels that are regulated by interactions between neurotransmitters and their receptors (also called ionotropic receptors) Metabotropic receptors G-protein-coupled receptors that respond to neurotransmitters either by a direct action of G proteins on ion channels or by G-protein-enzyme activation that leads to formation of diffusible second messengers EPSP Excitatory postsynaptic potential; a depolarizing potential change IPSP Inhibitory postsynaptic potential; a hyperpolarizing potential change Synaptic mimicry Ability of an administered chemical to mimic the actions of the natural neurotransmitter: a criterion for identification of a putative neurotransmitter

Sites & Mechanisms of Drug Action

A small number of neuropharmacologic agents exert their effects through direct interactions with molecular components of ion channels on axons. Examples include certain anticonvulsants (eg, carbamazepine, phenytoin), local anesthetics, and some drugs used in general anesthesia. However, the effects of most therapeutically important CNS drugs are exerted mainly at synapses. Possible mechanisms are indicated in Figure 21-2. Thus, drugs may act presynaptically to alter the synthesis, storage, release, reuptake, or metabolism of transmitter chemicals. Other drugs can activate or block both pre- and postsynaptic receptors for specific transmitters or can interfere with the actions of second messengers. The selectivity of CNS drug action is largely based on the fact that different groups of neurons use different neurotransmitters and that they are segregated into networks that subserve different CNS functions.

FIGURE 21-2

Sites of CNS drug action. Drugs may alter (1) the action potential in the presynaptic fiber; (2) synthesis of transmitter; (3) storage ; (4) metabolism; (5) release; (6) reuptake; (7) degradation; (8) receptor for the transmitter; or (9) receptor-induced decrease or increase in ionic conduction.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 10th ed. McGraw-Hill, 2007: Fig. 21-2.)

A few neurotoxic substances damage or kill nerve cells. For example, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) is cytotoxic to neurons of the nigrostriatal dopaminergic pathway.

Role of CNS Organization

The CNS contains 2 types of neuronal systems: hierarchical and diffuse.

Hierarchical Systems

These systems are delimited in their anatomic distribution and generally contain large myelinated, rapidly conducting fibers. Hierarchical systems control major sensory and motor functions. The major excitatory transmitters in these systems are aspartate and glutamate. These systems also include numerous small inhibitory interneurons, which use -aminobutyric acid (GABA) or glycine as transmitters. Drugs that affect hierarchical systems often have profound effects on the overall excitability of the CNS.

Diffuse Systems

Diffuse or nonspecific systems are broadly distributed, with single cells frequently sending processes to many different areas. The axons are fine and branch repeatedly to form synapses with many cells. Axons commonly have periodic enlargements (varicosities) that contain transmitter vesicles. The transmitters in diffuse systems are often amines (norepinephrine, dopamine, serotonin) or peptides that commonly exert actions on metabotropic receptors. Drugs that affect these systems often have marked effects on such CNS functions as attention, appetite, and emotional states.

Transmitters at Central Synapses

Criteria for Transmitter Status

To be accepted as a neurotransmitter, a candidate chemical must (1) be present in higher concentration in the synaptic area than in other areas (ie, must be localized in appropriate areas), (2) be released by electrical or chemical stimulation via a calcium-dependent mechanism, and (3) produce the same sort of postsynaptic response that is seen with physiologic activation of the synapse (ie, must exhibit synaptic mimicry). Table 21-1 lists the most important chemicals currently accepted as neurotransmitters in the CNS.

TABLE 21-1 Neurotransmitter pharmacology in the CNS.

Transmitter Anatomical Distribution Receptor Subtypes Receptor Mechanisms Acetylcholine Cell bodies at all levels, short and long axons Muscarinic, M1; blocked by pirenzepine and atropine

Excitatory;  K+ conductance;  IP 3 and DAG

Muscarinic, M2; blocked by atropine

Inhibitory;  K+ conductance;  cAMP

Motoneuron-Renshaw cell synapse Nicotinic, N Excitatory;  cation conductance Dopamine Cell bodies at all levels, short, medium, and long axons D1; blocked by phenothiazines

Inhibitory;  cAMP D2; blocked by phenothiazines and haloperidol

Inhibitory (presynaptic);  Ca2+ conductance;

Inhibitory (postsynaptic);  K+ conductance;  cAMP

Norepinephrine Cell bodies in pons and brain stem project to all levels Alpha1; blocked by prazosin

Excitatory;  K+ conductance;  IP3 and DAG

Alpha2; activated by clonidine

Inhibitory (presynaptic);  Ca2+ conductance

Inhibitory (postsynaptic);  K+ conductance;  cAMP

Beta1; blocked by propranolol

Excitatory;  K+ conductance;  cAMP

Beta2; blocked by propranolol

Inhibitory;  electrogenic sodium pump Serotonin (5-hydroxy-tryptamine) Cell bodies in midbrain and pons project to all levels 5-HT 1A; buspirone is a partial agonist

Inhibitory;  K+ conductance

5-HT2A; blocked by clozapine, risperidone, and olanzapine

Excitatory;  K+ conductance;  IP3 and DAG

5-HT3; blocked by ondansetron

Excitatory;  cation conductance 5-HT4

Excitatory;  K+ conductance;  cAMP

GABA Supraspinal interneurons; spinal interneurons involved in presynaptic inhibition GABAA; facilitated by benzodiazepines and zolpidem

Inhibitory;  Cl- conductance

GABAB; activated by baclofen

Inhibitory (presynaptic);  Ca2+ conductance Inhibitory (postsynaptic);  K+ conductance Glutamate, aspartate Relay neurons at all levels Four subtypes; NMDA subtype blocked by phencyclidine, ketamine, and memantine Excitatory;  Ca2+ or cation conductance

Metabotropic subtypes Inhibitory (presynaptic);  Ca2+ conductance  cAMP

Excitatory (postsynaptic);  K+ conductance,  IP3 and DAG

Glycine Interneurons in spinal cord and brain stem Single subtype; blocked by strychnine Inhibitory;  Cl- conductance

Opioid peptides Cell bodies at all levels Three major subtypes:  Inhibitory (presynaptic);  Ca2+ conductance;  cAMP

Inhibitory (postsynaptic);  K+ conductance;  cAMP

Adapted, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 10th ed. McGraw-Hill, 2007.

Acetylcholine

Approximately 5% of brain neurons have receptors for acetylcholine (ACh). Most CNS responses to ACh are mediated by a large family of G-protein-coupled muscarinic M1 receptors that lead to slow excitation when activated. The ionic mechanism of slow excitation involves a decrease in membrane permeability to potassium. Of the nicotinic receptors present in the CNS (they are less common than muscarinic receptors), those on the Renshaw cells activated by motor axon collaterals in the spinal cord are the best characterized. Drugs affecting the activity of cholinergic systems in the brain include the acetylcholinesterase inhibitors used in Alzheimer's disease (eg, tacrine) and the muscarinic blocking agents used in parkinsonism (eg, benztropine).

Dopamine

Dopamine exerts slow inhibitory actions at synapses in specific neuronal systems commonly via G-protein-coupled activation of potassium channels (postsynaptic) or inactivation of calcium channels (presynaptic). The D2 receptor is the main dopamine subtype in basal ganglia neurons, and it is widely distributed at the supraspinal level. Dopaminergic pathways include the nigrostriatal, mesolimbic, and tuberoinfundibular tracts. In addition to the 2 receptors listed in Table 21-1, 3 other dopamine receptor subtypes have been identified (D3 , D4, and D5). Drugs that block the activity of dopaminergic pathways include older antipsychotics (eg, chlorpromazine, haloperidol), which may cause parkinsonian symptoms. Drugs that increase brain dopaminergic activity include CNS stimulants (eg, amphetamine), and commonly used antiparkinsonism drugs (eg, levodopa).

Norepinephrine

Noradrenergic neuron cell bodies are mainly located in the brain stem and the lateral tegmental area of the pons. These neurons fan out broadly to provide most regions of the CNS with diffuse noradrenergic input. Excitatory effects are produced by activation of 1 and 1 receptors. Inhibitory effects are caused by activation of 2 and 2 receptors. CNS stimulants (eg, amphetamines, cocaine), monoamine oxidase inhibitors (eg, phenelzine), and tricyclic antidepressants (eg, amitriptyline) are examples of drugs that enhance the activity of noradrenergic pathways.

Serotonin

Most serotonin (5-hydroxytryptamine; 5-HT) pathways originate from cell bodies in the raphe or midline regions of the pons and upper brain stem; these pathways innervate most regions of the CNS. Multiple 5-HT receptor subtypes have been identified and, with the exception of the 5-HT3 subtype, all are metabotropic. 5-HT1A receptors and GABA B receptors share the same potassium channel. Serotonin can cause excitation or inhibition of CNS neurons depending on the receptor subtype activated. Both excitatory and inhibitory actions can occur on the same neuron if appropriate receptors are present. Most of the agents used in the treatment of major depressive disorders affect serotonergic pathways (eg, tricyclic antidepressants, selective serotonin reuptake inhibitors). The actions of some CNS stimulants and newer antipsychotic drugs (eg, olanzapine) also appear to be mediated via effects on serotonergic transmission. Reserpine, which may cause severe depression of mood, depletes vesicular stores of both serotonin and norepinephrine in CNS neurons.

Glutamic Acid

Most neurons in the brain are excited by glutamic acid. High concentrations of glutamic acid in synaptic vesicles is achieved by the vesicular glutamate transporter (VGLUT). Both ionotropic and metabotropic receptors have been characterized. Subtypes of glutamate receptors include the N-methyl-D-aspartate (NMDA) receptor, which is blocked by phencyclidine (PCP) and ketamine. NMDA receptors appear to play a role in synaptic plasticity related to learning and memory. Memantine is an NMDA antagonist introduced for treatment of Alzheimer's dementia. Excessive activation of NMDA receptors after neuronal injury may be responsible for cell death. Glutamate metabotropic receptor activation can result in G-protein-coupled activation of phospholipase C or inhibition of adenylyl cyclase.

GABA and Glycine

GABA is the primary neurotransmitter mediating IPSPs in neurons in the brain; it is also important in the spinal cord. GABAA receptor activation opens chloride ion channels. GABAB receptors (activated by baclofen, a centrally acting muscle relaxant) are coupled to G proteins that either open potassium channels or close calcium channels. Fast IPSPs are blocked by GABAA receptor antagonists, and slow IPSPs are blocked by GABAB receptor antagonists. Drugs that influence GABAA receptor systems include sedative-hypnotics (eg, barbiturates, benzodiazepines, zolpidem) and some anticonvulsants (eg, gabapentin, tiagabine, vigabatrin). Glycine receptors, which are more numerous in the cord than in the brain, are blocked by strychnine, a spinal convulsant.

Peptide Transmitters

Many peptides have been identified in the CNS, and some meet most or all of the criteria for acceptance as neurotransmitters. The best-defined peptides are the opioid peptides (beta-endorphin, met- and leu-enkephalin, and dynorphin), which are distributed at all levels of the neuraxis. Some of the important therapeutic actions of opioid analgesics (eg, morphine) are mediated via activation of receptors for these endogenous peptides. Another peptide substance P is a mediator of slow EPSPs in neurons involved in nociceptive sensory pathways in the spinal cord and brain stem. Peptide transmitters differ from nonpeptide transmitters in that (1) the peptides are synthesized in the cell body and transported to the nerve ending via axonal transport, and (2) no reuptake or specific enzyme mechanisms have been identified for terminating their actions.

Endocannabinoids

These are widely distributed brain lipid derivatives (eg, 2-arachidonyl-glycerol) that bind to receptors for cannabinoids found in marijuana. They are synthesized and released postsynaptically after membrane depolarization but travel backward acting presynaptically (retrograde) to decrease transmitter release.

Skill Keeper: Biodisposition of CNS Drugs

(See Chapter 1)

1. What characteristics of drug molecules afford access to the CNS?

2. What concerns do you have regarding CNS drug use in the pregnant patient?

3. How are most CNS drugs usually eliminated from the body?

The Skill Keeper Answers appear at the end of the chapter.

Skill Keeper Answers: Biodisposition of CNS Drugs

(See Chapter 1)

1. Lipid solubility is an important characteristic of most CNS drugs in terms of their ability to cross the blood-brain barrier. Access to the CNS of water-soluble (polar) molecules is limited to those of low molecular weight such as lithium ion and ethanol.

2. CNS drugs readily cross the placental barrier and enter the fetal circulation. Concerns during pregnancy include possible effects on fetal development and the potential for drug effects on the neonate if CNS drugs are used near the time of delivery.

3. With the exception of lithium, almost all CNS drugs require metabolism to more water-soluble (polar) metabolites for their elimination. Thus, drugs that modify the activities of drug-metabolizing enzymes may have an impact on the clearance of CNS drugs, perhaps affecting the intensity or duration of their effects.

Checklist

When you complete this chapter, you should be able to:

 Explain the difference between voltage-gated and ligand-gated ion channels.

 List the criteria for accepting a chemical as a neurotransmitter.

 Identify the major excitatory and inhibitory CNS neurotransmitters in the CNS.

 Identify the sites of drug action at synapses and the mechanisms by which drugs modulate synaptic transmission.

Give an example of a CNS drug that influences neurotransmitter functions at the level of (a) synthesis, (b) metabolism, (c) release, (d) reuptake, and (e) receptor.



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