Neuropharmacology can be defined as the study of drugs that alter processes controlled by the nervous system. Neuropharmacologic drugs produce effects equivalent to those produced by excitation or suppression of neuronal activity. Neuropharmacologic agents can be divided into two broad categories: (1) peripheral nervous system (PNS) drugs and (2) central nervous system (CNS) drugs.

The neuropharmacologic drugs constitute a large and important family of therapeutic agents. These drugs are used to treat conditions ranging from depression to epilepsy to hypertension to asthma. The clinical significance of these agents is reflected in the fact that over 25% of this text is dedicated to them.

Why do we have so many neuropharmacologic drugs? The answer lies in a concept discussed in Chapter 5: Most therapeutic agents act by helping the body help itself. That is, most drugs produce their therapeutic effects by coaxing the body to perform normal processes in a fashion that benefits the patient. Since the nervous system participates in the regulation of practically all bodily processes, practically all bodily processes can be influenced by drugs that alter neuronal regulation. By mimicking or blocking neuronal regulation, neuropharmacologic drugs can modify such diverse processes as skeletal muscle contraction, cardiac output, vascular tone, respiration, GI function, uterine motility, glandular secretion, and functions unique to the CNS, such as ideation, mood, and perception of pain. Given the broad spectrum of processes that neuropharmacologic drugs can alter, and given the potential benefits to be gained by manipulating those processes, it should be no surprise that neuropharmacologic drugs have widespread clinical applications.

We begin our study of neuropharmacology by discussing PNS drugs (Chapters 14 through 19), after which we discuss CNS drugs (Chapters 20 through 40). The principal rationale for this order of presentation is that our understanding of PNS pharmacology is much clearer than our understanding of CNS pharmacology. Why? Because the PNS is less complex than the CNS, and more accessible to experimentation. By placing our initial focus on the PNS, we can establish a firm knowledge base in neuropharmacology before proceeding to the less definitive and vastly more complex realm of CNS pharmacology.

How neurons regulate physiologic processes

As a rule, if we want to understand the effects of a drug on a particular physiologic process, we must first understand the process itself. Accordingly, if we wish to understand the impact of drugs on neuronal regulation of bodily function, we must first understand how neurons regulate bodily function when drugs are absent.

Figure 12–1 illustrates the basic process by which neurons elicit responses from other cells. The figure depicts two cells: a neuron and a postsynaptic cell. The postsynaptic cell might be another neuron, a muscle cell, or a cell within a secretory gland. As indicated, there are two basic steps—axonal conduction and synaptic transmission—in the process by which the neuron influences the behavior of the postsynaptic cell. Axonal conduction is simply the process of conducting an action potential down the axon of the neuron. Synaptic transmission is the process by which information is carried across the gap between the neuron and the postsynaptic cell. As shown in the figure, synaptic transmission requires the release of neurotransmitter molecules from the axon terminal followed by binding of these molecules to receptors on the postsynaptic cell. As a result of transmitter-receptor binding, a series of events is initiated in the postsynaptic cell, leading to a change in its behavior. The precise nature of the change depends on the identity of the neurotransmitter and the type of cell involved. If the postsynaptic cell is another neuron, it may increase or decrease its firing rate; if the cell is part of a muscle, it may contract or relax; and if the cell is glandular, it may increase or decrease secretion.

Basic mechanisms by which neuropharmacologic agents ACT

Sites of action: axons versus synapses

In order to influence a process under neuronal control, a drug can alter one of two basic neuronal activities: axonal conduction or synaptic transmission. Most neuropharmacologic agents act by altering synaptic transmission. Only a few alter axonal conduction. Why do drugs usually target synaptic transmission? Because drugs that alter synaptic transmission can produce effects that are much more selective than those produced by drugs that alter axonal conduction.

Axonal conduction

Drugs that act by altering axonal conduction are not very selective. Recall that the process of conducting an impulse along an axon is essentially the same in all neurons. As a consequence, a drug that alters axonal conduction will affect conduction in all nerves to which it has access. Such a drug cannot produce selective effects.

Local anesthetics are the only drugs proved to work by altering (decreasing) axonal conduction. Because these agents produce nonselective inhibition of axonal conduction, they suppress transmission in any nerve they reach. Hence, although local anesthetics are certainly valuable, their indications are limited.

Synaptic transmission

In contrast to drugs that alter axonal conduction, drugs that alter synaptic transmission can produce effects that are highly selective. Why? Because synapses, unlike axons, differ from one another. Synapses at different sites employ different transmitters. In addition, for most transmitters, the body employs more than one type of receptor. Hence, by using a drug that selectively influences a specific type of neurotransmitter or receptor, we can alter one neuronally regulated process while leaving most others unchanged. Because of their relative selectivity, drugs that alter synaptic transmission have many uses.

Receptors

The ability of a neuron to influence the behavior of another cell depends, ultimately, upon the ability of that neuron to alter receptor activity on the target cell. As discussed, neurons alter receptor activity by releasing transmitter molecules, which diffuse across the synaptic gap and bind to receptors on the postsynaptic cell. If the target cell lacked receptors for the transmitter that a neuron released, that neuron would be unable to affect the target cell.

The effects of neuropharmacologic drugs, like those of neurons, depend on altering receptor activity. That is, no matter what its precise mechanism of action, a neuropharmacologic drug ultimately works by influencing receptor activity on target cells. This commonsense concept is central to understanding the actions of neuropharmacologic drugs. In fact, this concept is so critical to our understanding of neuropharmacologic agents that I will repeat it: The impact of a drug on a neuronally regulated process is dependent on the ability of that drug to directly or indirectly influence receptor activity on target cells.

Steps in synaptic transmission

To understand how drugs alter receptor activity, we must first understand the steps by which synaptic transmission takes place—since it is by modifying these steps that neuropharmacologic drugs influence receptor function. The steps in synaptic transmission are summarized in Figure 12–2.

Step 1: transmitter synthesis.

For synaptic transmission to take place, molecules of transmitter must be present in the nerve terminal. Hence, we can look upon transmitter synthesis as the first step in transmission. In the figure, the letters Q, R, and S represent the precursor molecules from which the transmitter (T) is made.

Step 2: transmitter storage.

Once transmitter is synthesized, it must be stored until the time of its release. Transmitter storage takes place within vesicles—tiny packets present in the axon terminal. Each nerve terminal contains a large number of transmitter-filled vesicles.

Step 3: transmitter release.

Release of transmitter is triggered by the arrival of an action potential at the axon terminal. The action potential initiates a process in which vesicles undergo fusion with the terminal membrane, causing release of their contents into the synaptic gap. Each action potential causes only a small fraction of all vesicles present in the axon terminal to discharge their contents.

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