Basic Mechanisms by Which Neuropharmacologic Agents Act
Sites of Action: Axons Versus Synapses
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. This is to our advantage 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 drugs that 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, on 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 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 effect 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 because it is by modifying these steps that neuropharmacologic drugs influence receptor function. The steps in synaptic transmission are shown in Fig. 10.2.
Step 1: Transmitter Synthesis
For synaptic transmission to take place, molecules of transmitter must be present in the nerve terminal. Hence we can look on 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
After 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.
Step 4: Receptor Binding
After release, transmitter molecules diffuse across the synaptic gap and then undergo reversible binding to receptors on the postsynaptic cell. This binding initiates a cascade of events that result in altered behavior of the postsynaptic cell.
Step 5: Termination of Transmission
Transmission is terminated by dissociation of transmitter from its receptors, followed by removal of free transmitter from the synaptic gap. Transmitter can be removed from the synaptic gap by three processes: (1) reuptake, (2) enzymatic degradation, and (3) diffusion. In those synapses where transmission is terminated by reuptake, axon terminals contain “pumps” that transport transmitter molecules back into the neuron from which they were released (Step 5a in Fig. 10.2). After reuptake, molecules of transmitter may be degraded, or they may be packaged in vesicles for reuse. In synapses where transmitter is cleared by enzymatic degradation (Step 5b), the synapse contains large quantities of transmitter-inactivating enzymes. Although simple diffusion away from the synaptic gap (Step 5c) is a potential means of terminating transmitter action, this process is very slow and generally of little significance.
Effects of Drugs on the Steps of Synaptic Transmission
As emphatically noted, all neuropharmacologic agents (except local anesthetics) produce their effects by directly or indirectly altering receptor activity. We also noted that the way in which drugs alter receptor activity is by interfering with synaptic transmission. Because synaptic transmission has multiple steps, the process offers a number of potential targets for drugs. In this section, we examine the specific ways in which drugs can alter the steps of synaptic transmission.
Before discussing specific mechanisms by which drugs can alter receptor activity, we need to understand what drugs are capable of doing to receptors in general terms. From the broadest perspective, when a drug influences receptor function, that drug can do just one of two things: it can enhance receptor activation, or it can reduce receptor activation. What do we mean by receptor activation? For our purposes, we can define activation as an effect on receptor function equivalent to that produced by the natural neurotransmitter at a particular synapse. Hence a drug whose effects mimic the effects of a natural transmitter would be said to increase receptor activation. Conversely, a drug whose effects were equivalent to reducing the amount of natural transmitter available for receptor binding would be said to decrease receptor activation.
Please note that activation of a receptor does not necessarily mean that a physiologic process will go faster; receptor activation can also make a process go slower. For example, when the neurotransmitter acetylcholine activates cholinergic receptors on the heart, the heart rate will decline. Similarly, a drug that mimics acetylcholine at receptors on the heart will cause the heart to beat more slowly.
Having defined receptor activation, we are ready to discuss the mechanisms by which drugs, acting on specific steps of synaptic transmission, can increase or decrease receptor activity (Table 10.1). As we consider these mechanisms one by one, their commonsense nature should become apparent.
TABLE 10.1
Effects of Drugs on Synaptic Transmission and the Resulting Effect on Receptor Activation
| Step of Synaptic Transmission | Drug Action | Effect on Receptor Activation* |
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