Page 386 - Basic _ Clinical Pharmacology ( PDFDrive )

372 SECTION V Drugs That Act in the Central Nervous System

1

Presynaptic neuron
Action
potential
propagation

Glia
Synthesis Metabolism
2 4

3
Storage
6
5 6
Uptake
Retrograde 7
signaling Release Degradation
10
8
Receptor

Postsynaptic
neuron
9
Ionic conductance

FIGURE 21–4 Sites of drug action. Schematic drawing of steps at which drugs can alter synaptic transmission. (1) Action potential in pre-
synaptic fiber; (2) synthesis of transmitter; (3) storage; (4) metabolism; (5) release; (6) reuptake into the nerve ending or uptake into a glial cell;
(7) degradation; (8) receptor for the transmitter; (9) receptor-induced increase or decrease in ionic conductance; (10) retrograde signaling.

Drugs acting on the synthesis, storage, metabolism, and release In the postsynaptic region, the transmitter receptor provides
of neurotransmitters fall into the presynaptic category. Synaptic the primary site of drug action. Drugs can act either as neurotrans-
transmission can be depressed by blockade of transmitter synthesis mitter agonists, such as the opioids, which mimic the action
or storage. For example, reserpine depletes monoamine synapses of enkephalin, or they can block receptor function. Receptor
of transmitters by interfering with intracellular storage. Blockade antagonism is a common mechanism of action for CNS drugs. An
of transmitter catabolism inside the nerve terminal can increase example is strychnine’s blockade of the receptor for the inhibitory
transmitter concentrations and has been reported to increase the transmitter glycine. This block, which underlies strychnine’s con-
amount of transmitter released per impulse. Drugs can also alter vulsant action, illustrates how the blockade of inhibitory processes
the release of transmitters. The stimulant amphetamine induces the results in excitation. Drugs can also act directly on the ion chan-
release of catecholamines from adrenergic synapses (see Chapters 6, nel of ionotropic receptors. For example, the anesthetic ketamine
9, and 32). Capsaicin causes the release of the peptide substance blocks the NMDA subtype of glutamate ionotropic receptors
P from sensory neurons, and tetanus toxin blocks the release of by binding in the ion channel pore. In the case of metabotropic
transmitters. After a CNS transmitter has been released into the receptors, drugs can act at any of the steps downstream of the
synaptic cleft, its action is terminated either by uptake or by degra- receptor. Perhaps the best example is provided by the methylx-
dation. For most neurotransmitters, there are uptake mechanisms anthines, which can modify neurotransmitter responses mediated
into the synaptic terminal and also into surrounding neuroglia. through the second-messenger cAMP. At high concentrations,
Cocaine, for example, blocks the uptake of catecholamines at the methylxanthines elevate the level of cAMP by blocking its
adrenergic synapses and thus potentiates the action of these metabolism and thereby prolong its action.
amines. Acetylcholine, however, is inactivated by enzymatic degra- The traditional view of the synapse is that it functions like a
dation, not reuptake. Anticholinesterases block the degradation of valve, transmitting information in one direction. However, it is
acetylcholine and thereby prolong its action (see Chapter 7). No now clear that the synapse can generate signals that feed back onto
uptake mechanism has been found for any of the numerous CNS the presynaptic terminal to modify transmitter release. Endocan-
peptides, and it has yet to be demonstrated whether specific enzy- nabinoids are the best documented example of such retrograde
matic degradation terminates the action of peptide transmitters. signaling (see below). Postsynaptic activity leads to the synthesis