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Chapter: Basic & Clinical Pharmacology : Cholinoceptor Blocking Drugs

Basic & Clinical Pharmacology of the Ganglion Blocking Drugs

Ganglion-blocking agents competitively block the action of ace-tylcholine and similar agonists at nicotinic receptors of both para-sympathetic and sympathetic autonomic ganglia.


Ganglion-blocking agents competitively block the action of ace-tylcholine and similar agonists at nicotinic receptors of both para-sympathetic and sympathetic autonomic ganglia. Some members of the group also block the ion channel that is gated by the nico-tinic cholinoceptor. The ganglion-blocking drugs are important and used in pharmacologic and physiologic research because they can block all autonomic outflow. However, their lack of selectivity confers such a broad range of undesirable effects that they have limited clinical use.

Chemistry & Pharmacokinetics

All ganglion-blocking drugs of interest are synthetic amines. Tetraethylammonium (TEA), the first to be recognized as hav-ing this action, has a very short duration of action. Hexamethonium(“C6”) was developed and was introduced clinically as the firstdrug effective for management of hypertension. As shown in Mecamylamine, a secondary amine, was developed to improvethe degree and extent of absorption from the gastrointestinal tract because the quaternary amine ganglion-blocking compounds were poorly and erratically absorbed after oral administration. Trimethaphan, a short-acting ganglion blocker, is inactive orallyand is given by intravenous infusion.


A. Mechanism of Action

Ganglionic nicotinic receptors, like those of the skeletal muscle neuromuscular junction, are subject to both depolarizing and non-depolarizing blockade. Nicotine itself, carbamoylcholine, and even acetylcholine (if amplified with a cho-linesterase inhibitor) can produce depolarizing ganglion block.

Drugs now used as ganglion blockers are classified as nondepo-larizing competitive antagonists. However, hexamethonium actu-ally produces most of its blockade by occupying sites in or on the nicotinic ion channel, not by occupying the cholinoceptor itself. In contrast, trimethaphan appears to block the nicotinic receptor, not the channel pore. Blockade can be surmounted by increasing the concentration of an agonist, eg, acetylcholine.

B. Organ System Effects

1.     Central nervous system—Mecamylamine, unlike the qua-ternary amine agents and trimethaphan, crosses the blood-brain barrier and readily enters the CNS. Sedation, tremor, choreiform movements, and mental aberrations have been reported as effects of mecamylamine. Eye—The ganglion-blocking drugs cause a predictablecycloplegia with loss of accommodation because the ciliary muscle receives innervation primarily from the parasympathetic nervous system. The effect on the pupil is not so easily predicted, since the iris receives both sympathetic innervation (mediating pupillary dilation) and parasympathetic innervation (mediating pupillary constriction). Ganglionic blockade often causes moderate dilation of the pupil because parasympathetic tone usually dominates this tissue.


2.     Cardiovascular system—Blood vessels receive chiefly vaso-constrictor fibers from the sympathetic nervous system; therefore, ganglionic blockade causes a marked decrease in arteriolar and venomotor tone. The blood pressure may fall precipitously because both peripheral vascular resistance and venous return are decreased (see Figure 6–7). Hypotension is especially marked in the upright position (orthostatic or postural hypotension), because postural reflexes that normally prevent venous pooling are blocked.


Cardiac effects include diminished contractility and, because the sinoatrial node is usually dominated by the parasympathetic nervous system, a moderate tachycardia.

3.     Gastrointestinal tract—Secretion is reduced, although notenough to effectively treat peptic disease. Motility is profoundly inhibited, and constipation can be marked.


5. Other systems—Genitourinary smooth muscle is partiallydependent on autonomic innervation for normal function. Therefore, ganglionic blockade causes hesitancy in urination and may precipitate urinary retention in men with prostatic hyperplasia. Sexual function is impaired in that both erection and ejaculation may be prevented by moderate doses.

Thermoregulatory sweating is reduced by the ganglion-blocking drugs. However, hyperthermia is not a problem except in very warm environments, because cutaneous vasodilation is usually suf-ficient to maintain a normal body temperature.

6. Response to autonomic drugs—Patients receiving ganglion blocking drugs are fully responsive to autonomic drugs acting on muscarinic, α-, and β-adrenergic receptors because these effector cell receptors are not blocked. In fact, responses may be exagger-ated or even reversed (eg, intravenously administered norepineph-rine may cause tachycardia rather than bradycardia), because homeostatic reflexes, which normally moderate autonomic responses, are absent.


Clinical Applications & Toxicity

Ganglion blockers are used infrequently because more selective autonomic blocking agents are available. Mecamylamine blocks central nicotinic receptors and has been advocated as a possible adjunct with the transdermal nicotine patch to reduce nicotine craving in patients attempting to quit smoking. Trimethaphan is occasionally used in the treatment of hypertensive emergencies and dissecting aortic aneurysm; in producing hypotension, which can be of value in neurosurgery to reduce bleeding in the operative field; and in the treatment of patients undergoing electroconvul-sive therapy. The toxicity of the ganglion-blocking drugs is limited to the autonomic effects already described. For most patients, these effects are intolerable except for acute use.

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