Mecamylamine, a secondary amine, was developed to improve the 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, polar, ganglion-blocking drug, is no longer available for clinical use.
FIGURE 8–7 Some ganglion-blocking drugs. Acetylcholine is shown for reference.
A. Mechanism of Action
Ganglionic nicotinic receptors, like those of the skeletal muscle neuromuscular junction, are subject to both depolarizing and nondepolarizing blockade (see Chapters 7 and 27). Nicotine itself, carbamoylcholine, and even acetylcholine (if amplified with a cholinesterase inhibitor) can produce depolarizing ganglion block.
Drugs now used as ganglion-blocking drugs are classified as non-depolarizing competitive antagonists. Blockade can be surmounted by increasing the concentration of an agonist, eg, acetylcholine. However, hexamethonium actually produces most of its blockade by occupying sites in or on the nicotinic ion channel, not by occupying the cholinoceptor itself.
B. Organ System Effects 1.
Central nervous system—Mecamylamine, unlike the quaternary 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.
2.
Eye—The ganglion-blocking drugs cause a predictable cycloplegia 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.
3.
Cardiovascular system—Blood vessels receive chiefly vasoconstrictor 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.
4.
Gastrointestinal tract—Secretion is reduced, although not enough to treat peptic disease effectively. Motility is profoundly inhibited, and constipation can be marked.
5.
Other systems—Genitourinary smooth muscle is partially dependent 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 sufficient 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-adrenoceptors because these effector cell receptors are not blocked. In fact, responses may be exaggerated or even reversed (eg, intravenously administered norepinephrine may cause tachycardia rather than bradycardia), because homeostatic reflexes, which normally moderate autonomic responses, are absent.