Ganglion blockers

Mollusca and Arthropoda. A variety of pharmacological actions are induced by the toxins found in molluscs (17). For example, surugatoxin is a potent mydriatic (5J), ganglion blocker (84), and a potent hypotensive agent in cats. 

When studying competitive antagonism, it is sometimes necessary to include an uptake inhibitor or a ganglion blocker in all the bathing solutions used. If this compound has in addition some competitive blocking action at the receptor being studied, what effect will this have on estimation of the dissociation equilibrium constant for a competitive antagonist ... 

GaN-based laser diodes, 22 179 GaN devices, market for, 12 348 Gandolfi cameras, in fine art examination/ conservation, 11 406 Ganglionic blockers, antihypertensive agents, 5 159... 

Historically, the first effective pharmacologic agents for lowering the blood pressure were the ganglionic blockers. At the level of the ganglia, these compounds block both sympathetic and parasympathetic transmission. The decrease in parasympathetic function is responsible for urinary retention, for the failure to develop an erection in the male patient and for the paralytic ileus. 

The inhibition of sympathetic tone to the venous system (capacitance vessels) results in increased pooling of blood in the venous vascular bed with consequent decreased venous return to the heart and decreased cardiac output. This phenomenon is more pronounced in upright positions because of the effect of gravity. The hemodynamic effects of ganglionic blockers include decreases in cardiac output, renal blood flow, cerebral blood flow and orthostatic hypotension(20,21). 

The ganglionic effects of ACh can be blocked by tetraethylammonium, hexa-methonium, and other substances (ganglionic blockers). None of these has intrinsic activity, that is, they fail to stimulate ganglia even at low concentration some of them (e.g hexamethonium) actually block the cholinoceptor-linked ion channel, but others (mecamyla-mine, trimethaphan) are typical receptor antagonists. 

Nevertheless, the most widely used derivative in medicine is methamizol sodium (although it is prohibited in some countries) as well as combined drugs on its base in particular, baralgin, which represents a combined drug based on methamizol sodium with the spasmolytic 4 -(ethoxypiperidine)carbomethoxybenzophenone and the ganglionic blocker 2,2-diphenyl-4-piperidylacetamide. 

Like in the neuromuscular junction the neurotransmission can be inhibited either by receptor blockade (non-depolarizing) or by overstimulation (depolarizing) of the receptors. The alkaloid nicotine, in low doses, stimulates ganglia and the adrenaline release from the adrenal medulla. High doses lead to a continuous depolarization of the postsynaptic membrane and thereby to an inactivation of the neurotransmission. All ganglion blockers in clinical use were synthetic amines of the nondepolarizing type trimethaphan, hexamethonium and mecamylamide. 

Constantly positively charged ganglion blockers like the quaternary amine hexamethonium or the sulfur containing trimethaphane are unable to cross the blood brain barrier and thereby are devoid of central side effects. Mecamylamide, on the other hand, readily enters the central nervous system and has been reported to induce sedation, tremor, and mental aberrations. For the same reason mecamylamide is only orally available. 

The basis for the antihypertensive activity of the ganglionic blockers lies in their ability to block transmission through autonomic ganglia (Fig. 20.2C). This action, which results in a decrease in the number of impulses passing down the postganglionic sympathetic (and parasympathetic) nerves, decreases vascular tone, cardiac output, and blood pressure. These drugs prevent the interaction of acetylcholine (the transmitter of the preganglionic autonomic nerves) with the nicotinic receptors on postsynaptic neuronal membranes of both the sympathetic and parasympathetic nervous systems. 

L C. Rapacuronium is a skeletal muscle relaxant that works by competing with ACh for receptors at the postjunctional membrane. Nicotine and succinylcholine also act at the end plate receptors but cause depolarization. Hexamethonium is a ganglion blocker that has essentially no activity at the end plate receptors, and scopolamine blocks cholinergic muscarinic receptors and thus does not act at the end plate receptors. 

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 ganglion blocker, is inactive orally and is given by intravenous infusion. 

Effects of autonomic blockade on the response to phenylephrine (Phe) in a human subject. Left The cardiovascular effect of the selective K-agonist phenylephrine when given as an intravenous bolus to a subject with intact autonomic baroreflex function. Note that the increase in blood pressure (BP) is associated with a baroreflex-mediated compensatory decrease in heart rate (HR). Right The response in the same subject after autonomic reflexes were abolished by the ganglionic blocker trimethaphan. Note that resting blood pressure is decreased and heart rate is increased by trimethaphan because of sympathetic and parasympathetic withdrawal. In the absence of baroreflex buffering, approximately a tenfold lower dose of phenylephrine is required to produce a similar increase in blood pressure. Note also the lack of compensatory decrease in heart rate. 

Ganglion blockers competitively block nicotinic cholinoceptors on postganglionic neurons in both sympathetic and parasympathetic ganglia. In addition, these drugs may directly block the nicotinic acetylcholine channel, in the same fashion as neuromuscular nicotinic blockers (see Figure 27-6). 

The adverse effects of ganglion blockers are direct extensions of their pharmacologic effects. These effects include both sympathoplegia (excessive orthostatic hypotension and sexual dysfunction) and parasympathoplegia (constipation, urinary retention, precipitation of glaucoma, blurred vision, dry mouth, etc). These severe toxicities are the major reason for the abandonment of ganglion blockers for the therapy of hypertension. 

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