Trimethaphan

A systematic nomenclature for nAChRs has yet to evolve. An N nomenclature describes receptors present ia muscle as N. These are activated by phenyltrimethylammonium (PTMA) (15) and blocked by t5 -tubocurariae (16) and a-bungarotoxiu (a-BgT) (17). N2 receptors are present ia ganglia and are activated by l,l-dimethyl-4-phenylpipera2inium (DMPP) (18) and blocked by trimethaphan (19) and bis-quatemary agents, with hexamethonium (20) being the most potent. 

Trimethaphan camsylate, 3,545 Trimethobenzamide hydrochloride, 2,551 Trimethoprim, 7,445 Triprolidine hydrochloride, 8,509 Tropicamide, 3,565 Tubocurarine chloride, 7,477 Tybamate, 4,494... 

Abstract Behavioral discrimination procedures clearly demonstrate that nicotine elicits interoceptive stimulus effects in humans that are malleable by various pharmacological manipulations as well as by some behavioral manipulations. The parameters of nicotine discrimination and both chronic and acute factors that may alter discrimination behavior are addressed in this chapter, which emphasizes research by the author involving nicotine delivered by nasal spray. Human discrimination of nicotine is centrally mediated, as the central and peripheral nicotine antagonist mecamylamine blocks discrimination but the peripheral antagonist trimethaphan does not. The threshold dose for discrimination of nicotine via spray appears to be very low in smokers as well as nonsmokers. Because smoked tobacco delivers nicotine more rapidly than spray, the threshold dose of nicotine via smoking is probably even lower. In terms of individual differences, smokers may become tolerant to the discriminative stimulus effects of higher nicotine doses but not of low doses. 

In the preliminary study, any active mecamylamine dose, even 5 mg p.o., attenuated nicotine discrimination, relative to placebo pretreatment (as shown in Fig. 1), collapsed across active mecamylamine doses. Mecamylamine also attenuated some subjective effects of nicotine, as also shown in Fig. 1, including head rush (or buzzed ), which we have often found to relate to nicotine-appropriate responding. In the subsequent full study comparing mecamylamine and trimethaphan effects on discrimination, discrimination of the highest dose of nicotine was significantly attenuated following mecamylamine but not trimethaphan, as also shown in Fig. 1. Similar results were observed for subjective effects of nicotine (not shown). 

Sympathetic parasympathetic ganglia ACh Nicotine Trimethaphan Ganglionic type (o3p4) Nicotinic (N) cholinoceptor ligandgated cation channel formed by five transmembrane subunits muscular type (al2PlY5)... 

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. 

Trimethaphan is used for the controlled reduction in blood pressure during surgical interventions, for quick regulation during sharp increases in blood pressure, immediate interventions during pulmonary edema, ischemic illnesses of the heart, and in cases where other drugs cannot be used. Synonyms of this drug are arfonad and others. 

H-cholinoblockers (ganglioblockers) such as mecamylamine and trimethaphan act on autonomic ganglia to reduce blood pressure. 

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. 

The site of inhibition is in case of hexamethonium in the sodium channel, whereas trimethaphan blocks the acetylcholine binding site of the receptor. 

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. 

Trimethaphan camsylate (Arfonad) is an extremely short-acting agent whose major therapeutic use is in the production of controlled hypotension in certain surgical... 

Trimethaphan can produce prolonged neuromuscular blockade in some patients, and therefore, it should be used with caution as a hypotensive agent during surgery. It also has been reported to potentiate the neuromuscular blocking action of tubocurarine, and because of its histamine-releasing properties, trimethaphan should be used with caution in patients with allergies. 

C. Trimethaphan is a ganglionic blocking agent that will lower blood pressure very rapidly. Hydralazine is a vasodilator hydrochlorothiazide and spironolactone are diuretics and methyldopa is a sympatholytic acting in the central nervous system. All of these drugs are used clinically as antihypertensive agents. None work as rapidly as trimethaphan. Clinically, however, either nitroprusside or clonidine is used much more commonly than trimethaphan in this situation. 

A more complete description of trimethaphan and other ganglionic blocking agents can be found in Chapter 14. 

---