Parasympathomimetics

Acetylcholine (ACh) is too rapidly hydrolyzed and inactivated by acetylcholinesterase (AChE) to be of any therapeutic use however, its action can be mimicked by other substances, namely direct or indirect parasympathomimetics. 

The choline ester, carbachol, activates M-cholinoceptors, but is not hydrolyzed by AChE. Carbachol can thus be effectively employed for local application to the eye (glaucoma) and systemic administration (bowel atonia, bladder ato-nia). The alkaloids, pilocarpine (from Pilocarpus jaborandi) and arecoline (from Areca catechu betel nut) also act as direct parasympathomimetics. As tertiary amines, they moreover exert central effects. The central effect of muscarinelike substances consists of an enlivening, mild stimulation that is probably the effect desired in betel chewing, a widespread habit in South Asia. Of this group, only pilocarpine enjoys therapeutic use, which is limited to local application to the eye in glaucoma 

Tacrine is not an ester and interferes only with the choline-binding site of AChE. It is effective in alleviating symptoms of dementia in some subtypes of Alzheimer s disease. 

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Parasympathetic Nervous System Parasympatholytics Parasympathomimetics Parathyroid Hormone Paraventricular Nucleus Parkin... 

Giolinergic drugs mimic the activity of the parasympathetic nervous system (PNS). They also are called parasympathomimetic drugs. An understanding of the PNS is useful in understanding the cholinergic dni. ... 

Distigmine bromide (Hexamarium bromide) ATC Use N07AA03 parasympathomimetic ... 

Approaches (1) and (2) depend on sufficient cholinergic function remaining to make its supplementation feasible, while all three methods suffer from the fact that not only does ACh have other central effects (e.g. in striatum), but also numerous peripheral parasympathomimetic ones, such as increased bronchial and gastric secretion or reduced heart rate. 

The initial enthusiasm for tacrine and velnacrine, which are the anticholinesterases most studied clinically, has been tempered by the fact that not all patients respond. Most show the peripheral parasympathomimetic effects of cholinesterase inhibition, e.g. dyspepsia and diarrhoea, as well as nausea and vomiting, and about half of the patients develop hepatotoxicity with elevated levels of plasma alanine transaminase. While some peripheral effects can be attenuated with antimuscarinics that do not enter the brain, these add further side-effects and the drop-out rate from such trials is high (<75%) in most long-term studies. Donepezil appears to show less hepatotoxicity but its long-term value remains to be determined. 

In rats, we know that tolerance does not occur to parasympathomimetic effects of LSD at a time when sympathomimetically mediated and behavioral effects show tolerance. Apart from the postreserpine LSD-induced pupillary changes, such differential effects in man are not known. We know also that the bradycardia in unrestrained rats (19) converts readily to a tachycardia, and assertions that LSD elevates blood pressure or pulse in man should be viewed as reactivity rather than a direct effect. 

Some 2-amino derivatives (36) have been reported to show local anaesthetic, parasympathomimetic, long-lasting myorelaxant, brief hypotensive and mild antiarrhythmic activities [83]. Analogous cyclic amidines (37) with a 3-phenyl group were examined for potential hypoglycaemic agents [7]. Ten of 16 compounds showed weak to moderate activity in the rat. The most active compound was (37, R1 = OMe R2 = R3 = H, R4 = cyclopropyl), although it was less active than tolbutamide [84]. 

This matter is given some consideration in Chapter m. In passing we may note here that it is because of the parasympathomimetic action of D.F.P. and related compounds that the term nerve gas has been applied. 

The muscle fibres of the ciliary bodies are innervated by the mrd or oculomotor nerve. As explained above, when these fibres contract they allow the lens to take up its natural shape. Direct stimulation of the Illrd nerve therefore produces accommodation for near objects. Parasympathomimetic drugs have a similar action, whereas atropine paralyses this effect and so accommodates the lens for seeing distant objects. 

Q57 Pilocarpine is a tertiary amine parasympathomimetic agent that is mainly used in the treatment of glaucoma. Pilocarpine is commonly administered with timolol eye drops. 

Pilocarpine is classified as a tertiary amine that has parasympathomimetic activity. When administered as eye drops, it causes pupillary constriction or miosis and is therefore indicated in the treatment of glaucoma. In glaucoma, multiple-drug therapy may be necessary to achieve the desired intraocular control. Pilocarpine may be used in combination with topical beta-blockers such as timolol. 

Apart from symptomatic, general measures (gastric lavage, cooling with ice water), therapy of severe atropine intoxication includes the administration of the indirect parasympathomimetic physostigmine (p. 102). The most common instances of atropine" intoxication are observed after ingestion of the berry-like fruits of belladonna (children) or intentional overdosage with tricyclic antidepressants in attempted suicide. 

Parasympathomimetics and sym-pathomimetics act at membrane receptors for visceromotor neurotransmitters. The plasmalemma also harbors the sites of action of cardiac glycosides (the Na/K-ATPases, p. 130), of Ca + antagonists (Ca2+ channels, p. 122), and of agents that block Na channels (local anesthetics p. 134, p. 204). An intracellular site is the target for phosphodiesterase inhibitors (e.g., amrinone, p. 132). 

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