Acetylcholine nicotinic action

Nicotine is an agonist at the nicotinic acetylcholine receptor (nAChR) 921 The ventral tegmental area (VTA) is a critical site for nicotine action 921... 

It is effective orally and resistant to pseudo-cholinesterase and possesses longer duration of action. Its nicotinic action is less than acetylcholine and actions are more marked on CVS as compared to GIT and urinary system. Earlier it was used for CVS disorders such as peripheral vascular disease and paroxysmal supraventricular tachycardia. But now, it is rarely used in therapeutics. 

The tobacco compound nicotine has been used as an insecticide for over 200 years. It is especially effective against sucking insects, such as aphids, and has excellent contact activity. Related compounds are neonicotinoids (e.g., imidacloprid), which have similar insecticidal activity, but are less toxic to mammals. Nicotine and imidacloprid mimic the action of acetylcholine, which is the major excitatory neurotransmitter in an insect s central nervous system. The action of acetylcholine is stopped by the enzyme acetylcholinesterase, which rapidly breaks down acetylcholine. Nicotine and imidacloprid are also neuroexcitatory, but do so persistendy, since they are not affected by acetylcholinesterase. Overstimulation of the nervous system often leads to convulsions, paralysis, and death. 

Bethanechol [be THAN e kole] is structurally related to acetylcholine the acetate is replaced by carbamate and the choline is methylated (see Figure 4.5). Hence, it is not hydrolyzed by acetylcholinesterase, although it is inactivated through hydrolysis by other esterases. It has little or no nicotinic actions but does have strong muscarinic activity. Its major actions are on the smooth musculature of the bladder and gastrointestinal tract. It has a duration of action of about 1 hour. 

Actions Carbachol has profound effects on both the cardiovascular system and the gastrointestinal system because of its ganglion-stimulating activity and may first stimulate and then depress these systems. It can cause release of epinephrine from the adrenal medulla by its nicotinic action. Locally instilled into the eye, it mimics the effects of acetylcholine, causing miosis. 

Figure 9.8. Three-state model of nicotinic acetylcholine receptor action. The resting state is the most stable one in the absence of ligand. Ligand binding promotes transition first to the open state and from there to the inactivated state (some molecules may actually inactivate directly, red arrow). Reactivation requires dissociation of acetylcholine, which is promoted by the scavenging of acetylcholine by cholinesterase.

Bethanechol is a quaternary ammonium compound that shares both the muscarinic and nicotinic actions of acetylcholine but it is much more slowly deactivated. It has been used to treat clomipramine-induced orgasmic dysfunction (1). 

Carbachol is a quaternary ammonium compound that shares both the muscarinic and nicotinic actions of acetylcholine but is much more slowly deactivated. Carbachol has been used topically in ophthalmology and systemically (subcutaneously, for example in doses of 2 mg/day) for urinary retention. Severe cholinergic effects can result. In one instance they primarily involved the gastrointestinal tract and the patient died of esophageal rupture (1). In other cases patients have experienced extreme bradycardia with hypotension, requiring treatment with intravenous atropine. As carbachol is not destroyed by cholinesterase, a cumulative effect is possible in patients who receive regular doses at short intervals in one case, hypotension only developed on the third treatment day (2). 

Replacement of one or more of the hydrogen atoms of the ethylene bridge with alkyl groups produces marked changes in potency and activity. Acetyl /3-methylcholine (31) is equipotent to acetylcholine as a muscarinic agonist, but it has a much weaker nicotinic action (74). A factor in the observed potency of acetyl ]8-methylcholine is its slower rate of hydrolysis by acetylcholinesterase because of poor affinity of the compound for the enzyme s catalytic site (81) and its extremely high resistance to hydrolysis by nonspecific serum cholinesterases. 

Both the cis and trans isomers (224 and 225) display prominent nicotinic action the cis-isomer is approximately 20% as potent as acetylcholine and is approximately seven times as potent as the trans-isomer. In the trans-compound (224), the T2 angle (S-C-C-0) is described as anticlinal-antiplanar on the assumption that the chair conformer has an axial S-methyl and an equatorial acetoxy (270). However, the ability of the thianium ring to undergo ring inversion (175) presents the... 

Increased action AChN Acetylcholine nicotinic receptor... 

Large series of quaternary ammonium bases have further been synthesized. Some of those compounds have nicotinic actions and thus stimulate respiration, as acetylcholine. Diethylammonium and trimethylammo-nium chloride induce marked respiratory stimulation. Tetramethylammo-nium chloride first stimulates and then temporarily paralyzes respiration. Tetraethylammonium chloride has lesser respiratory effects. Phenyl- and benzyltrimethylammonium, and trimethylphenethylammonium are active nicotinic compounds (1, 18, 19) and stimulate reflexly the respiratory center. 

It possesses both muscarinic and nicotinic actions of acetylcholine. It is used for its miotic actions in the treatment of primary glaucoma. It is employed invariably in urinary retention, peripheral vascular disease and intestinal paresis. 

In 1936, Loewi received the Nobel Prize with Henry Dale. They discovered that acetylcholine has two types of action. The drug, atropine, produces the muscarinic effert of acetylcholine by binding to muscarinic acetyldioline receptors. Acetylcholine also has nicotinic actions, stimulating the autonomic nervous system and voluntary muscle fibers. Nicotine stimulates the noradrenergic system. It acts by opening ion chaimels across the membranes of post-synaptic neurons, which generates electrical action potentials. 

The most typical muscarinic agonist is methacholine 12.68) L-acetyl-/S-methylcholine. This simple molecule, which differs from that of acetylcholine only in possessing one extra methyl-group, has the full muscarinic action of that neurotransmitter, but none of the latter s nicotinic action. Interestingly, it is more than 200 times as active as its D-enantiomer (Ellenbroek and Van Rossum, 1960). In human medicine, methacholine is mainly used to overcome postoperative retention of the bowels. Bethanechol 12.69), constructed as a hybrid of methacholine and carbachol (2.11), has an almost purely muscarinic action and is similarly used in the clinic. The great advantage of these drugs over acetylcholine is that they are not quickly hydrolysed by acetylcholinesterase. 

In the alkyltrimethylammonium cation series (of which tetramethylammonium is the foundation member) maximal activity is reached at the n-pentyltrimethylammonium salts which are about eight times as active as acetylcholine (and about as active as nicotine) at nicotinic receptors (Willey, 1955). D-Lactoylcholine has strong nicotinic, but little muscarinic, potency (Sastry, Lasslo and Pfeiffer, 1960). Phenolic ethers of choline, such as (12.86), have a strong nicotinic (but little muscarinic) activity (Hey, 1952). However, this ratio is reversed by inserting methyl-groups into the two or/Ao-positions of the benzene ring, a reminder that nicotinic action is easily repressed by steric hindrance to which muscarinic action is indifferent (note the effect of the C-methyl-group in methacholine, p. 523). 

In human medicine, carbachol (carbamoylcholine chloride) 2.11), which is isosteric with acetylcholine 2.7), is used to block acetylcholinesterase and is slowly hydrolysed by it. It exhibits both the muscarinic and nicotinic actions of acetylcholine in a more prolonged and intense form. Other examples used in... 

The receptors for the synaptic transmitter substances show a high degree of specificity. Thus methacholine (L-acetyl-P-methy 1-choline) (ij. 6), has the full muscarinic action of acetylcholine, but almost none of the latter s nicotinic action. Moreover, it is at least 200 times as active as its D-enantiomer (Ellenbroek and van Rossum, i960). 

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