Cholinomimetic activity

Replacement of the acetyl group in Aceklidine by homologous acyl groups leads at first (propionic ester) to a decrease in cholinomimetic activity and then (butyric and isovaleric esters) to the appearance of cholinolytic properties. 

Very strong cholinomimetic activity was found for 3-hydroxyquinuclidine esters with arylaliphatic acids. For example, 3-(a,a-diphenylpropionyloxy)quinuclidine (162) (which is known in the USSR as Aprolidine219-218 significantly exceeds the similar 2-diethylaminoethyl ester (163) (in the USSRAprophen) in its influence on the central and peripheral cholinergic systems.219... 

C. Anticholinergic Hallucinogens (Clinical Effects) -Neubauer et al.9t claim that antagonism to Ditran may require both adrenolytic and cholinomimetic activities. Bauer d FlUgel93 were able to inhibit the psychotomimetic effects of Bayer 1443 and Ditran by the prior administration dihydro-ergotamine. Increased urinary excretion of catecholamine and serotonin metabolites after the administration of N-methyl-3-pyrrolidyl phenylcyclopentylglycolate was demonstrated by Bente et al. 9 ... 

Carbachol, pilocarpine, echothiophate Cholinomimetic Activation of M receptors causes contraction of ciliary muscle, which increases flow through the canal of Schlemm echothiophate is an organophosphate AChE inhibitor - T outflow... 

Urinary tract Urinary system adverse reactions, especially enuresis, have been associated with clozapine [SED-15, 832] with an estimated incidence greater than 6%. The mechanisms include overflow incontinence after urinary retention due to the anti-muscarinic action of clozapine or a cholinomimetic activity, and reduced internal urethral sphincter tone caused by aj adrenoceptor blockade enuresis has also been attributed to a non-specific action of clozapine such as excessive sedation, lowering of the seizure threshold, and constipation exacerbating urinary retention and over-fiow. Secondary enuresis in a 21-year man with schizophrenia settled with resolution of his psychotic symptoms but later remerged after starting clozapine [SS ]. 

The anionic site of ChE does not make such rigid demands on the structure of the cationic head of substrates and inhibitors. For instance, acetyltriethylcholine, which is completely devoid of cholinomimetic activity, is hydrolysed by the cholinesterases at nearly the same rate as ACh. 

Seizures- Cholinomimetics are believed to have some potential to cause generalized convulsions however, seizure activity may also be a manifestation of Alzheimer disease. 

Gl Cholinesterase inhibitors may be expected to increase gastric acid secretion because of increased cholinergic activity. Monitor patients closely for symptoms of active or occult Gl bleeding, especially those at increased risk for developing ulcers. GU Cholinomimetics may cause bladder outflow obstruction. 

Cisapride is a selective cholinomimetic agent with no antidopaminergic activity. It increases acetylcholine release from the myenteric neurons. It has the same indications as metoclopramide but is also useful for dysmotility problems of the lower GI tract. In many countries it has been either withdrawn or has had its indications limited due to reports about long QT syndrome due to cisapride. 

Classical studies by Sir Henry Dale demonstrated that the receptors activated by muscarine, an alkaloid isolated from the mushroom Amanita muscaria, are the same receptors activated by ACh released from parasympathetic nerve endings, from which the general notion that muscarinic agonists have parasympathomimetic properties was born. This conclusion is true but incomplete, and we now know that muscarinic receptors have a broader distribution and many functional roles. To understand the actions of cholinomimetic drugs it is essential to recognize that muscarinic receptors (1) mediate the activation of effectors by ACh released from parasympathetic nerve... 

Inhibition of AChE can increase the stimulation of both muscarinic and nicotinic receptors produced by synaptically released ACh. Nicotinic receptors can also be stimulated directly by AChE inhibitors with a quaternary ammonium group, and this can potentiate their cholinomimetic effect. Finally, although inhibition of true AChE is most important for potentiating the synaptic activity of ACh, several AChE inhibitors also inhibit the pseudo-ChE in plasma. This can permit plasma concentrations of ACh to rise markedly and activate endothelial muscarinic receptors. 

In summary, 2-PAM I was found by Kunkel et al.11 to act as a depolarizing compound at the neuromyal junction and to have acetyl-cholinomimetic properties in large doses. It had some ganglionic blocking activity, but no direct effect on the CNS was detected. 

The beneficial effect of precursors (e.g., lecithin), cholinesterase inhibitors (e.g., physostigmine, donepezil), or drugs with cholinomimetic effects (e.g., bethanechol) for actue mania was discovered in part from the work of Janowsky et al. ( 29), leading to their cholinergic—noradrenergic balance hypothesis. Interestingly, lithium is also able to raise RBC choline concentrations and CNS cholinergic activity ( 274). 

Some cholinesterase inhibitors also inhibit butyrylcholinesterase (pseudocholinesterase). Flowever, inhibition of butyrylcholinesterase plays little role in the action of indirect-acting cholinomimetic drugs because this enzyme is not important in the physiologic termination of synaptic acetylcholine action. Some quaternary cholinesterase inhibitors also have a modest direct action as well, eg, neostigmine, which activates neuromuscular nicotinic cholinoceptors directly in addition to blocking cholinesterase. 

The actions of acetylcholine released from autonomic and somatic motor nerves are terminated by enzymatic hydrolysis of the molecule. Hydrolysis is accomplished by the action of acetylcholinesterase, which is present in high concentrations in cholinergic synapses. The indirect-acting cholinomimetics have their primary effect at the active site of this enzyme, although some also have direct actions at nicotinic receptors. The chief differences between members of the group are chemical and pharmacokinetic—their pharmacodynamic properties are almost identical. 

ACh, cholinomimetics and acetylcholinesterase inhibitors have been shown to inhibit the movement of flatworms and to cause flaccid paralysis (for reviews, see Fbx et a/., 1996 Halton et a/., 1997 Halton and Maule, 2004 Ribeiro et a/., 2005). This is in contrast to the mainly myoexcitatory effects of ACh at the vertebrate neuromuscular junction and in many other invertebrates including nematodes. Although ACh has predominantly inhibitory actions on flatworm muscle it has been shown to have inconsistent effects on the muscle of the monogenean, Diclidophora merlangi (Maule et a/., 1989), to induce the contraction of muscle fibres dispersed from planarians (Blair and Anderson, 1994 Moneypenny eta/., 2001) and, to cause increased muscle activity... 

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