Acetylcholine 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. 

It has been repeatedly observed that atropine is more effective in blocking effects of exogenously introduced acetylcholine and other parasympathomimetics than in blocking effects resulting from stimulation of fibers of the parasympathetic and cholinergic nerves. There are two factors that could be the reason for this ... 

Pharmacology Direct-acting miotics are parasympathomimetic (cholinergic) drugs which duplicate the muscarinic effects of acetylcholine. When applied topically, these drugs produce pupillary constriction, stimulate ciliary muscles, and increase aqueous humor outflow facility. With the increase in outflow facility, there is a decrease in lOP. Topical ophthalmic instillation of acetylcholine causes no discernible P.1248... 

Drugs that mimic the actions of acetylcholine are termed cholinomimetic, and those that mimic epinephrine and/or norepinephrine are adrenomimetic. The cholinomimetic drugs are also called parasympathomimetic drugs. The adrenomimetic drugs are often called sympathomimetic. 

Mechanism of Action A cholinergic, parasympathomimetic, synthetic analog of acetylcholine that stimulates muscarinic, postganglionic parasympathetic receptors. TherapeuticEffect Results in smooth muscle contraction of the airways and increased tracheobronchial secretions. 

Muscarine Muscarine, molecular formula C9H2qN02, first isolated from fly agaric Amanita muscaria, occurs in certain mushrooms, especially in the species of the genera Inocybe and Clitocybe. It is a parasympathomimetic substance. It causes profound activation of the peripheral parasympathetic nervous system, which may result in convulsions and death. Muscarine mimics the action of the neurotransmitter acetylcholine at the muscarinic acetylcholine receptors. 

Edrophonium Alcohol, binds briefly to active site of acetylcholinesterase (AChE) and prevents access of acetylcholine (ACh) Amplifies all actions of ACh increases parasympathetic activity and somatic neuromuscular transmission Diagnosis and acute treatment of myasthenia gravis Parenteral quaternary amine does not enter CNS Toxicity Parasympathomimetic excess Interactions Additive with parasympathomimetics... 

Effects of increasing doses of atropine on heart rate (A) and salivary flow (B) compared with muscarinic receptor occupancy in humans. The parasympathomimetic effect of low-dose atropine is attributed to blockade of prejunctional muscarinic receptors that suppress acetylcholine release. 

Pathophysiology can influence muscarinic activity in other ways as well. Circulating autoantibodies against the second extracellular loop of cardiac M2 muscarinic receptors have been detected in some patients with idiopathic dilated cardiomyopathy and those afflicted with Chagas1 disease caused by the protozoan Trypanosoma cruzi. These antibodies exert parasympathomimetic actions on the heart that are prevented by atropine. In animals immunized with a peptide from the second extracellular loop of the M2 receptor, the antibody is an allosteric modulator of the receptor. Although their role in the pathology of heart failure is unknown, these antibodies should provide clues to the molecular basis of receptor activation because their site of action differs from the orthosteric site where acetylcholine binds (see Chapter 2). 

Effects of increasing doses of atropine on heart rate (A) and salivary flow (B) compared with muscarinic receptor occupancy in humans. The parasympathomimetic effect of low-dose atropine is attributed to blockade of prejunctional muscarinic receptors that suppress acetylcholine release. (Modified and reproduced, with permission, from Wellstein A, Pitschner HF Complex dose-response curves of atropine in man explained by different functions of Mi and M2 cholinoceptors. Naunyn Schmiedebergs Arch Pharmacol 1988 338 19.)... 

Excitation of the parasympathetic division causes release of acetylcholine at neuroeffector junctions in different target organs. The major effects are summarized in (A) (blue arrows). Some of these effects have therapeutic applications, as indicated by the clinical uses of parasympathomimetics (P-106). 

Parasympathomimetics such as physostigmine sulfate increase the level of acetylcholine, which contracts the ciliary muscle and opens the fluid pathway which leads to reduction in IOP. They are usually used with pilocarpine hydrochloride or pilocarpine nitrate, which acts on cholinoceptors. Parasympathomimetics cause poor night vision because of miosis. 

Q12 Bethanechol is a parasympathomimetic agent which mimics the actions of acetylcholine. It is capable of stimulating the muscarinic receptors on the detrusor muscle and can contract the bladder, leading to more effective emptying of urine. 

Parasympathomimetics inhibit the enzyme cholinesterase, which is responsible for the breakdown of the neurotransmitter acetylcholine, They are a mainstay in the investigation (edrophonium) and treatment (distigmine, neostigmine,... 

The situation is complex in smooth muscles. Both acetylcholine and the phosphodiesterase inhibitor, l-methyl-3-iso-butylxanthine, elevate cyclic GMP levels, but acetylcholine causes contraction of the muscle preparation whereas the phosphodiesterase inhibitor produces relaxation [69]. In the guinea-pig ileum, the increase in cyclic GMP brought about by a parasympathomimetic drug can be prevented by the inclusion of isoprenaline in the incubation medium however, isoprenaline causes an increase in the concentration of cyclic AMP that can be inhibited by a parasympathomimetic drug [70]. In guinea-pig lung slices, acetylcholine and bradykinin increase both cyclic GMP and cyclic AMP yet indometha-cin and aspirin inhibit the effect on cyclic AMP but not that on cyclic GMP [71]. 

Atropine is the mainstay of treatment 2 mg is given i.m. or i.v. as soon as possible and repeated every 15-60 min until dryness of the mouth and a heart rate in excess of 70 beats per minute indicate that its effect is adequate. A poisoned patient may require 100 mg or more for a single episode. Atropine antagonises the muscarinic parasympathomimetic effects of the poison, i.e. due to the accumulated acetylcholine stimulating postganglionic nerve endings (excessive secretion and vasodilatation), but has no effect on the neuromuscular block, which is nicotinic. 

Cholinergic (parasympathomimetics) medications mimic acetylcholine. They initiate a response and inhibit the effect of acetylcholine. Medications that block the effect of acetylcholine are called anticholinergic (parasym-patholytics) or cholinergic antagonists because they inhibit the effect of acetylcholine. 

Cholinergic (parasympathomimetics) medications mimic acetylcholine. They initiate a response and inhibit the effect of acetylcholine. 

Parasympathomimetic substance with the same effects as acetylcholine. 

Pilocarpine nitrate is a parasympathomimetic agent possessing muscarinic effects of acetylcholine. It is mostly used as a solution (1 to 5%) to exert an action on the eye to cause miosis and retard intraocular tension in the treatment of open-angle glaucoma. Pilocarpine nitrate being less hygroscopic than its corresponding hydrochloride and hence it is more easy to handle. 

In 1914, Dale defined two subdivisions of the parasympathetic nervous system when he observed that ethers and esters (including acetylcholine) of choline produced effects similar to those of muscarine (muscarinic effects) or nicotine (nicotinic effects) (2). The initial experiments were performed using an ergot extract contaminated with acetylcholine, although Dale was unaware of this contamination. Ewins, a chemist who collaborated with Dale, isolated acetylcholine from the ergot extract and subsequently synthesized acetylcholine, thus allowing Dale to show that the unexpected muscarinic effects observed with the ergot preparation were the result of acetylcholine. He proposed the term "parasympathomimetic" to describe ... 

Dmgs that mimic acetylcholine are cholinergic agonists because they initiate a response. These are also known as cholinergic dmgs or parasympathomimet-ics (see chart). 

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