Atropine muscarinic receptor blocking

Even low doses of scopolamine have central effects. Sedation, amnesia, and drowsiness are common during the clinical use of this drug. Large doses of scopolamine can produce all of the responses seen with atropine. Other tertiary amine compounds with muscarinic receptor blocking activity have similar central effects. 

Two distinct receptor groups have been identified for acetylcholine, the nicotinic and the muscarinic groups (Table 11.1). Furthermore, there are at least four subtypes of nicotinic and five subtypes of muscarinic receptors. Nicotinic receptors are ubiquitous and exist at the neuromuscular junctions of skeletal muscles and on ganglion cells in the autonomic nervous system. Nicotinic receptors located on cation-specific ion channels, when opened, evoke fast, transient depolarizations of the recipient cell. Muscarinic receptors are found in smooth muscle receiving parasympathetic innervation and elsewhere, and can be blocked by atropine. Muscarinic receptors are coupled indirectly to slow and fast ion channels via G proteins. 

B. Interactions Based on Additive Effects Additive interaction describes the algebraic summing of the effects of two drugs. The two drugs may or may not act on the same receptor to produce such effects. The combined use of tricyclic antidepressants with diphenhydramine or promethazine predictably causes excessive atropine-like effects since all of these drugs have significant muscarinic receptor-blocking actions. Tricyclic antidepressants may increase the pressor responses to sympathomimetics by interference with amine transporter systems. 

These include atropine, scopolamine (hyoscine), trihexyphenidyl (benzhexol) and benzatropine. They block central muscarinic receptors involved in various afferent pathways of the vomiting reflex (Fig. 1). They have been used to control motion sickness, emesis in Meniere s disease and postoperative vomiting. Currently, hyoscine is largely restricted to the treatment of motion sickness where it has a fast onset of action but a short duration (4-6 h). Administration of hyoscine by transdermal patch produces a prolonged, low-level release of the drug with minimal side effects. To control postoperative vomiting, it should be applied >8 h before emesis is anticipated. 

To illustrate this notation we consider the ability of atropine to block the muscarinic receptors for acetylcholine. The presence of atropine at a concentration of only 1 nM makes it necessary to double the acetylcholine concentration required to elicit a given submaximal response of a tissue. Hence, pA2 = 9 for this action of atropine (-log(K) 9) = 9). 

The answer is d. (Hardman, pp 142—M3.) ACh will stimulate both muscarinic and nicotinic receptors. Skeletal muscle contraction is mediated through NM receptors, and ganglionic stimulation is an effect of NN receptors All of the other effects listed in the question occur following muscarinic receptor activation and will be blocked by atropine and scopolamine, both of which are muscarinic receptor antagonists. Skeletal muscle contraction will not be affected by these drugs rather, a neuromuscular blocker (e.g., tubocurarine) is required to antagonize this effect of ACh. 

Other plants of the nightshade family, including Atropa belladonna (deadly nightshade), Hyoscyamus niger (black henbane), and Datura stramonium (Jimson weed), contain atropine-like toxins that are anticholinergic, blocking the muscarinic receptors. An incidence in southern Utah of cattle poisoned on black henbane, with many death losses, was recently reported (Pfister, 2003). Atropine and atropine-like alkaloids are discussed Section 2.2.1.7. 

Sir Henry Dale noticed that the different esters of choline elicited responses in isolated organ preparations which were similar to those seen following the application of either of the natural substances muscarine (from poisonous toadstools) or nicotine. This led Dale to conclude that, in the appropriate organs, acetylcholine could act on either muscarinic or nicotinic receptors. Later it was found that the effects of muscarine and nicotine could be blocked by atropine and tubocurarine, respectively. Further studies showed that these receptors differed not only in their molecular structure but also in the ways in which they brought about their physiological responses once the receptor has been stimulated by an agonist. Thus nicotinic receptors were found to be linked directly to an ion channel and their activation always caused a rapid increase in cellular permeability to sodium and potassium ions. Conversely, the responses to muscarinic receptor stimulation were slower and involved the activation of a second messenger system which was linked to the receptor by G-proteins. 

Irreversible anticholinesterases include the organophosphorus inhibitors and ambenonium, which irreversibly phosphorylate the esteratic site. Such drugs have few clinical uses but have been developed as insecticides and nerve gases. Besides blocking the muscarinic receptors with atropine sulphate in an attempt to reduce the toxic effects that result from an accumulation of acetylcholine, the only specific treatment for organopho-sphate poisoning would appear to be the administration of 2-pyridine aldoxime methiodide, which increases the rate of dissociation of the organophosphate from the esteratic site on the enzyme surface. 

The snbgronps of muscarinic receptors (Mj and M2) are activated or blocked by various substances however, both types of muscarinic receptors are activated by an endogenic nenrotransmitter—acetylcholine—and are blocked by atropine or scopolamine. Despite the fact that atropine and scopolamine are reversible cholinoblocking agents, the constants of their dissociation with M-receptors are several times less than acetylcholine. Accordingly, their action is more prolonged (for a few days). 

The first step in treatment of anticholinesterase poisoning should be injection of increasing doses of atropine sulfate to block all adverse effects resulting from stimulation of muscarinic receptors. Since atropine will not alleviate skeletal and respiratory muscle paralysis, mechanical respiratory support may be required. 

Interaction of ACh with the postsynaptic ganglionic cell muscarinic receptor is responsible for slowly developing depolarization, the slow EPSP, which has a longer latency than the fast EPSP and a duration of 30 to 60 seconds. The slow EPSP is due to inhibition of a voltage-dependent K+ current called the M current, and inhibition of the M current involves activation of G proteins. At least five types of muscarinic receptors (Mj, M2, M3, M4 and M5) have been identified using functional studies and at least five subtypes (mj, m2, m3, rru, and m5) identified by molecular cloning techniques. The Mj receptor, which appears responsible for inhibiting the M current, can be blocked by atropine. 

Muscarinic Receptor Interactions. Excitatory muscarinic effects, such as temporary stimulation of salivation and stimulation of intestinal peristalsis, were seen with 2-PAM. Atropine-like actions were seen at high concentrations (15-20 mg/kg or more), and, when injected rapidly, 2-PAM caused temporary diplopia (nicotinic block) and loss of accommodation in the eye.Both TMB-4 and 2-PAM blocked bradycardia induced by vagal stimulation. At low concentrations, neither compound affected normal intestinal peristalsis, but they did block peristalsis caused by increased vagal stimulation. TMB-4, 2-PAM, and toxogonin antagonized the effect of acetylcholine, acetyl- -methyl-choline, and other agonists on Isolated guinea pig ileum.62... 

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