Case: Muscarinic cholinomimetic agents. Class

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The efferent nerves of the parasympathetic autonomic nervous system release the neurotransmitter ACh at both preganglionic and postganglionic (i.e., “cholinergic”) nerve endings, and also at somatic nerve endings. Nitric oxide is a cotransmitter at many of the parasympathetic postganglionic sites.

The ACh released from nerve endings of the parasympathetic nervous system interacts at specialized cell membrane components called cholinoreceptors that are classified as either nicotinic or muscarinic after the alkaloids initially used to distinguish them.

Nicotinic cholinoreceptors are localized at all postganglionic neurons (the autonomic ganglia), including the adrenal medulla, and skeletal muscle endplates innervated by somatic nerves. Muscarinic cholinoreceptors are localized at organs innervated by parasympathetic postganglionic nerve endings, for example, on cardiac atrial muscle, sinoatrial node cells, and atrioventricular node cells, where activation can cause a negative chronotropic effect and delayed atrioventricular conduction. Cholinergic stimulation of muscarinic receptors in the smooth muscle, exocrine glands, and vascular endothelium can cause, respectively, bronchoconstriction, increased acid secretion, and vasodilation (Table:Effects of cholinoreceptor activation).

Table: Effects of cholinoreceptor activation

* There is no parasympathetic innervation of blood vessels. However, they have cholinoreceptors that when activated result in their dilation.

There are two subtypes of the nicotinic cholinoreceptors: N_N, localized to postganglionic neurons, and N_M, localized to the skeletal muscle endplates. There are three pharmacologically important subtypes of the muscarinic cholinoreceptors, M₁, M₂, and M₃ (two additional subtypes have been identified by cloning), that alone or in combination are localized to sympathetic postganglionic neurons (and the CNS), to the atrial muscle, sinoatrial (SA) cells, and atrioventricular (AV) node of the heart, to smooth muscle, to exocrine glands, and to the vascular endothelium that does not receive parasympathetic innervation.

Directly and indirectly acting parasympathetic cholinomimetic agents, primarily pilocarpine and bethanechol, and neostigmine, are used most often therapeutically to treat certain diseases of the eye (acute angle-closure glaucoma), the urinary tract (urinary tract retention), the gastrointestinal tract (postoperative ileus), salivary glands (xerostomia), and the neuromuscular junction (myasthenia gravis). The ACh is generally not used clinically because of its numerous actions and very rapid hydrolysis by AChE and pseudocholinesterase.

The adverse effects of direct- and indirect-acting cholinomimetics result from cholinergic excess and may include diarrhea, salivation, sweating, bronchial constriction, vasodilation, and bradycardia. Nausea and vomiting are also common. Adverse effects of cholinesterase inhibitors (most often as a result of toxicity from pesticide exposure, e.g., organophosphates) also may include muscle weakness, convulsions, and respiratory failure.

Structure

ACh is a choline ester that is not very lipid soluble because of its charged quaternary ammonium group. It interacts with both muscarinic and nicotinic cholinoreceptors. Choline esters similar in structure to ACh that are used therapeutically include methacholine, carbachol, and bethanechol. Unlike ACh and carbachol, methacholine and bethanechol are highly selective for muscarinic cholinoreceptors. Pilocarpine is a tertiary amine alkaloid.

Mechanism of Action

Muscarinic cholinoreceptors activate inhibitory G-proteins (G_i) to stimulate the activity of phospholipase C, which, through increased phospholipid metabolism, results in production of inositol triphosphate (IP₃) and DAG that lead to the mobilization, respectively, of intracellular calcium from the endoplasmic and sarcoplasmic reticulum and, through activation of protein kinase C (PK-C), the opening of smooth muscle calcium channels with an influx of extracellular calcium. Activation of muscarinic cholinoreceptors also results in altered potassium flux that results in cell hyperpolarization, and in inhibition of adenylyl cyclase activity and cAMP accumulation induced by other hormones, including the catecholamines.

The nicotinic receptor functions as a cell membrane ligand-gated ion channel pore. On interaction with ACh, the receptor undergoes a conformational change that results in influx of sodium with membrane depolarization of the nerve cell or the skeletal muscle neuromuscular endplate.

Indirectly acting parasympathetic cholinomimetic agents inhibit AChE and thereby increase ACh levels at both muscarinic and nicotinic cholinoreceptors.

Administration

Directly acting muscarinic cholinomimetic agents may be administered topically as ophthalmic preparations (pilocarpine, carbachol), orally (bethanechol, pilocarpine), or parenterally (bethanechol). Depending on the agent, an indirectly acting cholinesterase inhibitor may be administered topically, orally, or parenterally.

Pharmacokinetics

ACh is synthesized from choline and acetyl-coenzyme A (acetyl-CoA) by the enzyme choline acetyltransferase and then transported into nerve ending vesicles. Like ACh, methacholine, carbachol, and bethanechol are poorly absorbed by the oral route and have limited penetration into the CNS. Pilocarpine is more lipid soluble and can be absorbed and can penetrate the CNS.

After release from nerve endings, ACh is rapidly metabolized into choline and acetate, and its effects are terminated by the action of the enzymes AChE and pseudocholinesterase. Methacholine and particularly carbachol and bethanechol are resistant to the action of cholinesterases.

Continuation: Case: Muscarinic cholinomimetic agents. Questions – Answers