Directly and Indirectly Acting Cholinomimetics

Directly and Indirectly Acting Cholinomimetics

Cholinomimetic drugs can elicit some or all of the effects that acetylcholine (ACh) produces. This class of drugs includes agents that act directly as agonists at cholinoreceptors and agents that act indirectly by in-hibiting the enzymatic destruction of endogenous ACh (i.e., cholinesterase inhibitors). The directly acting choli-nomimetics can be subdivided into agents that exert their effects primarily through stimulation of mus-carinic receptors at parasympathetic neuroeffector junctions (parasympathomimetic drugs) and agents that stimulate nicotinic receptors in autonomic ganglia and at the neuromuscular junction.

Muscarinic Receptors and Signal Transduction

Classical studies by Sir Henry Dale demonstrated that the receptors activated by muscarine, an alkaloid iso-lated 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 parasympatho-mimetic properties was born. This conclusion is true but incomplete, and we now know that muscarinic re-ceptors have a broader distribution and many func-tional roles. To understand the actions of choli-nomimetic drugs it is essential to recognize that muscarinic receptors: (1) mediate the activation of ef-fectors by ACh released from parasympathetic nerve endings; (2) mediate the activation of sweat glands by ACh released from sympathetic fibers; (3) are found on vascular endothelial cells that receive no cholinergic in-nervation; (4) are widely distributed in the central ner-vous system (CNS), from basal ganglia to neocortex; and (5) are present on presynaptic nerve terminals, including terminals that release ACh and terminals associated with other neurotransmitter systems, such as the cate-cholamines. Therefore, the activation of muscarinic re-ceptors may influence most of the organ systems along with CNS pathways involved in regulating voluntary motor activity, memory, and cognition. Activation of presynaptic muscarinic receptors can inhibit the release of endogenous neurotransmitters, and may account for some paradoxical effects of cholinomimetic stimulation.

Binding studies with high-affinity receptor antago-nists revealed four subtypes of muscarinic receptors that can be distinguished on the basis of (1) the rank or-der of potency of specific antagonists in functional ex-periments and (2) the affinity of these antagonists for muscarinic receptors in the same tissues. More recently, molecular studies have revealed five genetically distinct receptor subtypes, named M1 through M5, the first four of which correspond to functionally defined receptors. The different subtypes of muscarinic receptors are het-erogeneously distributed: (1) M1 receptors are present in brain, exocrine glands, and autonomic ganglia. (2) M2 receptors are found in the heart, brain, autonomic gan-glia, and smooth muscle. (3) M3 receptors are present in smooth muscle, exocrine glands, brain, and endothelial cells. (4) M4 receptors are present in brain and auto-nomic ganglia. (5) M5 receptors are found in the CNS.

All muscarinic receptors are members of the seven transmembrane domain, G protein–coupled receptors, and they are structurally and functionally unrelated to nicotinic ACh receptors. Activation of muscarinic re-ceptors by an agonist triggers the release of an intracel-lular G-protein complex that can specifically activate one or more signal transduction pathways. Fortunately, the cellular responses elicited by odd- versus even-numbered receptor subtypes can be conveniently dis-tinguished. Activation of M1, M3, and M5 receptors produces an inosine triphosphate (IP3) mediated re-lease of intracellular calcium, the release of diacylglyc-erol (which can activate protein kinase C), and stimula-tion of adenylyl cyclase. These receptors are primarily responsible for activating calcium-dependent responses, such as secretion by glands and the contraction of smooth muscle.

Activation of M2 and M4 receptors inhibits adeny-lyl cyclase, and activation of M2 receptors opens potas-sium channels. The opening of potassium channels hy-perpolarizes the membrane potential and decreases the excitability of cells in the sinoatrial (SA) and atrioven-tricular (A-V) nodes in the heart. The inhibition of adenylyl cyclase decreases cellular cyclic adenosine monophosphate (cAMP) levels, which can override the opposing stimulation of adenylyl cyclase by β-adreno-ceptor agonists.

Although muscarinic receptors as a class can be se-lectively activated and they demonstrate strong stereo-selectivity among both agonists and antagonists , the therapeutic use of cholinomimetics is limited by the paucity of drugs selective for specific sub-types of muscarinic receptors. This lack of specificity combined with the broad-ranging effects of muscarinic stimulation on different organ systems makes the ther-apeutic use of cholinomimetic drugs a challenge, and the careful consideration of the pharmacokinetic prop-erties of the drugs plays an especially important role in making therapeutic decisions.