Acetylcholine Receptor Agonists

Acetylcholine Receptor Agonists

Overview of Cholinergic Pharmacology

Acetylcholine Receptors

Acetylcholine receptors (cholinergic receptors) are divided into two types, muscarinic receptors and nicotinic receptors, based on their selective activation by the alkaloids muscarine and nicotine.

Muscarinic Receptors

Muscarinic receptors are found in smooth muscle, cardiac tissue, and glands at parasympathetic neuroeffector junctions. They are also found in the central nervous system, on presynaptic sympathetic and parasympathetic nerves, and at autonomic ganglia. Activation of muscarinic receptors on presynaptic autonomic nerves inhibits further neurotransmitter release. The presence of muscarinic receptors on sympathetic nerve terminals provides for interaction between the parasympathetic and sympathetic nervous systems: the release of acetylcholine from parasympathetic nerves inhibits the release of norepinephrine from sympathetic nerves.

Muscarinic receptors are divided into five subtypes, M1 through M5, based on their pharmacologic properties and molecular structures. The principal subtypes found in most tissues are M1, M2, and M3 receptors (Table 6-1). Muscarinic receptor stimulation leads to the activation of guanine nucleotide-binding proteins (G proteins), which increases or decreases the formation of other second messengers (see Chapter 3). The M1, M3, and M5 receptors are coupled with Gq proteins and their activation stimulates phospholipase C, leading to the formation of inositol triphosphate (IP3) and diacylglycerol from membrane phospholipids. In smooth muscles, IP3 increases calcium release from the sarcoplasmic reticulum and promotes muscle contraction. In exocrine glands, IP3 causes calcium release and glandular secretion. In vascular endothelial cells, IP3-activated calcium release stimulates nitric oxide synthesis, leading to vascular smooth muscle relaxation.

The M2 and M4 receptors are coupled with i proteins; their activation decreases cyclic adenosine monophosphate (cAMP) levels by inhibiting adenylate cyclase and also increases potassium efflux. The effects produced by activation of muscarinic receptors are summarized in Table 6-1.

The acetylcholine receptor agonists that are currently available for clinical use do not selectively activate subtypes of muscarinic receptors, but an M1 selective antagonist, pirenzepine, has been developed (see Chapter 7).

Nicotinic Receptors

Nicotinic receptors are found at all autonomic ganglia, at somatic neuromuscular junctions, and in the central nervous system. These receptors are ligand-gated sodium channels whose activation leads to sodium influx and membrane depolarization. At autonomic ganglia, activation of nicotinic receptors produces excitation of postganglionic neurons leading to the release of neurotransmitters at postganglionic neuroeffector junctions. At junctions of somatic nerves and skeletal muscle, activation of nicotinic receptors depolarizes the motor end plate and leads both to the release of calcium from the sarcoplasmic reticulum and to the contraction of muscles. In the brain, activation of nicotinic receptors causes excitation of presynaptic and postsynaptic neurons.

Nicotinic receptors are pentamers formed by the assembly of five transmembrane polypeptide subunits (Fig. 6-1). These subunits are divided into classes (alpha [α] through epsilon [ε]) according to their molecular structure. Each type of nicotinic receptor (muscle, ganglionic, brain) is composed of a unique combination of these subunits. All subunits appear to participate in the formation of acetylcholine-binding sites and influence the functional properties of the receptors, but a clear understanding of the unique roles of the different classes of subunits has not yet been obtained.

Direct-Acting Acetylcholine Receptor Agonists

The direct-acting agonists include the choline esters, the plant alkaloids, and synthetic drugs called cevimeline and varenicline. These drugs all bind and activate acetylcholine receptors, but they differ with respect to their affinity for muscarinic and nicotinic receptors and their susceptibility to hydrolysis by cholinesterase (Table 6-2).

Choline Esters

The choline esters include acetylcholine and synthetic acetylcholine analogues, such as bethanechol and carbachol.

General Properties

The choline esters are positively charged quaternary ammonium compounds that are poorly absorbed from the gastrointestinal tract and are not distributed to the central nervous system. Acetylcholine and carbachol activate both muscarinic and nicotinic receptors, whereas bethanechol activates only muscarinic receptors. Because of their lack of specificity for muscarinic receptor subtypes, the muscarinic receptor agonists cause a wide range of effects on many organ systems.

Ocular Effects

Muscarinic receptor agonists increase lacrimal gland secretion and stimulate contraction of the iris sphincter muscle and the ciliary muscles. Contraction of the iris sphincter muscle produces pupillary constriction (miosis), whereas contraction of the ciliary muscles enables accommodation of the lens to focus on close objects (Fig. 6-2).

< div class='tao-gold-member'>

Stay updated, free articles. Join our Telegram channel

Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Acetylcholine Receptor Agonists

Full access? Get Clinical Tree

Get Clinical Tree app for offline access