Chapter 9: Muscarinic Receptor Agonists and Antagonists

ACETYLCHOLINE AND ITS MUSCARINIC RECEPTOR TARGET

Muscarinic acetylcholine receptors in the peripheral nervous system occur primarily on autonomic effector cells innervated by postganglionic parasympathetic nerves. Muscarinic receptors are also present in autonomic ganglia and on some cells (e.g., vascular endothelial cells) that, paradoxically, receive little or no cholinergic innervation. Within the CNS, the hippocampus, cortex, and thalamus have high densities of muscarinic receptors. Acetylcholine (ACh), the naturally occurring neurotransmitter for these receptors, has virtually no systemic therapeutic applications because its actions are diffuse, and its hydrolysis, catalyzed by both acetylcholinesterase (AChE) and plasma butyrylcholinesterase, is rapid. Muscarinic agonists mimic the effects of ACh at these sites and are longer-acting congeners of ACh or natural alkaloids.

Cholinergic synapses are found at:

• Autonomic effector sites innervated by postganglionic parasympathetic nerves (or, in the sweat glands, by postganglionic sympathetic nerves)

• Sympathetic and parasympathetic ganglia and the adrenal medulla, innervated by preganglionic autonomic nerves

• Motor end plates on skeletal muscle, innervated by somatic motor nerves

• Certain synapses in the CNS, where ACh can have either pre- or postsynaptic actions

The actions of ACh and related drugs at autonomic effector sites are termed muscarinic, based on the observation that the alkaloid muscarine acts selectively at those sites and produces the same qualitative effects as ACh (see Table 8–1). Muscarinic receptors are present in autonomic ganglia and the adrenal medulla but primarily function to modulate the nicotinic actions of ACh at these sites (see Chapter 11). In the CNS, muscarinic receptors are widely distributed and mediate many important responses. The actions of ACh and its congeners at muscarinic receptors can be blocked competitively by atropine.

PROPERTIES AND SUBTYPES OF MUSCARINIC RECEPTORS

Muscarinic receptors comprise 5 distinct gene products, designated as M₁ through M₅ (see Table 8–3). Muscarinic receptors are GPCRs that in turn couple to various cellular effectors. Selectivity is not absolute but, in general, stimulation of M₁, M₃, and M₅ receptors activates the G_q-PLC-IP₃/DAG-Ca²⁺ pathway, resulting in a variety of Ca²⁺-mediated responses. By contrast, M₂ and M₄ muscarinic receptors couple to the pertussis toxin–sensitive G proteins, G_i and G_o, to inhibit adenylyl cyclase and regulate specific ion channels.

PHARMACOLOGICAL EFFECTS OF ACETYLCHOLINE