oral route), they differ markedly in their susceptibility to hydrolysis by cholinesterase. Acetylcholine is very rapidly hydrolyzed (see Chapter 6); large amounts must be infused intravenously to achieve concentrations sufficient to produce detectable effects. A large intravenous bolus injection has a brief effect, typically 5–20 seconds, whereas intramuscular and subcutaneous injections produce only local effects. Methacholine is more resistant to hydrolysis, and the carbamic acid esters carbachol and bethanechol are still more resistant to hydrolysis by cholinesterase and have correspondingly longer durations of action. The β-methyl group (methacholine, bethanechol) reduces the potency of these drugs at nicotinic receptors (Table 7–2).
The tertiary natural cholinomimetic alkaloids (pilocarpine, nicotine, lobeline) are well absorbed from most sites of administration. Nicotine, a liquid, is sufficiently lipid-soluble to be absorbed across the skin. Muscarine, a quaternary amine, is less completely absorbed from the gastrointestinal tract than the tertiary amines but is nevertheless toxic when ingested—eg, in certain mushrooms—and it even enters the brain. Lobeline is a plant derivative similar to nicotine. These amines are excreted chiefly by the kidneys. Acidification of the urine accelerates clearance of the tertiary amines (see Chapter 1).
FIGURE 7–3 Structures of some cholinomimetic alkaloids.
A. Mechanism of Action
Activation of the parasympathetic nervous system modifies organ function by two major mechanisms. First, acetylcholine released from parasympathetic nerves activates muscarinic receptors on effector cells to alter organ function directly. Second, acetylcholine released from parasympathetic nerves interacts with muscarinic receptors on nerve terminals to inhibit the release of their neurotransmitter. By this mechanism, acetylcholine release and circulating muscarinic agonists indirectly alter organ function by modulating the effects of the parasympathetic and sympathetic nervous systems and perhaps nonadrenergic, noncholinergic (NANC) systems.
As indicated in Chapter 6, muscarinic receptor subtypes have been characterized by binding studies and cloned. Several cellular events occur when muscarinic receptors are activated, one or more of which might serve as second messengers for muscarinic activation. All muscarinic receptors appear to be of the G protein-coupled type (see Chapter 2 and Table 7–1). Muscarinic agonist
TABLE 7–2 Properties of choline esters.
binding to M1, M3, and M5 receptors activates the inositol trisphosphate (IP3), diacylglycerol (DAG) cascade. Some evidence implicates DAG in the opening of smooth muscle calcium channels; IP3 releases calcium from endoplasmic and sarcoplasmic reticulum. Muscarinic agonists also increase cellular cGMP concentrations. Activation of muscarinic receptors also increases potassium flux across cardiac cell membranes (Figure 7–4A) and decreases it in ganglion and smooth muscle cells. This effect is mediated by the binding of an activated G protein βγ subunit directly to the channel. Finally, activation of M2 and M4 muscarinic receptors inhibits adenylyl cyclase activity in tissues (eg, heart, intestine). Moreover, muscarinic agonists attenuate the activation of adenylyl cyclase and modulate the increase in cAMP levels induced by hormones such as catecholamines. These muscarinic effects on cAMP generation reduce the physiologic response of the organ to stimulatory hormones.