Chapter 7. Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs

Drugs with acetylcholine-like effects (cholinomimetics) consist of 2 major subgroups on the basis of their mode of action (ie, whether they act directly at the acetylcholine receptor or indirectly through inhibition of cholinesterase). Drugs in the direct-acting subgroup are further subdivided on the basis of their spectrum of action (ie, whether they act on muscarinic or nicotinic cholinoceptors).

Acetylcholine may be considered the prototype that acts directly at both muscarinic and nicotinic receptors. Neostigmine is a prototype for the indirect-acting cholinesterase inhibitors.

This class comprises a group of choline esters (acetylcholine, methacholine, carbachol, and bethanechol) and a second group of naturally occurring alkaloids (muscarine, pilocarpine, nicotine, lobeline). Newer drugs are occasionally introduced for special applications. The members differ in their spectrum of action (amount of muscarinic versus nicotinic stimulation) and in their pharmacokinetics (Table 7–1). Both factors influence their clinical use.

Classification

Muscarinic agonists are parasympathomimetic; that is, they mimic the actions of parasympathetic nerve stimulation in addition to other effects. Five subgroups of muscarinic receptors have been identified (Table 7–2), but the muscarinic agonists available for clinical use activate them nonselectively. Nicotinic agonists are rarely classified on the basis of whether ganglionic or neuromuscular stimulation predominates; agonist selectivity is limited. On the other hand, relatively selective antagonists are available for the two nicotinic receptor types (Chapter 8).

Molecular Mechanisms of Action

Muscarinic Mechanism

Muscarinic receptors are G protein-coupled receptors (GPCRs) (Table 7–2). Gq protein coupling of M1 and M3 muscarinic receptors to phospholipase C, a membrane-bound enzyme, leads to the release of the second messengers, diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3). DAG modulates the action of protein kinase C, an enzyme important in secretion, whereas IP3 evokes the release of calcium from intracellular storage sites, which results in contraction in smooth muscle. M2 muscarinic receptors couple to adenylyl cyclase through the inhibitory Gi-coupling protein. A third mechanism couples the same M2 receptors via the βγ subunit of the G protein to potassium channels in the heart and elsewhere; muscarinic agonists facilitate opening of these channels. M4 and M5 receptors may be important in the central nervous system (CNS) but have not been shown to play major roles in peripheral organs.

Nicotinic Mechanism

The mechanism of nicotinic action has been clearly defined. The nicotinic acetylcholine ACh receptor is located on a channel protein that is selective for sodium and potassium. When the receptor is activated, the channel opens and depolarization of the cell occurs as a direct result of the influx of sodium, causing an excitatory postsynaptic potential (EPSP). If large enough, the EPSP evokes a propagated action potential in the surrounding membrane. The nicotinic receptors on sympathetic and parasympathetic ganglion cells (NN, also denoted NG) differ slightly from those on neuromuscular end plates (NM).

Tissue and Organ Effects

The tissue and organ system effects of cholinomimetics are summarized in Table 7–3. Note that vasodilation (and decreased blood pressure) is not a parasympathomimetic response (ie, it is not evoked by parasympathetic nerve discharge, even though directly acting cholinomimetics cause vasodilation). This vasodilation results from the release of endothelium-derived relaxing factor (EDRF; nitric oxide and possibly other substances) in the vessels, mediated by uninnervated muscarinic receptors on the endothelial cells. Note also that decreased blood pressure evokes the baroreceptor reflex, resulting in strong compensatory sympathetic discharge to the heart. As a result, injections of small to moderate amounts of direct-acting muscarinic cholinomimetics often cause tachycardia, whereas parasympathetic (vagal) nerve discharge to the heart causes bradycardia. Another effect seen with cholinomimetic drugs but not with parasympathetic nerve stimulation is thermoregulatory sweating; this is a sympathetic cholinergic effect (see Chapter 6).

The tissue and organ level effects of nicotinic ganglionic stimulation depend on the autonomic innervation of the organ involved. The blood vessels are dominated by sympathetic innervation; therefore, nicotinic receptor activation results in vasoconstriction mediated by sympathetic postganglionic nerve discharge. The gut is dominated by parasympathetic control; nicotinic drugs increase motility and secretion because of increased parasympathetic postganglionic neuron discharge. Nicotinic neuromuscular end plate activation by direct-acting drugs results in fasciculations and spasm of the muscles involved. Prolonged activation results in paralysis (see Chapter 27), which is an important hazard of exposure to nicotine-containing and organophosphate insecticides.

Clinical Use

Several clinical conditions benefit from an increase in cholinergic activity, including glaucoma, Sjogren's syndrome, and loss of normal PANS activity in the bowel and bladder. Direct-acting nicotinic agonists are used in smoking cessation and to produce skeletal muscle paralysis (succinylcholine, Chapter 27). Indirect-acting agents are used when increased nicotinic activation is needed at the neuromuscular junction (see discussion of myasthenia gravis). Nicotine is still used as an insecticide. Varenicline is a newer nicotinic agonist with partial agonist properties. It appears to reduce craving in persons addicted to nicotine.

Toxicity

The signs and symptoms of overdosage are readily predicted from the general pharmacology of acetylcholine.

Muscarinic Toxicity

These effects include CNS stimulation (uncommon with choline esters and pilocarpine), miosis, spasm of accommodation, bronchoconstriction, excessive gastrointestinal and genitourinary smooth muscle activity, increased secretory activity (sweat glands, airway, gastrointestinal tract, lacrimal glands), and vasodilation. Transient bradycardia occurs, followed by reflex tachycardia if the drug is administered as an intravenous bolus; reflex tachycardia occurs otherwise. Muscarine and similar alkaloids are found in certain mushrooms (Inocybe species and Amanita muscaria) and are responsible for the short-acting form of mushroom poisoning, which is characterized by nausea, vomiting, and diarrhea. (The much more dangerous and potentially lethal form of mushroom poisoning from Amanita phalloides and related species involves initial vomiting and diarrhea but is followed by hepatic and renal necrosis. It is not caused by muscarinic agonists but by amanitin and phalloidin, RNA polymerase inhibitors.)

Nicotinic Toxicity

Toxic effects include ganglionic stimulation and block and neuromuscular end plate depolarization leading to fasciculations and then paralysis. CNS toxicity includes stimulation (including convulsions) followed by depression. Nicotine in small doses is strongly addicting.

See Chapter 4.

Acetylcholine is metabolized in the body by hydrolysis of the ester bond. Is this a phase I or phase II metabolic reaction? The Skill Keeper Answer appears at the end of the chapter.

Classification and Prototypes

Hundreds of indirect-acting cholinomimetic drugs have been synthesized in 2 major chemical classes: carbamic acid esters (carbamates) and phosphoric acid esters (organophosphates). Neostigmine is a prototypic carbamate, whereas parathion, an important insecticide, is a prototypic organophosphate. A third class has only one clinically useful member: edrophonium is an alcohol (not an ester) with a very short duration of action.

Mechanism of Action

Both carbamate and organophosphate inhibitors bind to cholinesterase and undergo prompt hydrolysis. The alcohol portion of the molecule is then released. The acidic portion (carbamate ion or phosphate ion) is released much more slowly, preventing the binding and hydrolysis of endogenous acetylcholine. As a result, these drugs amplify acetylcholine effects wherever the transmitter is released. Edrophonium, though not an ester, has sufficient affinity for the enzyme active site to similarly prevent access of acetylcholine for 5–15 min. After hydrolysis, carbamates are released by cholinesterase over a period of 2–8 h. Organophosphates are long-acting drugs; they form an extremely stable phosphate complex with the enzyme. After initial hydrolysis, the phosphoric acid residue is released over periods of days to weeks. Recovery is due in part to synthesis of new enzyme.

Effects

By inhibiting cholinesterase, these agents cause an increase in the concentration, half-life, and actions of acetylcholine in synapses where acetylcholine is released physiologically. Therefore, the indirect agents have muscarinic or nicotinic effects depending on which organ system is under consideration. Cholinesterase inhibitors do not have significant actions at uninnervated sites where acetylcholine is not normally released (eg, vascular endothelial cells).

Clinical Use

The clinical applications of the indirect-acting cholinomimetics are predictable from a consideration of the organs and the diseases that benefit from an amplification of cholinergic activity. These applications are summarized in the Drug Summary Table. Carbamates, which include neostigmine, physostigmine, pyridostigmine, and ambenonium, are used far more commonly in therapeutics than are organophosphates. The treatment of myasthenia is especially important. (Because myasthenia is an autoimmune disorder, treatment may also include thymectomy and immunosuppressant drugs.) Rivastigmine, a carbamate, and several other cholinesterase inhibitors are used exclusively in Alzheimer's disease. A portion of their action may be due to other, unknown mechanisms. Although their effects are modest and temporary, these drugs are frequently used in this devastating condition. Some carbamates (eg, carbaryl) are used in agriculture as insecticides. Two organophosphates used in medicine are malathion (a scabicide) and metrifonate (an antihelminthic agent).

Edrophonium is used for the rapid reversal of nondepolarizing neuromuscular blockade (Chapter 27), in the diagnosis of myasthenia, and in differentiating myasthenic crisis from cholinergic crisis in patients with this disease. Because cholinergic crisis can result in muscle weakness like that of myasthenic crisis, distinguishing the 2 conditions may be difficult. Administration of a short-acting cholinomimetic, such as edrophonium, will improve muscle strength in myasthenic crisis but weaken it in cholinergic crisis.

Toxicity

In addition to their therapeutic uses, some indirect-acting agents (especially organophosphates) have clinical importance because of accidental exposures to toxic amounts of pesticides. The most toxic of these drugs (eg, parathion) can be rapidly fatal if exposure is not immediately recognized and treated. After standard protection of vital signs (see Chapter 58), the antidote of first choice is the antimuscarinic agent atropine, but this drug has no effect on the nicotinic signs of toxicity. Nicotinic toxicity is treated by regenerating active cholinesterase. Immediately after binding to cholinesterase, most organophosphate inhibitors can be removed from the enzyme by the use of regenerator compounds such as pralidoxime (see Chapter 8), and this may reverse both nicotinic and muscarinic signs. If the enzyme-phosphate binding is allowed to persist, however, aging (a further chemical change) occurs and regenerator drugs can no longer remove the inhibitor. Treatment is described in more detail in Chapter 8.

Because of their toxicity and short persistence in the environment, organophosphates are used extensively in agriculture as insecticides and antihelminthic agents; examples are malathion and parathion. Some of these agents (eg, malathion, dichlorvos) are relatively safe in humans because they are metabolized rapidly to inactive products in mammals (and birds) but not in insects. Some are prodrugs (eg, malathion, parathion) and must be metabolized to the active product (malaoxon from malathion, paraoxon from parathion). The signs and symptoms of poisoning are the same as those described for the direct-acting agents, with the following exceptions: vasodilation is a late and uncommon effect; bradycardia is more common than tachycardia; CNS stimulation is common with organophosphate and physostigmine overdosage and includes convulsions, followed by respiratory and cardiovascular depression. The spectrum of toxicity can be remembered with the aid of the mnemonic DUMBBELSS (diarrhea, urination, miosis, bronchoconstriction, bradycardia, excitation [of skeletal muscle and CNS], lacrimation, and salivation and sweating).

See Chapter 4.

The esters acetylcholine and methacholine are hydrolyzed by acetylcholinesterase. Hydrolytic drug metabolism reactions are classified as phase I.

When you complete this chapter, you should be able to:

• □ List the locations and types of acetylcholine receptors in the major organ systems (CNS, autonomic ganglia, eye, heart, vessels, bronchi, gut, genitourinary tract, skeletal muscle, exocrine glands).
• □ Describe the second messengers involved and the effects of acetylcholine on the major organs.
• □ List the major clinical uses of cholinomimetic agonists.
• □ Describe the pharmacodynamic differences between direct-acting and indirect-acting cholinomimetic agents.
• □ List the major pharmacokinetic differences of the direct- and indirect-acting cholinomimetics.
• □ List the major signs and symptoms of (1) organophosphate insecticide poisoning and (2) acute nicotine toxicity.