Cholinergic Agonists

Drugs affecting the autonomic nervous system are divided into two groups according to the type of neuron involved in their mechanism of action. The cholinergic drugs, which are described in this and the following chapter, act on receptors that are activated by acetylcholine. The second group act on receptors that are stimulated by norepinephrine or epinephrine. Cholinergic and adrenergic drugs both act by either stimulating or blocking receptors of the autonomic nervous system. 

Figure 4.1 summarizes the cholinergic agonists discussed in this chapter

• The Cholinergic Neuron

The preganglionic fibers terminating in the adrenal medulla, the autonomic ganglia (both parasympathetic and sympathetic), and the postganglionic fibers of the parasympathetic division use acetylcholine as a neurotransmitter.

Figure : Sites of actions of cholinergic agonists in the autonomic and somatic nervous systems.

In addition, cholinergic neurons innervate the muscles of the somatic system and also play an important role in the central nervous system (CNS) .[Note: Patients with Alzheimer's disease have a significant loss of cholinergic neurons in the temporal lobe and entorhinal cortex. Most of the drugs available to treat the disease are acetylcholinesterase inhibitors ]

  

•  Cholinergic Receptors (Cholinoceptors) 

Two families of cholinoceptors, designated muscarinic and nicotinic receptors, can be distinguished from each other on the basis of their different affinities for agents that mimic the action of acetylcholine (cholinomimetic agents or parasympathomimetics.

A. Muscarinic receptors
These receptors, in addition to binding acetylcholine, also recognize muscarine, an alkaloid that is present in certain poisonous mushrooms. By contrast, the muscarinic receptors show only a weak affinity for nicotine

Figure : Types of cholinergic receptors.

Binding studies and specific inhibitors, as well as cDNA characterization, have distinguished five subclasses of muscarinic receptors: M1, M2, M3, M4, and M5. Although five muscarinic receptors have been identified by gene cloning, only M1, M2 and M3, receptors have been functionally characterized.

 1. Locations of muscarinic receptors: These receptors have been found on ganglia of the peripheral nervous system and on the autonomic effector organs, such as the heart, smooth muscle, brain, and exocrine glands

Figure : Action of sympathetic and parasympathetic nervous systems on effector organs.

Specifically, although all five subtypes have been found on neurons, M1 receptors are also found on gastric parietal cells, M2 receptors on cardiac cells and smooth muscle, and M3 receptors on the bladder, exocrine glands, and smooth muscle. [Note: Drugs with muscarinic actions preferentially stimulate muscarinic receptors on these tissues, but at high concentration they may show some activity at nicotinic receptors.] 

2. Mechanisms of acetylcholine signal transduction: A number of different molecular mechanisms transmit the signal generated by acetylcholine occupation of the receptor. For example, when the M1 or M3 receptors are activated, the receptor undergoes a conformational change and interacts with a G protein, designated Gq, which in turn activates phospholipase C.1 This leads to the hydrolysis of phosphatidylinositol-(4,5)-bisphosphate-P2 to yield diacylglycerol and inositol (1,4,5)-trisphosphate (formerly called inositol (1,4,5)-triphosphate), which cause an increase in intracellular Ca2+ 

Figure  Three mechanisms whereby binding of a neurotransmitter leads to a cellular effect.

This cation can then interact to stimulate or inhibit enzymes, or cause hyperpolarization, secretion, or contraction. In contrast, activation of the M2 subtype on the cardiac muscle stimulates a G protein

designated Gi, that inhibits adenylyl cyclase responds with a decrease in rate and force of contraction. 2 and increases K + conductance (see Figure above B ), to which the heart .


3. Muscarinic agonists and antagonists: Attempts are currently underway to develop muscarinic agonists and antagonists that are directed against specific receptor subtypes. For example, pirenzepine, a tricyclic anticholinergic drug, has a greater selectivity for inhibiting M1 muscarinic receptors, such as in the gastric mucosa. At therapeutic doses, pirenzepine does not cause many of the side effects seen with the non-subtype-specific drugs; however, it does produce a reflex tachycardia on rapid infusion due to blockade of M2 receptors in the heart. Therefore, the usefulness of pirenzepine as an alternative to proton pump inhibitors in the treatment of gastric and duodenal ulcers is questionable. Darifenacin is a competitive muscarinic receptor antagonist with a greater affinity for the M3 receptor than for the other muscarinic receptors. The drug is used in the treatment of overactive bladder. [Note: At present, no clinically important agents interact solely with the M4 and M5 receptors

4. Nicotinic receptors: These receptors, in addition to binding acetylcholine, also recognize nicotine but show only a weak affinity for muscarine . The nicotinic receptor is composed of five subunits, and it functions as a ligandgated ion channel . Binding of two acetylcholine molecules elicits a conformational change that allows the entry of sodium ions, resulting in the depolarization of the effector cell. Nicotine (or acetylcholine) initially stimulates and then blocks the receptor. Nicotinic receptors are located in the CNS, adrenal medulla, autonomic ganglia, and the neuromuscular junction. Those at the neuromuscular junction are sometimes designated NM and the others NN. The nicotinic receptors of autonomic ganglia differ from those of the neuromuscular junction. For example, ganglionic receptors are selectively blocked by hexamethonium, whereas neuromuscular junction receptors are specifically blocked by tubocurarine.

•   Direct-Acting Cholinergic Agonists

Cholinergic agonists (also known as parasympathomimetics) mimic the effects of acetylcholine by binding directly to cholinoceptors. These agents may be broadly classified into two groups: choline esters, which include acetylcholine and synthetic esters of choline, such as carbachol and bethanechol.Naturally occurring alkaloids, such as pilocarpine constitue the second group. 

Figure :Comparison of the structures of some cholinergic agonists.

All of the direct-acting cholinergic drugs have longer durations of action than acetylcholine. Some of the more therapeutically useful drugs (pilocarpine and bethanechol) preferentially bind to muscarinic receptors and are sometimes referred to as muscarinic agents. [Note: Muscarinic receptors are located primarily, but not exclusively, at the neuroeffector junction of the parasympathetic nervous system.] However, as a group, the direct-acting agonists show little specificity in their actions, which limits their clinical usefulness. 

A. Acetylcholine

B. Bethanechol

C. Carbachol

D. Pilocarpine

• Indirect-Acting Cholinergic Agonsists:

Anticholinesterases (Reversible) Acetylcholinesterase is an enzyme that specifically cleaves acetylcholine to acetate and choline and, thus, terminates its actions. It is located both pre- and postsynaptically in the nerve terminal, where it is membrane bound. Inhibitors of acetylcholinesterase indirectly provide a cholinergic action by prolonging the lifetime of acetylcholine produced endogenously at the cholinergic nerve endings. This results in the accumulation of acetylcholine in the synaptic space

Figure : Mechanisms of action of indirect (reversible) cholinergic agonists.



 These drugs can thus provoke a response at all cholinoceptors in the body, including both muscarinic and nicotinic receptors of the autonomic nervous system, as well as at neuromuscular junctions and in the brain. 

A. Physostigmine

B. Neostigmine

C. Pyridostigmine and ambenomium

 D. Demecarium

E. Edrophonium

F. Echothiophate

Figure :Summary of actions of some cholinergic agonists.

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