Cholinergic Antagonists

The cholinergic antagonists (also called cholinergic blockers, parasympatholytics or anticholinergic drugs) bind to cholinoceptors, but they do not trigger the usual receptor-mediated intracellular effects. The most useful of these agents selectively block muscarinic synapses of the parasympathetic nerves. The effects of parasympathetic innervation are thus interrupted, and the actions of sympathetic stimulation are left unopposed. A second group of drugs, the ganglionic blockers, show a preference for the nicotinic receptors of the sympathetic and parasympathetic ganglia. Clinically, they are the least important of the anticholinergic drugs. A third family of compounds, the neuromuscular blocking agents, interfere with transmission of efferent impulses to skeletal muscles. These agent are used as adjuvants in anesthesia during surgery.

 Figure : summarizes the cholinergic antagonists discussed in this chapter

  • Antimuscarinic Agents 

Commonly known as antimuscarinics, these agents (for example, atropine and scopolamine) block muscarinic receptors  causing inhibition of all muscarinic functions.

Figure: Sites of actions of cholinergic antagonists.

In addition, these drugs block the few exceptional sympathetic neurons that are cholinergic, such as those innervating salivary and sweat glands. In contrast to the cholinergic agonists, which have limited usefulness therapeutically, the cholinergic blockers are beneficial in a variety of clinical situations. Because they do not block nicotinic receptors, the antimuscarinic drugs have little or no action at skeletal neuromuscular junctions or autonomic ganglia. [Note: A number of antihistaminic and antidepressant drugs also have antimuscarinic activity.] 

D. Tropicamide and cyclopentolate
These agents are used as ophthalmic solutions for similar conditions as atropine (mydriasis and cyclopegia). Their duration of action is shorter than that of atropine; tropicamide produces mydriasis for 6 hours and cyclopentolate for 24 hours.

Figure : Summary of cholinergic antagonists. *Contraindicated in narrowangle glaucoma. GI = gastrointestinal.

  • Ganglionic Blockers 
Ganglionic blockers specifically act on the nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia. Some also block the ion channels of the autonomic ganglia. These drugs show no selectivity toward the parasympathetic or sympathetic ganglia and are not effective as neuromuscular antagonists. Thus, these drugs block the entire output of the autonomic nervous system at the nicotinic receptor. Except for nicotine, the other drugs mentioned in this category are nondepolarizing, competitive antagonists. The responses observed are complex and unpredictable, making it impossible to achieve selective actions. Therefore, ganglionic blockade is rarely used therapeutically. However, ganglionic blockers often serve as tools in experimental pharmacology.

A. Nicotine
A component of cigarette smoke, nicotine [NIC-oh-teen] is a poison with many undesirable actions. It is without therapeutic benefit and is deleterious to health. [Note: Nicotine is available as patches, lozenges, gums, and other forms. Patches are available for application to the skin. The drug is absorbed and is effective in reducing the craving for nicotine in people who wish to stop smoking.] Depending on the dose, nicotine depolarizes autonomic ganglia, resulting first in stimulation and then in paralysis of all ganglia. The stimulatory effects are complex due to effects on both sympathetic and parasympathetic ganglia. The effects include increased blood pressure and cardiac rate (due to release of transmitter from adrenergic terminals and from the adrenal medulla) and increased peristalsis and secretions. At higher doses, the blood pressure falls because of ganglionic blockade, and activity both in the GI tract and bladder musculature ceases.

B. Mecamylamine
Mecamylamine [mek-a-MILL-a-meen] produces a competitive nicotinic blockade of the ganglia. The duration of action is about 10 hours after a single administration. The uptake of the drug via oral absorption is good, in contrast to that of trimethaphan. As with trimethaphan, it is primarily used to lower blood pressure in emergency situations.

  •  Neuromuscular Blocking Drugs 
These drugs block cholinergic transmission between motor nerve endings and the nicotinic receptors on the neuromuscular end plate of skeletal muscle . These neuromuscular blockers are structural analogs of acetylcholine, and they act either as antagonists (nondepolarizing type) or agonists (depolarizing type) at the receptors on the end plate of the neuromuscular junction. Neuromuscular blockers are clinically useful during surgery for producing complete muscle relaxation, without having to employ higher anesthetic doses to achieve comparable muscular relaxation. Agents are also useful in facilitating intubation as well.

 A second group of muscle relaxants, the central muscle relaxants, are used to control spastic muscle tone. These drugs include diazepam, which binds at γ-aminobutyric acid (GABA) receptors; dantrolene, which acts directly on muscles by interfering with the release of calcium from the sarcoplasmic reticulum; and baclofen, which probably acts at GABA receptors in the CNS.

A. Nondepolarizing (competitive) blockers

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