Cholinergic Antagonists Overview

Cholinergic Antagonists

• Cholinergic antagonists are agents that bind to cholinoceptors and prevent the effects of acetylcholine (ACh) and other cholinergic agonists.

Antimuscarinic Agents

• Antimuscarinic agents, also known as anticholinergic drugs, block muscarinic receptors, causing inhibition of muscarinic functions.
• Examples of antimuscarinic agents include atropine and scopolamine.
• These drugs block some sympathetic neurons that are cholinergic, such as the salivary and sweat glands.
• They do not block nicotinic receptors, and therefore have little or no action at skeletal neuromuscular junctions (NMJs) or autonomic ganglia.

Atropine

• Atropine is a tertiary amine belladonna alkaloid with a high affinity for muscarinic receptors.
• It binds competitively and prevents ACh from binding to those sites.
• Atropine acts both centrally and peripherally, with general actions lasting about 4 hours, except when placed topically in the eye, where the action may last for days.
• Neuroeffector organs have varying sensitivity to atropine, with the greatest inhibitory effects on bronchial tissue and the secretion of sweat and saliva.

Actions of Atropine

• Eye: Atropine blocks muscarinic activity in the eye, resulting in mydriasis (dilation of the pupil), unresponsiveness to light, and cycloplegia (inability to focus for near vision).
• Cardiovascular: Atropine is used to treat bradycardia of varying etiologies.
• Antisecretory: Atropine is sometimes used as an antisecretory agent to block secretions in the upper and lower respiratory tracts prior to surgery.
• Antidote for cholinergic agonists: Atropine is used for the treatment of organophosphate (insecticides, nerve gases) poisoning, overdose of anticholinesterases such as physostigmine, and some types of mushroom poisoning.

Pharmacokinetics of Atropine

• Atropine is readily absorbed, partially metabolized by the liver, and eliminated primarily in urine.
• It has a half-life of about 4 hours.

Adverse Effects of Atropine

• Depending on the dose, atropine may cause dry mouth, blurred vision, “sandy eyes,” tachycardia, urinary retention, and constipation.
• Effects on the CNS include restlessness, confusion, hallucinations, and delirium, collapse of the circulatory and respiratory systems, and death.

Scopolamine

• Scopolamine, another tertiary amine plant alkaloid, produces peripheral effects similar to those of atropine.
• However, scopolamine has greater action on the CNS (unlike atropine, CNS effects are observed at therapeutic doses) and a longer duration of action as compared to atropine.

Neuromuscular-Blocking Agents (Nicotinic Antagonists)

• These agents interfere with the efferent impulses to skeletal muscles.
• They are used as skeletal muscle relaxant adjuvants in anesthesia during surgery, intubation, and various orthopedic procedures.

Mechanism of Action

• At low doses, nondepolarizing agents competitively block the nicotinic receptors without stimulating it.
• They prevent depolarization of the muscle cell membrane and inhibit muscular contraction.
• Their competitive action can be overcome by administration of cholinesterase inhibitors, such as neostigmine and edrophonium, which increase the concentration of ACh in the neuromuscular junction.

Actions

• Muscles have differing sensitivity to blockade by competitive agents.
• Small, rapidly contracting muscles of the face and eye are most susceptible and are paralyzed first, followed by the fingers, limbs, neck, and trunk muscles.
• Next, the intercostal muscles are affected, and lastly, the diaphragm.
• The muscles recover in the reverse manner.

Sugammadex

• Sugammadex is a selective relaxant-binding agent that terminates the action of both rocuronium and vecuronium and can be used to speed recovery.

Pharmacokinetics of Neuromuscular-Blocking Agents

• All neuromuscular-blocking agents are injected intravenously or occasionally intramuscularly since they are not effective orally.
• These agents possess two or more quaternary amines in their bulky ring structure that prevent their absorption from the gut.
• They penetrate membranes very poorly and do not enter cells or cross the blood–brain barrier.
• Many of the drugs are not metabolized, and their actions are terminated by redistribution.
• For example, pancuronium is excreted unchanged in urine.

Adverse Effects

• In general, these agents are safe with minimal side effects.
• However, succinylcholine can potentially induce malignant hyperthermia in susceptible patients.
• Administration of succinylcholine to a patient who is deficient in plasma cholinesterase or who has an atypical form of the enzyme can lead to prolonged apnea due to paralysis of the diaphragm.
• The rapid release of potassium may also contribute to prolonged apnea in patients with electrolyte imbalances who receive this drug.