Cholinergic Antagonists

Cholinergic Antagonists

• Cholinergic antagonists bind to cholinoceptors and prevent the effects of acetylcholine (ACh) and other cholinergic agonists.
• There are three types of cholinergic antagonists:
  • Antimuscarinic agents (e.g., atropine, scopolamine)
  • Ganglionic blockers (e.g., nicotinic receptors of sympathetic and parasympathetic ganglia)
  • Neuromuscular-blocking agents (e.g., nicotinic antagonists, used as skeletal muscle relaxant adjuvants in anesthesia)

Antimuscarinic Agents

• Antimuscarinic agents block muscarinic receptors, causing inhibition of muscarinic functions.
• Examples: atropine, scopolamine, and some antihistamines and antidepressants (mainly tricyclic antidepressants).
• Atropine:
  • Tertiary amine belladonna alkaloid with high affinity for muscarinic receptors.
  • Acts both centrally and peripherally.
  • General actions last about 4 hours, except when placed topically in the eye, where the action may last for days.
  • Neuroeffector organs have varying sensitivity to atropine.
  • Greatest inhibitory effects are on bronchial tissue and the secretion of sweat and saliva.
• Actions of atropine:
  • Eye: blocks muscarinic activity in the eye, resulting in mydriasis, unresponsiveness to light, and cycloplegia.
  • Cardiovascular: used to treat bradycardia of varying etiologies.
  • Antisecretory: used to block secretions in the upper and lower respiratory tracts prior to surgery.
  • Antidote for cholinergic agonists: used to treat organophosphate poisoning, overdose of anticholinesterases, and some types of mushroom poisoning.

Pharmacokinetics and Adverse Effects of Atropine

• Atropine is readily absorbed, partially metabolized by the liver, and eliminated primarily in urine.
• Half-life is about 4 hours.
• Adverse effects:
  • Dry mouth
  • Blurred vision
  • "Sandy eyes"
  • Tachycardia
  • Urinary retention
  • Constipation
  • Effects on the CNS include restlessness, confusion, hallucinations, and delirium.

Scopolamine

• Scopolamine is a tertiary amine plant alkaloid with peripheral effects similar to those of atropine.
• Greater action on the CNS (unlike atropine, CNS effects are observed at therapeutic doses).
• Longer duration of action as compared to atropine.
• Actions:
  • Blocks short-term memory.
  • Produces sedation, but at higher doses, can produce excitement.
  • May produce euphoria and is susceptible to abuse.
• Therapeutic uses:
  • Prevention of motion sickness.
  • Postoperative nausea and vomiting.

Other Antimuscarinic Agents

• Ipratropium, tiotropium, aclidinium, and glycopyrrolate:
  • Quaternary derivatives of atropine or synthetic quaternary compounds.
  • Used as bronchodilators for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD).
  • Delivered via inhalation.
• Tropicamide and cyclopentolate:
  • Used as ophthalmic solutions for mydriasis and cycloplegia.
  • Duration of action is shorter than that of atropine.
• Benztropine and trihexyphenidyl:
  • Used as adjuncts with other antiparkinsonian agents to treat Parkinson's disease and other types of parkinsonian syndromes.
• Oxybutynin and other antimuscarinic agents for overactive bladder:
  • Synthetic atropine-like drugs with antimuscarinic actions.
  • Actions:
    • Competitively block muscarinic (M3) receptors in the bladder, lowering intravesical pressure, increasing bladder capacity, and reducing the frequency of bladder contractions.
    • May cause adverse effects, including dry mouth, constipation, and blurred vision.

Succinylcholine

• Neuromuscular-blocking agent (nicotinic antagonist).
• Used in anesthesia to provide rapid muscle relaxation.
• Therapeutic uses:
  • Rapid endotracheal intubation during the induction of anesthesia.
  • Electroconvulsive shock treatment.
• Pharmacokinetics:
  • Administered intravenously.
  • Brief duration of action results from redistribution and rapid hydrolysis by plasma pseudocholinesterase.
  • Continuous infusion can be used to maintain a longer duration of effect.
• Adverse effects:
  • Hyperthermia (malignant hyperthermia in susceptible patients).
  • Apnea (prolonged apnea due to paralysis of the diaphragm, especially in patients with electrolyte imbalances).
  • Hyperkalemia (rapid release of potassium from intracellular stores, particularly dangerous in burn patients and patients with massive tissue damage).