Cholinergic Antagonist

• Cholinergic antagonists


  Agents that bind to cholinoceptors and prevent the effects of ACh and other cholinergic agonists
• Antimuscarinics


  Also known as "anticholinergic" drugs, bind to M-receptor causing inhibition of muscarinic functions
• Muscarinic receptor subtypes


  • M1
  • M2
  • M3
• Antimuscarinics


  • Can be subdivided according to their selectivity for specific M-receptors or their lack of such selectivity; based on their affected organs
• Effects of muscarinic blocking drugs

  • CNS: Sedation, Anti-motion sickness action, Antiparkinson action, Amnesia, Delirium
  • Eye: Cycloplegia, Mydriasis
  • Bronchi: Bronchodilation
  • GIT: Relaxation, Slowed peristalsis, Reduced salivation
  • Heart: Initial bradycardia, then tachycardia
  • Blood vessels: Block of muscarinic vasodilation
  • Glands: Reduced salivation, lacrimation, sweating, gastric secretion
• Atropine


  Alkaloid found in the plant source Atropa belladonna, the prototypical nonselective muscarinic blocker
• Atropine


  • Relatively lipid-soluble and readily crosses membrane barriers, binds competitively and prevents ACh from binding to muscarinic receptors
• Atropine has a half-life of approximately 2 hours and a duration of action of normal doses of 4-8 hours except when placed topically in the eye, where the action may last for days
• Summary of action of atropine

  • Eye: Mydriasis, Unresponsiveness to light, Cycloplegia
  • GIT: Constipation, Reduced gastric motility but not hydrochloric acid
  • Cardiovascular: ↓ doses - slightly decrease in heart rate, ↑ doses - progressive increase in heart rate
  • Secretions: Inhibits secretions in the salivary, sweat, and lacrimal glands
• Atropine can produce divergent cardiovascular effects depending on the dose
• Simplified table of dose dependent effects of atropine

  • 0.5mg: Slight cardiac slowing, Some dryness of the mouth, Inhibition of sweating
  • 5mg: Rapid heart rate, Palpitations, Marked dryness of the mouth, Dilation of pupil, Some blurring of near vision
  • 10mg+: Hallucinations, Delirium, Coma
• Therapeutic uses of atropine

  • Treatment of organophosphate poisoning
  • Overdose of clinically used anticholinesterases (physostigmine)
  • Some types of mushroom poisoning
  • Reverses the excessive stimulation of cholinomimetic agents in the parasympathetic nervous system
• Adverse effects of atropine

  • Dry mouth, Blurred vision, Sandy eyes, Tachycardia, Urinary retention, Constipation, Restlessness, Confusion, Hallucinations, Delirium
• CNS acting muscarinics


  Drugs that block the activity of ACh at muscarinic receptors in the central nervous system
• Scopolamine


  Tertiary amine alkaloid that produces peripheral effects similar to those of Atropine but has a greater action on the CNS, with a longer duration of action
• Therapeutic uses of scopolamine

  • Prevention of motion sickness
  • Treatment of postoperative nausea and vomiting
  • Can cause sedation but in higher doses it can produce excitement
• Benztropine and trihexyphenidyl


  • Useful in alleviating tremor, rigidity and other motor symptoms associated with Parkinson's disease
  • Adjuncts with other anti-Parkinson agents to treat Parkinson Disease and other types of parkinsonian syndrome, including anti-psychotic induced extrapyramidal symptoms
• Short-acting muscarinic antagonists (SAMAs)


  Beneficial for providing quick relief of symptoms like wheezing, shortness of breath and coughing in bronchospasms and improving airflow in the lungs, used in managing acute exacerbations of COPD and asthma
• Long-acting muscarinic antagonists (LAMAs)


  Agents beneficial for providing sustained and long-lasting relief of bronchospasms and reduced symptoms, used as maintenance therapy to help control the symptoms and prevent exacerbations in individuals with COPD and asthma
• Examples of LAMAs


  • Tiotropium
  • Glycopyrrolate
  • Aclidinium
• Mydriatics


  Agents that dilate the pupil of the eye
• Cycloplegics


  Agents that temporarily paralyze the ciliary muscles in the eye
• Examples of mydriatics and cycloplegics

  • Tropicamide
  • Cyclopentolate
• Tropicamide produces mydriasis for 6 hours, while cyclopentolate produces mydriasis for 24 hours
• Antimuscarinics acting on the genitourinary tract

  • Oxybutynin
  • Darifenacin
  • Fesoterodine
  • Solifenacin
  • Tolterodine
  • Trospium
• Antimuscarinics acting on the genitourinary tract


  Used for the management of overactive bladder and urinary incontinence by blocking the muscarinic receptors (M3-receptors)
• Darifenacin and solifenacin are relatively more selective M3 muscarinic receptor antagonists
• Antimuscarinics acting on the genitourinary tract

  • Most agents have a long half-life, allowing once-daily administration and are available in oral dosage forms
  • Oxybutynin is also available in a transdermal patch and topical gel formulation
  • Hepatically metabolized by the cytochrome P450 system, except trospium which undergoes ester hydrolysis
• Adverse effects of antimuscarinics acting on the genitourinary tract

  • Dry mouth
  • Constipation
  • Blurred vision
  • Trospium has fewer CNS effects than other agents due to minimal blood-brain barrier penetration
• Ganglionic blockers


  Act on the nicotinic receptors of both sympathetic and parasympathetic autonomic ganglia, showing no selectivity toward the two divisions of the autonomic nervous system
• Nicotine


  Both an agonist and antagonist, stimulates and later depresses the ganglia, not clinically useful but a tool in experimental pharmacology
• Other ganglionic blockers


  • Hexamethonium
  • Trimethaphan
  • Mecamylamine
• Neuromuscular blocking agents


  Block cholinergic transmission between motor nerve endings and the nicotinic receptors on skeletal muscle
• Classification of neuromuscular blocking agents

  • Non-depolarizing (Competitive)
  • Depolarizing
• Mechanism of action of neuromuscular blocking agents

  1. Nerve ending meets the skeletal muscle fiber where nicotinic receptors are located

  2. Opening of these channels lets sodium ions enter the muscle fiber and trigger muscular action potential

  3. The action potential travels along the sarcolemma and through the T-tubules to the sarcoplasmic reticulum

  4. This triggers the release of calcium ions, which bind to troponin and cause muscle contraction
• Non-depolarizing (Competitive)


  Blockers that competitively inhibit ACh at nicotinic ACh receptors located on the postsynaptic membrane of skeletal muscular preventing depolarization and muscle contraction
• Depolarizing


  Blockers that work by depolarizing the plasma membrane of the muscle fiber, similar to the action of ACh
• Nerve ending meets the skeletal muscle fiber

  Nicotinic receptors to which acetylcholine can bind and induce their opening
• Opening of these channels

  Lets sodium ions enter the muscle fiber and trigger muscular action potential
• Potential travels along the surface of sarcolemma


  The excitable membrane that surrounds the myofibrils