PCOL-Chapter 8

• Cholinoceptor-blocking drugs


  • Anti-muscarinic
  • Anti-nicotinic
• Muscarinic receptor subtypes


  • M1
  • M2
  • M3
  • M4
  • M5
• M1


  Located in CNS, autonomic postganglionic cell bodies, and many presynaptic sites
• M2


  Located in myocardium, smooth muscle organs, and some neuronal sites
• M3


  Located in effector cell membranes, especially glandular and smooth muscle cells
• M4 and M5


  Less prominent; play a greater role in the CNS than in the periphery
• Muscarinic antagonists

  • Parasympatholytic
  • Antimuscarinic
  • Block the effects of parasympathetic autonomic discharge
• Atropine


  Prototype of muscarinic receptor-blocking drugs
• Atropine (hyoscyamine)


  Found in the plant Atropa belladonna (deadly nightshade) and in Datura stramonium (Jamestwon weed, sacred Datura, or thorn apple)
• Scopolamine (hyoscine)


  Occurs in Hyoscyamus niger, or henbane, as the l(−) stereoisomer
• The l(−) isomers of atropine and scopolamine are at least 100 times more potent than the d(+) isomers
• Tertiary antimuscarinic drugs for peripheral applications


  • Tropicamide (mydriatic, cycloplegic)
  • Dicyclomine (peptic disease, hypermotility)
• Tertiary antimuscarinic drug for Parkinson's disease

  • Benztropine
• Quaternary antimuscarinic drugs for gastrointestinal and pulmonary applications

  • Propantheline
  • Glycopyrrolate
• Quaternary antimuscarinic drug for use in asthma


  • Tiotropium
• Absorption


  • Natural alkaloids and most tertiary antimuscarinic drugs are well absorbed from the gut and conjunctival membranes
  • Scopolamine is absorbed from the skin (transdermal route)
  • Quaternary antimuscarinic drugs have only 10-30% oral absorption
• Distribution


  • Atropine and other tertiary antimuscarinic agents are widely distributed in the body
  • Significant CNS levels are achieved within 30 minutes to 1 hour
  • Scopolamine is rapidly and fully distributed and has greater CNS effects
  • Quaternary antimuscarinic drugs are poorly taken up by the brain and have relatively fewer CNS effects
• Metabolism and Excretion


  • Atropine elimination has a rapid half-life of 2 hours and a slow phase of 13 hours
  • About 50% of the dose is excreted unchanged in the urine, the rest is metabolized
  • Effects on the iris and ciliary muscle persist for ≥ 72 hours
• Mechanism of Action


  • Competitively inhibit the neurotransmitter ACh at receptor sites within the cholinergic system
  • This inhibition leads to blockade of the parasympathetic nervous system
• Tissues most sensitive to atropine are the salivary, bronchial, and sweat glands. Gastric acid secretion is the least sensitive.
• Antimuscarinic agents block exogenous cholinoceptor agonists more effectively than endogenously released agonists.
• Central Nervous System effects


  • Atropine has minimal stimulant effects
  • Scopolamine has more marked central effects like drowsiness and amnesia
  • In toxic doses, scopolamine and atropine can cause excitement, agitation, hallucinations, and coma
  • Antimuscarinic drugs can reduce Parkinsonian tremor and rigidity
  • Scopolamine is effective in preventing or reversing vestibular disturbances
• Eye effects


  • Atropine and other tertiary antimuscarinic drugs block M3 receptor activation in the pupillary constrictor muscle, leading to mydriasis
  • Antimuscarinic drugs cause cycloplegia and reduce lacrimal secretion
• Cardiovascular effects


  • The SA node is very sensitive to muscarinic receptor blockade
  • Atropine causes tachycardia by vagal block, but low doses can initially cause bradycardia
  • The ventricles are less affected
  • Antimuscarinic drugs block endothelial muscarinic receptors that mediate vasodilation
• Respiratory effects


  • Atropine causes bronchodilation and reduces secretions
  • Antimuscarinic drugs are limited in treating asthma because block of M2 receptors opposes the bronchodilation from M3 blockade
  • Antimuscarinic drugs are often taken before inhalant anesthetics to reduce tracheal secretions
• Gastrointestinal effects


  • Muscarinic receptor blockade decreases motility and secretory functions of the GI tract
  • Complete muscarinic blockade cannot abolish all GI activity due to local hormones and noncholinergic neurons
  • Antimuscarinic drugs lead to dry mouth, reduced acid/pepsin/mucin secretion, and prolonged gastric emptying and intestinal transit time
  • Diarrhea can occur with overdosage
• M2


  Oppose the bronchodilation caused by block of M3 receptors on airway
• Antimuscarinic drugs


  Frequently taken before the administration of inhalant anesthetics (reduce the accumulation of secretions in the trachea)
• Muscarinic receptor blockade


  • Decrease motility (from stomach to colon)
  • Decrease secretory functions of the gut
• Complete muscarinic blockade cannot abolish activity in the GI tract
• Local hormones and noncholinergic neurons in the enteric nervous system


  Also modulate GI function
• Antimuscarinic drugs


  • Dry mouth
  • Reduced acid, pepsin, and mucin
  • Basal secretion is blocked more effectively than that stimulated by food, nicotine, or alcohol
• Pirenzepine and telenzepine


  M1 blockers
• Antimuscarinic drugs


  • Both tone and propulsive movements of the GI tract are diminished (walls of the viscera are relaxed)
  • Gastric emptying time is prolonged, and intestinal transit time is lengthened
• Diarrhea due to overdosage with muscarinic agents is readily stopped
• Diarrhea due to nonautonomic agents can usually be temporarily controlled
• Relaxation of smooth muscle of the ureters and bladder wall and slows voiding
• Useful in the treatment of spasm induced by mild inflammation, surgery, and certain neurological conditions


  But it can precipitate urinary retention in men who have prostatic hyperplasia
• Atropine


  • Suppresses thermoregulatory sweating
  • In adults, body temperature is elevated only with large doses, but in infants and children even ordinary doses may cause "atropine fever"
• Effects of antimuscarinic drugs on different organ systems

  • Central Nervous System: Initial stimulation followed by depression
  • Eye: Mydriasis, Cycloplegia
  • Cardiovascular System: Tachycardia
  • Respiratory System: Bronchodilation, Decrease Secretion
  • Gastrointestinal Tract: Decrease peristalsis, Decrease section, Sphincter contraction, Constipation
  • Genitourinary Tract: Muscle relaxation, Sphincter contraction, Urinary retention
  • Sweat Glands: Suppression of thermoregulatory sweating