parasympathetic

• CHOLINE

  A chemical compound important for neurotransmission
• Distribution of Muscarinic receptors

  • M1 receptors = brain, exocrine glands, & autonomic ganglia
  • M2 receptors = heart, brain, autonomic ganglia, smooth muscle
  • M3 receptors = smooth muscle, exocrine glands, brain, endothelial cells
  • M4 receptors = brain & autonomic ganglia
  • M5 receptors = CNS
• Cholinergic receptors

  • Muscarinic receptor
  • Nicotinic receptor I
  • Nicotinic receptor II
• Indirect-Acting Cholinomimetics and their Major Clinical Uses

  • Ambenomium (Mytelase): Treatment of myasthenia gravis
  • Edrophonium (Enlon; Tensilon): Diagnosis of myasthenia gravis; antidote for curare type drugs
  • Isofluorophate: Treatment of glaucoma; postoperative retention
  • Neostigmine (Prostigmin): Treatment of myasthenia gravis; antidote for curare type drugs
  • Physostigmine (Antilirium): Treatment of glaucoma; antidote to anticholinergic drugs
  • Pyridostigmine (Mestinon): Treatment of myasthenia gravis; antidote to curare type drugs
  • Donepezil (Aricept): AChE inhibitor; treatment of Alzheimer’s disease
  • Tacrine (Cognex): AChE inhibitor; treatment of Alzheimer’s disease
  • Galanthamine (Reminyl): AChE inhibitor; treatment of Alzheimer’s disease
• Direct-acting Cholinomimetics

  • Esters: Metacholine, Carbachol, Betanechol
  • Alkaloids: Muscarine, Pilocarpine, arecoline
• Effects of Cholinomimetics

  • Eye: miosis
  • CV: decrease in heart rate and contractility
  • Resp: bronchial constriction and increased secretions
  • GI: increased motility, relaxation of sphincters
  • GU: relaxation of sphincters and bladder wall contraction glands increase secretion
• ACETATE + CHOLINE = ACH

  • ACH
• Activation of Muscarinic receptors

  1. Produces an inosine triphosphate (IP3) mediated release of intracellular Calcium, the release of diacylglycerol, and stimulation of adenylyl cyclase

  2. Inhibits adenylyl cyclase; Activation of M2 receptors opens potassium channels
• Direct-Acting Cholinomimetics and their Major Clinical Uses

  • Betanechol (Urecholine): Miotic; postoperative retention
  • Carbachol (Isopto Carbachol; Miostat): Treatment of glaucoma
  • Metacholine (Provocholine): Miotic; postoperative retention; peripheral vascular disease
  • Pilocarpine: Treatment of glaucoma
• Indirect-acting Cholinomimetics

  • Reversible Inhibitors: Ambenomium, demecarium, Physostigmine, Neostigmine, Edrophonium, Pyridostigmine
  • Irreversible Inhibitors: Isofluorophate, Echothiophate
• Muscarinic antagonists

  • Atropine
  • Scopolamine
• Muscarinic receptors

  • Mediate the activation of effectors by Ach released from parasympathetic nerve endings
  • Mediate the activation of sweat glands by Ach released from sympathetic fibers
  • Are found on vascular endothelial cells that receive no cholinergic innervations
  • Are widely distributed in the CNS, from basal ganglia to neocortex
  • Are present on presynaptic nerve terminals
• Oldest known muscarinic blocking compounds

  • Atropine
  • Scopolamine
• Clinical uses of Ganglionic Blockers

  1. Hypertensive Cardiovascular disease

  2. Controlled hypotension
• Trimethaphan camsylate (Arfonad) produces controlled hypotension in certain surgical procedures and in the emergency treatment of hypertensive crisis
• Inhibitor

  Used in the treatment of Alzheimer’s disease
• Effects of Muscarinic Blocking Drugs

  1. Skin: Inhibition of sweating, flushing

  2. Visual: Cycloplegia, mydriasis, increase in aqueous outflow resistance

  3. Digestive: Decreased salivation, reduced tone and motility in the GIT, decrease in vagus-stimulated secretions

  4. Urinary: Urinary retention, relaxation of ureter

  5. Respiratory: Bronchial dilation, decreased secretions

  6. Cardiovascular: Bradycardia at low doses, tachycardia at higher doses, increased cardiac output if patient is recumbent

  7. CNS: Decreased concentration and memory, drowsiness, sedation, excitation, ataxia, asynergia, decrease in alpha EEG, increase in low-voltage slow waves, hallucinations, coma
• Muscarinic blocking drugs

  Compounds that selectively antagonize the responses to acetylcholine (Ach) and other parasympathomimetics mediated by activation of muscarinic receptors
• Mecamylamine HCl (Inversine) can cause CNS effects such as tremors, mental confusion, seizures, mania, depression
• Mechanism of Action of Ganglionic Blockers

  1. Presynaptically, affecting nerve conduction or neurotransmitter synthesis, release, or reuptake

  2. Postjunctionally, affecting the interaction between Ach and its receptor, or depolarization of the ganglion cell or initiation of a propagated action potential
• Mechanism of Action of Nicotine

  • Cardiovascular system: + inotropic and chronotropic effects on myocardium, increase in cardiac output
  • Respiratory system: Low doses stimulate respiration, toxic doses depress respiration
  • CNS: tremors, convulsions, respiratory stimulation or depression, release of antidiuretic hormone from the pituitary
  • Other systems: increase in gastric acid secretion, increase in tone and motility of the GIT
• Adverse effects of Ganglionic Blockers

  • Mydriasis
  • Difficulty in vision accommodation
  • Dry mouth
  • Urinary hesitancy
  • Constipation, diarrhea
  • Abdominal discomfort
  • Anorexia
  • Syncope
• Main uses of muscarinic blocking drugs

  1. Belladona alkaloids: Atropine - ↑ heart rate, preoperative medication

  2. Belladona alkaloids: Hyoscyamine (Daturine) - Mydriatic, cycloplegic

  3. Belladona alkaloids: Scopolamine - Same as Atropine

  4. Semisynthetic drug: Homatropine - Mydriatic

  5. Synthetic drugs: Dicyclomine (Bentyl) - Treatment of GI disorders

  6. Synthetic drugs: Glycopyrrolate bromide (Robinul) - Treatment of ulcers

  7. Synthetic drugs: Ipratropium bromide (Atrovent) - Treatment of respiratory disorders

  8. Synthetic drugs: Propantheline (Pro-Banthine) - Treatment of GI disorders
• Other names for muscarinic blocking drugs

  • Muscarinic antagonists
  • Antimuscarinic drugs
  • Anticholinergics