Parasympathomimetics

• Parasympathomimetics


  Also known as "cholinergic agonists" or "cholinomimetic agents"
• Parasympathomimetics


  A class of drugs that mimic the effects of the endogenous Acetylcholine in the parasympathetic nervous system
• Parasympathomimetics


  • Work by activating cholinergic receptors, specifically the muscarinic and nicotinic receptors
• Direct acting


  Classified based on what type of receptor it binds to, or activates
• Indirect acting


  Agents that have an important effect on the release, synthesis and metabolic degradation of ACh / inhibit AChE; classified based on the duration of action
• Direct Acting Cholinergic Agonists

  • Cholinergic agonists mimic the effects of ACh by binding directly to cholinoceptors – muscarinic and nicotinic receptors
  • All direct-cholinergic drugs have a longer duration of action than ACh
• Effects of Muscarinic Agents

  • Increase salivation
  • Increase lacrimation
  • Increase bronchial tone
  • Increase intestine motility
  • Increase GI secretions
  • Increase urinary bladder tone
  • Decrease heart rate and conduction velocity
  • Decrease arteriole tone
  • Decrease blood pressure
  • Decrease pupil size
• Acetylcholine


  Has both muscarinic and nicotinic activity, meaning it is non-selective
• Acetylcholine


  Causes decrease in heart rate and cardiac output
• Acetylcholine


  Decreases blood pressure indirectly by activating M3 receptors in blood vessel smooth muscle, leading to nitric oxide production and vasodilation
• Effects of Acetylcholine


  • Increases salivary secretions
  • Increases gastric acid
  • Increases intestinal secretions
  • Increases intestinal motility
  • Increases bronchiolar secretions
  • Causes bronchoconstriction
  • Increases urination
  • Stimulates ciliary muscle contraction and pupillae sphincter muscle constriction
• Acetylcholine lacks therapeutic importance because of its multiplicity of actions (due to non-selectivity) and its rapid inactivation by cholinesterases
• Carbachol (Miostat)


  Also known as carbamylcholine, has both muscarinic and nicotinic actions (non-selective)
• Carbachol


  Used intraocularly to provide miosis for eye surgery and lower intraocular pressure in the treatment of glaucoma
• With ophthalmologic use, few adverse effects occur due to lack of systemic penetration
• Metacholine (Mecholyl)


  A synthetic choline ester, non-selective cholinergic agonist with a known effect mainly on muscarinic M3 receptors in smooth muscles including airways
• Metacholine


  Used as a diagnostic agent for asthma in the Metacholine Challenge Test or Bronchial Provocation Test
• Bethanecol (Uriflow)


  A synthetic ester structurally and pharmacologically related to acetylcholine, but not affected by acetylcholinesterase, with strong muscarinic M3 receptor activity
• Bethanecol


  • Duration of action is 1 hour
  • Major actions are on the smooth musculature of the bladder and GI tract
  • Can only be administered PO or SQ, not IM or IV
• Bethanecol


  Causes an increase in intestinal motility and tone, and stimulates the detrusor muscle of the bladder while relaxing the trigone and sphincter muscles, promoting urination
• Cholinomimetic Alkaloids


  Includes non-selective agents like arecoline, muscarinic selective agents like muscarine and pilocarpine, and nicotinic selective agents like nicotine, lobeline and varenicline
• Pilocarpine (Isopto Carpine)


  Exhibits muscarinic activity and is used primarily in ophthalmology
• Pilocarpine


  • Used to treat glaucoma, both open-angle and angle-closure, and to treat Sjögren's syndrome
  • Adverse effects include blurred vision, night blindness, and brow ache
• Adverse Effects of Direct-Acting Muscarinic Cholinoceptor Agonists

  • Nausea and vomiting
  • Sweating
  • Increased salivation
  • Bronchoconstriction
  • Decreased blood pressure
  • Diarrhea
• Contraindications for Direct-Acting Muscarinic Cholinoceptor Agonists

  • Peptic ulcer
  • Asthma
  • Cardiac disease
  • Parkinson's disease
  • Mechanical obstruction of the GI or urinary tract
• Selected Therapeutic Uses of Direct-Acting Cholinoceptor Agonists

  • Bethanechol: Prevents urine retention, treats postoperative abdominal distension, treats gastric atony
  • Methacholine: Diagnostic for bronchial hypersensitivity
  • Pilocarpine: Treats open-angle glaucoma, acute narrow-angle glaucoma, Sjögren's syndrome
• Indirect Acting Cholinergic Agonists

  Inhibit acetylcholinesterase and increase acetylcholine levels at both muscarinic and nicotinic receptors
• Reversible AChE Inhibitors


  Bind reversibly (weak bonds) to the active center of acetylcholinesterase, preventing hydrolysis of acetylcholine
• Edrophonium (Enlon)


  Prototype short-acting acetylcholinesterase inhibitor, used for diagnosis of Myasthenia Gravis
• Physostigmine


  Intermediate-acting acetylcholinesterase inhibitor, often used concurrently with pilocarpine for acute angle-closure glaucoma
• Neostigmine (Myostigmin)


  Synthetic, intermediate-duration acetylcholinesterase inhibitor, used to stimulate the bladder and GI tract, and as an antidote for neuromuscular blocking agents
• Pyridostigmine (Mestinon)


  Cholinesterase inhibitor used in the chronic management of Myasthenia Gravis, with an intermediate but longer duration of action than neostigmine
• Intermediate-acting agent


  Duration of action: 30 minutes–2 hours
• Neostigmine (Myostigmin)


  • Synthetic compound that is also a carbamic acid ester, and it reversibly inhibits AChE in a manner similar to physostigmine
  • Intermediate duration of action: 30 minutes–2 hours
  • Polar and is absorbed poorly from the GI tract
  • Does not enter the CNS
  • Its effect on skeletal muscles is greater than physostigmine
• Pyridostigmine (Mestinon)


  • Another cholinesterase inhibitor used in the chronic management of MG
  • Its duration of action is intermediate but longer than that of neostigmine
  • Duration of action: 36hrs (Main Reference Lippincott), 4–8hrs (Katzung)
• Tacrine (Cognex), Donepezil (Aricept/ Dopezil), Rivastigmine (Exelon), Galantamine (Razadyne)

  They delay the progression of Alzheimer's disease, but none can stop its progression (it can be delayed, but cannot be stopped)
• Alzheimer's disease


  • Neurodegenerative disorder that causes a significant reduction ACh levels in the brain
  • Characterized by progressive memory loss and cognitive decline
• Irreversible AChE inhibitors


  • Includes synthetic organophosphate compounds that bind covalently to AChE
  • Many are extremely toxic and were developed by the military as nerve agents (used in warfare and chemical terrorism)
• Echothiophate


  • Organophosphate that covalently binds via its phosphate group at the active site of AChE
  • Binding makes the enzyme permanently inactivated and restoration of AChE activity requires the synthesis of new enzyme molecules
  • Actions include generalized cholinergic stimulation, paralysis of motor function (causing breathing difficulties), and convulsions
• Myasthenia gravis


  • Latin expression that literally means "grave muscle weakness"
  • Autoimmune disease that affects the skeletal muscles