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
• 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
• Carbachol can cause parasympathomimetic activation due to its high potency, receptor non-selectivity and relative long duration of action, even at low concentrations
• 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 lacks nicotinic activity and has strong muscarinic M3 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


  Stimulates the detrusor muscle of the bladder and relaxes the trigone and sphincter muscles causing urination, beneficial in treating urologic conditions like postpartum or postoperative nonobstructive urinary retention and neurogenic atony
• Bethanecol


  Causes an increase in intestinal motility and tone, and promotes diuresis
• Arecoline


  A naturally occurring alkaloid found in the betel nut, with mild CNS stimulant effects similar to caffeine
• Muscarine


  A cholinomimetic alkaloid with muscarinic selectivity
• Pilocarpine (Isopto Carpine)


  A cholinomimetic alkaloid with muscarinic activity, used primarily in ophthalmology
• 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
• Therapeutic uses of selected 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 AChE and increase ACh levels at both muscarinic and nicotinic cholinoceptors, mimicking the physiologic effects of increased ACh
• Reversible AChE Inhibitors


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


  The prototype short-acting AChE inhibitor, used for diagnosis of Myasthenia Gravis
• Physostigmine


  An intermediate-acting AChE inhibitor, often used concurrently with pilocarpine for acute angle-closure glaucoma
• Neostigmine (Myostigmin)


  A synthetic, intermediate-duration AChE inhibitor, with greater effect on skeletal muscles than physostigmine
• Neostigmine


  Used to stimulate the bladder and GI tract, and as an antidote for competitive neuromuscular blocking agents and to manage Myasthenia Gravis symptoms
• Pyridostigmine (Mestinon)


  Another 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)
• Tachrine (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
• AChE inhibitors


  Given to decrease metabolic degradation and increase ACh levels in the brain
• Adverse effects of AChE inhibitors

  GI distress