L6 Parasympathomimetics

• Parasympathomimetics


  Drugs that act on the parasympathetic nervous system
• Cholinomimetics


  Drugs that mimic the action of acetylcholine

  
• Autonomic nervous system (ANS)


  Divided into parasympathetic (PANS) and sympathetic (SANS) systems

  
• Parasympathetic autonomic nervous system (PANS)


  Also called craniosacral division, has acetylcholine as major transmitter

  
• Sympathetic autonomic nervous system (SANS)

  Also called thoracolumbar division, has norepinephrine as major transmitter

  
• Neurotransmitter


  A chemical substance synthesized, stored and released from nerve endings after stimulus, and transported from nerve to neurone or effector organs. Can be excitatory, inhibitory or both.

  
• Types of neurotransmitters


  • Excitatory - Aspartate, Glutamate
  • Inhibitory - GABA, Glycine
  • Mixed - Adrenaline, Noradrenaline, Dopamine, Serotonin

  
• Criteria of a neurotransmitter


  • Release on nerve stimulation
  • Found inside vesicles with enzymes responsible for synthesis and metabolism
  • Application of neurotransmitter and nerve stimulation produce similar response
  • Effects should be modified by specific agents, which similarly alter effects of nerve stimulation
• Synaptic Transmission


  1. Nerve impulse arrives at presynaptic terminal

  2. Calcium influx causes neurotransmitter release into synaptic cleft

  3. Neurotransmitter binds to receptors on postsynaptic membrane

  4. Postsynaptic response generated

  
• Cholinergic fibres


  Nerve fibres that secrete acetylcholine as neurotransmitter, including all preganglionic fibres of parasympathetic and sympathetic system, postganglionic fibres of parasympathetic system, and postganglionic fibres of sympathetic system supplying sweat glands and piloerector muscle

  
• Acetylcholine Metabolism


  ACh -> acetylcholinesterase -> choline + acetate

  
• Muscarinic receptors


  M1 - located in CNS, gastric parietal cells; M2 - located in heart, GIT smooth muscle; M3 - located in smooth muscles, exocrine glands
• Nicotinic receptors


  NM - located at neuromuscular junction; NN - located in autonomic ganglia and adrenal medulla
• Cholinergic drugs / Cholinomimetic drugs / Parasympathomimetics


  Drugs that act on cholinergic receptors

  
• Pharmacological actions of ACh (muscarinic)

  1. Cardiovascular system - ↓HR, ↓contractility, vasodilation

  2. Gastrointestinal tract - ↑motility, ↑secretions

  3. Respiratory tract - bronchoconstriction, ↑mucus secretion

  4. Eye - miosis, accommodation, ↓intraocular pressure

  5. Urinary bladder - contraction of detrusor, relaxation of trigone & sphincter

  6. Glands - ↑secretion of sweat, saliva, tears
• Pharmacological actions of ACh (nicotinic)

  1. Autonomic ganglia - stimulates both PANS and SANS

  2. Adrenal medulla - secretion of epinephrine and norepinephrine

  3. Skeletal muscle - contraction (twitching)

  
• Myasthenia gravis


  Autoimmune disorder affecting the skeletal muscle neuromuscular junction, caused by autoimmune antibodies decreasing functional nicotinic receptors
• Mechanism of action of neostigmine in myasthenia gravis

  Inhibits cholinesterase enzyme, increasing acetylcholine concentration at the neuromuscular junction, opposite effect of myasthenia gravis
• Bethanechol


  Cholinomimetic drug with no nicotinic actions, preferred for GIT and urinary bladder effects
• Bethanechol is used to treat post-operative paralytic ileus, congenital megacolon, and postpartum/postoperative urinary retention
• Myasthenia gravis


  Autoimmune disorder that decreases the number of functional nicotinic receptors on the post functional end plate
• Neostigmine


  Inhibits cholinesterase enzyme, no hydrolysis of Ach, increases concentration of Ach in the NMJ, opposite effect of Myasthenia gravis
• Bethanechol


  Long acting, no nicotinic effects, more selective to GIT & urinary bladder
• Therapeutic uses of Bethanechol


  • Post operative paralytic ileus
  • Congenital megacolon
  • Postpartum and postoperative urinary retention
  • Neurogenic bladder following spinal cord injury
• Pilocarpine


  Stimulates only muscarinic receptors, topically used in eye to produce rapid miosis and contraction of ciliary muscle
• Uses of Pilocarpine


  • Acute congestive glaucoma
  • Sjögren's Syndrome
  • Xerostomia
• Indirectly acting cholinomimetics (Anticholinesterases)

  • Produce effects by increasing endogenous ACh concentration, no effect on blood vessels & alteration in BP, increases muscle strength in patients with myasthenia gravis & in patients on curare like drugs
• Mechanism of action of anticholinesterases

  1. Acetyl ChE inhibition

  2. Inactivation of ChE

  3. Decrease hydrolysis of Ach

  4. Increase concentration of Ach

  5. Prolong action of Ach

  
• Physostigmine


  Naturally occurring alkaloid, tertiary amine, lipid soluble, crosses BBB, topical application produces miosis, accommodation, decreased intraocular pressure, lacrimation and twitching of eyelids

  
• Uses of Physostigmine


  • Treatment of glaucoma
  • Increase gut and bladder motility in atonic state
  • Break adhesions between iris and lens
  • Counteract mydriatic action of homatropine
  • Antidote in atropine poisoning
• Adverse effects of Physostigmine

  • Stimulation of CNS followed by depression
  • Convulsions
  • Skeletal muscle paralysis
  • Respiratory centre paralysis
  • Bradycardia
  • Death due to respiratory failure
• Neostigmine


  Synthetic quaternary amine, poor oral absorption, low bioavailability, do not cross BBB, predominantly act on skeletal muscles, short acting

  
• Therapeutic uses of Neostigmine

  • Paralytic ileus
  • Urinary retention
  • Symptomatic treatment of myasthenia gravis
  • Antidote to tubocurarine like drugs after anesthesia/surgery
• Edrophonium


  Shortest acting anticholinesterase, used to diagnose myasthenia gravis and differentiate muscle weakness
• Irreversible anticholinesterases


  Organophosphorus compounds like Parathion, Malathion, nerve/war gases, therapeutically not useful, important as poisonous substances, used as insecticides, poisoning due to occupational exposure is common
• Mechanism of action of Organophosphates

  1. Phosphorylate the active site of AChE enzyme

  2. Covalent phosphorus-enzyme bond extremely stable and undergo hydrolysis at very slow rate

  3. Phosphorylated-enzyme undergo ageing and become extremely strong bond, hydrolysis is much slower
• Signs and symptoms of Organophosphate poisoning

  • Miosis
  • Salivation
  • Sweating
  • Bronchial constriction
  • Dyspnoea
  • Bradycardia
  • Vomiting
  • Involuntary defaecation
  • Involuntary micturition
  • Cognitive disturbances
  • Muscle weakness
  • Twitching
  • Flaccid paralysis
  • Convulsions
  • Coma
  • Death
• Treatment of Organophosphate poisoning

  • Maintenance of vital signs
  • Removal of all clothing and washing of skin
  • Gastric lavage
  • Atropine (muscarinic antagonist)
  • Pralidoxime (enzyme reactivator) within 12 hrs