Med org 1

• MUSCARINIC RECEPTORS


  Play an essential role in regulating the functions of organs innervated by the ANS to maintain homeostasis
• Acetylcholine


  • Stimulates secretions from salivary and sweat glands
  • Stimulates secretions and contractions of the gut
  • Constriction of airways of the respiratory tract
  • Inhibits contraction of the heart and relaxes smooth muscle of blood vessels
• Muscarinic receptors play an essential role in regulating the functions of organs innervated by the ANS to maintain homeostasis
• In the classical studies of Dale, he suggested that acetylcholine was a chemical neurotransmitter in the parasympathetic nervous system
• Acetylcholine is short-lived due to esterases that hydrolyze it
• Parasympathomimetic or cholinomimetic agents


  Drugs and chemicals that cause the parasympathetic division to react
• Agonists


  Act directly on cholinergic receptors and function as inhibitors of acetylcholinesterase (AChE), the enzyme responsible for ACh hydrolysis
• Cholinergic antagonists, Anticholinergics, Cholinolytic or Parasympatholytic agents


  Compounds that possess affinity for cholinergic receptors but exhibit no intrinsic activity
• Affinity


  Ability of a drug to bind to its receptor
• Intrinsic activity


  Ability of a drug to exert its pharmacological action
• Agonist


  Drug with affinity and intrinsic activity
• Antagonist


  Drug with affinity but no intrinsic activity
• Sympathomimetic


  Agents that mimic the sympathetic division
• Sympatholytic


  Agents that block the actions of the sympathetic division
• Acetylcholine metabolism


  1. Acetyl-CoA

  2. Acetylcholine

  3. Choline

  4. Acetate

  5. Acetylcholinesterase
• Muscarinic receptor stimulation


  • Inhibition of adenylyl cyclase
  • Activation of phospholipase C and subsequent biosynthesis of secondary messengers
• Gs


  Increases adenylyl cyclase and increases calcium currents
• Gi


  Decreases adenylyl cyclase and increases K currents
• Go


  Decreases Ca currents
• Gq


  Increases phospholipase C activity
• Acetylcholine (ACh) plays a critical role in the mechanisms of regulation of human physiology
• Mimic the ACh effects

  • Act directly on the cholinergic receptors in the tissue
  • Inhibiting acetylcholinesterase (AChE), the enzyme that inactivates ACh at the nerve terminal (indirectly)
• Muscarinic receptor activation


  1. Decreases cAMP levels

  2. Reduces cAMP protein-dependent kinase activity

  3. Causes relaxation of muscle contraction
• Muscarinic receptor activation


  1. Activates phospholipase C

  2. Increases IP3 and DAG

  3. Mobilizes Ca

  4. Causes smooth muscle contraction
• M1 receptor


  • Located in the CNS, exocrine glands and autonomic ganglia
  • Believed to participate in memory and learning
  • Found in smooth muscles, in the parietal cells in the GI tract
  • When stimulated, causes gastric secretion
• M2 receptor


  • Cardiac muscarinic receptors
  • Stimulation causes a decrease in the strength and rate of cardiac muscle contraction
  • Affects K+ and Ca2+ levels in heart tissue
  • Hyperpolarization results in bradycardia
  • Act through Gi protein to reduce adenylate cyclase activity and lower cAMP levels in cardiac cells
• M3 receptor


  • Glandular muscarinic receptors
  • Found in exocrine glands and smooth muscle
  • Stimulation causes glandular secretions from lacrimal, salivary, bronchial, pancreatic and mucosal cells in the GI tract
  • Mediated through G-protein activation of PLC to form IP3 and DAG
  • When stimulated, causes release of EDRF or known as nitrous oxide vasodilation
• M4 receptor


  • Like M2 receptors, act through Gi protein to inhibit adenylate cyclase
  • Direct regulatory action on K+ and Ca2+ ion channels
• M5 receptor


  Regulates dopamine release at terminals within the striatum
• Nicotinic receptors (nAChRs)


  • Found at the skeletal neuromuscular junction, adrenal medulla, and autonomic ganglia
  • Classified as ligand-gated ion channel receptors
• Nicotinic receptor activation


  1. Creates a transmembrane ion channel

  2. Acetylcholine (ligand) binds to nAChR to modulate the passage of Na+ and K+ through the channel

  3. Opens Na+ channel causing depolarization and subsequent action potential at neuromuscular junction
• N1 nicotinic receptor


  Depolarizes the end plate which results in muscular contraction at a neuromuscular junction
• N2 nicotinic receptor


  Continuation of a nerve impulse at the autonomic ganglia
• Neuromuscular nicotinic ACh receptors are targets for autoimmune antibodies in myasthenia gravis
• Nicotinic receptors in autonomic ganglia, when blocked by drugs, can play a role in the control of hypertension
• Cholinomimetic (cholinergic) drugs


  • Direct-acting nicotinic
  • Direct-acting muscarinic
  • Indirect-acting (organophosphates, carbamates, edrophonium)
• Antimuscarinic (anticholinergic) drugs


  • M1-selective
  • Nonselective
  • Ganglion blockers (NN)
  • Neuromuscular blockers (NM)