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Slide2 cholinergics and cholinomimetics


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Slide2 cholinergics and cholinomimetics

  1. 1. Pharmacology Cholinergics And Cholinomimetics Slide-2
  2. 2. Overview Drugs affecting the ANS are divided into two groups according to the type of neuron involved in the mechanism of action: a) The cholinergic drugs: they act on receptors that are activated by acetylcholine (Ach) b) The adrenergic drugs: they act on receptors that are activated by norepinephrine or epinephrine
  3. 3. Cholinergic Receptors (Cholinoceptors) • Cholinoceptor denotes receptors that respond to acetylcholine. • Two families/subtypes of cholinoceptors were named after the alkaloids originally used in their identification: muscarinic (M) and nicotinic (N) receptors.
  4. 4. I. Muscarinic (M) receptors • These receptors, in addition to binding acetylcholine, also recognize muscarine, but show a weak affinity for nicotine. • Five subclasses of muscarinic receptors: M1, M2, M3, M4, and M5 have been identified
  5. 5. I. Muscarinic (M) receptors • responsible for activating Ca+2-dependent responses, such as secretion by glands and the contraction of smooth muscle
  6. 6. II. Nicotinic (N) receptors • These receptors, in addition to binding ACh, also recognize nicotine, but show a week affinity for muscarine. • N receptors are located on plasma membranes of postganglionic cells in all autonomic ganglia, of muscles innervated by somatic motor fibers (i.e. Neuromuscular junction), and of some CNS neurons.
  7. 7. II. Nicotinic (N) receptors • When the nicotnic AchR is stimulated, the channel opens and allows Na+ to rush into the cell • This triggers depolarization of the cell and elicits a neruronal action potential (in postganglionic nerve) or muscle contraction (in skeletal muscles).
  8. 8. Cholinomimetic agents • Cholinomimetic drugs can elicit some or all of the effects that acetylcholine (ACh) produces. • Include agents that act directly (cholinoceptor agonists/stimulants) or indirectly acting mechanisms (cholinesterase inhibitors).
  9. 9. Direct acting cholinergic stimulants
  10. 10. • Cholinergic receptor agonists mimic the effects of ACh by binding directly to cholinoceptors • The directly acting cholinomimetics can be subdivided into: • 1- Parasympathomimetic drugs: primarily work through binding to muscarinic receptors. • 2- Agents that stimulate nicotinic receptors.
  11. 11. • These agents can be divided into two groups: • 1-Choline esters (acetylcholine, metacholine, carbachol, & bethanechol) • 2-Naturally occurring cholinomimetic alkaloids (muscarine, nicotine, pilocarpine, & lobeline)
  12. 12. Choline Ester Susceptibility to Cholinesterase Muscarinic Action Nicotinic Action Acetylcholine chloride ++++ +++ +++ Carbachol Negligible ++ +++ Methacholine + +++ None Bethanechol Negligible +++ None Muscarine Negligible +++ None Pilocarpine Negligible +++ None Pharmacology of acetylcholine-like agonists
  13. 13. Direct acting cholinergic stimulants Organ system effect • Cardiovascular system: 1. Vasodilation. 2. Decrease in heart rate. 3. Decrease in the force of cardiac contraction • Eye:  cause contraction of the smooth muscle of the: 1) Iris sphincter*: resulting in miosis 2) Ciliary muscle*: resulting in accommodation of the eye for near vision
  14. 14. Direct acting cholinergic stimulants Organ system effect c. Other Organ Systems  Respiratory system: bronchoconstriction & increase tracheobronchial secretion  GIT: stimulation of salivation and acid secretion.  Genitourinary tract: promoting urination.
  15. 15. Direct acting cholinergic stimulants Organ system effect  CNS: Muscarinic agonists are able to produce marked CNS owing to activation of M1-receptors in the brain areas involved in cognition.
  16. 16. Clinical uses of the direct acting cholinomimetics a) Glaucoma: cholinomimetics reduce intraocular pressure by causing contraction of the ciliary body so as to facilitate outflow of aqueous humor (e.g pilocarpine and carbachol) b) Bladder and bowel atony after surgery: Bethanechol c) Xerostomia associated with Sjögren's syndrome and that caused by radiation damage of the salivary glands: pilocarpine & cevimeline
  17. 17. Nicotinic receptors • Direct acting nicotine agonists have no therapeutic applications exept in smoking cessation (nicotine and varenicline) and producing skeletal muscle paralysis (succinylcholine).
  18. 18. Nicotine replacement therapy • To help patients stop smoking . • Available in the form of gum, transdermal patch, nasal spray, or inhaler.
  19. 19. Varenicline (Chantix®) • Is a partial agonist at α4β2 nicotinic receptors. • Varenicline prevents the stimulant effect of nicotine at presynaptic α4β2 receptors that causes release of dopamine. • ADRs: nausea, insomnia, and exacerbation of psychiatric illnesses, including anxiety and depression
  20. 20. Indirect acting cholinomimetics
  21. 21. Indirect acting cholinomimetics Acetylcholinesterase (AChE) is an enzyme that specifically cleave ACh to (acetate and choline) and, thus, terminates its action. Inhibitors of AChE indirectly provide a cholinergic action by prolonging the lifetime of acetylcholine (i.e. they have both muscarinic and nicotinic effects)
  22. 22. Indirect acting cholinomimetics • There are three chemical groups of cholinesterase inhibitors: (1) Simple alcohols bearing a quaternary ammonium group, eg, edrophonium (2) Carbamates (eg, neostigmine) (3) Organophosphates (eg, echothiophate)
  23. 23. Therapeutic Uses and Durations of Action of Cholinesterase Inhibitors Uses Approximate Duration of Action Alcohols Edrophonium Myasthenia gravis, arrhythmias 5–15 minutes Carbamates and related agents Neostigmine Myasthenia gravis, 0.5–2 hours Pyridostigmine Myasthenia gravis 3–6 hours Physostigmine Glaucoma 0.5–2 hours Ambenonium Myasthenia gravis 4–8 hours Demecarium Glaucoma 4–6 hours Organophosphates Echothiophate Glaucoma 100 hours Types and some uses:
  24. 24. Indirect acting cholinomimetics Organ system effect • Central nervous system (CNS)  In higher concentrations, they cause generalized convulsions, which may be followed by coma and respiratory arrest. • Eye, Respiratory Tract, GIT, & Urinary Tract  The effects of the cholinesterase inhibitors are qualitatively quite similar to the effects of the direct- acting cholinomimetics.
  25. 25. Clinical uses • Glaucoma: physostigmine, demecarium, echothiophate, isoflurophate • Gastrointestinal and Urinary Tracts: Neostigmine to treatment of adynamic ileus and atony of the urinary bladder. • Myasthenia gravis:Carbamates (Pyridostigmine, neostigmine , and ambenonium): anticholinesterase agents used in the long-term therapy for myasthenia gravis.