Pharmacology of Autonomic System

1. Pharmacology of Autonomic System MunirGharaibehMD, PhD, MHPE Departmrnt of Pharmacology School of Medicine mgharaib@ju.edu.jo

2. The Nervous System Munir Gharaibeh, MD,PhD, MHPE • Central Nervous System: • Brain and Spinal cord • Peripheral Nervous System: • Autonomic nervous System: • Parasympathetic System • Sympathetic System or Adrenergic System • Somatic Nervous System:

3. Munir Gharaibeh, MD,PhD, MHPE

4. Effects of Sympathetic and Parasympathetic Activity Munir Gharaibeh, MD,PhD, MHPE

5. The Cholinergic Junction Munir Gharaibeh, MD,PhD, MHPE

6. Nicotinic transmission at the skeletal neuromuscular junction Munir Gharaibeh, MD,PhD, MHPE

7. Life Cycle of Acetylcholine • Choline is transported into the presynaptic nerve terminal by a sodium-dependent choline transporter (ChT). This transporter can be inhibited by drugs. • In the cytoplasm, acetylcholine is synthesized from choline and acetyl Co-A (AcCoA) by the enzyme choline acetyltransferase (ChAT). • Acetylcholine is then transported into the storage vesicles by a second carrier, which can be inhibited by drugs • Peptides (P), adenosine triphosphate (ATP), and proteoglycan are also stored in the vesicle. Munir Gharaibeh, MD,PhD, MHPE

8. Life Cycle of Acetylcholine • Release of transmitter occurs when voltage-sensitive calcium channels in the terminal membrane are opened, allowing an influx of calcium. The resulting increase in intracellular calcium causes fusion of vesicles with the surface membrane and exocytotic expulsion of acetylcholine and cotransmitters into the junctional cleft. This step can be blocked by botulinum toxin. • Acetylcholine's action is terminated by metabolism by the enzyme acetylcholinesterase. • Receptors on the presynaptic nerve ending modulate transmitter release. Munir Gharaibeh, MD,PhD, MHPE

9. The Noradrenergic Junction Munir Gharaibeh, MD,PhD, MHPE

10. Life Cycle of Noradrenaline • Tyrosine is transported into the noradrenergic ending or varicosity. • Tyrosine is converted to dopa and then to dopamine which is then transported into the vesicle by the vesicular monoamine transporter (VMAT), which can be blocked by reserpine. • Dopamine is converted to NE in the vesicle. Munir Gharaibeh, MD,PhD, MHPE

11. Life Cycle of Noradrenaline • Physiologic release of transmitter occurs when an action potential opens voltage-sensitive calcium channels and increases intracellular calcium. Fusion of vesicles with the surface membrane results in expulsion of norepinephrine. • Release can be blocked by drugs. • Norepinephrine diffuses out of the cleft or is transported into the cytoplasm of the terminal by the norepinephrine transporter (NET), which can be blocked by cocaine and tricyclic antidepressants, or into postjunctional or perijunctional cells. • Regulatory receptors are present on the presynaptic terminal. Munir Gharaibeh, MD,PhD, MHPE

12. Cholinergic Receptors Munir Gharaibeh, MD, PhD, MHPE

13. The major groups of cholinoceptor-activating drugs, receptors, and target tissues. Munir Gharaibeh, MD,PhD, MHPE

14. Cholinergic Agonists or Parasympathomimetics Cholinergic agonists can work on all parts of the parasympathetic system, parts of the sympathetic system, and the somatic system. • Choline Esters. • Alkaloids. • Cholinesterase Inhibitors or Anticholinesterases. Munir Gharaibeh, MD,PhD, MHPE

15. Cholinergic Agonists or Parasympathomimetcs • Choline Esters: • Acetylcholine: • Naturally released from the cholinergic nerve endings, is very short acting because of rapid hydrolysis by AChase enzyme. • Used only in experimentation. • Methacholine. • Bethanechol. • Carbachol: • Synthetic, long acting. • Used in postoperative atony. • Cause flushing, sweating, colic. Munir Gharaibeh, MD,PhD, MHPE

16. Structures of Four Choline Esters. Munir Gharaibeh, MD,PhD, MHPE

17. Cholinergic Agonists or Parasympathomimetcs • Alkaloids: • Muscarine • Nicotine. • Pilocarpine. Munir Gharaibeh, MD,PhD, MHPE

18. Structures of some cholinomimetic alkaloids. Munir Gharaibeh, MD,PhD, MHPE

19. Cholinergic Agonists or Parasympathomimetcs • Cholinesterase Inhibitors or Anticholinesterases: • Prevent breakdown of ACh by cholinestearse. • Reversible: • Neostigmine: • Used in Myasthenia Gravis, Paralytic Ileus, and postoperative atony of the bladder. • Irreversible: • Parathion, Malathion: • Used as potent insecticides • Tabun, Sarin, Soman: • Used as war or nerve gases. Munir Gharaibeh, MD,PhD, MHPE

20. Reversible Cholinesterase Inhibitors. Munir Gharaibeh, MD,PhD, MHPE

21. Organophosphorous Irreversible Cholinesterase Inhibitors. Munir Gharaibeh, MD,PhD, MHPE

22. Organophosphate Poisoning • Very potent agricultural insecticides and lethal war weapons. • Very easily absorbed through all parts of the skin. • Inhibit the enzyme and cause accumulation of ACh at all sites. Munir Gharaibeh, MD,PhD, MHPE

23. Organophosphate Poisoning Munir Gharaibeh, MD,PhD, MHPE

24. Treatment of Organophosphate Poisoning • Stop the exposure, wash extensively, very lipid soluble. • Atropine, a parasympatholytic drug, in very large doses, until the appearance of Atropine Poisoning. • Pralidoxime, when given very early after the poisoning, can regenerate the enzyme. Munir Gharaibeh, MD,PhD, MHPE

25. Cholinergic Blockers or Parasympatholytics • Nicotinic Blockers: Curare-like drugs. • Muscarinic Blockers: Atropine –like drugs. Munir Gharaibeh, MD,PhD, MHPE

26. Atropine –like Drugs • Atropine: • Natural. • Absorbed from all routes. • Actions: • GIT: Reduces motility and secretions. • Heart: inhibits vagus nerve causing tachycardia. • Lungs: relaxes bronchioles but reduces secretions. • Smooth muscles: relaxes renal and biliary tracts. • Eye: mydriasis with paralysis of accommodation and can raise pressure in the eyeball. Munir Gharaibeh, MD,PhD, MHPE

27. Atropine –like Drugs • Atropine: • Clinical Uses: • Smooth muscle spasm. • Eye examination. • Preoperative medication. • Organophosphate poisoning • Adverse effects: • Dryness, redness, Hotness. • Constipation, Urinary retention. • Paralysis of accommodation. • Restlessness, hallucinations, and Delirium. • Antidote for toxicity: Physostigmine. Munir Gharaibeh, MD,PhD, MHPE

28. Atropine –like Drugs • Hyoscine (Scopolamine): • Also natural product. • Similar peripheral effects. • CNS depressant leading to drowsiness and sleep. • Used for motion sickness • Mebeverine • Propantheline • Both are synthetic. • Were used in peptic ulcer disease. • Still used for irrtiable bowel syndrome (combined with anxiolytic). • Also used for irritable bladders. Munir Gharaibeh, MD,PhD, MHPE

29. Sympathomimetic Drugs or Adrenergic Agonists • These are the drugs which are given to mimic the actions of the sympathetic nervous system. • They are given in high concentrations relative to the endogenously released neurotransmitters after sympathetic nerve endings. • Directly Acting • Indirectly Acting Munir Gharaibeh, MD,PhD, MHPE

30. Munir Gharaibeh MD, PhD, MHPE

31. Sympathomimetic Drugs or Adrenergic Agonists • Directly Acting Drugs: These work directly on the adrenergic receptors. • Norepinephrine or Noradrenalin • Epinephrine or Adrenaline • Isoprenaline • Dopamine • Salbutamole • Indirectly Acting: • Cocaine. • Amphetamine • Ephedrine Munir Gharaibeh, MD,PhD, MHPE

32. Sympathomimetic Drugs or Adrenergic Agonists • Directly Acting: • Norepinephrine or Noradrenalin: • Natural product which is purely α receptor agonist, so it is a potent vasoconstrictor. • Given only IV. • Raises both systolic and diastolic pressure. • Was widely use in shock but caused limb gangrene. Munir Gharaibeh, MD,PhD, MHPE

33. Sympathomimetic Drugs or Adrenergic Agonists • Directly Acting: • Epinephrine or Adrenaline: • Has mixed α and β agonistic activities. • Given IM, SC, also intracardiac. • Increases force and rate of contraction of the heart. • Raises systolic blood pressure. • Bronchodilator. • Increases blood sugar. • Used in anaphylactic shock and as a last resort in cardiac arrest . Munir Gharaibeh, MD,PhD, MHPE

34. Sympathomimetic Drugs or Adrenergic Agonists • Directly Acting: • Isoprenaline: • Purely β1 and β2 agonist. • Has little effects on BP • Can cause cardiac arrhythmias. • Was used in bronchial asthma, but cardiotoxic. Munir Gharaibeh, MD,PhD, MHPE

35. Sympathomimetic Drugs or Adrenergic Agonists • Directly Acting: • Dopamine: • Has mixed α , β, and dopamine receptor (DA) agonistic activities. • DA receptors are present in the renal vessels and cause vasodilation. • Vasoconstriction elsewhere. • Increases BP. • Stimulates the heart. • Very useful in shock. Munir Gharaibeh, MD,PhD, MHPE

36. Sympathomimetic Drugs or Adrenergic Agonists Dopamine: Widely used in cardiogenic shock. Low doses: stimulates DA1 receptors leading to renal vasodilation and improved renal function. Intermediate doses: works on β1 receptors leading to positive inotropic actions. High doses: stimulates α receptors leading to vasoconstriction and elevation of blood pressure. Can cause arrhythmias and ischemic changes. Munir Gharaibeh, MD,PhD, MHPE

37. Sympathomimetic Drugs or Adrenergic Agonists • Directly Acting: • Salbutamol: • Selectiveβ2 agonist. • Powerful bronchodilator. • Can inhibit uterine muscle. • Given orally, IV, inhalation. • In high doses can cause tremor and tachycardia. Munir Gharaibeh, MD,PhD, MHPE

38. Sympathomimetic Drugs or Adrenergic Agonists • Directly Acting. • Indirectly Acting: • Cocaine. • Amphetamine • Ephedrine. These are lipophilic compounds, so can cross the BBB causing mainly CNS effects: Euphoria, abolish fatigue, increase activity, and reduce appetite. Carry the risk of dependence. Use limited to narcolepsy and hyperactive children. Were used for appetite suppression. Munir Gharaibeh, MD,PhD, MHPE

39. Bronchial Asthma • Is a chronic relapsing disease characterized by wheezing due to bronchospasm, infection, and excessive mucus production. • Due to antigen -antibody interaction which causes the release of inflammatory mediators. • Precipitated by cold exposure, exercise, infection, stress, dust, etc… Munir Gharaibeh, MD,PhD, MHPE

40. Drug Treatment of Bronchial Asthma. • Bronchdilators. • Corticosteroids. • Mast cell stabilizers. • Leukotriene Modifiers. • Antimicrobials. • Hydration, expectorants and mucolytic drugs. Munir Gharaibeh, MD,PhD, MHPE

41. Drug Treatment of Bronchial Asthma. • Bronchdilators. • Β2 agonists: e.g. Salbutamol, Terbutaline • Used just before, or during the attack, or regularly. • Can be given by inhalation, IV, or orally. • Methylxanthines; e.g. Aminophylline and Theophylline: • Inhibit Phosphodiesterase enzyme which breaks down cAMP. • Toxic: so blood levels should be monitored. • Given slowly IV, or orally, and rectally. • Can cause nausea, anxiety, tachycardia, arrhythmias, and convulsions. • Interactions are very common. • Ipratropium Bromide: • Atropine-like drug which is given by inhalation. • Localized action, no systemic side effects. Munir Gharaibeh, MD,PhD, MHPE

42. Adrenergic Blocking Drugs“Sympatholytics” • α-adrenergic blockers: • Block the sympathetic effects on α-adrenergic receptors. • Used in hypertension and bladder neck obstruction (benign prostatic hypertrophy). • Prazosin. • Terazosin. • Doxazocin (Cardura) • β-adrenergic blockers: • Block the sympathetic effects on β-adrenergic receptors. • Differ in their Selectivity and Pharmacokinetics • Have wide applications in medicine. Munir Gharaibeh, MD,PhD, MHPE

43. β-adrenergic Blockers • Nonselectiveβ-Blockers: • Block both β1 and β2 receptors. • Propranolol: prototype. • Nadolol • Sotalol. • Selectiveβ-Blockers: • Block β1 more than β2 receptors. • Metoprolol • Atenolol • Bisoprolol • Combined α and β-Blockers: • Labetalol • Carvedilol Munir Gharaibeh, MD,PhD, MHPE

44. β-adrenergic Blockers • Actions: • Prevent the actions of the sympathetic system, i.e. more active when the system is overactive. • Reduce heart’s: rate, contractility, and excitability, and consequently reduce cardiac output. • Reduce BP. • Bronchoconstriction. • Prevent glycogenolysis (the rise in blood sugar). • Mask the symptoms of hypoglycemia. • CNS: sedation, dreams, hallucinations, depression. Munir Gharaibeh, MD,PhD, MHPE

45. β-adrenergic Blockers • Clinical Uses: • Ischemic heart disease. • Hypertension. • Cardiac arrhythmias. • Thyrotoxicosis. • Anxiety: actually only block the sympathetic symptoms of anxiety. So very effective in Stage-Fright. • Essential tremor. • Migraine. Munir Gharaibeh, MD,PhD, MHPE

46. β-adrenergic Blockers • Adverse Effects: • Myocardial suppression, i.e. ? possibility of heart failure with high doses. • Bronchospasm or bronchial asthma. • CNS effects: fatigue, bad dreams, depression, sexual impairment. • Cold extremities, due to unmasking of αreceptors. • Mask the symptoms of hypoglycemia which might lead to more hypoglycemia and coma. Munir Gharaibeh, MD,PhD, MHPE