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Autacoids

Munir Gharaibeh, MD, PhD, MHPE School of Medicine, The University of Jordan March, 2019. Autacoids. Endogenous substances with complex physiologic and pathophysiologic functions; commonly understood to include histamine, serotonin, prostaglandins, and vasoactive peptides. Autacoids.

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Autacoids

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  1. Munir Gharaibeh, MD, PhD, MHPE School of Medicine, The University of Jordan March, 2019 Autacoids

  2. Endogenous substances with complex physiologic and pathophysiologic functions; commonly understood to include histamine, serotonin, prostaglandins, and vasoactive peptides. Autacoids

  3. Histamine • Occurs in plants, animals, venoms, and stinging secretions. • Formed in the body from l- histidine. • Mediator of immediate allergic , and inflammatory reactions. • Plays only a modest role in anaphylaxis. • Involved in gastric acid secretion. • Neurotransmitter. Munir Gharaibeh MD, PhD, MHPE

  4. Histamine • Stored in granules in mast cells and basophils, and inactivated. Released by: • Immunologic Reactions: • IgE and antigen interaction causes explosive degranulation and release of histamine, ATP, and other mediators from mast cells. • Chemical and Mechanical Factors: • Drugs like morphine and tubocurarine. Munir Gharaibeh MD, PhD, MHPE

  5. Histamine Receptors • H 1, H2, H3, H4 types, no subfamilies. • H1 receptors are present in endothelium, smooth muscle cells, and nerve endings. • H2 receptors are present in gastric mucosa, cardiac muscle, and some immune cells. Munir Gharaibeh MD, PhD, MHPE

  6. Pharmacologic Effects of Histamine • Satiety effect(الشبع او القناعة) • Decreases BP and increase HR. • Constricts bronchial muscle. • Stimulates GI smooth muscle. • Stimulates gastric acid secretion. • Triple Response: intradermal injection causes red spot, edema, and flare response. • Pain sensation. Munir Gharaibeh MD, PhD, MHPE

  7. Histamine Antagonists • Physiologic Antagonists: • Epinehrine • Release Inhibitors: • Cromolyn • Nedocromil • Receptor Antagonists: • H1 antagonists • H2 antagonists Munir Gharaibeh MD, PhD, MHPE

  8. H1 Receptor Antagonists • Reversible competitive binding to H1 receptors. • Known long time ago, 60 years. • Used in the treatment of allergy. • Available without a prescription(OTC), both alone, or in combination as “cold preparations” and “sleeping aids” Munir Gharaibeh MD, PhD, MHPE

  9. H1 Receptor Antagonists • First Generation: • Strong sedatives because they can cross BBB. Dangers???. • Diphenhydramine, • Chlorpheneramine • Have autonomic blocking effects • Second Generation: • Less lipid soluble, so no sedative activity. • Fexofenadine, • Loratidine, • Cetrizine Munir Gharaibeh MD, PhD, MHPE

  10. Pharmacodynamics of H1 Antagonists • Sedation: • Very common with first generation agents. • Varies among agents and patients. • No abuse potential. • Cause stimulation and convulsions at high doses. • Antinausea and antiemetic. • Antiparkinsonism. • Anticholinergic. • Alpha blocking. • Serotonin blocking. Munir Gharaibeh MD, PhD, MHPE

  11. Clinical uses of H1 Antagonists • Allergic reactions: • More effective when given before exposure. • Sedative effect reduces awareness of itching. • Local application may induce allergy by itself. • Motion Sickness and Vestibular Disturbances: Menier’s Syndrome. • Nausea and vomiting of Pregnancy (Morning Sickness). Munir Gharaibeh MD, PhD, MHPE

  12. H2 Antagonists • Breakthrough treatment for peptic ulcer disease(1972). • Do not completely abolish acid secretion(40-60%). • Replaced by proton pump inhibitors(100% inhibition). • Cimetidine. • Ranitidine. • Famotidine. • Naziditine. Munir Gharaibeh MD, PhD, MHPE

  13. Serotonin= Enteramine=5-Hydroxytryptamine • Serotonin: a vsoconstrictor discovered in the blood clot. • Enteramine: a smooth muscle stimulant found in intestinal mucosa. • 5-Hydroxytryptamine( synthesized in 1951) Munir Gharaibeh MD, PhD, MHPE

  14. Serotonin or 5-Hydroxytryptamine • Widely distributed in nature, found in plant ( (Banana) and animal tissues, venoms, and stings. • In the body, synthesized from L-tryptophan. • Stored, or rapidly inactivated by MAO. • 90% is found in the enterochromaffin cells of the GIT. • Also found in platelets and nervous system. Munir Gharaibeh MD, PhD, MHPE

  15. 5-Hydroxytryptamine(5-HT) or Serotonin • Important neurotransmitter. • Have actions in the brain, intestine, & blood vessels. • Abnormalities are involved in several disorders: • Depression, anxiety, sleep, temperature, and pain • Vomiting caused by cytotoxic drugs. • Migraine headache. • Carcinoid Tumor of the GIT Munir Gharaibeh MD, PhD, MHPE

  16. Pharmacologic Effects of Serotonin • Nervous System: • Melatonin • Cardiovascular System: • Peripheral vasoconstriction. • Vasodilation in skeletal muscles and coronary arteries. • Platelets aggregation. Munir Gharaibeh MD, PhD, MHPE

  17. Pharmacologic Effects of Serotonin • Respiratory System: • Bronchoconstriction and hyperventilation. • GIT: • Stimulation and diarrhea. • Carcinoid Syndrome: due to a tumor of the enterochromaffin cells which secretes serotonin. Munir Gharaibeh MD, PhD, MHPE

  18. Clinical Uses of Serotonin Agonists • Serotonin: • Has no clinical application. • Buspirone: • 5HT1A agonist, anxiolytic, nonsedating. • Triptans: e.g. Sumatriptan • 5HT1D/1B agonists • First line drugs for migraine headache. • Fluoxetine: • SSRI, widely used in depression. Munir Gharaibeh MD, PhD, MHPE

  19. Serotonin Antagonists • Cyproheptadine: • 5HT2 and H1 blocker. • Useful in carcinoid. • Ketanserine: • 5HT2 blocker, antihypertensive agent. • Ondansetron: • 5HT3 blocker, used to prevent nausea and vomiting of cancer chemotherapy. Munir Gharaibeh MD, PhD, MHPE

  20. Migraine Headache • Migraine is characterized by recurrent attacks of headache, which is unilateral and pulsating, may be preceded by visual disturbances (Aura), often familial and may be precipitated by trigger factors. • Mechanism: • Vasospasm followed by vasodilation of the cerebral vessels associated with release of mediators causing pain sensation in the area of the trigeminal nerve. Munir Gharaibeh MD, PhD, MHPE

  21. Treatment of Migraine Headache • Acute Attack: • Analgesics: Aspirin, Paracetamole. • Sumatriptan: • Stimulates 5-HT receptors resulting in constriction. • Given SC immediately after onset. • Also given orally and as nasal spray. • Can cause tightness in the chest, dizziness and nausea. • Expensive. Munir Gharaibeh MD, PhD, MHPE

  22. Treatment of Migraine Headache • Acute Attack: • Analgesics: Aspirin, Paracetamole. • Sumatriptan. • Ergotamine: • From a fungus. • Stimulates α (vasoconstriction) and 5-HT receptors. • Was widely used, orally, rectally, and aerosol. • Combined with caffeine or Cyclizine (an anti emetic). • Toxic: vomiting, diarrhea, gangrene, tingling, numbness. • Withdrawal causes headache. Munir Gharaibeh MD, PhD, MHPE

  23. Prevention of Migraine Headache All cause vasoconstriction • β-Blockers: • Reduce vasodilation. • Pizotifen: • 5-HT antagonist. • Causes drowsiness, weight gain. • Sodium valproate; • Antiepileptic • Can cause fetal malformations, liver damage, and platelet dysfunction • Antidepressants • Methysergide: • 5-HT antagonist. Munir Gharaibeh MD, PhD, MHPE

  24. Ecosanoids • Prostaglandins. • Thromboxane and Prostacyclin. • Leukotrienes. Munir Gharaibeh MD, PhD, MHPE

  25. Munir Gharaibeh MD, PhD, MHPE

  26. Renin-Angiotensin-Aldosterone System Munir Gharaibeh MD, PhD, MHPE

  27. Angiotensin-converting enzyme inhibitors (ACEI) • ACEI lower systemic vascular resistance and venous pressure, and reduce levels of circulating catecholamines, thus improving myocardial performance. Munir Gharaibeh MD, PhD, MHPE

  28. Angiotensin-converting enzyme inhibitors ACEI • Captopril • Benazepril • Enalapril • Fosinopril • Lisinopril • Moexipril • Quinapril • Ramipril Munir Gharaibeh MD, PhD, MHPE

  29. Cardiorenal Effects of ACE Inhibitors • Vasodilation (arterial & venous):- reduce arterial & venous pressure.- reduce ventricular afterload and preload. • Decrease blood volume:- natriuretic.- diuretic. • Depress sympathetic activity. • Inhibit cardiac and vascular hypertrophy. Munir Gharaibeh MD, PhD, MHPE

  30. Angiotensin - Converting Enzyme Inhibitors(ACEI) Therapeutic Benefits: Hypertension. HF and Ischemic Heart Disease. Diabetic Nephropathy, dilate efferent arterioles No need for a diuretic but can be added. Can be combined with Ca channel blockers. No metabolic effects(DM, Lipids, Uric Acid). Mar-19 30 Munir Gharaibeh MD, PhD, MHPE

  31. Angiotensin - Converting Enzyme Inhibitors(ACEI) Side Effects: Captopril is very toxic Hypotension( First Dose Phenomena) especially with renovascular hypertension. K+ retention, especially in the presence of renal dysfunction Cough(10% of patients) Mar-19 31 Munir Gharaibeh, MD, PhD, MHPE Munir Gharaibeh MD, PhD, MHPE

  32. Angiotensin Receptor Antagonists(ARBs) Losartan. Irbersartan. Candesartan. Valsartan Have similar haemodynamic effects to ACEI Do not cause cough. Munir Gharaibeh MD, PhD, MHPE

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