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AUTACOIDS

AUTACOIDS. Histamine Bradykinin & Kallidin 5 Hydroxytryptamine (5HT) Autacoids derived from membrane phospholipid Eicosanoids – arachidonic acid (PG, PGI, TXA2, LT) Modified phospholipids – PAF. HISTAMINES. Chemistry: imidazole ring + amino group connected by 2 methylene groups.

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AUTACOIDS

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  1. AUTACOIDS • Histamine • Bradykinin & Kallidin • 5 Hydroxytryptamine (5HT) • Autacoids derived from membrane phospholipid • Eicosanoids – arachidonic acid • (PG, PGI, TXA2, LT) • Modified phospholipids – PAF

  2. HISTAMINES Chemistry: imidazole ring + amino group connected by 2 methylene groups

  3. Synthesis • Decarboxylation of amino acid L-histidine catalyzed by pyridoxal PO4-dependent L-histidine decarboxylase. • Ingested from food or formed by bacteria in the GIT • Storage sites: • perivascular tissue – mast cell • circulation – basophil (bound to chondroitin SO4) • others – GIT, lungs, skin, heart, liver, neural tissue, reproductive mucosa, rapidly growing tissues and body fluids

  4. Metabolism : • Major pathways • Deamination – small intestine, liver, kidney and monocytes • Methylation – small intestine, liver, skin, kidney, thymus & leukocytes • N-methylimidazole acetic acid - principal urinary metabolite

  5. Metabolism :

  6. Functions: • Role in allergic responses – Ag + IgE (bound to mast cells & basophils) • Preformed mediators • Most important mechanism of release/controlled by H2 esp. in skin & blood • Release of other autacoids • Release by drugs (morphine, urase, amines), peptides, venoms & other agents • Release by urticarias • Gastric secretagogue • Neurotransmitter  increased wakefulness, thermoregulation

  7. Selected Actions of Histamine in Humans

  8. Selected Actions of Histamine in Humans

  9. Selected Actions of Histamine in Humans • H1, H2 - located in post synaptic membrane • H3 – presynaptic • H1 - predominant in endotracheal & smooth muscle • H2 - facial veins, carotid a, pulm. a, heart • gastric mucosa, heart, smooth muscle & some immune cells • H3 - several ares in CNS • Triple response - wheal, flare & redness

  10. H1 RECEPTOR ANTAGONISTS Pharmacokinetics: • Well absorbed from GIT (oral) • Onset – 30 minutes, duration – 3 to 6 hours • Widely distributed • Biotransformed in the liver; microsomal enzyme inducer • Excretion – kidneys

  11. Adverse Effects: • CNS : sedation, agitation, nervousness, delirium, tremors, incoordination, hallucinations, & convulsions - common in first generation antihistamines • GIT : vomiting, diarrhea, anorexia, nausea, epigastric distress, constipation - dryness of mouth, throat & airway, urinary retention - first generation • Headache, faintness • Chest tightness, palpitations, hypotension • Visual disturbances • Hematological - leukopenia, agranulocytosis, HA

  12. Therapeutic Uses: • dermatosis • allergic rhinitis • motion sickness & emesis • Parkinson’s disease • EPS • Insomnia • Adverse reactions

  13. I. First Generation Agents A. Ethanolamines Carbinoxamine maleate Clemastine fumarate Diphenhydramine HCl Dimenhydrinate B. Ethylenediamines Pyrilamine maleate Tripelennemine HCL/citrate PPA C. Alkylamines Chlorpheniramine maleate Brompheniramine maleate II. Second Generation Agents A. Alkylamines Acrivastine B. Piperazines Cetirizines HCl C. Piperidines Astemizole Levocabastine Loratadine Terfenadine Fexofenadine Histamine Antagonists

  14. FIRST GENERATION AGENTS D. Piperazines 1. Hydroxyzine HCl/pamoate (long acting) 2. Cyclizine HCl/lactate 3. Meclizine HCl 4. Chlorcyclizine E. Phenothiazines 1. Promethazine HCl

  15. H2 RECEPTOR ANTAGONISTS Pharmacodynamics: • Inhibit gastric acid secretion • (-) effect of gastric motility, emptying time, LES sphincter, pancreatic & mucous secretion

  16. Cimetidine:  headache, dizziness • constipation, diarrhea • skin rashes • alterations of hepatic function • CNS disturbances (elderly & impaired RF) • BM depression – rare • Serum prolactin elevation • Sexual dysfunction & gynecomastia • Ranitidine:  Serum prolactin elevation Adverse Effects

  17. Drug Interactions: • Cimetidine inhibits cyto p-450 – accumulation of warfarin, phenytoin, theophylline, propanolol, diazepam & phenobarbital • Ranitidine – weak inhibitor • Nizatidine & famotidine – do not inhibit cyto P – 450 • Therapeutic Uses: Peptic acid disorders

  18. Vasoactive Peptides • Vasoconstrictors—angiotensin II,vasopressin, endothelins, neuropeptide Y • Vasodilators—bradykinin, natri-uretic peptides, vasoactive intestinal peptides, substance P, neurotensin and calcitonin gene-related peptide (CGRP)

  19. BRADYKININ & KALLIDIN • Peptides that act locally to produce pain, vasodilatation,  vascular permeability & PG synthesis Synthesis: • Liver • Percursors: kininogens—SERINE PROTEASES (HMW & LMW)

  20. Pharmacologic Properties • CVS : (+) inotropic & chronotropic effects vasoconstriction • Smooth Muscle: Bronchoconstriction • GIT: Enhanced motility

  21. Functions • pain – excites primary sensory neurons & provokes release of substance P, neurokinin A & CGRP • inflammation -  permeability in microcirculation • production of IL-1 & TNF -  • respiratory disease

  22. Pharmacological Properties 1. CVS – potent vasodilator (10x more than histamine) • Stimulate histamine release 2. Kidney -  RBF 3. Others: • spermatogenesis & promotes sperm motility • dilatation of fetal pulmonary arteryclosure of ductus arteriosus constriction of umbilical vessels

  23. 5 HYDROXYTRYPTAMINE(5HT) • Found in enterochromaffin cells (90%), platelets and CNS • Sources : tunicates, mollusks, anthropods, colenterates, fruits, nuts, wasps & scorpions

  24. Synthesis: Tryptophan Hydroxytryptophan 5 hydroxytryptamine (Serotonin) 5-hydroxyindole acetaldehyde 5-hydroxyindole acetic acid acid 5-hydroxytrytophol(principal metabolite) N-acetyl- 5-HT Melatonin

  25. Antagonists: 1. Clozapine: Reduce incidence of EPS High affinity for dopamine receptors Reduced negative symptoms of schizophrenia 2. Risperidone: D2 receptor blocker Reduced negative symptoms of schizophrenia Low incidence of EPS

  26. 1. Clozapine: • Reduce incidence of EPS • High affinity for dopamine receptors • Reduced negative symptoms of schizophrenia • 2. Risperidone: • D2 receptor blocker • Reduced negative symptoms of schizophrenia • Low incidence of EPS 3. Methysergide: used for diarrhea & malabsorption in patients with carcinoid tumors

  27. Cyproheptadine: • H1 blocker • Weak anticholinergic and mild CNS depressant • Used for skin allergies, cold urticaria • Counteract the sexual side effects of SSRI’s

  28. LIPID-DERIVED AUTOCOIDS Eicosanoids • formed from PUFA (AA) • release from cellular stores by PLA2 • human platelets – DAG lipase • coupled to G proteins

  29. EFA (diet) Esterified acid Arachidonic acid in cell lipid PLA2 Lipoxygenase Cyclooxygenase X ASA, indomethacin 12-HPETE 5-HPETE 84 12-HETE 5-HETE LTA4 LTC4 LTB4 LTD4 LTE4 LTF4

  30. Cycloxygenase PGG2 PGH2 PGG2 PGE2 PGF2 PGD2 TXA2 PGF1 TXB2

  31. Inhibitors of Biosynthesis • drugs that reduce the availability of Ca • glucocorticoids – induce lipocortin synthesis which inhibits PLA2 • ASA & related NSAID

  32. Pharmacological Properties

  33. Therapeutic Uses • PGE1 (Misoprostol) – suppress gastric ulceration • PGE1 & PGI2 – improve harvest and storage of platelets for therapeutic transfusion - improve blood flow & tissue oxygenation in neonates (ductus arteriosus – vasodilatation) 3. PGE1 – treatment of impotence

  34. PLATELET ACTIVATING FACTOR (PAF) Synthesized by platelets, neutophils,monocytes, mast cells, eosinophils, renal mesangial cells, renal medullary cells & vascular endothelial cells

  35. Pharmacological Properties A. CVS: Potent vasodilator vascular permeability 1000x more than histamine/bradykinin B. Leukocyte: Chemotaxis C. Smooth Muscle: • Contraction • Airway resistance & responsiveness to other bronchoconstrictors D. Stomach • Potent ulcerogen

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