Autacoids....With Slide No

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Autacoids....With Slide No

  1. 1. AUTACOIDS <ul><li>Prof. Dr. Shah Murad </li></ul><ul><li>[email_address] </li></ul>
  2. 2. <ul><li>AUTACOIDS </li></ul><ul><li>Histamine </li></ul><ul><li>Bradykinin & Kallidin </li></ul><ul><li>5 Hydroxytryptamine (5HT) </li></ul><ul><li>Autacoids derived from membrane phospholipid </li></ul><ul><ul><li>Eicosanoids – arachidonic acid </li></ul></ul><ul><ul><ul><li>(PG, PGI, TXA2, LT) </li></ul></ul></ul><ul><ul><li>Modified phospholipids – PAF(platelet activating factor) </li></ul></ul>
  3. 3. HISTAMINES <ul><li>Chemistry: </li></ul><ul><li>imidazole ring + amino group connected by 2 methylene groups </li></ul>
  4. 4. Synthesis <ul><li>Decarboxylation of amino acid L-histidine catalyzed by L-histidine decarboxylase. </li></ul><ul><li>Ingested from food or formed by bacteria in the GIT </li></ul><ul><li>Storage sites: </li></ul><ul><ul><li>perivascular tissue – mast cell </li></ul></ul><ul><ul><li>circulation – basophil </li></ul></ul><ul><ul><li>others – GIT, lungs, skin, heart, liver, neural tissue, reproductive mucosa, rapidly growing tissues and body fluids </li></ul></ul>
  5. 5. Metabolism : <ul><li>Major pathways </li></ul><ul><ul><li>Deamination – small intestine, liver, kidney and monocytes </li></ul></ul><ul><ul><li>Methylation – small intestine, liver, skin, kidney, thymus & leukocytes </li></ul></ul><ul><li>N-methylimidazole acetic acid - principal urinary metabolite </li></ul>
  6. 6. Metabolism :
  7. 7. Functions: <ul><li>Role in allergic responses – Ag + IgE (bound to mast cells & basophils) </li></ul><ul><ul><li>Preformed mediators </li></ul></ul><ul><ul><li>Most important mechanism of release/controlled by H2 esp. in skin & blood </li></ul></ul><ul><li>Release of other autacoids </li></ul><ul><li>Release by drugs (morphine, urase, amines), peptides, venoms & other agents </li></ul><ul><li>Release by urticarias </li></ul><ul><li>Gastric secretagogue </li></ul><ul><li>Neurotransmitter  increased wakefulness, thermoregulation </li></ul>
  8. 8. Selected Actions of Histamine in Humans H1, H2 H2 H1, H2 H2 (?) H1 H2 H2 H1 H1 H2 H2  TPR Vasodilatation  Blood flow  Blood flow,relaxation Constriction Relaxation Constriction Constriction Vasodilatation  Permeability  SA rate  Force of contraction Atrial & vent automaticity CARDIOVASCULAR Vascular Facial cutaneous Forearm Gastric mucosa Carotid artery Pulmonary artery Basilar artery Coronary artery Other pre & post cap Arterioles Postcapillary venules Heart Receptor Action Organ Tissue
  9. 9. Selected Actions of Histamine in Humans H1 Epinephrine release ADRENAL MEDULLA H2 H1 H2 (?) Acid and pepsin secretion, If Relaxation & Contraction (more prominent) Relaxation (?) GASTROINTESTINAL Oxyntic mucosa GI smooth muscle Gallbladder smooth muscle H1, H2 (?) Pain & itching (esp to insect bites & needle stings) CUTANEOUS NERVE ENDINGS (Sensory) H1 H2 Contraction (more prominent) Relaxation RESPIRATORY Bronchiolar smooth muscle H2 Inhibition of IgE – dependent degranulation BASOPHILS Receptor Action Organ Tissue
  10. 10. Selected Actions of Histamine in Humans <ul><li>H1, H2 - located in post synaptic membrane </li></ul><ul><li>H3 – presynaptic </li></ul><ul><li>H1 - predominant in endotracheal & smooth muscle </li></ul><ul><li>H2 - facial veins, carotid a, pulm. a, heart </li></ul><ul><li>gastric mucosa, heart, smooth muscle & some immune cells </li></ul><ul><li>H3 - several ares in CNS </li></ul><ul><li>Triple response - wheal, flare & redness </li></ul>
  11. 11. H1 RECEPTOR ANTAGONISTS <ul><li>Pharmacokinetics: </li></ul><ul><li>Well absorbed from GIT (oral) </li></ul><ul><li>Onset – 30 minutes, duration – 3 to 6 hours </li></ul><ul><li>Widely distributed </li></ul><ul><li>Biotransformed in the liver; microsomal enzyme inducer </li></ul><ul><li>Excretion – kidneys </li></ul>
  12. 12. Adverse Effects: <ul><li>CNS : sedation, agitation, nervousness, delirium, tremors, incoordination, hallucinations, & </li></ul><ul><li>convulsions - common in first generation antihistamines </li></ul><ul><li>GIT : vomiting, diarrhea, anorexia, nausea, epigastric distress, constipation </li></ul><ul><li>- dryness of mouth, throat & airway, urinary retention - first generation </li></ul><ul><li>Headache, faintness </li></ul><ul><li>Chest tightness, palpitations, hypotension </li></ul><ul><li>Visual disturbances </li></ul><ul><li>Hematological - leukopenia, agranulocytosis </li></ul>
  13. 13. Therapeutic Uses: <ul><li>dermatosis </li></ul><ul><li>allergic rhinitis </li></ul><ul><li>motion sickness & emesis </li></ul><ul><li>Parkinson’s disease </li></ul><ul><li>Insomnia </li></ul><ul><li>Adverse reactions </li></ul>
  14. 14. Histamine Antagonists <ul><li>I. First Generation Agents </li></ul><ul><li>A. Ethanolamines </li></ul><ul><li>Carbinoxamine maleate </li></ul><ul><li>Clemastine fumarate </li></ul><ul><li>Diphenhydramine HCl </li></ul><ul><li>Dimenhydrinate </li></ul><ul><li>B. Ethylenediamines </li></ul><ul><li>Pyrilamine maleate </li></ul><ul><li>Tripelennemine HCL/citrate </li></ul><ul><li>C. Alkylamines </li></ul><ul><li>Chlorpheniramine maleate </li></ul><ul><li>Brompheniramine maleate </li></ul><ul><li>II. Second Generation Agents </li></ul><ul><li>A. Alkylamines </li></ul><ul><li>Acrivastine </li></ul><ul><li>B. Piperazines </li></ul><ul><li>Cetirizines HCl </li></ul><ul><li>C. Piperidines </li></ul><ul><li>Astemizole </li></ul><ul><li>Levocabastine </li></ul><ul><li>Loratadine </li></ul><ul><li>Terfenadine </li></ul><ul><li>Fexofenadine </li></ul>
  15. 15. <ul><li>FIRST GENERATION AGENTS </li></ul><ul><li>D. Piperazines </li></ul><ul><li>1. Hydroxyzine HCl/pamoate (long acting) </li></ul><ul><li>2. Cyclizine HCl/lactate </li></ul><ul><li>3. Meclizine HCl </li></ul><ul><li>4. Chlorcyclizine </li></ul><ul><li>E. Phenothiazines </li></ul><ul><li>1. Promethazine HCl </li></ul>
  16. 16. Oldest member More prolonged action  Incidence of drowsiness Chlorcyclizine 4. Piperazine Most potent Not so prone to develop drowsiness More suitable for older patients Sedation/CNS stimulation Chlorpheniramine Pheniramine Chlorphenamine 3. Alkylamine Most specific H1 antagonist  Anticholinergic activity Feeble CNS effects Somnolence GI s/s common Pyrilamine Mepyramine Pyranesamine 2.Ethylenediamine/ Ethylamine Significant antimuscarinic activity Sedation, somnolence  Incidence of GI symptoms Effective in emesis & motion sickness Diphenhydramine First Gen. Agents: 1. Ethanolamine Characteristics Prototype Structural Class
  17. 17. Counters motion sickness & emesis Meclizine/Meclozine Counters motion sickness (primarily) Cyclizine Long acting Widely used for skin allergies CNS depressant More prominent antipruritic action Hydroxyzine Characteristics Prototype Structural Class
  18. 18. Rhinitis, urticaria (-) pass BBB Cetirizine 3. Piperazine Rapid onset of action (30 mins) (-) anticholinergic effects Reduce both wheal & flare response  Potential to penetrate BBB Skin allergy Allergic rhinitis Acrivastine 2. Alkylamine Highly selective for H1 receptor Non-sedating (-) anticholonergic action (-) pass BBB  incidence of S/E Terfenadine Second Gen.Agents 1. Piperidine Anticholinergic Prominent sedation Counters motion sickness primarily antiemetic Promethazine 5. Phenothiazine Characteristics Prototype Structural Class
  19. 19. H2 RECEPTOR ANTAGONISTS <ul><li>Pharmacodynamics: </li></ul><ul><li>Inhibit gastric acid secretion </li></ul><ul><li>(-) effect of gastric motility, emptying time, sphincter, pancreatic & mucous secretion </li></ul>
  20. 20. <ul><li>Adverse Effects </li></ul><ul><li>Cimetidine:  headache, dizziness </li></ul><ul><ul><ul><ul><ul><li>constipation, diarrhea </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>skin rashes </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>alterations of hepatic function </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>CNS disturbances (elderly & impaired RF) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>depression – rare </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Serum prolactin elevation </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Sexual dysfunction & gynecomastia </li></ul></ul></ul></ul></ul><ul><li>Ranitidine:  Serum prolactin elevation </li></ul>
  21. 21. Drug Interactions: <ul><li>Cimetidine inhibits cyto p-450 – accumulation of warfarin, phenytoin, theophylline, propanolol, diazepam & phenobarbital </li></ul><ul><li>Ranitidine – weak inhibitor </li></ul><ul><li>Nizatidine & famotidine – do not inhibit cyto P – 450 </li></ul><ul><li>Therapeutic Uses: Peptic acid disorders </li></ul>
  22. 22. Vasoactive Peptides <ul><li>Vasoconstrictors —angiotensin II,vasopressin, endothelins, neuropeptide Y </li></ul><ul><li>Vasodilators —bradykinin, natri-uretic peptides, vasoactive intestinal peptides, </li></ul><ul><li>substance P, neurotensin and calcitonin gene-related peptide (CGRP) </li></ul>
  23. 23. BRADYKININ & KALLIDIN <ul><li>Peptides that act locally to produce pain, vasodilatation,  vascular permeability & PG synthesis </li></ul><ul><li>Synthesis: </li></ul><ul><li>Liver </li></ul><ul><li>Precursurs: kininogens—SERINE PROTEASES (HMW & LMW) </li></ul>
  24. 24. Pharmacologic Properties <ul><li>CVS : </li></ul><ul><li>(+) inotropic & chronotropic effects </li></ul><ul><li>vasoconstriction </li></ul><ul><li>Smooth Muscle: </li></ul><ul><li>Bronchoconstriction </li></ul><ul><li>GIT: </li></ul><ul><li>Enhanced motility </li></ul>
  25. 25. Functions <ul><li>pain – excites primary sensory neurons & provokes release of substance P, neurokinin A </li></ul><ul><li>inflammation -  permeability in microcirculation </li></ul><ul><li>respiratory disease </li></ul>
  26. 26. Pharmacological Properties <ul><li>1. CVS – potent vasodilator (10x more than histamine) </li></ul><ul><li>Stimulate histamine release </li></ul><ul><li>2. Kidney -  RBF </li></ul><ul><li>3. Others: </li></ul><ul><li>spermatogenesis & promotes sperm motility </li></ul><ul><li>dilatation of fetal pulmonary artery closure of ductus arteriosus </li></ul><ul><li>constriction of umbilical vessels </li></ul>
  27. 27. 5 HYDROXYTRYPTAMINE (5HT) <ul><li>Found in enterochromaffin cells (90%), platelets and CNS </li></ul><ul><li>Sources : tunicates, mollusks, anthropods, colenterates, fruits, nuts, wasps & scorpions </li></ul>
  28. 28. <ul><li>Synthesis: Tryptophan </li></ul><ul><li> Hydroxytryptophan </li></ul><ul><li> 5 hydroxytryptamine </li></ul><ul><li>(Serotonin ) </li></ul><ul><li> 5-hydroxyindole acetaldehyde </li></ul><ul><li>5-hydroxyindole acetic acid acid 5-hydroxytrytophol (principal metabolite) </li></ul><ul><li> N-acetyl- 5-HT </li></ul><ul><li> Melatonin </li></ul>
  29. 29. <ul><li>Antagonists: </li></ul>1. Clozapine: High affinity for dopamine receptors Reduced negative symptoms of schizophrenia 2. Risperidone: D2 receptor blocker Reduced negative symptoms of schizophrenia
  30. 30. <ul><li>1. Clozapine: </li></ul><ul><li> High affinity for dopamine receptors </li></ul><ul><li>Reduced negative symptoms of schizophrenia </li></ul><ul><li>2. Risperidone: </li></ul><ul><li> D2 receptor blocker </li></ul><ul><li> Reduced negative symptoms of schizophrenia </li></ul>3. Methysergide: used for diarrhea & malabsorption in patients with carcinoid tumors
  31. 31. <ul><li>Cyproheptadine: </li></ul><ul><ul><ul><ul><ul><li>H1 blocker </li></ul></ul></ul></ul></ul><ul><li> Weak anticholinergic and mild CNS depressant </li></ul><ul><li>Used for skin allergies, cold urticaria </li></ul><ul><li>Counteract the sexual side effects of SSRI’s </li></ul>
  32. 32. LIPID-DERIVED AUTOCOIDS <ul><li>Eicosanoids </li></ul><ul><li>formed from PUFA </li></ul><ul><li>release from cellular stores by PLA2 </li></ul><ul><li>human platelets – DAG lipase </li></ul><ul><li>coupled to G proteins </li></ul>
  33. 33. <ul><li>EFA (diet) Esterified acid Arachidonic acid in cell lipid PLA2 </li></ul><ul><li>Lipoxygenase Cyclooxygenase X ASA, indomethacin </li></ul><ul><li> 12-HPETE 5-HPETE </li></ul><ul><li>84 </li></ul><ul><li>12-HETE 5-HETE LTA4 LTC4 </li></ul><ul><li>LTB4 LTD4 </li></ul><ul><li>LTE4 </li></ul><ul><li>LTF4 </li></ul>
  34. 34. <ul><li>Cycloxygenase </li></ul><ul><li>PGG2 </li></ul><ul><li>PGH2 </li></ul><ul><li>PGG2 PGE2 PGF2  PGD2 TXA2 </li></ul><ul><li>PGF1  TXB2 </li></ul>
  35. 35. Inhibitors of Biosynthesis <ul><li>drugs that reduce the availability of Ca </li></ul><ul><li>glucocorticoids – induce lipocortin synthesis which inhibits PLA2 </li></ul><ul><li>ASA & related NSAID </li></ul>
  36. 36. Pharmacological Properties
  37. 37. Therapeutic Uses <ul><li>PGE1 (Misoprostol) – suppress gastric ulceration </li></ul><ul><li>PGE1 & PGI2 – improve harvest and storage of platelets for therapeutic transfusion </li></ul><ul><li>- improve blood flow & tissue oxygenation in neonates (ductus arteriosus – vasodilatation) </li></ul><ul><li>3 . PGE1 – treatment of impotence </li></ul>
  38. 38. PLATELET ACTIVATING FACTOR (PAF) <ul><li>Synthesized by platelets, neutophils,monocytes, mast cells, eosinophils, renal mesangial cells, renal medullary cells & vascular endothelial cells </li></ul>
  39. 39. Pharmacological Properties <ul><li>A. CVS: Potent vasodilator </li></ul><ul><li>vascular permeability 1000x more than histamine/bradykinin </li></ul><ul><li>B. Leukocyte: Chemotaxis </li></ul><ul><li>C. Smooth Muscle: </li></ul><ul><li>Contraction </li></ul><ul><li>Airway resistance & responsiveness to other bronchoconstrictors </li></ul><ul><li>D. Stomach </li></ul><ul><li>Potent ulcerogen </li></ul>

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