Histamine & bradykinin
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  • 1. AUTOCOIDS : HISTAMINE AND BRADYKININ Page 1
  • 2. AUTOCOIDS• Autocoids are naturally ocurring substances that produce wide range of pharmacological actions in small amounts• They are also termed as local hormone since they produced locally in response to some stimulus (e.g. during inflamation)• The term autocoid derived from auto=self and akos=remedy or medicinal agent Page 2
  • 3. HISTAMINE• Histamine is a basic amine , stored in granules within mast cells & basophils• Secreted when complement components C3a & C5a interact with specific membrane receptors or when antigen interact with cell- fixed IgE• It produce effect by acting on H1,H2 or H3 receptors on target cells Page 3
  • 4. Main Action In Human• Stimulation of gastric secretion(H2)• Contraction of smooth musle other than that of blood vessels(H1)• Cardiac stimulation(H2)• Vasodilation(H1)• Increased vascular permeability(H1) Page 4
  • 5. • The main pathophysiological roles of histamine are: – as a stimulant of gastric acid secretion (treated with H2-receptor antagonists) – as a mediator of type I hypersensitivity reactions such as urticaria and hay fever (treated with H1- receptor antagonists).• H3 receptors occur at presynaptic sites and inhibit the release of a variety of neurotransmitters Page 5
  • 6. Contd..• Injected intradermally, histamine causes the triple response:• reddening (local vasodilatation),• weal (direct action on blood vessels)• flare (from an axon reflex in sensory nerves releasing a peptide mediator) Page 6
  • 7. Page 7
  • 8. What is agonist???• An agonist is a drug that once bound to the receptor, initiates a change in cellular activity.• The binding of the agonist often triggers a series of biochemical events which ultimately lead to the alteration in function Page 8
  • 9. CONT…• Agonist  Receptor  Generation of secondary messenger  Change in cellular activity• Some important secondary messenger systems activated by the binding of agonists to cell surface receptors include: • 1) The cyclic AMP and GMP systems • 2) Calcium and calmodulin • 3) Phosphoinositides and diacylglycerol Page 9
  • 10. HISTAMINE AGONIST• Selective agonist for H1:2-methylhistamine• Selective agonist forH2:4-methylhistamine Dimaprit impromidine• Selective agonist for H3:(R) α- methylhistamine Imetit Page 10
  • 11. BETAHISTINE• A histamine analogue and H1 receptor agonist that serves as a vasodilator• Betahistine has a very strong affinity for histamine H3 receptors and a weak affinity for histamine H1 receptors Page 11
  • 12. PHARMACOKINETICS• Protein binding : Very low• Metabolism : To 2-(2-aminoethyl)pyridine and 2-pyridylacetic acid• Half-life: 3–4 hours• Excretion : complete in the urine within 24 hours Page 12
  • 13. SIDE EFFECTS• Low level of gastric side effects• Nausea can be a side effect• Decreased appetite, leading to weight loss• Patients taking betahistine hydrochloride may experience several hypersensitivity and allergic reactions• Headache Page 13
  • 14. THERAPEUTIC USES• Betahistine hydrochloride is an antivertigo drug• For the treatment of Menieres disease Page 14
  • 15. Contd..• Antagonists can bind to receptors but do not initiate a change in cellular function.• However, occupation of the receptor can prevent the binding and actions of agonists.• Antagonists are also referred to as blockers Page 15
  • 16. HISTAMINE ANTAGONIST Page 16
  • 17. CONT…1. Physiologic antagonists:Epinephrine has smooth muscle actions opposite to histamine but by actiong on different types of receptors2. Histamine release inhibitors:Reduce immunologic release of histamine from mast cellsa) Mast cell stabilizers: Cromolyn and nedocromilb) Beta 2 adrenergic agonists --- used in Bronchial Asthma3. Histamine receptor antagonists Compounds that competitively block histamine, mainly H1& H2 receptors. Page 17
  • 18. HISTAMINE ANTAGONIST• Selective antagonist for H1:Mepyramide Chlorpheniramine• Selective antagonist for H2:Cimetidine Ranitidine• Selective antagonist for H3:Thioperamide Impromidine Clobenpropit Page 18
  • 19. Classification of H1-Receptor AntagonistsA)FIRST GENERATION (Sedating , Shorter DOA 4-6 hrs.)Alkylamines – Chlorpheniramine – BrompheniramineEthylaminediamine: – TripelennamineEthanolamines: – Diphenhydramine – Dimenhydrinate – Carbinoxamine Page 19
  • 20. CONT..Piperazines – Cyclizine – Meclizine – HydroxyzinePhenothiazines derivatives Promethazine HClMisc:– Cyproheptadine Page 20
  • 21. CONT… B)SECOND GENERATION NON-SEDATING, LONGER DOA (12 - 24hrs)Piperidines: FexofenadineMiscellaneous Cetirizine Loratadine Desoratadine Page 21
  • 22. MECHANISM & EFFECTS1. H1-Receptor Blockade2. Sedation3. Antinausea and antiemetic actions: preventing motion sickness4. Antiparkinsonism effects5. Anticholinoceptor action: atropine-like effects on peripheral muscarinic receptors.6. Adrenoceptor-blocking actions7. Serotonin-blocking actions8. Local anesthesia: block Na+-channel Page 22
  • 23. PHARMACOKINETICS1- First Generation Agents: Rapidly absorbed from the GIT Widely distributed Cross blood-brain barrier Extensively metabolized by the cytochrome P450 and metabolites are active and are excreted by the kidney Duration of action 4-6 hours Page 23
  • 24. PHARMACOKINETICS2- Second Generation Rapidly absorbed from the GIT Widely distributed Do not cross the blood-brain barrier (less lipid soluble) Elimination: Cetirizine (urine) and fexofenadine (bile) Page 24
  • 25. THERAPEUTIC USES• Allergic rhinitis• Allergic conjunctivitis• Allergic dermatological conditions (contact dermatitis)• Urticaria , Angioedema Diarrhea Anaphylactic or anaphylactoid reactions— adjunct only• Nausea and vomiting• Sedation Page 25
  • 26. SIDE EFFECTS & TOXICITY• Sedation, drowsiness & euphoria• Dryness of mouth, headache, dizziness, skin rashes, distress , tremors , g.i. muscle incordination• Acute dose produce central excitation, hallucination,convulsion,flushing, fever• Death due to respiratory & cardiovascular failure• α-blocking actions may cause orthostatic hypotension Page 26
  • 27. H2 RECEPTOR ANTAGONIST• H2 receptors are widely present on parietal cell of gastric mucosa . Their antagonists are• Cimetidine• Famotidine• Oxmetidine• Ranitidine• Nizatidine• SKF 93474 Page 27
  • 28. PHARMACOKINETICS• Absorbed orally well• Oral bioavaibility of nizatidine-90% & with a t1/2 of 1.5 hours ,where as ,others have 50% because of first pass metabolism.• Peak effect is reached within 2 hours Excreted unchanged in kidney by tubular secretion Page 28
  • 29. Contd…• Fomotidine• It has inverse agonistic action on H2 receptor & half life is 2.5-3.5 hr.• Oral bioavailability is 40-50 % and 70 % excreted unchanged in urine Page 29
  • 30. THERAPEUTIC USES• Peptic ulcer• Duodenal ulcer• Zollinger Ellison syndrome Page 30
  • 31. SIDE EFFECT & TOXIC EFFECT• Skin rash• Headache• Gynecomastia• Impotence• Mental confusion• Hepatotoxicity Page 31
  • 32. H3 ANTAGONIST• Thioperamide• Clobenpropit• JNJ 5207852• ABT 239 Page 32
  • 33. Contd..• Centrally acting H3 antagonists are under study• JNJ 5207852 increase wakefullness ,and ABT-239 is being evaluated for cognitive disorders Page 33
  • 34. H4 ANTAGONIST• JNJ 7777120• It block histamine induced chemotaxis in mast cells & eosinophils• Usefull in autoimmune inflammatory & allergic disorders• Nasal stuffness & blockage in allergic rhinitis(Poor treatment by H1 & H2 antagonist, can be improve by H4 antagonist) Page 34
  • 35. Bradykinin• Bradykinin formed by proteolytic cleavage of circulating proteins termed kininogens.• Synthesis and metabolism of bradykinin Page 35
  • 36. Kinins Receptors, Actions & Therapy• The activate B1, B2, B3 receptors linked to PLC/A2• Powerful Vasodilation→ decreased blood pressure via B2 receptor stimulation (NO- dependent)• Increase in capillary permeability inducing edema. It produces inflammation & analgesia (B2) Page 36
  • 37. Pharmacological actions:– vasodilatation– increased vascular permeability– stimulation of pain nerve endings– stimulation of epithelial ion transport and fluid secretion in airways and gastrointestinal tract– contraction of intestinal and uterine smooth muscle. Page 37
  • 38. CONT..• Cardiac stimulation: Compensatory indirect & direct tachycardia & increase in cardiac output• It produces coronary vasodilationBradykinin has a cardiac anti-ischemic effect, inhibited by B2 antagonists (NO & PI2 dependent) Page 38
  • 39. Kinins Actions & Therapy• Kinins produce broncho-constriction & itching in respiratory system .• Therapeutic Use:No current use of kinin analoguesIncreased bradykinin is possibly involved in the therapeutic efficiency & cough produced by ACEIs Page 39
  • 40. kallekrein inhibitor• Aprotinin (Trasylolol), a kallekrein inhibitor, used in treatment of acute pancreatitis, carcinoid syndrome & hyperfibrinolysis.• Ecallantide :is a human plasma kallikrein inhibitor injection for subcutaneous use in inflammation. Page 40
  • 41. Bradykinin Antagonist• Deltibant : It is a novel Bradykinin Antagonist used in treatment of Severe Systemic Inflammatory Response Syndrome and Sepsis.• Icatibant :It is a synthetic decapeptide functioning as a potent,competative antagonist of the bradykinin 2 receptor• used in management of Heriditary angioedema Page 41
  • 42. pharmacokinetics  Given by subcutaneous injection 3ml (30mg), half life1- 2 hours  Rapid onset usually within an hour, systemic side effects rare and local side effects at site of injection are common but transient Drug interaction : ACE inhibitors like captopril block B(2) receptor desensitization, thereby potentiating bradykinin beyond blocking its hydrolysis. Page 42
  • 43. REFERENCES• Essentials of medical pharmacology;KD Tripathi;sixth edition;2008;published by Jaypee brothers;page no:135-144• Rang and Dale’s pharmacology;H.P.Rang, M.M.Dale; sixth edition;2008;published by Churchill Livingstone; Page 43
  • 44. Thank you !!!! Page 44
  • 45. Page 45
  • 46. • Betahistine comes in tablet form and is taken orally.• It is rapidly and completely absorbed.• The mean plasma half-life is 3-4 hours• Excretion is virtually complete in the urine within 24 hours.• Very low Plasma protein binding• Betahistine is transformed into aminoethylpyridine & hydroxyethylpyridine & excreted with the urine as pyridylacetic acid Page 46
  • 47. Impromidine• Potent and selective histamine H2 receptor agonist• The role of histamine in the control of gastric acid secretion and blood flow in both healthy man and in patients with peptic ulcer disease Page 47
  • 48. CONTRAINDICATIONS• Betahistine is contraindicated for people with peptic ulcers or tumours of the adrenal gland(pheochromocytoma)• People with bronchial asthma should be closely monitored. Page 48
  • 49. Page 49