Histamine and bradykinin

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Histamine and bradykinin

  1. 1. Page 1 AUTOCOIDS : HISTAMINE AND BRADYKININ PRESENTED BY : CHAUDHARY NEHA DEPARTMENT OF PHARMACOLOGY
  2. 2. Page 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
  3. 3. Page 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
  4. 4. Page 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)
  5. 5. Page 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
  6. 6. Page 6 • Injected intradermally, histamine causes the 'triple response': • reddening (local vasodilatation), • wheal (direct action on blood vessels) • flare (from an 'axon' reflex in sensory nerves releasing a peptide mediator)
  7. 7. Page 7
  8. 8. Page 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
  9. 9. Page 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
  10. 10. Page 10 HISTAMINE AGONIST • Selective agonist for H1:2-methylhistamine • Selective agonist forH2:4-methylhistamine Dimaprit impromidine • Selective agonist for H3:(R) α- methylhistamine Imetit
  11. 11. Page 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
  12. 12. Page 12 PHARMACOKINETIC • 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
  13. 13. Page 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
  14. 14. Page 14 THERAPEUTIC USES • Betahistine hydrochloride is an antivertigo drug • For the treatment of Menieres disease
  15. 15. Page 15 • 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
  16. 16. Page 16 HISTAMINE ANTAGONIST
  17. 17. Page 17 CONT… 1. Physiologic antagonists: Epinephrine has smooth muscle actions opposite to histamine but by actiong on different types of receptors 2. Histamine release inhibitors: Reduce immunologic release of histamine from mast cells a) Mast cell stabilizers: Cromolyn and nedocromil b) Beta 2 adrenergic agonists --- used in Bronchial Asthma 3. Histamine receptor antagonists Compounds that competitively block histamine, mainly H1& H2 receptors.
  18. 18. Page 18 HISTAMINE ANTAGONIST • Selective antagonist for H1:Mepyramide Chlorpheniramine • Selective antagonist for H2:Cimetidine Ranitidine • Selective antagonist for H3:Thioperamide Impromidine Clobenpropit
  19. 19. Page 19 Classification of H1-Receptor Antagonists A)FIRST GENERATION (Sedating , Shorter DOA 4-6 hrs.) Alkylamines – Chlorpheniramine – Brompheniramine Ethylaminediamine: – Tripelennamine Ethanolamines: – Diphenhydramine – Dimenhydrinate – Carbinoxamine
  20. 20. Page 20 CONT.. Piperazines – Cyclizine – Meclizine – Hydroxyzine Phenothiazines derivatives Promethazine HCl Misc: – Cyproheptadine
  21. 21. Page 21 CONT… B)SECOND GENERATION NON-SEDATING, LONGER DOA (12 - 24hrs) Piperidines: Fexofenadine Miscellaneous Cetirizine Loratadine Desoratadine
  22. 22. Page 22 MECHANISM & EFFECTS 1. H1-Receptor Blockade 2. Sedation 3. Antinausea and antiemetic actions: preventing motion sickness 4. Antiparkinsonism effects 5. Anticholinoceptor action: atropine-like effects on peripheral muscarinic receptors. 6. Adrenoceptor-blocking actions 7. Serotonin-blocking actions 8. Local anesthesia: block Na+-channel
  23. 23. Page 23 PHARMACOKINETICS 1- 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
  24. 24. Page 24 PHARMACOKINETICS 2- 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)
  25. 25. Page 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
  26. 26. Page 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
  27. 27. Page 27 H2 RECEPTOR ANTAGONIST • Cimetidine • Famotidine • Oxmetidine • Ranitidine • Nizatidine • SKF 93474
  28. 28. Page 28 PHARMACOKINETIC • Absorbed orally well • Oral bioavaibility of nizatidine-90% , where as ,others have 50% because of first pass metabolism Peak effect is reached within 2 hours Excreted unchanged in kidney by tubular secretion
  29. 29. Page 29 THERAPEUTIC USES • Peptic ulcer • Duodenal ulcer • Zolliger ellison syndrome
  30. 30. Page 30 SIDE EFFECT & TOXIC EFFECT • Skin rash • Headache • Gynecomastia • Impotence • Mental confusion • Hepatotoxicity
  31. 31. Page 31 Bradykinin • Bradykinin formed by proteolytic cleavage of circulating proteins termed kininogens. • Synthesis and metabolism of bradykinin
  32. 32. Page 32 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)
  33. 33. Page 33 CONT.. • Cardiac stimulation: Compensatory indirect & direct tachycardia & increase in cardiac output • It produces coronary vasodilation Bradykinin has a cardiac anti-ischemic effect, inhibited by B2 antagonists (NO & PI2 dependent)
  34. 34. Page 34 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.
  35. 35. Page 35 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
  36. 36. Page 36 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.
  37. 37. Page 37 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 • usedinmanagement of Heriditary angioedema • 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
  38. 38. Page 38 Drug interaction • ACE inhibitors like captopril block B(2) receptor desensitization, thereby potentiating bradykinin beyond blocking its hydrolysis.
  39. 39. Page 39 REFERENCES • Essentials of medical pharmacology;KD Thripathi;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;
  40. 40. Page 40 Thank you !!!!
  41. 41. Page 41
  42. 42. Page 42 • 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
  43. 43. Page 43 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
  44. 44. Page 44 CONTRAINDICATIONS • Betahistine is contraindicated for people with peptic ulcers or tumours of the adrenal gland(pheochromocytoma) • People with bronchial asthma should be closely monitored.
  45. 45. Page 45

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