Histamine & bradykinin

1. AUTOCOIDS : HISTAMINE AND BRADYKININ

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. 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. 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. The main pathophysiological roles of histamine are: as a stimulant of gastric acid secretion (treated with H 2 -receptor antagonists) as a mediator of type I hypersensitivity reactions such as urticaria and hay fever (treated with H 1 -receptor antagonists). H 3 receptors occur at presynaptic sites and inhibit the release of a variety of neurotransmitters

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)

7. 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

8. 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  

9. HISTAMINE AGONIST Selective agonist for H1:2-methylhistamine Selective agonist forH2:4-methylhistamine Dimaprit impromidine Selective agonist for H3: (R) α - methylhistamine Imetit

10. BETAHISTINE A histamine analogue and H1 receptor agonist that serves as a vasodilator Betahistine has a very strong affinity for histamine H 3 receptors and a weak affinity for histamine H 1 receptors

11. 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

12. 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

13. THERAPEUTIC USES Betahistine hydrochloride is an antivertigo drug For the treatment of Menieres disease

14. 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

15. HISTAMINE ANTAGONIST

16. CONT… Physiologic antagonists: Epinephrine has smooth muscle actions opposite to histamine but by actiong on different types of receptors Histamine release inhibitors : Reduce immunologic release of histamine from mast cells Mast cell stabilizers: Cromolyn and nedocromil Beta 2 adrenergic agonists --- used in Bronchial Asthma Histamine receptor antagonists Compounds that competitively block histamine, mainly H 1 & H 2 receptors .

17. HISTAMINE ANTAGONIST Selective antagonist for H1:Mepyramide Chlorpheniramine Selective antagonist for H2:Cimetidine Ranitidine Selective antagonist for H3:Thioperamide Impromidine Clobenpropit

18. Classification of H 1 -Receptor Antagonists A)FIRST GENERATION (Sedating , Shorter DOA 4-6 hrs.) Alkylamines Chlorpheniramine Brompheniramine Ethylaminediamine : Tripelennamine Ethanolamines : Diphenhydramine Dimenhydrinate Carbinoxamine

19. CONT.. Piperazines Cyclizine Meclizine Hydroxyzine Phenothiazines derivatives Promethazine HCl Misc: Cyproheptadine

20. CONT… B)SECOND GENERATION NON-SEDATING, LONGER DOA (12 -24hrs) Piperidines : Fexofenadine Miscellaneous Cetirizine Loratadine Desoratad ine

21. MECHANISM & EFFECTS H 1 -Receptor Blockade Sedation Antinausea and antiemetic actions: preventing motion sickness Antiparkinsonism effects Anticholinoceptor action: atropine-like effects on peripheral muscarinic receptors. Adrenoceptor -blocking actions Serotonin-blocking actions Local anesthesia: block Na + -channel

22. PHARMACOKINETICS 1- First Generation Agents: Rapidly absorbed from the GIT Widely distributed Cross blood-brain barrier Extensively metabolized by the cytochrome P 450 and metabolites are active and are excreted by the kidney Duration of action 4-6 hours

23. 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)

24. THERAPEUTIC USES Allergic rhinitis Allergic conjunctivitis Allergic dermatological conditions (contact dermatitis) Urticaria , Angioedema Diarrhea Anaphylactic or anaphylactoid reactions—adjunct only Nausea and vomiting Sedation

25. 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

26. H2 RECEPTOR ANTAGONIST H 2 receptors are widely present on parietal cell of gastric mucosa . Their antagonists are Cimetidine Famotidine Oxmetidine Ranitidine Nizatidine SKF 93474

27. PHARMACOKINETICS Absorbed orally well Oral bioavaibility of nizatidine-90% & with a t 1/2 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

28. Contd … Fomotidine It has inverse agonistic action on H 2 receptor & half life is 2.5-3.5 hr. Oral bioavailability is 40-50 % and 70 % excreted unchanged in urine

29. THERAPEUTIC USES Peptic ulcer Duodenal ulcer Zollinger Ellison syndrome

30. SIDE EFFECT & TOXIC EFFECT Skin rash Headache Gynecomastia Impotence Mental confusion Hepatotoxicity

31. H3 ANTAGONIST Thioperamide Clobenpropit JNJ 5207852 ABT 239

32. Contd.. Centrally acting H3 antagonists are under study JNJ 5207852 increase wakefullness ,and ABT-239 is being evaluated for cognitive disorders

33. 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 )

34. Bradykinin Bradykinin formed by proteolytic cleavage of circulating proteins termed kininogens . Synthesis and metabolism of bradykinin

35. Kinins Receptors, Actions & Therapy The activate B 1 , B 2, B 3 receptors linked to PLC/A 2 Powerful Vasodilation → decreased blood pressure via B2 receptor stimulation (NO-dependent) Increase in capillary permeability inducing edema. It produces inflammation & analgesia (B2)

36. 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.

37. 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 & PI 2 dependent)

38. 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

39. 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.

40. 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

41. 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 .

42. 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;

43. Thank you !!!!

44. 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

45. 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

46. CONTRAINDICATIONS Betahistine is contraindicated for people with peptic ulcers or tumours of the adrenal gland( pheochromocytoma ) People with bronchial asthma should be closely monitored.