Histamine and Antihistamines

1. Histamine and Antihistamines

2. HistamineSynthesis

5. Release of histamine can occur by two processes: • Energy- and Ca2+-dependent degranulation reaction.The release of histamine from mast cells is induced by: • immunoglobulin E (IgE) fixation to mast cells (sensitization) and subsequent exposure to a specific antigen; • complement activation (mediated by immunoglobulin G or immunoglobulin M) may also induce degranulation.

7. Energy- and Ca2+-independent release (displacement). • Displacement is induced by: • drugs such as morphine, tubocurarine, guanethidine, and amine antibiotics. • mast cell damage, which is caused by noxious agents such as venom or by mechanical trauma, can release histamine.

8. Mechanism of action • Histamine (H1)-receptors • H1-receptors are found in the brain, heart, bronchi, gastrointestinal tract, vascular smooth muscles, and leukocytes. • H1-receptors are membrane bound and coupled to G-proteins, specifically Gq/11, and their activation causes: • increase in phospholipase A2 and D activity • increases in diacylglycerol and intracellular Ca2+ • increased cyclic guanosine 5′-monophosphate (cGMP)

9. Activation of H1-receptors in the brain increases wakefulness. • Activation of H1-receptors in vessels causes vasodilation and an increase in permeability. • Activation of H1-receptors typically stimulates nonvascular smooth muscle.

10. Histamine (H2)-receptors • H2-receptors are membrane bound; they are found in the brain, heart, vascular smooth muscles, leukocytes, and parietal cells. • The response of H2-receptors is coupled via Gαs to increased cyclic AMP (cAMP) production. • Activation of H2-receptors: • increases gastric acid production • causes vasodilation • generally relaxes smooth muscles.

11. Histamine (H3)-receptors • H3-receptors are found in the central nervous system (CNS) and peripheral nervous system (PNS) at presynaptic nerve terminals. • H3-receptors are membrane bound and coupled to Gi/o; their activation increases intracellular Ca2+ and decreases cAMP.

12. Stimulation of H3-receptors • on nerve cells causes a decrease in histamine release • in the CNS, stimulation of H3 modulates the release of dopamine, acetylcholine, serotonin, and norepinephrine. • Activation of H3-receptors on the vagus nerve decreases acetylcholine (ACh) release.

13. Histamine (H4)-receptors • H4-receptors are found on hematopoietic cells and in the spleen, thymus, and colon. • Stimulation of H4 receptors increases chemotaxis of mast cells and leukocytes cells toward sites of inflammation. • H4 receptors are coupled to Gi/Go and thereby inhibit the production of cAMP and increase intracellular Ca2+

14. Histamine agonists • Histamine, betazole, and impromidine. • Betazole has approximately tenfold greater activity at H2-receptors than at H1-receptors. • Impromidine is an investigational agent; its ratio of H2 to H1 activity is about 10,000. • Methimepip is an H3-specific agonist.

15. The uses of histamine agonists are primarily diagnostic. • These agents are used: • in allergy testing to assess histamine sensitivity • in the test of gastric secretory function

16. The adverse effects of these agents can be quite severe; they include: • flushing • a burning sensation • hypotension • tachycardia • bronchoconstriction.

17. Clinical Uses of Antihistamines • Allergic rhinitis (common cold) • Allergic conjunctivitis (pink eye) • Allergic dermatological conditions • Urticaria (hives) • Angioedema (swelling of the skin) • Puritus (atopic dermatitis, insect bites) • Anaphylactic reactions (severe allergies) • Nausea and vomiting (first generation H1-antihistamines) • Sedation (first generation H1-antihistamines)

18. Histamine (H1)-receptor antagonists • Competitive inhibitors. • Classification: • First-generation agents • Second-generation agents

19. First-generation agents • Groups: • Alkylamines • Ethanolamines • Ethylenediamines • Piperazines • Tricyclics

20. First-generation agents • Alkylamines • Alkylamines include • Chlorpheniramine • Brompheniramine • These agents produce slight sedation.

21. 2. Ethanolamines • Include • diphenhydramine • doxylamine • clemastine • dimenhydrinate (combination of diphenhydramine and 8-chlorotheophylline) • Ethanolamines produce marked sedation; • doxylamine is marketed only as a sleeping aid. • Ethanolamines also act as antiemetics.

22. 3. Ethylenediamines • Include: • pyrilamine and antazoline. • Ethylenediamines produce moderate sedation and can cause gastrointestinal upset.

23. Piperazines • include meclizine and cyclizine. • Piperazines produce marked adverse gastrointestinal effects and moderate sedation. • These agents have • antiemetic • antivertigo activities.

24. Phenothiazines • include promethazine. • Phenothazines produce marked sedation. • These agents have antiemetic activity. • Phenothiazines are also weak α-adrenoceptor antagonists.

25. Methylpiperidines • include cyproheptadine. • have antihistamine, anticholinergic, and antiserotonin activities.

26. Second-generation agents • Piperidines • Loratadine [Claritin] • Desloratadine [Clarinex] • Poor CNS penetration: reduced sedation • Little or no anticholinergic activity • Desloratadine: • is the active metabolite of loratadine • has about 15-fold greater affinity for the H1 receptor than the parent compound

27. Fexophenadine • is structurally different than the other piperidine antihistamines, • sedative activity is low but dose dependent.

28. Clemastine • is a second-generation ethanolamine • longer duration of action than dimenhydramine • it has some antiemetic activity. • Alkylamines: • acrivastine. • Acrivastine is not associated with cardiac effects.

29. Cetirizine [Zyrtec] • Cetirizine is not associated with cardiac abnormalities. • Cetirizine has poor penetration into the CNS. • Cetirizine is less sedating; • it is ineffective for motion sickness or antiemesis.

30. Pharmacologic propertiesof Histamine (H1)-receptor antagonists • well absorbed after oral administration.

31. H1-receptor antagonists are lipid soluble; most first-generation agents cross the blood— brain barrier. • H1-receptor antagonists are metabolized in the liver; • many induce microsomal enzymes and alter their own metabolism and that of other drugs.

32. Pharmacologic Actions • Many H1-receptor antagonists, especially the ethanolamines, phenothiazines, and ethylenediamines, have muscarinic—cholinergic antagonist activity. • Most of these agents are effective local anesthetics, probably because of a blockade of sodium channels in excitable tissues. • Dimenhydrinate and promethazine are potent local anesthetics.

33. H1-receptor antagonists relax histamine-induced contraction of bronchial smooth muscle and have some use in allergic bronchospasm. • These agents block the vasodilator action of histamine. • H1-receptor antagonists inhibit histamine-induced increases in capillary permeability. • These agents block mucus secretion and sensory nerve stimulation.

34. H1-receptor antagonists, especially the first-generation agents, frequently cause CNS depression (marked by sedation, decreased alertness, and decreased appetite). • In children and some adults, these agents stimulate the CNS.

35. Therapeutic Uses • Treatment of allergic rhinitis and conjunctivitis. • Clemastine is approved for the treatment of rhinorrhea. • Many antihistamines are used to treat the common cold, based on their anticholinergic properties, but they are only marginally effective for this use. • Diphenhydramine also has an antitussive effect not mediated by H1-receptor antagonism.

36. Treatment of urticaria and atopic dermatitis, including hives • Sedatives.Several (doxylamine, diphenhydramine) are marketed as over-the-counter (OTC) sleep aids. • Prevention of motion sickness • Appetite suppressants

37. Adverse effects • (significantly reduced with second-generation agents) • Sedation, dizziness, and loss of appetite. • These agents can cause gastrointestinal upset, nausea, and constipation or diarrhea. • H1-receptor antagonists produce anticholinergic effects (dry mouth, blurred vision, and urine retention). • Two second-generation H1 antagonists, astemizole and terfenadine (a prodrug of fexofenadine) were discontinued or removed from the market because they were associated with Q-T prolongation and ventricular tachycardias.

39. Histamine (H2)-receptor antagonists • Cimetidine [Tagamet] • Ranitidine[Zantac] • Famotidine[Pepcid AC] • Nizatidine [Axid] Competitive antagonists at the H2-receptor, which predominates in the gastric parietal cell.

41. Used in the treatment of: • Gastrointestinal disorders, including heartburn and acid-induced indigestion. • These agents promote the healing of gastric and duodenal ulcers. • Used to treat hypersecretory states such as Zollinger-Ellison syndrome.

42. Pharmacokinetics • The bioavailability of H2-antagonists goes from 50% for ranitidine and famotidine to approximately 90% for nizatidine and advised dosages take this into account. • They are taken especially in the evening to reduce night gastric acidity. • Their elimination is primarily renal. • Cimetidine inhibits cytochrome P-450 and increases the concentrations and the effects of many other drugs.

43. Adverse effects • H2 antagonists are generally well-tolerated, except for cimetidine where all of the following adverse drug reactions (ADRs) are common. • Infrequent ADRs include hypotension. • Rare ADRs include: headache, tiredness, dizziness, confusion, diarrhea, constipation, and rash. • Additionally, cimetidine may also cause gynecomastia in males, loss of libido, and impotence, which are reversible upon discontinuation.

44. The chromones: • Cromolyn[Intal] • Nedocromil sodium[Tilade]

45. These are administered by inhalation. • They inhibit the release of histamine and other autocoids from the mast cell. • Each is used prophylactically in the treatment of asthma • they do not reverse bronchospasm.

46. Adverse effects: • confined to the site of application • Include: • sore throat • dry mouth. • Nedocromil sodium • more effective in reducing bronchospasm caused by exercise or cold air.