histamin antihist .pptx histamin, antihistamin, cetrizine

histamin, histamine antihistamin

1. By Mr. Riyaz Ahmed Assistant Professor Department of Pharmacology Yenepoya Pharmacy College & Research Centre HISTAMINE & ANTIHISTAMINES

2. Contents Autocoids Histamine Sites, synthesis and storage Types of receptors Pathophysiological roles Histamine analogues Pharmacological action of histamine Antihistamines M.O.A. and Pharmacological actions of antihistamines Classification Therapeutic uses.

3. Define autocoids and types Explain Histamine Explain types of receptors Explain antihistamines and classifications. Pharmacological actions of Antihistamines Therapeutic uses of Antihistamines. Specific Learning Objectives

4. AUTACOIDS :- auto=self akos =healing/remedy These are diverse substances produced by a wide variety of cells in the body, having intense biological activity, but generally act locally (e.g. within inflammatory pockets) at the site of synthesis and release. They have also been called ‘local hormones’ AUTACOIDS

5. Amine derived autocoids : Histamine (amino acid: Histidine ), Serotonin (5H-Tryptamine) Peptide derived autocoids : Angiotensin , Bradykinin Lipid derived autocoids : Prostaglandins, Leukotrienes , Interleukins, Platelet Activating Factor, etc. CLASSIFICATION

6. Physiological functions of autocoids Smooth musle contraction, relaxation Secretion of gastric acids, bp regulation, etc Pathophysiological functions of autocoids reaction to injuries Mediators of inflammation, , immune response Transmission and modulation . Regulating secretions, impacting nerve transmission, local hormone, transmitting signals within nervous system. FUNCTIONS OF AUTOCOIDS

7. Derived from natural amino acids Histamine and serotonin are the major autacoids in this class. AMINE AUTACOIDS:

8. HISTAMINE

9. Imidazole ethylamine Formed from the amino acid Histidine Important inflammatory mediator Potent biogenic amine and plays an important role in inflammation, anaphylaxis, allergies, gastric acid secretion and drug reaction. INTRODUCTION

10. As part of an immune response to foreign pathogens, histamine is produced by basophils and mast cells found in nearby connective tissues.

11. 1) Mast cell site: Pulmonary tissue (mucosa of bronchial tree) Skin GIT(intestinal mucosa) Conc. Of histamine is particularly high in these tissues 2) Non-mast cell sites: CNS (neurons) Epidermis of skin. GIT(gastric cells) Cells in regenerating or rapidly growing tissues Basophils (in the blood) SITES OF HISTAMINE RELEASE

12. Synthesis:- from decarboxylation of amino acid histidine Storage:- In mast cells, histamine (positively charged) is held by an acidic protein and heparin (negatively charged) within intracellular granules. Degradation:- oxidation and methylation . SYNTHESIS, STORAGE AND DESTRUCTION

13. Synthesis and degradation of histamine

14. Histamine held by an acidic protein and heparin within intracellular granules → Granules extrude by exocytosis → Na + gets exchanged for histamine MECHANISM OF RELEASE

15. IgE -Mediated (Antigen-Induced) Release Upon first exposure, IgE antibodies bind to mast cells and "sensitize" them. On re-exposure to the allergen, the allergen binds to IgE on the mast cell surface, triggering degranulation and releasing histamine along with other mediators (e.g., prostaglandins, leukotrienes ). Non–Antigen-Mediated Release Some drugs (e.g., morphine, codeine), venoms, or physical factors (e.g., heat, trauma) can cause non- exocytotic release by disrupting mast cell membranes or displacing histamine from storage.

16. Chemical & mechanical mast cell injury cause degranulation of cytoplasmic granules & histamine is released Certain amines accumulate in mast cells due to affinity for heparin, displace histamine → form heparin liberator complex → increases permeability of mast cell membrane and diffuse histamine.

17. Mechanism of antigen-antibody reaction induced release of histamine from mast cell.

18. Histamine Receptors Histamine produce its action by activating histamine receptors H1 Receptors H2 Receptors H3 Receptors H4 Receptors

19. H1 Receptors Mechanism : Gq → IP3/DAG → ↑ Ca²⁺ → PK-C activation histamine binds to H1 receptors,-activates Gq proteins , - trigger the phospholipase C (PLC) pathway- formation of IP₃ and DAG , increasing intracellular calcium Location & Function : Smooth muscle (GIT, airway, uterus): contraction Blood vessels: endothelium – vasodilation ; Broncho -constriction Brain : neurotransmission -Adrenal medulla: ↑catecholamine release. (itching, pain) Agonists : 2-methyl histamine, 2-pyridyl ethylamine Antagonists : Mepyramine , Chlorpheniramine

20. H2 Receptors Mechanism : Gs → ↑ cAMP → Protein phosphorylation Histamine activates Gs proteins at H2 receptors, which stimulate adenylate cyclase to increase cyclic AMP ( cAMP ) levels. Location & Function : Stomach: ↑ acid secretion Blood vessels: vasodilation Heart: ↑ heart rate & contractility Brain: neurotransmission activity Agonists : 4-methyl histamine, Dimaprit , Impromidine Antagonists : Cimetidine , Ranitidine

21. H3 Receptors Mechanism : Gi → ↓ Ca²⁺ influx, ↓ cAMP H3 receptors are mainly found on nerve endings. When activated, they couple with Gi proteins to inhibit adenylate cyclase , thereby decreasing cAMP . This reduces the release of neurotransmitters like histamine, acetylcholine, and norepinephrine —acting as a feedback control in the CNS. Location & Function : Brain ( presynaptic ): ↓ neurotransmitter release → sedation Ileum: ↓ ACh release Blood vessels: ↓ NA release → vasodilation Agonists : (R)- α- methyl histamine, Imetit Antagonists : Thioperamide , Impromidine , Ciprofloxacin

22. H4 Receptors Mechanism: Gi → ↓ cAMP Similar to H3, H4 receptors also couple with Gi proteins and reduce cAMP levels . help in chemotaxis (movement) of eosinophils and mast cells, contributing to allergic and inflammatory responses . Location-Bone marrow, eosinophils , mast cells, basophils Function: Mast cell chemotaxis- Chemotaxis is how immune cells "smell" chemical signals and move toward the site of infection, injury, or inflammation where those signals are strongest. Antagonist: Thioperamide

23. Ulcers :- excessive stimulation of H2 produces excess acid secretion. Allergic phenomenon :- mediation of hypersensitivity reactions has been the first role ascribed to histamine. Causes inflammation - chemotaxis , opsonisation ( Coating of microbes by immune cells to enhance phagocytosis or recognize antigens) PATHOPHYSIOLOGICAL ROLES

24. As transmitter:- initiates the sensation of itch and pain at sensory nerve endings. Headache :– due to sudden vasodilatation produce headache.

25. No therapeutic value Occasionally used in some diagnostic tests: Testing gastric acid secretion. Diagnosis of phenchromocytoma . Pulmonary function: to test for bronchial hyperreactivity . USES

26. Betahistine H1 agonist Used to control vertigo in patients of Meniere’s disease . Vertigo is a type of dizziness characterized by the illusion of rotational movement, caused by disturbances in the vestibular system (inner ear or its connections in the brain). Acts by causing vasodilation in internal ear. Betazole H2 agonist. Used in gastric function tests HISTAMINE ANALOGUES (SUBSTITUTES)

27. Blood vessels Causes marked dilation of smaller blood vessels Dilation of cranial vessels causes pulsatile headache. Causes increased Capillary permeability due to separation of endothelial cells → exudation of plasma:- H1 response Pharmacological Actions

28. Intradermal injection→elicits the ‘triple response’ Red spot : due to intense capillary dilatation. Immediate reddening at the injection site Wheal : due to exudation of fluid from capillaries and venules . Local swelling (edematous elevation) Flare : i.e. redness in the surrounding area due to arteriolar dilatation mediated by axon reflex.

29. Glands H2 receptors- (on parietal cells) causes marked increase in gastric secretion—primarily of acid but also of pepsin → increases cAMP generation, which in turn activates the membrane proton pump (H+/K+ ATPase ). Sensory nerve endings Injection ( i.v . or intracutaneous ):- Itching

30. CNS Does not penetrate blood brain barrier Intracerebroventricular administration:- (H1 and H2 receptors) produces rise in BP, cardiac stimulation, behavioural arousal, hypothermia, vomiting and ADH release.

31. Anti histamines

32. Blocks action of histamine at receptor Competes with histamine for binding Displaces histamine from receptor General Mechanism of Action of Antihistamines

33. H1 Receptor Antagonist Sedative (first generation) antihistamines: Highly lipid soluble and easily enters into the CNS: Potent and marked sedative: Promethazine ( phenergan ) widely used , Diphenhydramine , Dimenhydrinate Potent and moderate sedative: Chloryclizine , Chlorpheniramine , Tetrahydeoxy carboline Less potent and less sedative: Mepyramine , Pheniramine . ANTIHISTAMINE CLASSIFICATION:

34. Non-sedative (second generation ) antihistamines: Less lipid soluble therefore cannot enter into the CNS: Cetirizine , Fexofenadine , Ebastine , Loratadine , Ketotifen , Azelastine

35. Mechanism of action: H1 antihistamines antagonize the effects of histamine by competitively blocking the H1 receptors (competitive antagonism).

36. They are conventional antihistamines. Pharmacological actions: Antagonism of histamine will lead to block: Histamine induced bronchoconstriction . Contraction of intestine, smooth muscle and triple response. Anti-allergic action: Most of the manifestations of immediate hypersensitivity (type 1 reactions) are suppressed. FIRST GENERATION H1 BLOCKERS

37. CNS: Produce variable degree of CNS depression, sedation and drowsiness. At toxic doses, excitement and convulsions are seen. As most of these drugs are lipophilic , easily cross BBB and act on CNS .

38. Anticholinergic action: Dryness of mouth, blurring of vision, constipation, urinary retention. At higher doses act as local anesthetics. They block Na + channels in excitable tissues ( Eg :- pheniramine , promethazine , diphenhydramine )

39. Advantages over classical antihistamines: Higher H1 selectivitiy : no anticholinergic side effects. Do not impair psychomotor performance. Absence of CNS depressant property. They poorly cross BBB. SECOND GENERATION H1 BLOCKERS

40. Additional antiallergic mechanisms apart from histamine blockade: some also inhibit late phase allergic reaction by acting on leukotrienes or by antiplatelet activating factor effect. Some of them are long acting.

41. First generation H1 blockers

42. Second generation H1 blockers

43. Allergic diseases: Oral antihistamines for allergic rhinitis and urticaria because histamine is the principal mediator released by mast cells. Ophthalmic antihistamines, such as azelastine , olopatadine , ketotifen are useful for the treatment of allergic conjunctivitis. Common cold: symptomatic relief by anticholinergic (reduce rhinorrhoea ) and sedative actions. THERAPEUTIC USES

44. Motion sickness: given 30 – 60 min before journey ( anticholinergic action) Preanesthic medication: Promethazine as sedative and anticholinergic . Vertigo Parkinsonism Promethazine and diphenhydramine are used for the treatment of drug induced parkinsonism.

45. Cough Antihistaminics like chlorpheniramine , diphenhydramine and promethazine are used. As sedative, hypnotic, anxiolytic Induce sleep, especially in children.

46. Sedation, drowsiness, lack of concentration, headache, fatigue, nausea, vomiting, loss of appetite and epigastric discomfort, dry mouth, blurring of vision. ADVERSE EFFECTS

47. They are gastroselective antihistamines. Eg :- cemetidine , ranitidine, nizatidine , famotidine Blocks H₂ receptors on parietal cells in the stomach lining. H2 BLOCKERS

48. Therapeutic Uses H2 BLOCKERS Peptic Ulcer Disease (PUD) Duodenal & gastric ulcers Gastroesophageal Reflux Disease (GERD) Symptomatic relief of heartburn Prophylaxis of Stress Ulcers In ICU patients or those with severe stress Pre-anesthetic medication ( famotidine ) To reduce acid aspiration risk

49. They modulate the histaminergic neurotransmission in brain. They have application in obesity, sleep disorders, neuropsychiatric disoders and cognitive functions. Eg :- Thioperamide and clobenpropit . H3 BLOCKERS

50. Summary Histamine is an important amine autacoid involved in inflammation, allergy, and gastric acid secretion. Synthesized from histidine , stored in mast cells and basophils , and released during allergic reactions. Acts through H1, H2, H3, and H4 receptors , each with distinct locations and functions.

51. Histamine analogues like betahistine and betazole have diagnostic and therapeutic uses. Antihistamines are classified into: H1 blockers : First and second generation (sedative vs non-sedative) H2 blockers : Reduce gastric acid (e.g., ranitidine) H1 antihistamines are useful in allergy, cold, motion sickness, insomnia, and cough. Side effects include sedation , dry mouth , and GI discomfort .

52. References Tripati KD. Essentials of medical pharmacology 6th. Edi Text book of principles of pharmacology by H.L.Sharma & K.K.Sharma . Text book of pharmacology by Lippincott Williams & wilkins .