histamin antihist .pptx histamin, antihistamin, cetrizine

histamin antihist .pptx histamin, antihistamin, cetrizine

• 1.
  By Mr. Riyaz Ahmed AssistantProfessor Department of Pharmacology Yenepoya Pharmacy College & Research Centre HISTAMINE & ANTIHISTAMINES
• 2.
  Contents •Autocoids •Histamine •Sites, synthesis andstorage •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 autocoidsand 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 derivedautocoids : – 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 functionsof 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 fromnatural 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 ofan immune response to foreign pathogens, histamine is produced by basophils and mast cells found in nearby connective tissues.
• 11.
  1) Mast cellsite: – 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:- fromdecarboxylation 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 degradationof histamine
• 14.
  • Histamine heldby 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 Uponfirst 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 & mechanicalmast 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-antibodyreaction induced release of histamine from mast cell.
• 18.
  Histamine Receptors Histamine produceits action by activating histamine receptors 1. H1 Receptors 2. H2 Receptors 3. H3 Receptors 4. 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:- excessivestimulation 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 therapeuticvalue • Occasionally used in some diagnostic tests: – Testing gastric acid secretion. – Diagnosis of phenchromocytoma. – Pulmonary function: to test for bronchial hyperreactivity. USES
• 26.
  • Betahistine – H1agonist • 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 • Causesmarked 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→elicitsthe ‘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 notpenetrate 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 actionof 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 (secondgeneration ) antihistamines: Less lipid soluble therefore cannot enter into the CNS: • Cetirizine , Fexofenadine, Ebastine, Loratadine, Ketotifen , Azelastine
• 35.
  • Mechanism ofaction: – H1 antihistamines antagonize the effects of histamine by competitively blocking the H1 receptors (competitive antagonism).
• 36.
  • They areconventional 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: • Producevariable 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 classicalantihistamines: – 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 antiallergicmechanisms 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 H1blockers
• 42.
  Second generation H1blockers
• 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 – Antihistaminicslike 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 aregastroselective antihistamines. • Eg:- cemetidine, ranitidine, nizatidine, famotidine • Blocks H₂ receptors on parietal cells in the stomach lining. H2 BLOCKERS
• 48.
  Therapeutic Uses H2BLOCKERS • 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 modulatethe 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 isan 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 analogueslike 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.