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Histamines pathophysiological roles by aks.pptx
- 1. PATHOPHYSIOLOGICAL ROLE OF HISTAMINES & ANTIHISTAMINICS BY- Dr.Savitha A K JUNIOR RESIDENT 1st YEAR DEPARTMENT OF PHARMACOLOGY AND THERAPEUTICS KING’S GEORGE MEDICAL COLLEGE,LUCKNOW
- 2. OBJECTIVES: At the endof the session, able to answer Histamine receptors – Distribution and actions Pathophysiological role List of 1st generation antihistaminics – Uses & Disadvantages List 2nd generation antihistaminics - Uses and Side effects
- 3. • Histamine ispresent mostly in • Four types of Histaminergic receptors – H1,H2,H3,H4 MAST CELL (STORAGE GRANULES) NON MAST CELL • SKIN • GI MUCOSA • LIVER • LUNGS • PLACENTA SLOW TURN OVER • BRAIN • EPIDERMIS • GASTRIC MUCOSA & • GROWING REGIONS FAST TURN OVER
- 4. DISTRIBUTION AND ACTION H1Receptors Distribution in body Actions Smooth Muscles • Intestine • Airway • Uterus Contraction Blood Vessels • Endothelium • Smooth Muscle of Larger vessels • Release of NO and PGI2-Vasodilation • Widening of Gap Junction-Increased capillary permeability • Vasoconstriction Afferent Nerve ending Stimulation Pain and Itching Ganglionic cell Stimulation- Release of Adrenaline Rise in BP Adrenal Medulla Stimulation- Release of CAs Rise in BP Brain(Post synaptic) Impulse generation wakefulness;Hypothermia
- 5. H2 Receptors • Gastringlands- Acid secretion • Blood vessels(Smooth muscle)- Dilatation • Heart Atria: Positive chronotropy Ventricles: Positive Inotropy • Uterus(Rat)-Relaxation • Brain (Post synaptic)-Impulse generation H3 Receptors • CNS (Pre synaptic) –Inhibition of Histamine release- Sedation • Lung, Spleen, Gastric mucosa – decreases histamine • Ileum – Inhibition of Ach release No Clinical application. H4 Receptors • Eosinophils, Basophils – enhances Chemotaxis
- 6. PATHOPHYSIOLOGICAL ROLE Gastric Secretion AllergicPhenomena As Transmitter Mediator of Inflammation Tissue Growth and Repair Headache
- 7. Gastric secretion: Dominant physiologicalrole in mediating HCL secretion • Non Mast cell Histamine * Gastric Secretions (Histaminocytes) (Stimuli)(Release) * Activates Proton Pump (H2 receptors) Stimulus : Feeding Vagal stimulation Cholinergic drugs (Ach) Gastrin
- 8. Allergic Phenomena: Histamine releasedfrom Mast cells in Immediate hypersensitivity reaction is causative in • Urticaria • Angioedema • Bronchoconstriction • Anaphylactic shock • Not involved in delayed or retarded type of allergic reactions.
- 9. As a Transmitter: •Believed to be Afferent transmitter Sensation of pain and itch in sensory nerve endings. • Non Mast cell histamine in Brain (Hypothalamus & Midbrain) Maintaining Wakefulness. • H1 Agonism in brain- suppresses Appetite. • Regulating Body Temperature & Thirst
- 10. Inflammation: • Mediator ofVasodilation and other changes during inflammation • By expressing Adhesion molecule P-Selectin Promotes adhesion of leukocytes to vascular endothelium, Sequestration of leucocytes to site of inflammation. • Regulates Micro circulation. Tissue growth and repair: • Suggested to play Essential role in the process of Growth and repair • Implicated in certain Vascular headaches –no conclusive evidence.
- 11. USES • Histamine hasno therapeutic use. • Betahistine : • H1 Selective (somewhat) Histamine Analogue • Control Vertigo in Meniere’s Disease patients • By causing Vasodilation in Internal ear • Contraindicated in Asthmatics and Ulcer patients.
- 12. H1 ANTAGONISTS • Competitivelyantagonize histamine actions at H1 receptor. • Clinical classification • Sedative First Generation (Conventional Antihistaminics) • Highly sedative • Moderately sedative • Mild sedative • Non/less sedative Second Generation
- 13. First Generation Highly SedativeModerately sedative Mild Sedative Diphenhydramine Pheniramine Chlorpheniramine Dimenhydrinate Cyproheptadine Dexchlorpheniramine Promethazine Meclizine Triprolidine Hydroxyzine Cinnarizine Clemastine
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- 15. PHARMACOLOGICAL ACTIONS • Antagonismof Histamine • Antiallergic action • In CNS – Eg.Sedation • Anti cholinergic action • Local Anaesthetic • BP Qualitatively all H1 Antihistaminics have similar actions Quantitatively differs in Sedative property
- 16. Antagonism of Histamine: H1antagonists blocks Histamine induced • Bronchoconstriction • Contraction of intestinal and other smooth muscle • Triple response • Partially blocking fall in BP • Adrenaline release from adrenal medulla • Constriction of larger blood vessels also antagonized Action on Gastric secretion is not effected
- 17. Antiallergic action: • Manifestationsof Immediate hypersensitivity reactions are suppressed • Urticaria, Angioedema, itching are well controlled. • Anaphylactic fall in BP is partially prevented • Asthma in man is unaffected – it is established that Leukotrienes and PAF are more important mediators in Human Asthma (Though anaphylactic bronchoconstriction in guinea pig is largely prevented).
- 18. CNS: • Older antihistaminesproduces variable degree of CNS Depression. • Depends on Compound’s ability to penetrate BBB and its Affinity for central H1 Receptors • Individual susceptibility to different agents varies considerably. • Some individuals also experience stimulant effects like restlessness and insomnia • Second Generation Antihistaminics are practically non sedating. • Action in preventing Motion Sickness • Has Appetite stimulating effects • Antitussives
- 19. Anticholinergic action: • Inaddition ,many H1 blockers antagonizes muscarinic actions of Ach. • Promethazine having high antimuscarinic action. Local Anaesthetic: • Has Membrane stabilizing property – not suitable LA as they cause irritation on S/c Injection. BP: • On IV injection –Fall in BP (α adrenergic blockade or direct smooth muscle relaxation) • Not evident in oral administration, though postural hypotension occurs in susceptible individuals.
- 20. PHARMACOKINETICS: • Well Absorbedfrom oral and parenteral routes. • Widely Distributed in the body and enter brain. • Metabolised in Liver • Excreted in urine • Newer compounds penetrate brain poorly- accounting for its low sedating action. • Duration – 4-6 hours • Second Generation antihistaminics :12-24 hours • Dosage form: Oral(Mainly),available for IM/IV use as well
- 21. First Generation Highly SedativeModerately sedative Mild Sedative Diphenhydramine Pheniramine Chlorpheniramine Dimenhydrinate Cyproheptadine Dexchlorpheniramine Promethazine Meclizine Triprolidine Hydroxyzine Cinnarizine Clemastine
- 22. ADVERSE EFFECTS: CNS: • Sedation •Diminished alertness and concentration • Light headedness • Motor incoordination • Fatigue • Tendency to fall asleep Paradoxical responses in few individuals • Restlessness • Nervous and • Unable to sleep • Headache Epigastric distress Contact Dermatitis
- 23. • Patient shouldbe cautioned not to operate vehicles or machinery requiring constant attention . • Sedation – Synergism with Alcohol Barbiturates Benzodiazepines Tricyclic Antidepressants • Regular use is not advisable in children – interfere with Learning and academic tasks.
- 24. Antimuscarinic effects • Drynessof mouth • Alteration of bowel movements • Urinary hesitancy • Blurring of vision Teratogenecity • Hydroxyzine, Cyclizine and Fexofenadine are teratogenic in animals, no evidence of excess malformations in humans . • It is advisable to proceed with caution when prescribing antihistamines during pregnancy.
- 25. ACUTE OVERDOSE: • Centralexcitation • Tremors • Hallucination • Muscular incoordination • Convulsion • Flushing • Hypotension • Fever • Death due to respiratory and Cardiovascular failure
- 26. Second Generation Antihistaminics: 2nd Generation drugs have one or more following properties: • Higher H1 Selectivity • No Anticholinergic side effects • Absence of CNS Depressant property • No Psychomotor impairment (No C/I for driving) • No Synergism with alcohol or benzodiazepines • Additional Antiallergic mechanisms apart from Histamine blockade : Inhibit Late phase allergic reaction by modifying release of Leukotrienes and PAF. • Poor antipruritic, antiemetic and antitussive actions.
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- 28. USES: 1. Allergic disorders 2.Common Cold/Cough 3. Motion sickness 4. Pre-anaesthetic medication 5. Parkinsonism 6. Vertigo 7. Acute muscle dystonia
- 29. H2 ANTAGONISTS • Competitivelyantagonize histamine actions at H2 receptor. • These drugs block histamine induced Gastric secretion –Antiulcerogenic effect. • Drugs: Cimetidine Ranitidine Famotidine Roxatidine Lafutidine • PPIs largely replaced H2 blockers
- 30. Adverse Effects: • RapidIV injection Bradycardia, Cardiac Arrhythmias or Cardiac arrest. • Gynaecomastia on longer period of Cimetidine usage. Uses: • Peptic Ulcer • Nonulcer dyspepsia • Bleeding from Stress ulcers and Erosive Gastritis • Gastroesophageal Reflux Disease(GERD) • Prophylaxis of Aspiration Pneumonia • Urticaria
- 31. • Though someH3 Antagonists have been produced – No clinical utility • H4 Antagonists are being explored for their potential role in Allergic inflammatory conditions like Rhinitis and Asthma
- 32. REFERENCES : • Tripathi,KD. Histamine and Antihistaminics. In; Tripathi M, Editor. Essentials of Medical Pharmacology. 8th Edition Revised and Updated Reprint 2023, New Delhi : Jaypee Brothers Medical Publishers: p 177- 184
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