Antihistaminics

anti-histaminics

1. ANTIHISTAMINICS DR ZIKRULLAH

2. INTRODUCTION Histamine is a low –molecular weight naturally occurring hydrophilic endogenous amine that produces a variety of physiolgic and pathologic responses in different tissues and cells through G- protien coupled membrane receptors. It is an important chemical mediator of inflammation in allergic disease.

3. Mast cells located in the skin,lungs,and G.I tract as well as circulating basophils contains large amounts of histamine. Histamine does not easily cross the blood brain barrier and CNS effects are usually not evident.

4. SYNTHESIS Synthesis of Histamine in tissues is by decarboxylation of histidine.Histamine is stored in vesicles in a complex with Heparin, Stored histamine is subsequently released in response to An- Ab reaction or in response to certain drugs.

5. METABOLISM There are two pathways of metbolism in humans.The most important pathway involves methylation catalyzed by histamine-N- methytransferase,which is further degraded by monoamine oxidase . The other pathway involves oxidative deamination catalyzed by histaminase .

6. RECEPTORS There are three subtypes of Histamine receptors H1 Receptors are found in conductive tissue of the AV node and slow heart rate by decreasing AV nodal conduction. Histamine induces vascular endothelium to release NO causing vasodilatation.

7. Acting through H1 and H2 receptors it causes increase capillary permeability,hypotension,tachycardia , headache and flushing. Cardiac H1 receptors mediate coronary vasoconstriction.

8. H2 receptors are widely distributed through the myocardium and nodal tissue , where they exert positive inotropic and chronotropic effects as well as vasodilatation of coronary vessels. Activation of H2 receptors by histamine results in stimulation of gastric hydrogen ion secretion.

9. H3 receptors are found in the heart are localized to presynaptic postganglionic sympathethic nervous fibers where they act as autoinhibitory to presynaptic norepinephrine release. H3 receptors when stimulated causes the inhibition of the synthesis and release of histamine.

10. MOA of Histamine on H 1 RECEPTOR Histamine binds with H1 Receptor PIP2 Hydrolysis Activation of IP3/DAG Pathway Realease of Ca from intracellular stores Activation of Protein kinase C

11. MOA of Histamine on H2 Receptor Histamine binds with H2 Receptor Activation of Adenylyl Cyclase Increase Camp Phosphorylation of specific protein

12. MOA of Histamine on H3 Receptor Histamine binds with H3 Receptor Restrict Ca ion influx K channel activation Decrease cAMP

13. EFFECTS ON ORGAN SYSTEM CVS It reduces arterial blood pressure but increases HR and myocardial contractility.H1 receptor stimulation increases capillary permeability and enhance ventricular irritability,whereas H2 receptor stimulation increases HR and contractility. Both receptors mediate peripheral arteriolar dilatation and some coronary vasodilatation.

14. RESPIRATORY H1 receptors causes bronchial smooth muscle constriction whereas H2 receptors causes bronchodilatation . H1 receptors causes pulmonary vasodilatation whereas H2 receptors causes vasoconstriction.

15. GASTROINTESTINAL Activation of H2 receptors in parietal cells increases gastric acid secretion. Stimulation of H1 receptors leads to contraction of intestinal smooth muscles.

16. DERMAL The classic wheal and flare response of the skin to histamine results from increased capillary permeability and vasodilatation and is primarily via H1 receptor activation

17. IMMUNOLOGICAL Histamine is a major mediator of Type 1 hypersensitivity reaction. H1 receptor stimulation attracts leucocytes and induce synthesis of PG H2 receptor activates suppressor T lymphocytes

18. CLASSIFICATION OF H RECEPTOR ANTAGONIST H1 ANTAGONIST ( FIRST GENERATION) Diphenhydramine Pyrilamine Chlorpheniramine Promethazine Hydroxyzine Dimenhydrinate

19. H1 ANTAGONIST (SECOND GENERATION) Fexofenadine Loratidine Levocabastine Cetirizine Levocetirizine Azelastine Mizolastine Desloratidine Ebastine

20. H2 ANTAGONISTS Cimetidine Ranitidine Famotidine Nizatidine

21. H3 Antagonist Thioperamide Impromidine Clobenpropit

22. MOA of H1 Antagonist Binds competitively with H1 Receptor Blocks PIP2 Hydrolysis Prevents activation of IP3/DAG pathway Prevents Ca release & Protein kinase C activation

23. MOA of H2 Antagonist Binds competitively with H2 Receptors Prevents Adenylyl Cyclase activation Decrease cAMP level Prevents Phosphorylation of proteins

24. Pharmacokinetics of H1 Antagonist Well absorbed from oral as well as parenteral route. Metabolized in the liver. Excreted in the urine. Widely distributed in the body & enter the brain. Newer compounds penetrate the brain poorly. Duration of action of most agents are 4-6 hours. Newer agents like cetirizine,loratidine etc have prolonged duration of action.(12-24 hours)

25. ANTIHISTAMINES OF IMPORTANCE IN ANAESTHETHIC PRACTICE PROMETHAZINE( phenergan ) To treat anaphylactic reaction(Type 1 hypersensitivity) Sometimes in the ICU as a sedative agent. Dose Oral : 25-50mg IM : 1mg/kg IV : 0.5 mg/kg

26. CHLORPHENIRAMINE(AVIL) This is used for anaphylactic reactions along with Adrenaline and Hydrocortisone in anticipated surgeries such as orthopedics for BCIS. Dose : Oral : 2-4 mg IV/IM : 0.1 mg/kg

27. DIPHENHYDRAMINE It is first generation antihistaminics . It has also anticholinergic , antitussive , antiemetics and sedative effect. Uses Allergic symtoms Common cold Insomnia Motion sickness Bronchial astma and COPD

28. CETRIZINE It is metabolites of hydroxyzine Having marked affinity for H1 receptor. It penetrate blood brain barrier poorly MOA- It act by inhibiting release of histamine and cytotoxic mediators from platelets as well as eosinophill DOSE- Oral- 10 mg

29. RANITIDINE This is administered as a premedication, for chemoprophylaxis against aspiration pneumonitis , to increase the Ph of the gastric fluid ,should aspiration occur during the perioperative period. Dose : In premedication : 50 mg im , slow iv infusion

30. Pharmacokinetics Orally absorbed. Bioavailability 60-80%. Absorption not interfered by food in stomach. Cant cross BBB. Lesser permeability in placenta and milk. T1/2: 2-3 hours. Excreted unchanged through urine as well as bile.

31. ADVERSE EFFECTS OF H1 ANTAGONISTS The first generation drugs have adverse effects on the CNS including somnolence,diminished alertness , slow reaction time ,and impairment of cognitive function. Anticholinergic effects such as dry mouth,blurred vision,urinary retention,impotence ,tachycardia are seen.

32. Second generation antihistamines are unlikely to produce CNS effects such as somnolence unless the recommended doses are exceeded.

33. ADVERSE EFFECTS OF H2 ANTAGONIST Headache,somnolence,confusion Bradycardia,hypotension,heart block Hyperprolactinemia Acute pancreatitis Thrombocytopenia Agranulocytosis Interstitial nephritis

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