antihistaminesby Ada Atilano-Bautista M.D.

HISTAMINES low molecular weight amines derived from Lhistidine that is produced throughout the body affect cellular growth & proliferation, modulate inammation & act as a neurotransmitter

H1 AntihistaminesMECHANISM OF ACTION inverse agonists that reversibly bind and stabilize the inactive form of H1 receptor favoring the inactive state decrease production of pro-inammatory cytokines, expression of adhesion molecules & chemotaxis of eosinophils and other cells

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pharmacokinetics of sedating rst generation H1 antihistamines

effects are observed 30 mins to 1 hr and persists for 4-6 hrs metabolized by hepatic cytochrome p450 enzyme 3A4 forming glucoronides before excretion in urine administered in divided doses at intervals of 4-6 hrs

pharmacokinetics of low sedating second generation h1 antihistamines

administered once or twice daily achieve higher concentrations in the skin than the rst generation Terfenadine, astemizole, loratadine, acrivastine, ebastine, mizolastine, oxatomide are metabolized in the liver Cetirizine, fexofenadine, levocabastine, desloratadine undergo minimal hepatic metabolism reducing likelihood of drug interactions Cetirizine: lower dosage for renal and hepatic impairment Fexofenadine: almost no hepatic metabolism so no dosage adjustment for hepatic disease

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Adverse effects of H1 antihistaminesSedation: phenothiazine and ethanolamine groups Second gen with sedation: cetirizine and acrivastine Stimulatory effects such as irritability, insomnia, nervousness, tremor: alkylamine group GI complaints: ethylenediamine groups Anticholinergic effects: ethanolamine, piperazine, phenothiazine groups Arrhythmias (most serious side effect): terfenadine and astemizole

drug interactions

interact with imidazole antifungals,cimetidine and macrolide antibiotics. diphenhydramine increases levels of metoprolol and venlafaxine contraindicated for patients using MAO inhibitors

special patient population

Children: more susceptible to side effects associated with 1st generation drugs such as excitation and insomnia. Elderly: more susceptible to anticholinergic effects such as urinary retention and hesitancy, constipation and postural hypotension. Pregnant women: most are classied as FDA Pregnancy Category B or C. Metaanalysis of 200,000 1st trimester exposures showed no risk of congenital malformations. Breast feeding women: 1st generation drugs may diminish milk supply due to anticholinergic effects. Cetirizine, diphenhydramine, loratadine,fexofenadine and desloratadine are excreted in breast milk but effects to infant are not known.

H2 antihistaminesMECHANISM OF ACTION inverse agonists that bind to H2 receptors located throughout the body including epithelial and endothelial cells. expressed on mast cells and dermal dendritic cells and mediate cutaneous vascular permeability and local release of inammatory cells.

pharmacokinetics of h2 antihistamines

rapidly absorbed in the GI tract with peak levels 1-2 hrs after administration undergo extensive hepatic metabolism with renal clearance

CIMETIDINE absorption occurs in the small intestine plasma half-life is 2 hrs 69% excreted unchanged in urine RANITIDINE plasma half-life is 2-3 hrs in healthy adults excreted in urine

FAMOTIDINE plasma half-life of 3-8 hrs. In patients with renal failure plasma half-life >20 hrs NIZATIDINE plasma half-life of 1-2 hrs & duration of action is > 10hrs

dermatologic indications for the treatment of H2 antihistamines

Allergic reactions Chronic urticaria Urticaria pigmentosa and systemic mastocytosis Pruritus assoc with other conditions

used in addition to H1 antihistamines in refractory cases of chronic urticaria and angioedema, reducing whealing and pruritus in urticaria pigmentosa usually follows an unsuccessful trial of H1 antihistamne alone. potential drug interaction is major concern. Ranitidine has lesser drug interaction than cimetidine since less inhibitory of the CYP system. Cimetidine contraindicated in patients using the cardiac drug dofetilide because of risk of arrhythmias. cimetidine increases levels of warfarin, interacts with beta blockers, ca channel blockers, phenytoin, benzodiazepines, metformin, sulfonylureas and SSRI

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Cimetidine: gymecomastia, impotence, loss of libido Ranitidine: alters cardiac sympathovagal balance leading to bradyarrhythmias Famotidine & Nizatidine: few side effects and drug interactions

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special patient populationChildren: Ranitidine and famotidine are safe. Cimetidine and Nizatidine are not recommended. Unique but uncommon to neonates is neonatal enterocolitis. Elderly: dose adjustments for renal disease. More susceptible to CNS disturbances like confusion and dizziness Pregnant women: FDA pregnancy category B; excreted in breast milk but effects to infants not studied

OTHER therapeutic medications with antihistaminic activity

TRICYCLIC ANTIDEPRESSANTSOral Doxepin is successful in treatment of refractory chronic idiopathic urticaria, physical urticaria and pruritus assoc with systemic conditions. Topical doxepin used for pruritus of atopic dermatitis and lichen simplex chronicus Sedation is most common side effect Oral doxepin: pregnancy category C. Topical doxepin is pregnancy category B. Contraindicated during breastfeeding. Not proven under age 12 Not to be used with MAO inhibitors and patients with glaucoma

KETOTIFEN an H1 type antihistamine with additional mast cell and basophil stabilizing properties. used for chronic idiopathic urticaria, physical urticaria and urticaria pigmentosa Sedation and atropine-like effects No studies on safety in pregnant and breast-feeding women

MIRTAZAPINEtricyclic antidepressant with antihistaminic properties reduces pruritus attributable to uremia, cholestasis and various cancers monitoring of blood count for agranulocytosis and neutropenia (rare) and lipid levels for hyperlipidemia FDA black box warning of increased risk of suicide contraindicated with use of MAO inhibitors FDA Pregnancy category C; not studied for breast-feeding women and children