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ANTIHISTAMINESDR AAKANKSHA SINGH

What is an antihistamine?A drug that reduces or eliminates the effects mediated by the chemical histamineHistamine is released by your body during an allergic reaction and acts on specific histamine receptorsThe term antihistamine usually refers to H1 receptor antagonists (actually inverse agonists)Antihistamines compete with histamine for binding sites at the receptors. Antihistamine cannot remove the histamine if it is already bound

Histamine: Histamine was first identified in 1910 and recognized in the 1920s as a major pathogenic mediator of allergic disorders. Histamine receptor antagonist was introduced in 1937, and from 1942 to 1981, more than 40 compounds have reached the market.

Histamine is derived from thedecarboxylationof theaminoacidhistidine, a reactioncatalyzedby theenzymeL-histidine decarboxylase

it is an endogenous substance synthesized and stored in and released by (a) mast cells, which are abundant in the skin, GI, and the respiratory tract, (b) basophils in the blood

Allergies are caused by hypersensitivity reaction involving antibody class IgE (which are located on mast cells in the tissues and basophils in the blood)When an allergen is encountered, it binds to IgE, which activates the mast cells or basophils, leading them to release massive amounts of histamines.

Pharmalogical effects of Histamine1)Histamine promotes( intestinal and Bronchiolar ) smooth muscle contraction which is an H1 receptor mediated effect

2)Histamine significantly increases gastric acid and gastric pepsin secretion which is an H2 receptor mediated effect

3) Vasodilation of arterioles and precapillary sphincters which is an H1and H2 receptor mediated effect

The different Histamine receptorsLOCATIONEFFECTTREATMENTH1Throughout the body, specifically in smooth muscles, on vascular endothelial cells, in the heart and the CNSMediate an increase in vascular permeability at sites of inflammation induced by histamineAllergies, nausea, sleep disorders

H2In more specific locations in the body mainly in gastric parietal cells, a low level can be found in vascular smooth muscle, neutrophils, CNS, heart, uterusIncreases the release of gastric acidStomach ulcers

H3Found mostly in the CNS, with a high level in the thalamus, caudate nucleus and cortex, also a low level detected in small intestine, testis and prostate.Neural presynaptic receptor, may function to release histamineUnknownH4They were recently discovered in 2000. They are widely expressed in components of the immune system such as the spleen, thymus and leukocytes.unkonwnIn addition to benefiting allergic conditions, research in the h4 receptor may lead to the treatment of autoimmune diseases. (rheumatoid arthritis)

Clinical Symptoms Associated With Histamine Releasemild/cutaneousmild to moderate

severe/anaphylacticerythema, urticaria, and/or itching

skin reactions, tachycardia, dysrhythmias, moderate hypotension, mild respiratory distresssevere hypotension, ventricular fibrillations, cardiac arrest, bronchospasm, respiratory arrest

CLINICAL CLASSIFICATION OF H1 ANTIHISTAMINICSDRUG1) HIGHLY SEDATIVEDiphenhydramine Dimenhydrinate Promethazine

Hydroxyzine

2)MODERATLEY SEDATIVEPheniramine

Cinnarizine

Cyproheptadine

3) MILD SEDATIVEChlorpheniramine

Cyclizine

First generation H1 antihistaminesEthanolamine- Diphenhydramine

Piperidine- cyproheptidine

Phenothiazine- promethazine

Alkylamine- chlorpheniramine

Piperazine- hydroxyzine

4) SECOND GENERATION ANTIHISTAMINICSTerfenadineFexofenadineAstemizoleLoratidineDesloratidineCetrizine

5)NEW SECOND GENERATION- Levocetrizine

Hydroxyzine

Hydroxyzine can be administered orally or via intramuscular injection. When given orally, hydroxyzine is rapidly absorbed from the gastro-intestinal tract. The effect of hydroxyzine is notable in 30 minuteshydroxyzine is rapidly absorbed and distributed in oral and intramuscular administration, and is metabolized in the liver; the main metabolite (45%) is formediscetirizine

Pheniramine

is anantihistaminewithanticholinergicproperties used to treatallergicconditions such ashay feverorurticaria. It has relatively strong sedative effects, Pheniramine may cause drowsiness,bradycardiaand sleep disorders. Overdose may lead toseizures, especially in combination with alcohol.

Cetrizine

Cetrizine is the carboxylic metabolite of first generation H1 antihistamine hydroxyzine.It is rapidly absorbed after oral administration.A single 10 mg oral dose causes significant histamine wheal suppression in 20-60 minutes and lasts for 24 hours.Indication urticariaIt is formulated as 1o mg tablets and a 1mg/ml syrup.

Levocetrizine

It is the most recently introduced second generation H1 antihistamine.More potent in supressing the histamine wheal in healthy volunteers with low sedation.It is licensed for patients over 6 years of age in dosage of 5 mg daily for the indication of urticaria.

Terfenadine and fexofenadineTerfenadinewas anantihistamineformerly used for the treatment ofallergicconditions.Terfenadine is aprodrug, generally completely metabolized to the active formfexofenadinein the liver . Due to its near complete metabolism by the liver immediately after leaving the gut, terfenadine normally is not measurable in the plasma. Terfenadine itself iscardiotoxic(specificallycardiac arrhythmiacaused byQT intervalprolongation).at higher doses, while its major active metabolite is not.

Terfenadine, in addition to its antihistamine effects, also acts as a potassium channel blocker . Since its active metabolite is not a potassium channel blocker, there is no cardiotoxicity associated withfexofenadine.Fexofenadine is absorbed by oral route with peak plasma levels being achieved at 1 to 3 hours after administration.After a single dose 80% is recovered unchanged in the faeces and 12% excreted in urine. dose of fexofenadine 30,60,180mg

LoratadineIt is a piperidine tricyclic selective long acting H1 antihistamine with minimal sedation Loratadine is given orally, is well absorbed from thegastrointestinal tract, and has rapidfirst-pass hepatic metabolism Its metabolite desloratadine, which is largely responsible for the antihistaminergic effects.Indication is administered as 10 mg capsules and syrup(1mg/ml) for the treatment of chronic urticaria

Systemic and topical doxepinDoxepin is tricyclic antidepressent drug with potent H1 and H2 antihistamine activity.It has proved useful when given systemically in the treatment of severe urticaria.Doxepin has also been formulated as a 5% cream with indication of pruritus in eczematous dermatitis.Although effective,5% doxepin cream may cause significant drowsiness because of percutaneous absorption

It can also cause allergic contact dermatitis (dermatitis medicamentosa)Topical doxepin should be used for 8 days at the most.

Pharmacokinetics

The classical H1 antihistaminics are well absorbed from oral and parenteral routes,metabolized in liver and excreted in urine except fexofenadine which is excreted in faecesDuration of action of most agents is 4-6 hours,except newer antihistamines which act for 12-24 hours or more.

Drug interactions-H1 antihistaminesInteracting drug groupExamplesThese drugs may increase serum levels of Several H1 antihistaminesAntibacterialErythromycin,clarithromycinAzole antifungal agentsFluconazole at doses 300 mg daily or higherH2 antihistaminescimetidineThese drugs may decrease serum levels ofSeveral H1 antihistaminesAntibacterialRifamycin,rifabutin (risk with fexofenadine,loratidine)anticonvulsantsCarbamazepine,phenytoin

Diphenhydramine may increase serum Levels of these drugsBeta blockersMetoprolol,propanolol,,risk bradycadia

Tolerance(tachyphylaxis and subsentivity)Development of tolerance after continued regular administration of H1 antihistamines is frequently perceived as a problem.In a comparison of several antihistamines administered daily for 3 weeks ,hydroxyzine(75mg daily) proved to be the most effective in suppressing intracutaneously injected histamine wheel.Hydroxyzine showed greatest degree of tolerance in contrast chlorpheniramine showed little or no tendency to produce subsentivity.

Therapeutic uses

1Allergic Reactions: allergic rhinitis , Atopic dermatitis, hay fever, urticaria2)Sedation and hypnotics. : these agents to be used has sleep-aids, i.e. hypnotics. The newer H1 antagonists, by contrast, cause minimal or no sedation.

USE IN PREGNANCY AND LACTATION

Chlorpheniramine, one of the first-generation antihistamines, is reportedly safe in pregnancy. There is little information on the use of the new antihistamines during pregnancy although cetirizine,levocetrizine,hydroxyzine,fexofenadine and loratadine are considered relatively safe for use during pregnancy(FDA category B).H1antihistamines are excreted in small amounts in breast milk (