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Second Generation Anti-Histaminics

Second-generation H1-antihistamines

The two first H1-antihistamines without sedating effect to be marketed were terfenadine and astemizole. They were withdrawn from the market because they could induce ventricular arrhrythmias, prolongation of QT interval which can lead to torsades de pointes. This adverse effect is linked to their effect on potassium channels leading to slowing of repolarization rate.

H1-antihistamines without sedating effect currently marketed are mequitazine, cetirizine, loratadine, mizolastine, fexofenadine because they do not cross blood-brain and thus their effects remain peripheral.

They have a longer duration of action and longer plasma half-life than the first generationdrugs, which makes it possible to reduce the number of daily intakes. They do not have, in normal dose, antimuscarinic effect, except mequitazine which has a mild antimuscarinic effect.

Mequitazine has an antimuscarinic effect parallel to its H1-antihistamine activity, which can result for example in dryness of mouth or accommodation disturbances.

Loratadine acts mainly via one of its metabolites, decarboethoxyloratadine, also called desloratadine, which is also marketed. In case of overdose, loratadine can cause sedation and antimuscarinic effects.

Cetirizine, carboxyl derivative of hydroxyzine which is used as a sedative and anxiolytic, in addition to its H1-antihistamine effect, inhibits release of various cytokines and leukotrienes. Ceterizine is a racemic; one of its isomers called levocetirizine is also released on the market.

Mizolastine does not induce, in usual dosage, prolongation of QT interval; however its combination with macrolides and imidazol antifungal agents is disadvised because of a possible inhibition of its catabolism.

Fexofenadine, the active metabolite of terfenadine is not associated with an averse prolongation of the QT interval.

Ebastine, which is transformed in the body into an active metabolite, carebastine, is a H1-antihistamine in theory not sedative and not antimuscarinic.

Azelastine is a H1-antihistamine usable by local route, in nasal pulverization, in the treatment of allergic rhinitis.

Therapeutic use

H1-antihistamines are used for supportive care of allergic manifestations, cutaneous (urticaria) or mucous membranes (rhinitis, hayfever, conjunctivitis). They are not effective in asthma. Insufficient alone to treat anaphylactic shock or edema of the larynx, they could prevent them. The drug to use in severe situations is adrenaline

Adverse effects

The early H1-antihistamines usually induce drowsiness and their prescription to patients with an activity requiring a normal vigilance, like control of a vehicle, is contra-indicated. By their alpha-adrenolytic effect especially when they are given by parenteral route, they could reduce the vasoconstrictive effect of adrenaline, administered for example in case of anaphylactic shock.

New H1-antihistamines induce only exceptionally drowsiness. This possibility, even rare, must however be taken into account, particularly at time of a first prescription. It is not advised to prescribe a sedating a H1-antihistamine to infants because, although this is not documented, it could increase the risk of sudden death.

New H1-antihistamines, terfenadine and astemizole, which were associated with cardiac adverse effects, prolongation of QT interval, torsades depointes by inhibition of potassium channels, are no longer approved for use. .

Other adverse effects of H1-antihistamines have been reported, in particular allergic reactions.

All H1-antihistamines, including those which are intended for treatment of motion sickness, are disadvised during the first three months of pregnancy, more for reasons of principle than for observations of malformations. Promethazine has been prescribed to pregnant women without inducing malformations.

November 1, 2010

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