Antihistamines are inhibitors of histamine receptors. One distinguishes H1 and H2 antagonists.
H1-antihistamines have been used for more than fifty years in treating various allergic manifestations.
H1-antihistamines, inhibit competitively H1 receptors and the corresponding effects i. e. vasodilation and capillary permeability increase. H1-antihistamines which penetrate into brain elicit, by inhibiting stimulant effect of histamine, drowsiness. They do not inhibit antigen/antibodies reactions, nor histamine release, they inhibit H1 effects. In addition to this antihistamine effect, they can have parallel pharmacological properties, for example antimuscarinic and adrenolytic effects which must be considered.
It is usual to classify H1-antihistamines into two classes: old ones, called first-generation agents, which are sedating and recent ones, called second-generation agents which have slight or no sedating effects because they do not cross the blood-brain barrier. In addition, each compound can have or not have parallel properties, antimuscarinic effects for example. This distinction between generations must be taken with caution because a product considered as non sedative or not antimuscarinic can, in certain circumstances, large doses or particular susceptibility of the patient ,have these effects.
The drugs of the first antihistamine generation are: promethazine, alimemazine, dexchlorpheniramine, brompheniramine, buclizine, carbinoxamine and doxylamine, are sedating and elicit a drowsiness which can be awkward.
The first-genaration antihistamines have alpha adrenolytic activity which can decrease the vasoconstrictive effect of adrenaline and noradrenaline and an antimuscarinic effect with the corresponding adverse effects. Certain H1 antagonists, such as promethazine, have a local anesthetic effect.
Other H1-antihistamines having an important antimuscarinic activity like diphenhydramine and dimenhydrinate, are used in preventive and curative treatment of motion sickness, but scopolamine which has no antihistamine effect seems more effective than them in preventive treatment.
Oxatomide, is a sedating H1-antihistamine, having mast-cell stabilising properties perhaps by a calcium-channel antagonist effect , without anticholinergic effect. It is used in treatment of chronic urticaria, atopic dermatitis and dermographisms. It can cause dyskinesia, especially in children.
Doxylamine is a sedating antihistamine also used as an hypnotic.
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.
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
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 de pointes 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.