Second Generation Antihistaminics

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Chapter: Essential pharmacology : Histamine And Antihistaminics

The second generation antihistaminics (SGAs) may be defined as those H1 receptor blockers marketed after 1980 which have one or more of the following properties :



The second generation antihistaminics (SGAs) may be defined as those H1 receptor blockers marketed after 1980 which have one or more of the following properties :


·        Higher H1 selectivitiy: no anticholinergic side effects.


·        Absence of CNS depressant property.


·        Additional antiallergic mechanisms apart from histamine blockade: some also inhibit late phase allergic reaction by acting on leukotrienes or by antiplatelet activating factor effect.


Some recent compounds like fexofenadine and cetirizine that are active metabolites of earlier drugs have also been referred as ‘third generation antihistamines’, but this has not been accepted by an international concensus group of experts.


These newer drugs have the advantage of not impairing psychomotor performance (driving etc. need not be contraindicated), produce no subjective effects, no sleepiness, do not potentiate alcohol or benzodiazepines. Some patients do complain of sedation, but incidence is similar to placebo. However, they have a narrow spectrum of therapeutic usefulness which is limited by the extent of involvement of histamine (acting through H1 receptors) in the disease state. Their principal indications are:


·        Allergic rhinitis and conjunctivitis, hay fever, pollinosis—control sneezing, runny but not blocked nose, and red, watering, itchy eyes.


·        Urticaria, dermographism, atopic eczema.


·        Acute allergic reactions to drugs and foods. They have poor antipruritic, antiemetic and antitussive actions.




It is the active metabolite of terfenadine, the first nonsedating SGA that was withdrawn because of several deaths due to polymorphic ventricular tachycarida (Torsades de pointes) occurring with its higher doses or when it was coadministered with CYP3A4 inhibitors (erythromycin, clarithromycin, ketoconazole, itraconazole, etc.). This toxicity is based on blockade of delayed rectifier K+ channels in the heart at higher concentrations. Astemizole is another SGA banned for the same reason. Fexofenadine has a low propensity to block delayed rectifier K+ channels, does not prolong QTc interval; no interaction with CYP3A4 inhibitors have been reported. It is largely free of arrhythmogenic potential, but some cases of ventricular arrhythmia in patients with preexisting long QT interval have been reported. Thus, it is not entirely safe in patients with long QT, bradycardia or hypokalemia.



Fexofenadine does not cross blood-brain barrier—does not produce sedation or impair psychomotor performance and is free of atropinic side effects. It is rapidly absorbed, excreted unchanged in urine and bile, has plasma t½ 11– 16 hours and duration of action 24 hours. Though erythromycin and ketoconazole increase its blood levels, but no arrhythmias have been observed.


Dose: For allergic rhinitis 120 mg OD; for urticaria and other skin allergies 180 mg OD.





Another longacting selective peripheral H1 antagonist which lacks CNS depressant effects and is fast acting. It is partly metabolized by CYP3A4 to an active metabolite with a longer t½ of 17 hr, but has not produced cardiac arrhythmia in overdose, though seizures are reported. No interaction with macrolides or antifungals has been noted. Good efficacy has been reported in urticaria and atopic dermatitis.





It is the major active metabolite of loratadine effective at half the dose. Noninterference with psychomotor performance and cardiac safety are documented.





It is a metabolite of hydroxyzine with marked affinity for peripheral H1 receptors; penetrates brain poorly, but subjective somnolence has been experienced at higher doses. It is not metabolized; does not prolong cardiac action potential or produce arrhythmias when given with erythromycin/ketoconazole.


Cetirizine in addition inhibits release of histamine and of cytotoxic mediators from platelets as well as eosinophil chemotaxis during the secondary phase of the allergic response. Thus, it may benefit allergic disorders by other actions as well. It attains high and longer lasting concentration in skin, which may be responsible for superior efficacy in urticaria/atopic dermatitis, as well as for once daily dosing despite elimination t½ of 710 hr. It is indicated in upper respiratory allergies, pollinosis, urticaria and atopic dermatitis; also used as adjuvant in seasonal asthma.





It is the active R(–) enantiomer of cetirizine. It is effective at half the dose and appears to produce few side effects.





This newer H1 blocker has good topical activity; in addition inhibits histamine release and inflammatory reaction triggered by LTs and PAF; and has bronchodilator property. After intranasal application it has been shown to down regulate intracellular adhesion molecule1 (ICAM1) expression on nasal mucosa. Its t½ is 24 hr, but action lasts longer due to active metabolite. Its metabolism is inhibited by CYP 3A4 inhibitors. Given by nasal spray for seasonal and perennial allergic rhinitis it provides quick symptomatic relief lasting 12 hr. Stinging in the nose and altered taste perception are the local side effects. Some somnolence has been reported on nasal application and a tendency to weight gain noted after oral use.




This nonsedating antihistaminic is effective in allergic rhinitis and urticaria by single daily dosing despite a t½ of 8–10 hr and no active metabolite.




Another newer SGA that rapidly gets converted to the active metabolite carbastine having a t½ of 10–16 hr. It is non-sedating and active in nasal and skin allergies. Animal studies have found it to prolong QTc interval which makes it liable to arrhythmogenic potential and CYP3A4 interaction, but actual reports are still few.




This recently introduced antihistaminic has additional PAF antagonistic property, and is indicated in allergic rhinitis.


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