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 :
SECOND GENERATION 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 :
·
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.
Fexofenadine
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nonsedating SGA that was withdrawn because of several deaths due to polymorphic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.
Loratadine
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.
Desloratadine
It is the major active metabolite of loratadine effective at half the dose. Noninterference
with psychomotor performance and cardiac safety are documented.
Cetirizine
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.
Levocetirizine
It is the active R(–) enantiomer of cetirizine. It is effective at half the dose
and appears to produce few side effects.
Azelastine
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.
Mizolastine
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.
Ebastine
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.
Rupatadine
This
recently introduced antihistaminic has additional PAF antagonistic property,
and is indicated in allergic rhinitis.
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