Dosage forms: Tablets (1 mg) Usual dosage: 1 to 2 mg twice daily
Initial design efforts toward new or second-generation anti-histamines focused on developing agents with a lower sedation potential and reduced binding affinities for nontarget proteins including muscarinic, adrenergic, and serotonergic receptors. These efforts led to the introduction of astemizole and terfenadine, derivatives of the first-generation agents with substantially larger N-tertiary amine substituents (Fig. 23.13). Astemizole and terfenadine proved to be "nonsedating" and target-receptor selective, but extensive clinical use uncovered serious cardiovascular toxicities (QT prolongation and arrhythmias).10,33,34 These cardiac actions appear to result from the blockade of the rapid component of delayed rectifier potassium current (IKr) by astemizole and terfenadine, even at therapeutic concentrations. Blocking the rectifier current causes prolongation of the monophasic cardiac action potential and QT interval, as well as induction of early after-depolarizations and dispersion (slowing) of repolarization, resulting in torsades de pointes.10 Furthermore, such cardiac effects were observed more commonly when astemizole and terfenadine were administered with other drugs that inhibit their cytochrome metabolism, such as the imidazole antifun-gals (ketoconazole, itraconazole) and the macrolides (erythromycin, clarithromycin). Through this drug interaction, astem-izole and terfenadine levels would rise and the incidence of untoward cardiac events increases. As a result of these concerns, both astemizole and terfenadine have been withdrawn from the U.S. market. The newer second-generation ^-antihistamines described later have significantly reduced IKr current-blocking capacity, and have demonstrated significantly lower cardiotoxicity in clinical use.
Further drug design efforts resulted in the discovery of new second-generation agents, which retained the nonsedat-ing and receptor-selectivity properties, but lacked the car-diotoxicity of astemizole and terfenadine. These newer agents are structurally diverse, but are derivatives of first-generation drugs, containing larger, polar functionality connected either to the terminal tertiary amine, or as a substituent of one of the aromatic rings. The new second-generation drugs currently on the market include acrivastine, an alkene-acid derivative of triprolidine; cetirizine and levocetirizine, oxidation metabolites of hydroxyzine; desloratadine, an oxidation-hydrolysis metabolite of loratadine; and fexofenadine, an oxidative metabolite of terfenadine.10 In addition to their H1-receptor selectivity, these second-generation agents do not accumulate in the CNS because their hydrophilicity (in some cases) and high affinity for P-glycoprotein efflux pumps of cells associated with the BBB.10,42,43 The propensity of these drugs to occupy CNS H1-receptors varies from 0% for fexofenadine to 30% for cetirizine. The properties of these drugs are described in more detail in the monographs that follow.44
Fexofenadine Hydrochloride. Fexofenadine hydrochloride, (± )-4-[1-hydroxy-4-[4-(hydroxyldiphenyl-methyl)-1-piperinyl]butyl-a,a-dimethylbenzeneacetic acid (Allegra), occurs as a white to off-white crystalline powder that is freely soluble in methanol and ethanol, slightly soluble in chloroform and water, and insoluble in hexane. This compound is marketed as a racemate and exists as a zwitterion in aqueous media at physiological pH.
Fexofenadine is a primary oxidative metabolite of terfenadine.45 Terfenadine was developed during a search for new butyrophenone antipsychotic drugs as evidenced by the presence of the N-phenylbutanol substituent. It also contains a diphenylmethyl-piperidine moiety analogous to that found in the piperazine antihistamines. Terfenadine is a selective, long-acting (>12 hours) ^-antihistamine with little affinity for muscarinic, serotonergic, or adrenergic receptors. The histamine receptor affinity of this compound is believed to be related primarily to the presence of the diphenylmethylpiperi-dine moiety. The prolonged action results from very slow dissociation from these receptors. The lack of anticholinergic, adrenergic, or serotonergic actions appears to be linked to the presence of the N-phenylbutanol substituent (Table 23.2). This substituent contributes to P-glycoprotein efflux pump affinity,
Figure 23.13 • Structures of terfenadine and astemizole.
which serves to limit accumulation of terfenadine in the CNS. Terfenadine undergoes significant first-pass cytochrome P450 (CYP)-based metabolism, with the predominant metabolite being fexofenadine, an active metabolite resulting from methyl group oxidation. When drugs that inhibit this transformation, such as the imidazole antifungals and macrolides, are used concurrently, terfenadine levels may rise to toxic levels, resulting in potentially fatal heart rhythm problems that were described. The observation that fexofenadine displays antihis-taminic activity comparable with that of terfenadine but is less cardiotoxic led to its development as an alternative to terfenadine for the relief of the symptoms of seasonal allergies.
Fexofenadine, like terfenadine, is a selective peripheral Hi-receptor ligand that produces no clinically significant anticholinergic effects or ^-adrenergic receptor blockade at therapeutic doses (Table 23.2). No sedative or other CNS effects have been reported for this drug, and animal studies indicate that fexofenadine does not cross the BBB. In vitro studies also suggest that unlike terfenadine, fexofenadine does not block potassium channels in cardiocytes. Furthermore, in drug interaction studies, no prolongation of the QTc interval or related heart rhythm abnormalities were detected when fexofenadine was administered concurrently with erythromycin or ketoconazole.10,46
Fexofenadine is indicated for the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria. It is rapidly absorbed after oral administration, producing peak serum concentrations in about 2.5 hours. Fexofenadine is 60% to 70% plasma protein bound. Unlike its parent drug, only 5% of the total dose of fexofenadine is metabolized. The re
mainder is excreted primarily in the urine; the mean elimination half-life is about 14 hours (Table 23.3).10
Dosage form: Tablets (30, 60, and 180 mg), oral disintegrating tablets (30 mg), and an oral suspension (6 mg/mL) Usual doses:
• Chronic idiopathic urticaria: 60 mg twice daily or 180 mg once daily in adults and children >12; lower doses are recommended in children
• Seasonal allergic rhinitis: 60 mg twice daily or 180 mg once daily in adults and children >12; lower doses are recommended in children
Loratadine. Loratadine, 4-(8-chloro-5, 6-dihydro- 11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-l 1-ylidene-1-carboxylic acid ethyl ester, is a white to off-white powder insoluble in water but very soluble in acetone, alcohols, and chloroform. Loratadine is structurally related to the antihistamines azata-dine and cyproheptadine, and to some tricyclic antidepressants. It differs from azatadine, in that a neutral carbamate group has replaced the basic tertiary amino moiety, and a phenyl ring has been substituted with a chlorine atom.
Loratadine is a selective peripheral ^-antihistamine with a receptor-binding profile like that of the other members of this series, except that it has more antiserotonergic activity (Table 23.2). Thus, it produces no substantial CNS or autonomic side effects or cardiac toxicity. Loratadine displays potency comparable with that of astemizole and greater than that of terfenadine.
Loratadine is indicated for the relief of nasal and nonnasal symptoms of seasonal allergic rhinitis. It is rapidly absorbed after oral administration, producing peak plasma levels in about 1.5 hours. This drug is extensively metabolized by oxidation of the carbamate methylene group, a reaction catalyzed by CYP3A4 and, to a lesser extent, CYP2D6 (Table 23.3). This oxidation metabolite readily undergoes O-demethylation and decarboxylation to form the descar-boethoxy metabolite (desloratadine), which appears to be responsible for antihistaminic activity.47-49 In the presence of a CYP3A4 inhibitor ketoconazole, loratadine is metabolized to descarboethoxyloratadine predominantly by CYP2D6. Concurrent administration of loratadine with either ketoconazole, erythromycin (both CYP3A4 inhibitors), or cimetidine (CYP2D6 and CYP3A4 inhibitor) is associated with substantially increased plasma concentrations of loratadine.10,48 Both parent drug and active metabolite have elimination half-lives ranging from 8 to 15 hours. The metabolite is excreted renally as a conjugate (Table 23.3).10
Dosage forms: Tablets (5 and 10 mg), oral disintegrating tablets (5 and 10 mg), syrup (5 mg/5 mL) Usual adult dose (allergic rhinitis): 10 mg once daily (adults and children 6 years of age and older), 5 mg (chewable tablets, syrup) once daily for children 2 to 5 years of age
Desloratadine. Desloratadine, 8-chloro-6,11 -dihydro-11-(4-piperdinylidene)-5H-benzo[5,6]cyclohepta[1,2-£]pyri-dine (Clarinex) is a white to off-white powder that is slightly soluble in water, but very soluble in ethanol and propylene glycol. It is the proposed active metabolite loratadine and has a very similar receptor binding and safety profile (Table 23.2). It is indicated for the symptomatic relief of pruritus and reduction in the number and size of hives in chronic idio-pathic urticaria patients 6 months of age and older and for the relief of the nasal and nonnasal symptoms of perennial allergic rhinitis (in patients 6 months of age and older) and seasonal allergic rhinitis (in patients 2 years of age and older).
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