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Clinical Pharmacology of New Histamine H1 Receptor Antagonists

  • Review Article
  • Pharmacokinetic-Pharmacodynamic Relationships
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Abstract

The recently introduced H1 receptor antagonists ebastine, fexofenadine and mizolastine, and the relatively new H1 antagonists acrivastine, astemizole, azelastine, cetirizine, levocabastine and loratadine, are diverse in terms of chemical structure and clinical pharmacology, although they have similar efficacy in the treatment of patients with allergic disorders.

Acrivastine is characterised by a short terminal elimination half-life (t1/2,β) [1.7 hours] and an 8-hour duration of action. Astemizole and its metabolites, in contrast, have relatively long terminal t1/2,β values; astemizole has a duration of action of at least 24 hours and is characterised by a long-lasting residual action after a short course of treatment. Azelastine, which has a half-life of approximately 22 hours, is primarily administered intranasally although an oral dosage formulation is used in some countries.

Cetirizine is eliminated largely unchanged in the urine, has a terminal t1/2,β of ∼7 hours and a duration of action of at least 24 hours. Ebastine is extensively and rapidly metabolised to its active metabolite; carebastine, has a half-life of ∼15 hours and duration of action of at least 24 hours. Fexofenadine, eliminated largely unchanged in the faeces and urine, has a terminal t1/2,β of ∼14 hours and duration of action of 24 hours, making it suitable for once or twice daily administration.

Levocabastine has a terminal t1/2,β of 35 to 40 hours regardless of the route of administration, but is only available as a topical application administered intranasally or ophthalmically in patients with allergic rhinoconjunctivitis. Loratadine is rapidly metabolised to an active metabolite descarboethoxyloratadine and has a 24-hour duration of action. Mizolastine has a terminal t1/2,β of ∼13 hours and duration of action of at least 24 hours.

Most orally administered new H1 receptor antagonists are well absorbed and appear to be extensively distributed into body tissues; many are highly protein-bound. Most of the new H1 antagonists do not accumulate in tissues during repeated administration and have a residual action of less than 3 days after a short course has been completed. Tachyphylaxis, or loss of peripheral H1 receptor blocking activity during regular daily use, has not been found for any new H1 antagonist.

Understanding the pharmacokinetics and pharmacodynamics of these new H1 antagonists provides the objective basis for selection of an appropriate dose and dosage interval and the rationale for modification in the dosage regimen that may be needed in special populations, including elderly patients, and those with hepatic dysfunction or renal dysfunction. The studies cited in this review provide the scientific foundation for using the new H1 antagonists with optimal effectiveness and safety.

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  1. Faculty of Medicine, The University of Manitoba, and the Children’s Hospital of Winnipeg, 820 Sherbrook Street, Winnipeg, Manitoba, R3A 1R9, Canada

    F. Estelle R. Simons

  2. Faculties of Pharmacy and Medicine, The University of Manitoba, Winnipeg, Manitoba, Canada

    Keith J. Simons

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Simons, F.E.R., Simons, K.J. Clinical Pharmacology of New Histamine H1 Receptor Antagonists. Clin Pharmacokinet 36, 329–352 (1999). https://doi.org/10.2165/00003088-199936050-00003

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