Background: Recent FDA approval for the over-the-counter (OTC) sale of Claritin® (loratadine) may increase ingestion of this class of antihistamine. Loratidine is a 2nd generation antihistamine.  Other 2nd generation antihistamines were recalled due to concerns with QT interval prolongation.  The question is unanswered as to whether high concentrations of Loratidine could prolong the QT.

There are three classes of H1 Antagonists:

First generation H₁ Antagonists

These agents have a similar structure including a main ring that binds competitively to BOTH histamine and muscarinic (anticholinergic) receptors and enables them to penetrate the central nervous system.  This accounts for the anticholinergic toxicity and CNS effects associated with their use and toxicity.

• Ethanolamine: diphenhydramine (Benadryl®), carbinoxamine (Rondec®) , doxylamine (NyQuil®)
  • Most sedating group, (carbinoxamine least sedating of the group)
• Alklamines: chlorpheniramine (Chlor-trimeton®), brompheniramine (Dimetapp®), tripolidine (Actifed®)
• Phenothiazines: promethazine (Phenergan®)
• Piperazine: hydroxyzine (Atarax®)
• Piperidine: cyproheptadine (Periactin®)
  • Also block serotonin receptors

Second Generation H₁ Antagonists

These agents lack the ring structure that binds to muscarinic (anticholinergic) receptors and have very little penetration into the central nervous system.

• Astemizole (Hismanal®) and Terfenadine (Seldane®) – both removed from the market following reports of Torsades de Pointes associated with their use.  Both had action as K⁺ channel blockers in the myocardium
• Loratadine –  studies show that in supratherapeutic dosing,  K⁺ channel blockade occurs in the myocardium.^*

At this time loratadine is considered to have a safety profile consistent with OTC availability.  However due to evidence of K⁺ channel blockade in the myocardium, some patients may be at increased risk of developing a prolonged QTc following administration.  The risk of this may be greatest in patients on multiple drugs which also prolong Qt, such as antipsychotics, tamoxifen, and erythromycin, or on drugs interfering with the metabolism of loratadine by  competing with microsomal enzymes CYP 450 3A4 and 2D6.

Third Generation H₁ Antagonists

These agents are all active metabolites of older agents.  They   lack the ring structure capable of binding to muscarinic receptors and have very little penetration into the central nervous system.  At this time, myocardial  K⁺ channel blockade  has not been observed.

• Fexofenadine (Allegra®, metabolite of terfenadine)
• Desloratadinne ( Clarinex®, metabolite of loratadine) – may have weak affinity for some variations of muscarinic receptors found on the iris and skin.
• Certriazine (Zyrtec®, metabolite of hydroxyzine) – does penetrate the CNS more than the other two.

References:

Lacerda AE, Roy ML, Lewis EW, Rampe D.  Interactions of the Nonsedating Antihistamine Loratadine with a Kv 1.5-Type Potassium Channel Cloned from Human Heart.  Molecular Pharmacology, 52:314-322 (1997)

Abernethy DR, Barbey JT, Franc J, et al.  Loratadine and terfenadine interaction with nefazodone: Both antihistamines are associated with QTc prolongation.  Clinical Pharmacology and Therapeutics, 69 (3):96-103 (2001).

Kosoglou T, Salfi M, Lim JM, et al.  Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine.  British Journal of Clinical Pharmacology, 50(6):581-589 (2000).

Paakkari I.  Cardiotoxicity of new antihistamines and cisapride.  Toxicology Letters, 127: 279-284 (2002).

Thanks to Kim Barker, Managing Director of the MTPC for the question of the week.

I am interested in any questions that you would like answered in “Question of the Week.”  Please e-mail me with any suggestions at donna.seger@Vanderbilt.edu

Donna Seger, M.D.

Medical Director, Middle Tennessee Poison Center