Q:

6/30/2014
Do you have an estimate as to how long it takes for an oral antihistamine to blunt the effect of histamine in the skin (such as for suppressing idiopathic urticaria or an allergy skin prick or intradermal test)? According to what I read, the time-to-peak plasma concentration for cetirizine and diphenhydramine is one hour after ingestion, but does that necessarily mean that the antihistamine concentration is also at its peak in the skin tissue one hr after ingestion?

A:

Thank you for your inquiry.

The pharmacodynamics of antihistamines vary according to the drug in question and the route of administration. There are several excellent studies on the pharmacodynamics which include the time of onset of action and peak activity. The two abstracts and the reference copied below are good sources of such information, and you will find in the Simons reference a number of other studies which you can use as a resource. You will see from these articles that the pharmacokinetics reflected in the time to peak plasma concentration do not necessarily correlate with the time of onset of action nor the time of peak tissue activity (pharmacodynamics activity).

Thank you again for your inquiry and we hope this response is helpful to you.

Time-dependent inhibition of histamine-induced cutaneous responses by oral and intramuscular diphenhydramine and oral fexofenadine.
Annals of Allergy, Asthma & Immunology
Volume 100, Issue 5, Pages 452–456, May 2008.
Background: Diphenhydramine is often the treatment of choice for acute urticarial or allergic reactions despite its adverse effects of sedation and impairment. Second- and third-generation histamine1-antihistamines are generally devoid of these adverse effects but are typically not used because of a perceived slower onset of action.
Objective: To examine the time-dependent effects of oral fexofenadine and oral and intramuscular diphenhydramine to reduce histamine-induced wheal-and-flare responses.
Methods: Eighteen healthy patients were included in a double-blind, placebo-controlled, 3-way, randomized, crossover study with oral fexofenadine (180 mg) and oral and intramuscular diphenhydramine (50 mg). Histamine-induced skin tests were performed before and more than 6 hours subsequent to dosing. The primary end point was time to induce a 50% reduction in histamine-induced flare. Secondary end points included change from baseline at each time point in wheal-and-flare responses and area under the curve at more than 6 hours for flare.
Results: No significant differences were found in the 50% inhibitory responses of histamine-induced flares among the 3 groups (P = .09). No significant differences were found among the 3 groups in change from baseline at each time point except for 30 minutes during which fexofenadine had no inhibitory effect. Area under the curve analyses for wheal-and-flare responses revealed no differences among treatments at more than 6 hours.
Conclusion: Diphenhydramine tended to work more rapidly than fexofenadine, but the differences were not statistically significant. Given the adverse effect profile of diphenhydramine, but only marginal onset of action advantage, the risk-to-benefit ratio may be more favorable for oral fexofenadine when treating an acute urticarial or allergic reaction.

A double-blind, randomized, single-dose, crossover comparison of levocetirizine with ebastine, fexofenadine, loratadine, mizolastine, and placebo: suppression of histamine-induced wheal-and-flare response during 24 hours in healthy male subjects. Annals of Allergy, Asthma & Immunology, Volume 88, Issue 2, Pages 190-197, February 2002.
Background: Levocetirizine is the active enantiomer of cetirizine, a potent drug with little metabolism widely used for allergic rhinitis and urticaria.
Objective: This study compares the potency, consistency, onset, and duration of action of levocetirizine with other popular antihistamines.
Methods: Levocetirizine 5 mg, ebastine 10 mg, fexofenadine 180 mg, loratadine 10 mg, mizolastine 10 mg, or placebo in single doses were given to 18 healthy male volunteers in a double-blind, crossover, randomized fashion. Wheal-and-flare responses to epicutaneous histamine dihydrochloride (100 mg/mL) challenge were measured at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after each dose.
Results: The overall effect of each drug was evaluated by the area under the curve (0 to 24 hours). Levocetirizine was the most potent and consistently effective drug for inhibiting the histamine-induced wheal-and-flare surface areas. Ebastine, fexofenadine, and mizolastine ranked next and had almost identical effects for inhibiting the wheal. Loratadine was the least potent drug. Levocetirizine, fexofenadine, and mizolastine inhibited the wheal-and-flare response after 1 hour and reached their peak for inhibition after 4 hours. Ebastine and loratadine could be distinguished from placebo only after 4 hours. After treatment with levocetirizine, all 18 subjects had >95% inhibition of the wheal response at one timepoint. Fexofenadine, mizolastine, and ebastine were inhibitory in declining order. All treatments were considered safe and well tolerated.
Conclusions: Levocetirizine, the active enantiomer of cetirizine, is more potent and consistent than other popular H1 antihistamines for blocking the cutaneous response to histamine. These findings may predict the efficacy of this drug in treating allergic disorders.

Reference:
F. Estelle R. Simons, M.D. Advances in H1-Antihistamines. N Engl J Med 2004; 351:2203-2217 November 18, 2004DOI: 10.1056/NEJMra033121.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology