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Clinician’s Corner: 2nd and 3rd Generation Antihistamines

Last week we discussed the role of antihistamines in the treatment of seasonal allergies, and delineated the three generations of antihistamines.  Since everything we do as practicing clinicians revolves around patient care, let’s discuss counseling points to share with each patient that utilizes our expertise.

SECOND GENERATION ANTIHISTAMINES:  do NOT cross BBB, causing minimal sedation, and NO anticholinergic side effects.

  • PREGNANCY: ACOG also recommends cetirizine and loratadine after the first trimester in patients who cannot tolerate or do not respond to maximal doses of chlorpheniramine. (All three drugs are Pregnancy Category B)
  • FYI: Cetirizine is the active metabolite of the prescription drug Hydroxyzine (Vistaril®, Atarax®)
  • REMEMBER SELDANE® ?? (removed from market in 1998) Fexofenadine is a primary metabolite of terfenadine (SeldaneRx). When terfenadine’s hepatic conversion to the fexofenadine was blocked by other drugs or disease, levels of the parent drug (terfenadine) rise resulting in heart rhythm disturbances. Fexofenadine is effective in allergic disorders, and less cardiotoxic.
  • REMEMBER HISMANAL®??(removed from market in 1999) Astemizole was the active ingredient in this second-generation antihistamine. This drug was also removed due to QTc interval prolongation and related arrhythmias when used with high doses, especially when taken with CYP inhibitors or grapefruit juice. This product was marketed by Janssen Pharmaceuticals.

THIRD GENERATION are the “active enantiomers” of the second generation antihistamines

  • FEXOFENADINE: Fruit juices such as grapefruit, orange and apple juice may decrease the oral bioavailability of fexofenadine by inhibiting the activity of OATP1A2. Fexofenadine is a substrate of the intestinal uptake transporters organic anion transporting polypeptide 1A2.
  • DESLORATADINE: Desloratadine is the active metabolite of loratadine.
    • Novel use for treatment Lyme Disease: Loratadine metabolite “desloratadine” blocks BmtA (Borrelia metal transporter A). Desloratadine (which is the brand name “Clarinex”) blocks manganese from entering the cell. Transition metals, including iron (Fe), zinc (Zn), and manganese (Mn), are critical to both bacterial metabolism and virulence. When these metals are blocked it starves the Borrelia burgdorferi and causing it to die in test tubes.  Obviously this is way too early in the research phase for us to recommend this to our patients, so we will have to wait and see. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330029/
Generic Brand Sedation Anticholinergic Maximum daily dose
FIRST GENERATION        
Chlorpheniramine Chlor-Trimeton Low-moderate Moderate 24mg
Clemastine Tavist-1 Moderate High 2.68mg
Diphenhydramine Benadryl High High 200mg
SECOND GENERATION        
Cetirizine Zyrtec Low-moderate Low to none 10mg
Loratadine Claritin Low to none Low to none 10mg
THIRD GENERATION        
Fexofenadine Allegra Low to none Low to none 180mg
Desloratadine (Rx) Clarinex Low to none Low to none 5mg/day
Levocetirizine (Rx) Xyzal Low to moderate Low to none 5mg/day