What medicines are they?
Five examples of famous second-generation antihistamines are cetirizine, terfenadine, astemizole, ebastine, and loratadine.
What are their advantages compared to first-generation antihistamines?
First-generation antihistamines have several weaknesses; namely their tendency to cross blood-brain barrier and consequent sedative-anticholinergic side effects. Their half-life is also shorter, thus limiting their efficacy against allergic symptoms. These weaknesses have been "covered" by the second-generation antihistamines.
Overall, antihistamines are rapidly and completely absorbed after oral administration with peak plasma concentration reached within 1-4 hours. Most of second-generation antihistamines undergo an extensive first-pass metabolism via cytochrome P450 (Cyp3A4). But several of them (e.g. mizolastine) is not metabolized by this pathway, but by glucuronidation enzyme.
What cardiotoxicity effect they cause?
QT prolongation and torsades de pointes.
Why do some second-generation antihistamines cause cardiotoxicity effect?
Some second-generation antihistamines have highly lipophilic general structure, so that the active ingredient binds stronger with lean tissue and may account for some organic toxicity. For examples: loratadine and cetirizine. Ventricular arrhythmia (torsades de pointes) firstly reported with astemizole, then with terfenadine. Finally, European Commission and US FDA withdrew these medications (terfenadine 120 mg, all terfenadine-pseudoephedrine and astemizole).
How astemizole and terfenadine cause cardiotoxicity effect?
Both of these medicines are metabolized by cytochrome system, to be therapeutically-active metabolite. Accumulation of unmetabolized compound can result in blockage of cardiac potassium ion channel, which is important in regulation of potential action of cardiac rhythm; especially QT interval. Disturbance on this regulation may cause fatal arrhythmia. The disturbance may occur more frequently in patients with history of liver disease, concomitant therapy with macrolides, congestive heart failure or ischemic heart disease, and electrolyte imbalance.
How about loratadine, cetirizine, and fexofenadine: are they really cardio-safe?
Based on cardio-safety, loratadine's results in animal trials and human data are conflicting. In human, loratadine has not shown any effect on QT prolongation. But in animal study, this effect still emerges.
Cetirizine is the only second-generation antihistamine which is considered as "really safe" for the heart. Cetirizine never show any prolongation of QT interval in any studies which have been conducted. Even in the case report of cetirizine accidental overdose. So does levocetirizine, newer generation of antihistamine that is derived from cetirizine's enantiomer.
Theoritically, fexofenadine is said to be the cardio-safe active metabolite of terfenadine. But from field experience, fexofenadine still causes QT interval lengthening and life-threatening arrhythmia in patients with mild hypertension or mild left-ventricular hypertrophy.
What about the interactions?
Second-generation antihistamines are interacting with several macrolides (erythromycin, clarithromycin, and azithromycin) and ketokonazole. This effect is due to CYP3A4 inhibitor effect. So it is better if macrolide antibiotics are not given concomitantly with second-generation antihistamines in patient with history of heart disease, liver disease, or electrolyte imbalance.
What about the Third-Generation Antihistamines?
This cardiotoxicity pushed scientists to create newer compound with safer effects to the heart. Desloratadine as cardio-safe-form of loratadine, while levocetirizine is an L-enantiomer of racemic cetirizine. Both of them are non-sedating antihistamines.
References
French LK. Antihistamine Toxicity. URL = http://emedicine.medscape.com/article/812828-overview (last updated: May 05, 2010)
Rang & Dale's Pharmacology 11th edition; 2010: 332-334
Walsh GM et al. Drugs 2001; 61 (2): 207-236
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