Astemizole, arrhythmia with

Azole anti fungal s Arrhythmias with astemizole... 

In vitro studies have shown that ketoconazole inhibits the metabolism of astemizole. Ketoconazole, and to a lesser extent itraconazole and miconazole, also appear to reduce the metabolism of terfenadine by inhibition of the cytochrome P450 isoenzyme CYP3A. " High serum levels of astemizole and terfenadine (but not its metabolites) block cardiac potassium channels leading to prolongation of the QT interval, which may precipitate the development of torsade de pointes arrhythmia (see Table 15.2 , (p.583)). The risk of cardiac arrhythmias with other non-sedating antihistamines appears to be non-existent or very much lower (see Table 15.2 , (p.583)), so any pharmacokinetic interactions do not result in clinically relevant cardiac toxicity. In fact, studies have shown that desloratadine at nine times the recommended dose, fexofenadine in overdose, and mizolastine at four times the recommended dose do not affect the QT interval. However, some questions remain about loratadine and ebastine. Additionally, some studies have reported that ketoconazole alone is associated with a small increase in QT interval, and at least one case of torsade de pointes has been reported for ketoconazole alone. Therefore the cardiac effects of ketoconazole may be additive with those of the antihistamines, and this may be important for ebastine and loratadine. 

Some macrolides (particularly erythromycin and clarithromycin) appear to reduce the metabolism of terfenadine and astemizole by inhibition of the cytochrome P450 isoenzyme CYP3A. High serum levels of astemizole and terfenadine cause a prolongation of the QT interval and may precipitate the development of torsade de pointes arrhythmia, see Table 15.2 , (p.583). The risk of cardiac arrhythmias with other non-sedating antihistamines appears to be non-existent or very much lower (see Table... 

Concomitant administration of clarithromycin with cisapride, pimozide, astemizole, or terfenadine is contraindicated. There have been postmarketing reports of drug interactions when clarithromycin and/ or erythromycin are coadministered with cisapride, pimozide, astemizole, or terfenadine resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes). 

The newer drugs therefore represent a substantial improvement over original antihistamines. They are not, however, devoid of side effects. For example, certain nonsedating antihistamines such as astemizole and terfenadine may be cardiotoxic, and problems such as severe ventricular arrhythmias (torsades de pointes) have occurred when these drugs are taken in high doses or taken by individuals with preexisting cardiac and liver problems.70,71 These cardiac effects, however,... 

The serious effects of terfenadine on K+-H ERG (human ether-a-go-go related gene) channels leading to cardiac arrhythmia are not seen with fexofenadine, and this is why terfenadine - despite widespread use - was subsequently replaced by fexofenadine. This serious adverse effect is also seen for astemizole, another second-generation antihistamine. This problem is not confined to second-generation antihistamines, as some older first-generation antihistamines produce similar effects [21]. 

Macrolide antibiotics are contraindicated in patients with known hypersensitivity or intolerance to any macrolide. Because clarithromycin can have adverse effects on embryo-fetal development in animals, this drug should be avoided in pregnant women unless no other therapy is appropriate. Concurrent administration of the macrolides and astemizole or terfenadine can cause elected antihistamine levels, resulting in life-threatening cardiac arrhythmias, and should be avoided. 

Astemizole is a second-generation antihistamine that has been withdrawn from the market becanse of the association with life-threatening cardiac arrhythmias. 

Torsades de pointes, a life-threatening ventricular arrhythmia associated with QT prolongation, can occur when these inhibitors are coadministered with terfena-dine, astemizole, or cisapride because they inhibit these agents from converting the parent compound into nontoxic, pharmacologically active metabolites. 

Erythromycin and propably clarithromycin inhibit this metabolism, and the increased terfenadine serum concentration can result in cardiac arrhythmias (e.g., torsades de pointes). Early evidence suggests that astemizole can produce the same result if combined with erythromycin. Erythromycin also inhibits the metabolism of loratadine however, loratadine does not appear to be cardiotoxic. 

The azole antifungals raise the levels of astemizole and terfena-dine, which can result in life-threatening arrhythmias. Arrhythmias have been reported for astemizole with ketoconazole, and terfenadine with itraconazole, ketoconazole, and even topical ox-iconazole. Consequently all azoles are contraindicated with astemizole and terfenadine. 

A 63-year old woman developed torsade de pointes arrhythmia and was found to have a prolonged QT interval after taking astemizole and ketoconazole. These two drugs were withdrawn and she was successfully treated with a temporary pacemaker, magnesium sulphate and lidocaine. She was later discharged with a normal ECG. ... 

Astemizole and terfenadine should generally not be used with other drugs that can also prolong the QT interval. The manufacturer of mizolastine issues the same advice. One early study found that hydroxyzine caused ECG abnormalities in high doses. The authors suggested that its use with other drugs that can cause cardiac abnormalities might increase the likelihood of arrhythmias and sudden death, but there is no published evidence of this. 

Erythromycin causes terfenadine and astemizole to accumulate in a few individuals, which can prolong the QT interval and lead to life-threatening torsade de pointes arrhythmias. Cases of torsade de pointes have been reported for astemizole with erythromycin, and terfenadine with erythromycin or troleandomycin. Other macrolides are believed to interact similarly, with the exception of azithromycin and possibly dirithromycin. 

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