Terfenadine, arrhythmia with

Interactions. Drugs that lower gastric acidity, e.g. antacids, histamine H2 receptor antagonists, impair the absorption of ketoconazole from the gastrointestinal tract. Like all imidazoles, ketoconazole binds strongly to several cytochrome P450 isoenzymes and thus inhibits the metabolism (and increases effects of) oral anticoagulants, phenytoin and cyclosporin, and increases the risk of cardiac arrhythmias with terfenadine. A disulfiram-like reaction occurs with alcohol. Concurrent use of rifampicin, by enzyme induction of CYP 3A, markedly reduces the plasma concentration of ketoconazole. 

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 occurrence of cardiac toxicity was closely correlated with terfenadine use, and subsequent in vitro studies confirmed that terfenadine (but not fexofenadine) efficiently blocks cardiac potassium channels (14). A study in healthy volunteers treated concomitantly with terfenadine and ketoconazole found a linear relationship between trough terfenadine concentrations and QTC intervals. The QTC interval lengthened up to 110 millisecond at the highest plasma concentrations of 45 ng/mL (9). Thus, the direct inhibitory effect of terfenadine on cardiac potassium channels results in prolongation of cardiac repolarization, which is a well-known cause of ventricular arrhythmias. In one death in which terfenadine was implicated, plasma level of the drug was 55 ng/mL several hours after the last ingestion of the drug (when it normally should be undetectable). 

Pratt CM, Hertz RP, Ellis BE, et al. Risk of developing life-threatening ventricular arrhythmia associated with terfenadine in comparison with over-the-counter antihistamines, ibuprofen and clemastine. Am J Cardiol 1994 73 346-352. 

A patient being treated for springtime allergies with terfenadine develops an upper respiratory problem. He receives an antibiotic and develops a cardiac arrhythmia. What was the likely antibiotic ... 

Readers should be aware that terfenadine (Seldane ), the once widely-used, selective Hi histamine receptor antagonist, has been voluntarily withdrawn from the market by the manufacturer. The withdrawal was instituted because of the risk of life-threatening cardiac arrhythmias when terfenadine was taken concomitantly with drugs such as keto-conazole that inhibit the CYP3A4 isozyme of cytochrome P-450. The active metabolite of terfenadine is currently being marketed as fexofenadine [fecks o FEN a deen] (carboxylated terfenadine), which lacks the cardiac toxicity of terfenadine. 

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]. 

PROPAFENONE I. ANTIARRHYTHMICS - disopyra-mide, procainamide 2. ANTIBIOTICS - macrolides (especially azithromycin, clarithromycin, parenteral erythromycin, telithromycin), quinolones (especially moxifloxacin), quinupristin/ dalfopristin 3. ANTICANCER AND IMMUNOMODULATING DRUGS -arsenic trioxide 4. ANTIDEPRESSANTS - TCAs, venlafaxine 5. ANTIEMETICS-dolasetron 6. ANTIFUNGALS-fluconazole, posaconazole, voriconazole 7. ANTIHISTAMINES - terfenadine, hydroxyzine, mizolastine 8. ANTI-M ALARIALS - artemether with lumefantrine, chloroquine, hydroxychloroquine, mefloquine, quinine 9. ANTIPROTOZOALS - pentamidine isetionate 10. ANTIPSYCHOTICS-atypicals, phenothiazines, pimozide II. BETA-BLOCKERS - sotalol 12. BRONCHODILATORS -parenteral bronchodilators 13. CNS STIMULANTS - atomoxetine Risk of ventricular arrhythmias, particularly torsades de pointes Additive effect these drugs prolong the Q-T interval. Also, amitriptyline, clomipramine and desipramine levels may be t by propafenone. Amitriptyline and clomipramine may t propafenone levels. Propafenone and these TCAs inhibit CYP2D6-mediated metabolism of each other Avoid co-administration... 

SSRIs TERFENADINE Possibility oft plasma concentrations of these drugs and potential risk of dangerous arrhythmias These drugs are metabolized mainly by CYP3A4. Fluvoxamine and fluoxetine are inhibitors of CYP3A4 but are relatively weak compared with ketoconazole, which is possibly 100 times more potent as an inhibitor The interaction is unlikely to be of clinical significance but need to be aware... 

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