Pharmacogenetic explanation for excessive beta-blockade following timolol eye drops: potential for oral-ophthalmic drug interaction

Article Abstract:

The simultaneous administration of topical timolol eye drops and oral quinidine can inhibit of metabolism of the timolol, possibly due to the CYP2D6-inhibiting qualities of the quinidine. Timolol is a common topical drug for glaucoma, and it is possible that the drug may be less effective in patients who lack the enzyme CYP2D6. Researchers studied the effects of timolol eye drops given topically with the oral administration of quinidine in 13 male subjects who were either extensive metabolizers (EMs) or poor metabolizers (PMs) of debridement, a marker for CYP2D6 metabolism. The participants exercised on a treadmill and their heart rates were measured before being administered two drops of timolol solution or artificial tears (placebo) in each nostril. The debrisoquin phenotype appeared to affect the systemic response of beta-blockade after using topical timolol. In EMs and PMs, the exercise heart rate dropped following administration of the timolol eye drops compared to the placebo, but a greater reduction was noted in the PMs. The CYP2D6 phenotype may be influential in determining beta-blockade following timolol.

Research, Drug therapy, Dosage and administration, Glaucoma, Pharmacogenetics, Pharmacogenomics, Quinidine, Timolol maleate

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Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences

Article Abstract:

The anti-fungal drug ketoconazole appears to interfere with the body's metabolism of terfenadine. Terfenadine is a commonly prescribed antihistamine that is normally metabolized rapidly. Previous studies have found though, that unmetabolized terfenadine is associated with abnormal electrical activity of the heart and increases the risk of potentially fatal arrhythmias. Six healthy volunteers began taking terfenadine twice daily. After six days they also began taking ketoconazole. Only one patient had detectable levels of unmetabolized terfenadine in the first six days. After starting ketoconazole however, all had detectable levels of unmetabolized terfenadine. All of the patients had normal electrical activity of the heart after six days of terfenadine alone. However, when both drugs were taken, all patients had abnormal electrocardiogram results. The magnitude in the change of electrical activity strongly corresponded with levels of unmetabolized terfenadine. These findings indicate that ketoconazole should not be taken with terfenadine.

Ketoconazole

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Mechanism of the cardiotoxic actions of terfenadine

Article Abstract:

Improper metabolism of the antihistamine terfenadine may induce torsades de pointes. Terfenadine is normally metabolized rapidly in the liver to its active form, terfenadine carboxylate. Torsades de pointes is an abnormally fast beating of the heart ventricle. Twenty-five reports of torsades de pointes associated with terfenadine therapy were studied. Two patients died and the others were all hospitalized. Three patients intentionally overdosed on terfenadine, and four took higher than recommended doses. Eleven had taken drugs known to inhibit terfenadine metabolism and six had cirrhosis, a kind of liver disease, or a history of alcohol abuse. Altogether, 20 of the patients either overdosed or had impaired metabolism that would contribute to abnormally high levels of terfenadine. Laboratory studies of terfenadine carboxylate found that even at very high concentrations, the active form did not impair electrical activity. These findings indicate that the drug itself, not its metabolite, induces torsades de pointes.

Risk factors, Drug metabolism, Torsade de pointes

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