Interactions between calcium channel antagonists and quinine/quinidine.

Fråga: Interactions between calcium channel antagonists and quinine/quinidine.

Sammanfattning: Verapamil administration to patients receiving quinidine treatment may result in a reduced clearance of quinidine. Nifedipine and quinidine co-administration may increase nifedipine concentration, though there are conflicting data. However, it seems more unlikely that nifedipine could affect the quinidine clearance, although the information is ambiguous. Felodipine was found to reduce the metabolite formation of quinidine in one study.

The plasma levels of patients with these drug combinations should be carefully monitored.

No reports of an interaction between calcium channel antagonists and quinine have been found in the literature.

Svar: Quinidine appears to be metabolised by an oxidative isoenzyme of cytochrome P450 (P4503A4) that also metabolises nifedipine, verapamil, felodipine and other dihydropyridine calcium channel antagonists (1,2). A metabolic interaction between these drugs could therefore be suspected.

Verapamil has been shown to inhibit the metabolism of quinidine, resulting in increased levels of quinidine (3,4). In three case reports hypotension has been described after receiving the combination of oral quinidine and intravenous verapamil (5). Doses of oral quinidine (702-1944 mg/day) were, at least in one case, given up to steady-state. In two of the cases verapamil 5 mg was then given as a bolus injection and in the third case 2.5 mg were given by slow intravenous injection. However, it was not mentioned whether plasma levels of quinidine were measured before or after verapamil administration in these cases. It was proposed that a contributing factor to this hypotension may be an additive blockade of alpha-adrenergic receptors by quinidine and verapamil (5). Serum concentrations of quinidine (dose: 2592 mg/day) at steady-state have been shown to double after the administration of verapamil (80 mg x3), followed by hypotension, blurred vision and complete atrio-ventricular heart block (3,4). In another study where quinidine (1944 mg/day) and verapamil (320 mg/day) were given to a 23-year-old man, quinidine oral clearance was halved after verapamil administration and quinidine concentration at steady-state and half-life increased (from 1.5 ug/ml to 2.2 ug/ml and 2.9 hours to 5.9 hours respectively) (3, 6). In a randomised cross-over study (7) six subjects received a single 400 mg oral dose of quinidine before and after three days of verapamil treatment (240 mg/day and 360 mg/day). Quinidine half-life was prolonged from 6.9 hours to about 9 hours, and quinidine clearance was reduced by 25-42 per cent after the two dosage regimens. The metabolism of quinidine to 3-hydroxyquinidine was reduced by 60-70 per cent. The addition of verapamil to quinidine therapy may necessitate a reduction in the dose of quinidine.

Some data indicate that quinidine also appears to increase the serum concentration of nifedipine. This has been shown in a randomised, cross-over study by Bowels and co-authors (8), where 10 healthy subjects received oral quinidine (200 mg), nifedipine (20 mg) or the combination of both drugs up to steady-state. Concurrent administration of nifedipine and quinidine resulted in a significant reduction of nifedipine clearance with an increase (37 per cent) in nifedipine AUC. However, administration of quinidine to 10 subjects one hour before ingestion of an oral mixture of nifedipine, sparteine and mephenytoin (9) led to a prolonged half-life of nifedipine but not a statistically significant reduction in oral clearance and AUC. The disparity in the results between these two studies (8 and 9) could be due to differences in the two protocols.

Conversely, quinidine clearance was increased following nifedipine administration, reducing the concentration of quinidine by 20-40 per cent. This is based only on a single case report. The mechanism for this possible interaction is unclear (3,10). A possible mechanism has, among others, been suggested to include an increase in the volume of distribution for quinidine. However, in one study by Munger and co-workers (11), 12 patients were divided into two groups and treated with oral quinidine/oral quinidine plus nifedipine. Only one of these 12 patients had a 70 per cent increase in quinidine clearance and a 41 per cent reduction in steady-state serum concentration when nifedipine was added. The rest of the patients failed to show any interaction. Nifedipine did not seem to affect the concentration of quinidine in the study by Schellens either (9). Also, in contrast to earlier above-mentioned reports (10), quinidine concentrations in the study by Bowels and co-workers (8), were unchanged by the co-administration of nifedipine. It is therefore suggested that (8) it is unlikely that nifedipine has any significant effect on the hepatic elimination of quinidine. This was confirmed by Bailey and co-authors (12) who performed a double-blind placebo-controlled study with 12 subjects receiving three days of pretreatment with nifedipine prolonged action (40 mg/day) or felodipine extended release (10 mg/day) up to steady-state followed by co-administration of quinidine (400 mg). The quinidine pharmacokinetics was not altered by the two calcium channel antagonists. However, the AUC of 3-hydroxyquinidine and the 3-hydroxyquinidine/quinidine AUC ratio were decreased by felodipine, consistent with reduced metabolite formation. In this paper it is concluded that quinidine disposition does not appear to be sufficiently changed by sustained-release forms of nifedipine and felodipine to be of clinical importance.

Diltiazem (120 mg/day) did not have any effect on quinidine concentrations (3).

No reports of an interaction between calcium channel antagonists and quinine have been found. 1 Guengerich FP, M:uller-Enoch D, Blair IA: Oxidation of quinidine by human liver cytochrome P450. Mol Pharmacol 1986; 30: 287-295 2 Guengerich FP, Brian WR, Iwasaki M, Sari MA, B:a:arnhielm C, Berntsson P: Oxidation of dihydropyridine calcium channel blockers and analogues by human liver cytochrome P450 IIIA4. J Med Chem 1991; 34: 1838-1844 3 Hansten, Horn, Drug Interactions & Updates, 1971- 4 FASS 1994 5 Maisel AS, Motulsky HJ, Insel PA: Hypotension after quinidine plus verapamil. N Engl J Med 1985; 312: 167-170 6 Trohman RG, Estes DM, Castellanos A, Palomo AR, Myerburg RJ, Kessler KM: Increased quinidine plasma concentrations during administration of verapamil: A new quinidine-verapamil interaction. Am J Cardiol 1986; 57: 706-707 7 Edwards DJ, Lavoie R, Beckman H, Blevins R, Rubenfire M: The effect of coadministration of verapamil on the pharmacokinetics and metabolism of quinidine. Clin Pharmacol Ther 1987; 41: 68-73 8 Bowles SK, Reeves Ra, Cardozo L, Edwards DJ: Evaluation of the pharmacokinetic and pharmacodynamic interaction between quinidine and nifedipine. J Clin Pharmacol 1993; 33: 727-731 9 Schellens JHM, Ghabrial H, van der Wart HHF, Bakker EN, Wilkinson GR, Breimer DD: Differential effects of quinidine on the disposition of nifedipine, sparteine, and mephenytoin in humans. Clin Pharmacol Ther 1991; 50: 520-528 10 Van Lith RM, Appleby DH: Quinidine-Nifedipine interaction. Drug Intell Clin Pharm 1985; 19: 829-831 11 Munger MA, Jarvis RC, Nair R, Kasmer RJ, Nara AR, Urbancic A, Green JA: Elucidation of the nifedipine-quinidine interaction. Clin Pharmacol Ther 1989; 45: 411-416 12 Bailey DG, Freeman DJ, Melendez LJ, Kreeft JH, Edgar B, Carruthers SG: Quinidine interaction with nifedipine and felodipine: Pharmacokinetic and pharmacodynamic evaluation. Clin Pharmacol Ther 1993; 53: 354-359