The effects of quinidine on pharmacokinetics and pharmacodynamics of propranolol were investigated in a double-blind, placebo-controlled design. Healthy subjects of group A (n = 5) and group B (n = 11) were given oral propranolol (dose: group A 10 mg, group B 20 mg) with placebo or propranolol with quinidine (dose: group A 100 mg, group B 200 mg) on separate occasions. Quinidine induced a significant rise in the plasma concentrations of propranolol, and the area under the propranolol concentration-time curves (AUC) was also increased about 3-fold in both groups, indicative of an alteration of propranolol pharmacokinetics. In order to estimate the pharmacodynamic action of the pharmacokinetic interaction, the change in the heart rate during treadmill exercise testing was studied in group A. A significant inhibition of exercise-induced tachycardia was observed after administration of propranolol alone, but in combination with quinidine an even greater suppression was evident. These results indicate that the coadministration of propranolol and quinidine provides not only the potentiation of quinidine action by propranolol, which has been reported, but also the enhancement of propranolol action by quinidine, due to an increased plasma concentration of propranolol

Kasuistik,der vedr°rer en 70-Õrig mand, der havde taget quinidine bisulfat 500 mg tre gange daglig gennem 6 mÕneder for ventriculµre premature beats. Gennem de sidste tre mÕneder yderligere behandlet med 0.5% Timolol °jendrÕber for glaucom.Indlµgges nu med svimmelhed og bradycardi pÕ 36.Seponeringsfors°g med genoptagelse tyder pÕ, at det er kombinationen af timolol og quinidine, der har udl°st symptomerne.

The drug-drug interactions discussed in this article have either documented or suspected clinical relevance for patients with cardiovascular disease and the clinician involved in the care of these patients. Oftentimes, drug-drug interactions are difficult, if not impossible, to predict because of the high degree of interpatient variability in drug disposition. Certain drug-drug interactions, however, may be avoided through knowledge and sound clinical judgment. Every clinician should maintain a working knowledge of reported drug-drug interactions and an understanding of basic pharmacokinetic and pharmacodynamic principles to help predict and minimize the incidence and severity of drug-drug interactions.

Ti normale frivillige mµnd fik en 300 mg kapsel quinidine sulfat ved to lejligheder med mindst to ugers interval.Den anden indgift var forudgÕet af 7 perorale propranololdoser pÕ 40 mg hver 6.time. Propranolol gav ingen significante µndringer i quinidines kinetik.

5 healthy volunteers received 4-5 mg/kg of quinidine base by 15 minutes iv. infusion on two occasions separated by at least one week. The second infusion was preceded by oral adminisration of propranolol during 12 hours (80-12o mg). Propranolol did not significantly alter the pharmacokinetics or electrocardiografic effects of quinidine.

The kinetics of quinidine and propranolol, administered singly and in combination, were evaluated in 5 healthy subjects. The orally administered doses resulted in plasma concentrations within the therapeutic range. For each drug the average steady-state plasma concentration, maximal plasma concentration, and time of maximum plasma concentration were not altered by the presence of the other drugs. This study shows no kinetic interaction between quinidine and propranolol in normal subjects

Orthostatic hypotension developed in a 65-year-old man during treatment with quinidine and propranolol. Quinidine reduced standing blood pressure, attenuated the Valsalva response, and increased plasma norepinephrine concentrations, suggesting the presence of nonselective alpha-adrenergic blockade. The addition of propranolol inhibited the compensatory tachycardia and produced symptomatic orthostatic hypotension. Physicians should be alerted to the possibility of orthostatic hypotension when the alpha blocking effects of quinidine are combined with a beta blocking agent such as propranolol

OBJECTIVE--To determine whether the effects of topically administered timolol in an individual would be dependent on the presence or absence in that individual of the P-450 enzyme CYP2D6 and whether the effects of topically administered timolol would be increased and its metabolism decreased by the oral administration of quinidine, a known inhibitor of CYP2D6. DESIGN--Single-blind randomized crossover comparison of topical timolol, placebo, and the effects of inhibition of timolol metabolism by oral quinidine. SETTING--Clinical research center of an academic medical center. PARTICIPANTS--Eight male extensive metabolizers (EMs) and five male poor metabolizers (PMs) of debrisoquin. INTERVENTION--Two drops of 0.5% timolol or artificial tears were administered into each nostril in random order, and placebo or 50 mg of quinidine was administered orally to the EMs in random order, followed 30 minutes later by either the timolol or placebo drops. MAIN OUTCOME MEASUREMENT--Plasma timolol concentrations were measured by high-pressure liquid chromatography, while the extent of beta-blockade was determined by the suppression of exercise-induced rise in heart rate. RESULTS--The exercise heart rate was reduced following timolol eye drops compared with placebo in both EMs (P < .001) and PMs (P < .001) with significantly greater heart rate reduction (P = .01) and higher plasma timolol concentration in PMs compared with EMs (P = .03). Administration of quinidine with timolol eye drops to EMs resulted in a further significant reduction in heart rate (P = .02) and increase in plasma timolol concentration (P = .04). CONCLUSIONS--An individual´s debrisoquin phenotype is an important determinant of beta-blockade following timolol eye drops, and metabolism of timolol is inhibited and beta-blockade increased by coadministration of oral quinidine. Clinicians should be aware of the potential for drug interactions that occur when orally administered drugs inhibit the metabolism of a topically administered drug

Because both quinidine and propranolol bind to the cytochrome P-450 responsible for the oxidation of debrisoquin, six healthy male subjects were studied to determine whether an interaction occurred between the two drugs and the pharmacodynamic consequences of that interaction. The coadministration of quinidine resulted in a doubling of the area under the plasma concentration-time curve of (+/-)-propranolol (530 +/- 99 versus 1051 +/- 138 ng.hr/ml; p less than 0.05) and a reduction in the clearance of (+/-)-propranolol from 3087 +/- 648 to 1378 +/- 173 ml/min (p less than 0.05). The metabolism of propranolol by the 4-hydroxylation pathway was almost abolished by quinidine, resulting in a fall in the partial metabolic clearance by this pathway from 678 +/- 246 to 56 +/- 11 ml/min (p less than 0.05). Quinidine differentially affected the metabolism of (+)-propranolol and (-)-propranolol, resulting in an increase of 176.6% +/- 45.5% and 100.4% +/- 25.5% in the area under the plasma concentration-time curve of (+)-propranolol and (-)-propranolol, respectively (p less than 0.05). The pharmacokinetic changes were associated with pharmacodynamic effects. The combination of propranolol and quinidine resulted in increased beta-blockade measured by reduction in exercise heart rate and prolongation of the QTc and PR intervals. We conclude that quinidine stereoselectively inhibits the metabolism of propranolol through inhibition of the debrisoquin isozyme. The increased concentration of propranolol produced by quinidine results in increased beta-blockade

The influence of phenotype (debrisoquine type of oxidation polymorphism) and quinidine on (+/-)-metoprolol distribution parameters was investigated in 7 young male volunteers (4 extensive and 3 poor metabolisers). (+/-)-Metoprolol tartrate 20 mg was administered as a 20 min infusion i) alone, ii) 12 h after an oral 50 mg quinidine sulphate capsule, and iii) on the last day of 3 days of treatment with 250 mg quinidine sulphate b.d. as a slow-release tablet. No stereoselectivity was apparent in either poor or extensive metabolizers. When (+/-)-metoprolol was administered alone the apparent volume of distribution at steady-state (Vss) was higher in extensive than in poor metabolisers (4.84 vs 2.83 l.kg-1, respectively). Pre-treatment with low or multiple high doses of quinidine decreased Vss in extensive metabolisers to values comparable to those in poor metabolisers (3.50 and 3.18 l.kg-1, respectively), but had no significant effect in poor metabolisers (3.24 and 3.42 l.kg-1, respectively). Estimation of Vss by noncompartmental analysis or assuming elimination exclusively from the peripheral compartment yielded similar, although somewhat higher, estimates. Despite the small number of subjects, (+/-)-metoprolol distribution appeared to be different both in genetically and environmentally (quinidine)-determined poor metabolisers, and quinidine inhibition was a good, reversible in vivo model of the genetic deficiency in handling (+/-)-metoprolol. Differences both in first pass pulmonary elimination or in tissue binding are logically consistent with these observations, but the amplitude of the effect exceeds expectations from available biological evidence on selective pulmonary metabolic activity and on specific tissue binding sites

Timolol has mainly been used topically for the treatment of glaucoma. It has been suggested that the drug is metabolized by cytochrome P450 CYP2D6. The matter has not, however, been extensively studied. The aim here was to tentatively identify timolol metabolites and to determine the P450-associated metabolic and interaction properties of timolol in vitro. Four metabolites were identified, the most abundant being a hydroxy metabolite, M1. The K(m) value for the formation of M1 was 23.8 microM in human liver microsomes. Metabolism of timolol with recombinant P450s and correlation analysis have confirmed the conception that the drug is metabolized principally by CYP2D6, CYP2C19 being only a minor contributor (<10%) to the intrinsic microsomal clearance. The CYP2D6 inhibitor quinidine proved a potent competitive inhibitor of timolol metabolism, with an in vitro K(i) value of 0.08 microM. Fluvoxamine, an inhibitor of CYP2C19, inhibited timolol metabolism to a lesser extent, confirming its minor contribution. Timolol itself did not inhibit CYP2D6-catalyzed dextromethorphan O-demethylation. Judging from the disappearance of timolol in human liver homogenate, the in vivo half-life was extrapolated to be about 3 h, an estimate close to the half-life of about 2 to 5 h observed in vivo. In conclusion, the inhibition of timolol metabolism by quinidine should be taken into account when patients are treated with timolol. However, when plasma timolol concentrations in patients remain low (< or = 0.2 microg/l), it is suggested that such interaction is of minor clinical relevance