Propafenone is an antiarrhythmic drug that produces a variable degree of P3-blockade in humans and is administered as a racemate. To examine the relative contribution of the individual enantiomers to pharmacologic effects seen during treatment with propafenone, we assessed the steady-state plasma concentrations of (+)-S-propafenone and (-)-R-propafenone in seven patients who were on long-term oral therapy, and we evaluated the electrophysiologic and p3-blocking properties of both enantiomers in vitro. The metabolism of propafenone is known to be polymorphic and to cosegregate with that of debrisoquine-4-hydroxylation. Among five patients with the extensive metabolizer phenotype (EM), the ratio of the area under the plasma concentration-time curve of (+)-S-propafenone to (-)-R-propafenone was 1.73+±0.15 (mean+SD). In the other two patients, who had the poor metabolizer phenotype (PM), the concentrations of both enantiomers were elevated but the SIR ratios were similar to those seen in patients with EM. In canine cardiac Purkinje fibers, both enantiomers produced similar frequency-dependent depression of maximum upstroke of phase 0. In contrast, the affinity of the human lymphocyte 1-adrenoceptor was approximately 100-fold greater for (+)-S-propafenone (K, 7.2±2.9 nM) than for the (-)-R-enantiomer (K;, 571±141 nM). We conclude that during relation has been reported. One explanation for this variability is the genetically determined impairment in approximately 7% of the Caucasian population to metabolize propafenone.1 This polymorphism cosegregates with the ability to 4-hydroxylate the antihypertensive debrisoquine and correlates with the functional presence or absence of the hepatic cytochrome P-450db1.6 Patients with the extensive metabolizer phenotype (EM) or the poor metabolizer phenotype (PM) can be distinguished,' and the metabolic pathway affected by polymorphic oxidation is the formation of the active metabolite 5-hydroxy propafenone.7,8 Propafenone is administered as a racemic mixture of (+)-S-and (-)-R-enantiomers. Pharmacokinetic differences between the enantiomers of other racemic drugs, such as metoprolol and N-propylajmaline, which are substrates for P-450db1, have been found in EM but not in PM subjects, indicating the potential for stereoselective metabolism of substrates for this cytochrome P 450.9, 1 The in vitro electrophys-

To determine the contribution of altered beta-receptor function in the vasculature to the increased peripheral vascular resistance seen in hypertension, the effects of intra-arterial infusions of isoproterenol and epinephrine on forearm blood flow were determined in 11 male normotensive subjects and 11 male hypertensive subjects during 10 and 250 mmol/day sodium diets. Increased sodium intake from 10 to 250 mmol produced contrasting effects in the hypertensive and normotensive subjects. In the hypertensive subjects, sensitivity to isoproterenol decreased when sodium intake increased (median effective dose increased from 39 [95% confidence limits, 30 to 50] to 70 [95% confidence limits, 42 to 116] ng/min, p less than 0.05). On the other hand, in the normotensive subjects increased sodium intake resulted in an increased sensitivity to isoproterenol induced vasodilation (median effective dose decreased from 52 [38 to 71] to 29 [22 to 38] ng/min, p less than 0.01). No change occurred in sensitivity to epinephrine or in the maximum vasodilatory response to ischemia during dietary changes. Changes in beta-receptors on lymphocyte membranes paralleled the changes seen in vascular sensitivity so that the proportion of receptors exhibiting high affinity for agonists, a reflection of receptor adenylate cyclase coupling, decreased in the hypertensive subjects from 38.0% +/- 3.8% when they were receiving 10 mmol/day sodium to 29.6% +/- 2.7% when they were receiving 250 mmol/day sodium (p less than 0.01). However, the proportion increased from 32.4% +/- 3.7% for normotensive subjects receiving 10 mmol/day sodium to 47.1% +/- 7.8% for normotensive subjects receiving 250 mmol/day sodium (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Propranolol and the sodium-channel-blocking antiarrhythmic agent propafenone share structural features. Although propafenone's beta-blocking actions are readily demonstrable in vitro, clinically significant beta-blockade occurs inconsistently in vivo. In this study, we tested the hypothesis that genetically determined variations in the biotransformation of propafenone to its 5-hydroxy metabolite account for variations in the drug's beta-blocking action. We assessed beta-blockade by measuring the reduction in tachycardia produced by boluses of isoproterenol and treadmill exercise in 14 normal subjects during treatment with placebo and with 150, 225, and 300 mg of propafenone every eight hours for five days each. Nine subjects (with the extensive-metabolizer phenotype) metabolized most of the propafenone to 5-hydroxy propafenone, and five (with the poor-metabolizer phenotype) did not produce this metabolite. At the lower dosages, beta-blockade was present in both groups but was significantly greater in the subjects with poor metabolism, in whom deficient 5-hydroxylation was associated with higher plasma propafenone levels. At the highest dose, a similar degree of beta-blockade was observed in the two groups. Propafenone also had a higher affinity for beta 2 receptors in vitro than either of its major metabolites. We conclude that the degree of beta-blockade during propafenone therapy reflects genetically determined variations in the metabolism of the parent drug, which is necessary for beta-blockade, and that this action of propafenone is considerably enhanced in patients with deficient 5-hydroxylation of propafenone.

To determine whether the pharmacokinetics and pharmacodynamics of beta-blockade differ among racial groups, we gave 10 men of Chinese descent and 10 American white men 10, 20, 40, and 80 mg of propranolol every eight hours; the dosages were given in random order, and each dose was given for one day. The degree of beta-blockade was measured as the reduction in the heart rate and blood pressure in the supine and upright positions and during treadmill exercise testing. The Chinese subjects had at least a twofold greater sensitivity to the beta-blocking effects of propranolol than the white subjects, as indicated by the mean (+/- SEM) plasma concentrations producing a 20 percent reduction in the heart rate in both the supine position (197 +/- 31 vs. 536 +/- 58 nmol per liter; P less than 0.05) and the upright position (131 +/- 27 vs. 343 +/- 39 nmol per liter; P less than 0.05) and after exercise testing (96 +/- 12 vs. 185 +/- 23 nmol per liter; P less than 0.05). In addition, the Chinese subjects had much greater sensitivity to the hypotensive effects of propranolol, as shown by the concentrations that reduced blood pressure by 10 percent in the supine position (73 +/- 5 vs. 748 +/- 7 nmol per liter; P less than 0.01) and in the upright position (89 +/- 5 vs. 401 +/- 6 nmol per liter; P less than 0.01). No difference in beta-receptor density or affinity of lymphocytes was found between the groups. The Chinese group had a 45 percent higher free fraction of propranolol in plasma, which may have contributed to the increased drug effect but cannot explain it entirely. This group metabolized propranolol more rapidly than the white group, which resulted in a 76 percent higher clearance of an oral dose (3740 +/- 737 vs. 2125 +/- 214 ml per minute; P less than 0.05) because of increased metabolism through multiple metabolic pathways. We conclude that Chinese men have greater sensitivity than white men to the effects of propranolol on heart rate and blood pressure. Decreased protein binding may be responsible in part, but most of the effect remains to be explained.

1 In order to determine whether the effects of d-or (+)-sotalol on heart rate are mediated by ,3-adrenoceptor antagonism or might be due to other actions, we administered (+)-sotalol (400 mg every 12 h), atenolol (50 mg every 12 h) and placebo to eight healthy volunteers in a randomized, double-blind, crossover study. We also studied the affinity of human lymphocyte ,32-adrenoceptor for (+)-sotalol, (-)-sotalol, and (±)-propranolol. 2 Compared with placebo, atenolol significantly reduced resting, standing and peak exercise heart rate whereas (+)-sotalol significantly reduced standing and peak exercise heart rate, but not resting heart rate. Atenolol significantly reduced resting, standing and peak exercise blood pressure while (+)-sotalol had no effect. 3 (+)-sotalol and atenolol both shifted the relationship between isoprenaline dose and heart rate to the right by similar degrees at the dosages tested. 4 (+)-sotalol but not atenolol significantly prolonged QTc interval. The degree of QTc prolongation due to (+)-sotalol, which has been shown to parallel action potential prolongation in the sinus node, correlated significantly with the reduction in peak exercise heart rate it produced (r = 0.71, n = 8, P < 0.05).5 The affinity of the human lymphocyte P2-adrenoceptor was approximately 60-fold greater for (-)-sotalol (Ki, 108 ± 12 nM) than for (+)-sotalol (Kj, 6,410 ± 1,020 nM), and approximately 20,000-fold greater for (±)-propranolol (K;, 0.33 ± 0.08 nM) than for (+)-sotalol.6 The low affinity of (+)-sotalol for binding to the human P2-adrenoceptor and the contrasting effects of (+)-sotalol on heart rate and blood pressure, indicate that Iadrenoceptor antagonism is unlikely to contribute to the effect of (+)-sotalol on heart rate.7 The relationship between (+)-sotalol's effects on repolarization and on exercise heart rate, suggest that class III activity of this enantiomer in the sinus node is responsible for its effects on heart rate in man.