The Anti-Ischemic Effect of Metoprolol in Patients with Chronic Angina Pectoris Is Gender-Specific

Abstract

Several gender-specific differences in cardiovascular diseases are known and pharmacokinetics of β-blockers shows relevant sex-specific differences. The plasma levels of metoprolol, for example, are higher in women compared to men. However, randomized studies have shown that metoprolol has little or no greater reduction in the mortality of women following myocardial infarction. We tested the hypothesis that metoprolol might have significant gender-specific effects in patients with chronic angina pectoris. Body weight of women was slightly (–9%) less than that of men and the daily dose of metoprolol was similar in both groups. Thus, according to pharmacokinetics women should have obtained higher plasma levels of this drug and the ensuing pharmacologic effects of metoprolol should have been greater. Our results do not confirm this assumption. Metoprolol reduced the frequency of angina episodes and the consumption of nitroglycerin tablets to a similar extent in both sexes. However, the pretreatment hemodynamic profiles confirmed the existence of gender-specific differences: women had significantly higher heart rate and blood pressure both at rest and during exercise. Since both groups were comparable in age, comorbidities, and medications, the existing difference is likely to be due to gender-specificity. The hemodynamic differences persisted during therapy with metoprolol: resting heart rate, blood pressure and rate pressure product were reduced to a greater extent in men. During cycloergometry, there was a slight difference in the time of onset of ST depression and time of onset of angina, which were slightly higher in men, but probably because of the limited number of cases, the difference between men and women did not reach significance. On the other hand, with metoprolol the duration of exercise and, in parallel, the number of metabolic equivalents was significantly greater in males than in females. Thus in spite of a presumed greater plasma concentration of metoprolol in women, we found a significant difference in anti-ischemic effect in favor of men. We conclude that metoprolol might exert a significantly greater therapeutic effect on stress-induced angina pectoris in men than in women and this difference should be taken into account when prescribing this β-blocker.

Sex-related differences in pharmacokinetics and pharmacodynamics of anti-hypertensive drugs

“…Therefore, women may require lower-than-standard doses to avoid adverse effects, whereas men may require larger doses to obtain therapeutic benefit. 38 On the other hand, Cocco et al 39 reported a sex-specific difference in the ischemic effect of metoprolol, specifically that metoprolol showed a favorable effect in men but not in women in spite of a presumed higher plasma concentration of metoprolol in women. They demonstrated that the hemodynamic effects (reduction of blood pressure and heart rate) in men lead to a longer duration of exercise and increased time to angina, ST depression and total metabolic equivalents during exercise, which could reflect a better anti-ischemic effect in men.…”

“…They demonstrated that the hemodynamic effects (reduction of blood pressure and heart rate) in men lead to a longer duration of exercise and increased time to angina, ST depression and total metabolic equivalents during exercise, which could reflect a better anti-ischemic effect in men. Cocco et al 39 indicated that we need to consider the sex-specific therapeutic effect of metoprolol and that it should be dosed according to the effect on the individual patient rather than according to fixed recommendations.…”

Effects of Metoprolol on Sympathetic Remodeling and Electrical Remodeling at Infarcted Border Zone after Myocardial Infarction in Rabbits

“…This may be an important mechanism for the protective effect of metoprolol on reduction of SCD risk after MI. However, it is noted that metoprolol has extensive pharmacological action [35, 36]; the mechanisms underlying improving electrical remodeling certainly included other important factors independent of nerve sprouting, such as adrenergic blockade and ion channel remodeling.…”

Chronic Coronary Syndromes in Women

“…62,63 With regard to pharmacodynamics, aspirin more potently inhibits platelet aggregation 64 and b-blockers more efficiently reduce exerciseinduced angina in men. 65 Of note, women have a 1.5-to 1.7-fold greater incidence of adverse drug reactions than men. 62,63 Indeed, inadequate consideration of sex differences in pharmacokinetics and pharmacodynamics may have serious consequences: Of 10 prescription drugs withdrawn from the market in the United States between 1997 and 2001, 8 posed greater health risks for women, including mibefradil dihydrochloride (PosicorÒ, Roche Laboratories, Nutley, NJ), which was approved for treatment of hypertension and angina and increased the risk for severe bradycardia, especially among elderly women.…”