Enalapril

Additional information

Pharmacokinetics and dosing

No significant sex differences in the pharmacokinetics of enalapril have been observed [19].

Effects

Heart failure

A European multicentre cohort study of patients with heart failure with reduced ejection fraction (HFrEF) (3609 men, 1114 women) found similar all-cause mortality for patients treated with ACE inhibitors (enalapril, lisinopril, or ramipril) given at equivalent doses. No differences between men and women or between age groups were seen [1].

In a large cohort study comparing angiotensin converting enzyme (ACE) inhibitors with angiotensin receptor blockers (ARBs) in patients with congestive heart failure (9 475 men, 10 223 women), women on ARBs had better survival than women on ACE inhibitors (HR 0.69, 95%CI 0.59-0.80) while men on ARBs had similar survival as men on ACE inhibitors (HR 1.10, 95%CI 0.95-1.30). However, other anti-hypertensive agents were more common in those on ARBs, especially women, leading to a larger blood pressure reduction and thus larger reduction in risk of death. Also, more of those on ARBs were hypertensive than those on ACE inhibitors, and more of those on ACE inhibitors had a history of myocardial infarction than those of ARBs [2]. Additional confounding by indication cannot be excluded. 

 Hypertension

In general, the activity level of the endogenous renin-angiotensin system (RAS), which regulates blood pressure, is higher in men than in premenopausal women. Postmenopausal women have higher activity than premenopausal women. This suggests that the efficacy of an RAS inhibitor would be lower in premenopausal women. However, studies on sex differences in the effect of RAS inhibition are contradictory [3, 4]. It has been suggested that black hypertensive patients have a smaller antihypertensive efficacy of ACE inhibitors than non-blacks, possibly due to a higher prevalence of low renin state in black hypertensive patients [5-7].A clinical trial showed that the angiotensin converting enzyme (ACE) activity was higher in men than in women at low plasma concentrations of enalapril (<5 ng/ml). However, no sex differences were observed at high plasma concentrations of enalapril (>5 ng/ml) [3].

The dose-dependent antihypertensive efficacy of enalapril seems to be similar in hypertensive boys and girls aged 6-16 years (n=110), despite patient’s age or ethnicity [5].

Diabetes

A small clinical trial (10 boys, 12 girls) has shown that adolescent girls with type 1 diabetes mellitus respond more favorably to ACE inhibitors than adolescent boys. Glomerular hyperfiltration is a factor for development of diabetic renal disease and is influenced by hyperglycemia and RAS blockade. Twenty-two adolescents with type 1 diabetes mellitus were studied before and after ACE inhibition. After 21 days of treatment with enalapril (0.1 mg/kg daily x 1 week and then 0.1 mg/kg twice a day for 2 weeks), the renal responses to ACE inhibition differed between boys and girls. Only girls received beneficial reductions in GFR (glomerular filtration rate) and FF (filtration fraction). This may be due to a synergistic effect of ACE inhibitors and estrogen on components of the RAS. Even though the experiments in this study were carried out during the follicular (low estrogen) phase of the menstrual cycle, an augmented response to ACE inhibitors were noted in girls, suggesting that any levels of estrogen may act synergistically with RAS blockade [20]. An interaction between ACE inhibitors and estrogen has also been discussed [21].

Myocardial infarction

A randomized controlled trial (46 men, 37 women) studied long-term effects of enalapril on plasma levels of the fibrinolytic factors tissue plasminogen activator (tPa), plasminogen activator inhibitor (PAI-1), tPA/PAI-1 complex and vWF in both men and women with uncomplicated myocardial infarction. Enalapril or placebo was initiated two months or later following an acute myocardial infarction. Initial dose was 2.5 mg enalapril once daily with increasing dosage every three days. Plasma levels of tPA decreased significantly after two weeks enalapril treatment in both men and women, but tPa/PAI-1 complex decreased significantly only in women [22].

Adverse effects

Several studies have reported a female predominance in the prevalence of ACE inhibitor induced cough [8-16]. The pathogenesis of the cough reaction is unknown. Different thresholds for coughing in men and women have been proposed [17], as well as ethnic differences in cough tendency [18]. One study suggests that sex hormones do not have any influence on cough, since most of the women in the study were postmenopausal [6].In the double-blind placebo-controlled SOLVD study (5794 men, 975 women), the most pronounced sex difference among reported side effects in the enalapril group was cough, which was more frequently reported by women (10.0% vs. 4.2%; odds ratio 2.38) [10].

A review has examined ACE inhibitor-associated angioedema/urticaria; the number of spontaneous reports among patients taking enalapril (mean dose 13 mg daily) were similar in men and women [23]. Another study indicates that ACE inhibitors cause angioedema to a greater extent in black patients than in non-black patients [5]