Ramipril

Additional information

Pharmacokinetics and dosing

In a pharmacokinetic study (18 men, 18 women), patients received a single 5 mg oral dose of ramipril. Cmax and half-lives of the active metabolite ramiprilat were identical in both sexes, but women showed a higher AUC/kg than men. Since both men and women received a fixed dose, the differences were explained by a higher dose/kg in women, as a consequence of their lower body weight [19].

Effects

Heart failureA 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. HypertensionIn 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]. Acute myocardial infarctionIn the large randomized double-blind AIRE trial (1461 men, 525 women), 2.5 mg ramipril daily was compared with placebo, 2-9 days after acute myocardial infarction. Ramipril reduced the risks of death from any cause by 27%. The benefits of ramipril therapy were similar in both men and women [20, 21].

Non-diabetic nephropathyAnother randomized clinical trial (269 men, 83 women) investigated the impact of sex on the outcome of non-diabetic chronic proteinuric nephropathy and effect of ramipril treatment. Ramipril decreased proteinuria less effectively in men than in women (-7.8 ± 4.2% vs. -21.9 ± 5.7%). Compared to conventional treatment (placebo plus antihypertensive therapy), ramipril decreased the difference in GFR (-52% vs. -19%) and progression to end-stage renal disease (-74% vs. -40%) more effectively in women than in men. Among patients with chronic proteinuric nephropathies, men are at increased risk of progression due to their lower response to ACE inhibitor treatment. ACE inhibition is similarly renoprotective in women regardless of the ACE polymorphism, and in men with a certain genotype (double deletion of the ACE gene) [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].A pharmacoepidemiological study (5259 men, 5111 women) of ramipril found an incidence of ramipril-induced cough of 7.1%. Female sex was significantly and independently associated with the onset of ramipril-related cough (odds ratio 1.35) [23].It is suggested that ACE inhibitors cause angioedema to a greater extent in black patients than in non-black patients [7].

Reproductive health issues

ACE inhibitors should not be used in pregnant women. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).