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Lisinopril

Classification: C

Drug products: Lisinopril 2care4, Lisinopril Actavis, Lisinopril Arrow, Lisinopril Ebb, Lisinopril EssPharm, Lisinopril Mylan, Lisinopril Orifarm, Lisinopril Ranbaxy, Lisinopril ratiopharm, Lisinopril STADA®, Lisinopril/Hydrochlorthiazid Sandoz, Lisinopril/Hydroklortiazid Actavis, Lisinopril/Hydroklortiazid Copyfarm, Lisinopril/Hydroklortiazid STADA, Zestoretic, Zestril®

ATC code: C09AA03, C09BA03

Substances: lisinopril, lisinopril dihydrate

Summary

Lisinopril reduces the blood pressure as efficiently in men and women.
Cough is a common non-dose dependent side effect of ACE-inhibitors which is more common in women. Angiotensin receptor blockers may then be an alternative.

Additional information

Pharmacokinetics and dosing

A pharmacokinetic study (16 men, 16 women) examined the sex-related differences after a single 20 mg dose of lisinopril. There were no differences in plasma concentration between men and women, or in effects on blood pressure or heart rate [19]. No studies with a clinically relevant sex analysis regarding the dosing of lisinopril have been found and no sex differentiation in dosing has been recommended by the pharmaceutical company [6].

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.Clinical trials have shown that men and women have similar antihypertensive responses to lisinopril [20-22]. However, in the large ALLHAT study, black men responded better to lisinopril compared to amlodipine than black women when receiving the same dose [23, 24].

Pulse pressure (the difference between systolic blood pressure and diastolic pressure) is suggested to be a predictor of cardiovascular disease and may be influenced by genetics. A study examined whether RAS polymorphism had different impact on pulse pressure in men and women taking lisinopril showed no sex differences [25].

The dose-dependent antihypertensive efficacy of lisinopril seems to be similar in hypertensive boys and girls aged 6-16 years (n=115), despite patient’s age or ethnicity [6, 26]. 

 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].

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 a Norwegian double-blind multicenter study (206 men, 206 women), nearly three times more women than men spontaneously reported cough with lisinopril (12.6% vs. 4.4%) [16, 27].

A review has examined ACE inhibitor-associated angioedema/urticaria; the number of reports among patients taking lisinopril (mean dose 12 mg daily) were similar in men and women [28]. It is suggested that ACE inhibitors cause angioedema to a greater extent in black patients than in non-black patients [6].

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).

Updated: 2019-10-07

Date of litterature search: 2019-05-16

References

  1. Fröhlich H, Henning F, Täger T, Schellberg D, Grundtvig M, Goode K et al. Comparative effectiveness of enalapril, lisinopril, and ramipril in the treatment of patients with chronic heart failure: a propensity score-matched cohort study. Eur Heart J Cardiovasc Pharmacother. 2018;4(2):82-92. PubMed
  2. Hudson M, Rahme E, Behlouli H, Sheppard R, Pilote L. Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure--a population study. Eur J Heart Fail. 2007;9(6):602-9. PubMed
  3. Coulter DM, Edwards IR. Cough associated with captopril and enalapril. Br Med J (Clin Res Ed). 1987;294:1521-3. PubMed
  4. Strocchi E, Valtancoli G, Ambrosioni E. The incidence of cough during treatment with angiotensin converting enzyme inhibitors. J Hypertens Suppl. 1989;7:S308-9. PubMed
  5. Kostis JB, Shelton B, Gosselin G, Goulet C, Hood WB, Kohn RM et al. Adverse effects of enalapril in the Studies of Left Ventricular Dysfunction (SOLVD) SOLVD Investigators. Am Heart J. 1996;131:350-5. PubMed
  6. Sharma S, Gupta U, Bapna JS, Sahai A. Tolerability of enalapril in mild to moderate hypertension. J Assoc Physicians India. 1995;43:475-6. PubMed
  7. Yeşil S, Yeşil M, Bayata S, Postaci N. ACE inhibitors and cough. Angiology. 1994;45:805-8. PubMed
  8. Yeo WW, Ramsay LE. Persistent dry cough with enalapril: incidence depends on method used. J Hum Hypertens. 1990;4:517-20. PubMed
  9. Just PM. The positive association of cough with angiotensin-converting enzyme inhibitors. Pharmacotherapy. 1989;9:82-7. PubMed
  10. Gibson GR. Enalapril-induced cough. Arch Intern Med. 1989;149:2701-3. PubMed
  11. Os I, Bratland B, Dahlöf B, Gisholt K, Syvertsen JO, Tretli S. Female sex as an important determinant of lisinopril-induced cough. Lancet. 1992;339:372. PubMed
  12. Dykewicz MS. Cough and angioedema from angiotensin-converting enzyme inhibitors: new insights into mechanisms and management. Curr Opin Allergy Clin Immunol. 2004;4:267-70. PubMed
  13. Morimoto T, Gandhi TK, Fiskio JM, Seger AC, So JW, Cook EF et al. An evaluation of risk factors for adverse drug events associated with angiotensin-converting enzyme inhibitors. J Eval Clin Pract. 2004;10:499-509. PubMed
  14. Sáenz-Campos D, Bayés MC, Masana E, Martín S, Barbanoj M, Jané F. Sex-related pharmacokinetic and pharmacodynamic variations of lisinopril. Methods Find Exp Clin Pharmacol. 1996;18:533-8. PubMed
  15. Zestril (lisinopril). Summary of Product Characteristics. Medical Products Agency Sweden; 2016.
  16. Alici G, Aliyev F, Bellur G, Okcun B, Türkoğlu C, Karpuz H. Effect of seven different modalities of antihypertensive therapy on pulse pressure in patients with newly diagnosed stage I hypertension. Cardiovasc Ther. 2009;27:4-9. PubMed
  17. Weir MR, Reisin E, Falkner B, Hutchinson HG, Sha L, Tuck ML. Nocturnal reduction of blood pressure and the antihypertensive response to a diuretic or angiotensin converting enzyme inhibitor in obese hypertensive patients TROPHY Study Group. Am J Hypertens. 1998;11:914-20. PubMed
  18. Oparil S, Davis BR, Cushman WC, Ford CE, Furberg CD, Habib GB et al. Mortality and morbidity during and after Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: results by sex. Hypertension. 2013;61:977-86. PubMed
  19. Falconnet C, Bochud M, Bovet P, Maillard M, Burnier M. Gender difference in the response to an angiotensin-converting enzyme inhibitor and a diuretic in hypertensive patients of African descent. J Hypertens. 2004;22:1213-20. PubMed
  20. Leenen FH, Nwachuku CE, Black HR, Cushman WC, Davis BR, Simpson LM et al. Clinical events in high-risk hypertensive patients randomly assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Hypertension. 2006;48:374-84. PubMed
  21. Lynch AI, Arnett DK, Davis BR, Boerwinkle E, Ford CE, Eckfeldt JH et al. Sex-specific effects of AGT-6 and ACE I/D on pulse pressure after 6 months on antihypertensive treatment: the GenHAT study. Ann Hum Genet. 2007;71:735-45. PubMed
  22. Soffer B, Zhang Z, Miller K, Vogt BA, Shahinfar S. A double-blind, placebo-controlled, dose-response study of the effectiveness and safety of lisinopril for children with hypertension. Am J Hypertens. 2003;16:795-800. PubMed
  23. Os I, Bratland B, Dahløf B, Gisholt K, Syvertsen JO, Tretli S. Lisinopril or nifedipine in essential hypertension? A Norwegian multicenter study on efficacy, tolerability and quality of life in 828 patients. J Hypertens. 1991;9:1097-104. PubMed
  24. Pillans PI, Coulter DM, Black P. Angiooedema and urticaria with angiotensin converting enzyme inhibitors. Eur J Clin Pharmacol. 1996;51:123-6. PubMed
  25. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2018 [cited 2019-03-08.] länk
  26. Zapater P, Novalbos J, Gallego-Sandín S, Hernández FT, Abad-Santos F. Gender differences in angiotensin-converting enzyme (ACE) activity and inhibition by enalaprilat in healthy volunteers. J Cardiovasc Pharmacol. 2004;43(5):737-44. PubMed
  27. Komukai K, Mochizuki S, Yoshimura M. Gender and the renin-angiotensin-aldosterone system. Fundam Clin Pharmacol. 2010;24(6):687-98. PubMed
  28. Renitec (enalapril). Summary of Product Characteristics. Swedish Medical Products Agency [updated 2019-05-14, cited 2019-05-16].
  29. Zestril (lisinopril). Summary of Product Characteristics. Medical Products Agency Sweden; 2016.
  30. Triatec (ramipril). Summary of Product Characteristics. Swedish Medical Products Agency [updated 2019-05-14, cited 2019-05-16].

Authors: Linnéa Karlsson Lind

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson