Ramipril Explained

Ramipril, sold under the brand name Altace among others, is an ACE inhibitor type medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It can also be used as a preventative medication in patients over 55 years old to reduce the risk of having a heart attack, stroke or cardiovascular death in patients shown to be at high risk, such as some diabetics and patients with vascular disease.^{[1] [2] [3]} It is a reasonable initial treatment for high blood pressure. It is taken by mouth.

Common side effects include headaches, dizziness, fatigue, and cough. Serious side effects may include liver problems, angioedema, kidney problems, and high blood potassium. Use in pregnancy and breastfeeding is not recommended.^[4] It is an ACE inhibitor and works by decreasing renin-angiotensin-aldosterone system activity.^[5]

Ramipril was patented in 1981 and approved for medical use in 1989.^[6] It is available as a generic medication.^[7] In 2021, it was the 201st most commonly prescribed medication in the United States, with more than 2million prescriptions.^{[8] [9]}

Activation and binding

Ramipril is a pro-drug. The molecule must be hydrolyzed by the esterase at the OCH2CH3 and form a carboxylate. This carboxylate then interacts with the positive Zn+2 to inhibit the ACE enzyme. The COOH helps orient it with the enzyme. Ramipril is similar in structure to another ACE Inhibitor, trandolapril, but it has a second cyclopentane ring instead of a cyclohexane ring.

Medical uses

Medical uses include:

• High blood pressure (Hypertension)
• Congestive heart failure^[10]
• Following heart attack in people with evidence of heart failure
• People over 55 years at high risk: prevention of heart attack, stroke, cardiovascular death, or in need of revascularization procedures
• Prevent the onset and/or delay the progression of diabetic kidney disease, with or without proteinuria.^[11] Randomized trial evidence suggests that a maximum tolerable dose prevents cardiovascular events and death in patients with diabetic kidney disease.

Contraindications

Contraindications to its use include volume-depleted patients, a history of angioedema while on an ACE inhibitor, pregnancy and hypotension.

People should not take ramipril (or any ACE inhibitors) if they have hyperkalemia. It is also recommended to avoid using salt-substitutes as this can further increase potassium levels in the blood.

Ramipril can be considered in patients with bilateral or unilateral significant renal artery stenosis (RAS).^[12] An early rise in serum creatinine above baseline is expected after initiation of therapy with Ramipril, however, monitoring serum biochemistry and renal function after initiation is crucial.^[13] Treatment with Ramipril in some patients with significant narrowing in both kidneys can increase serum creatinine concentration (measured in the blood test), which returns to baseline upon therapy cessation.^[14]

Adverse effects

• Shakiness
• Dry cough
• Dizziness and lightheadedness due to low blood pressure
• Fatigue, especially in the early stages
• Mouth dryness in the early stages
• Nausea
• Fainting
• Signs of infection (e.g., fever, chills, persistent sore throat)
• Chest pain
• Neutropenia (low white blood cells)
• Impotence (erectile dysfunction)^[15]
• Hyperkalemia

Serious allergic reactions to this drug are unlikely, but immediate medical attention must be sought if they occur. Symptoms of a serious allergic reaction include, but are not limited to a rash or swelling of the face, mouth, tongue, or throat. In extreme cases, ramipril may lead to potentially fatal liver problems.

Mechanism of action

See also: Renin–angiotensin system.

ACE inhibitors inhibit the actions of angiotensin converting enzyme (ACE), thereby lowering the production of angiotensin II and decreasing the breakdown of bradykinin. The decrease in angiotensin II results in relaxation of arteriole smooth muscle leading to a decrease in total peripheral resistance, reducing blood pressure as the blood is pumped through widened vessels. Its effect on bradykinin is responsible for the dry cough side effect.

Ramipril, a prodrug or precursor drug, is converted to the active metabolite ramiprilat by carboxylesterase 1.^{[16] [17]} Ramiprilat is mostly excreted by the kidneys. Its half-life is variable (3–16 hours), and is prolonged by heart and liver failure, as well as kidney failure. Peak effect occurs between 3 and 6 hours after dosing, with approximately 50% of this effect retained after 24 hours.^[18]

Society and culture

US patent

The compound was protected by a patent which was assigned to the German pharmaceutical company Hoechst AG (since merged into Aventis) on 29 October 1991. The patent was scheduled to expire on 29 October 2008. On 11 September 2007, in an appeal by the Indian company Lupin Ltd., the United States Court of Appeals for the Federal Circuit reversed a district court trial verdict and found that Aventis's patent on ramipril was invalid for "obviousness", opening this drug to generic manufacturers.

Brand names

Ramipril is marketed as Prilace by Arrow Pharmaceuticals in Australia, Ramipro by Westfield Pharma in the Philippines, Triatec by Sanofi-Aventis in Italy and United States and Altace by King Pharmaceuticals in the United States, Novapril by Pharmanova in Ghana, Ramitens by PharmaSwiss, Ampril by Krka in Slovenia, Corpril by Cemelog-BRS in Hungary, Piramil and Prilinda by Hemofarm in Serbia, by Lek in Poland and by Novartis and Opsonin Pharma Limited as Ramace in Bangladesh, and in Canada as Altace (Sanofi-Aventis) and Ramipril (Pharmascience).

Ramipril is marketed in India under the brand names Cardace, Zigpril, Ramistar, Odipril and Zorem . Ramipril is marketed in Myanmar under brand name Endpril .

Research

The 2001 Heart Outcomes and Prevention Evaluation trial seemed to show ramipril possessed cardioprotective qualities which extended beyond its qualities as an antihypertensive.^{[19] [20]} However, the trial and the interpretation of its results have been criticised.^[21]

The Acute Infarction Ramipril Efficacy (AIRE) trial^{[16] [22]} showed a 27% reduction in mortality for patients receiving ramipril for chronic heart failure following a myocardial infarction.

Ramipril was found to have similar results as telmisartan, an angiotensin II receptor blocker.^[23]

Notes and References

1. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G . Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients . The New England Journal of Medicine . 342 . 3 . 145–53 . January 2000 . 10639539 . 10.1056/NEJM200001203420301 . free .
2. January 2000. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. HOPE study investigators. The Lancet. 355. 9200. 253–259. 10.1016/S0140-6736(99)12323-7. 1863533.
3. Savarese G, Costanzo P, Cleland JG, Vassallo E, Ruggiero D, Rosano G, Perrone-Filardi P . A meta-analysis reporting effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients without heart failure . Journal of the American College of Cardiology . 61 . 2 . 131–42 . January 2013 . 23219304 . 10.1016/j.jacc.2012.10.011 . free .
4. Web site: Ramipril Pregnancy and Breastfeeding Warnings . Drugs.com . 3 March 2019 .
5. Web site: Ramipril Monograph for Professionals . Drugs.com . American Society of Health-System Pharmacists . 3 March 2019 .
6. Book: Fischer J, Ganellin CR . Analogue-based Drug Discovery . 2006 . John Wiley & Sons . 9783527607495 . 469 .
7. Book: British national formulary : BNF 76. 2018. Pharmaceutical Press. 9780857113382. 172–173. 76.
8. Web site: The Top 300 of 2021 . ClinCalc . 14 January 2024 . 15 January 2024 . https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
9. Web site: Ramipril - Drug Usage Statistics . ClinCalc . 14 January 2024.
10. Pilote L, Abrahamowicz M, Eisenberg M, Humphries K, Behlouli H, Tu JV . Effect of different angiotensin-converting-enzyme inhibitors on mortality among elderly patients with congestive heart failure . CMAJ . 178 . 10 . 1303–11 . May 2008 . 18458262 . 2335176 . 10.1503/cmaj.060068 .
11. Remuzzi G, Macia M, Ruggenenti P . Prevention and treatment of diabetic renal disease in type 2 diabetes: the BENEDICT study . Journal of the American Society of Nephrology . 17 . 4 Suppl 2 . S90-7 . April 2006 . 16565256 . 10.1681/ASN.2005121324 . free .
12. Chrysochou C, Foley RN, Young JF, Khavandi K, Cheung CM, Kalra PA . Dispelling the myth: the use of renin-angiotensin blockade in atheromatous renovascular disease . Nephrology, Dialysis, Transplantation . 27 . 4 . 1403–1409 . April 2012 . 21993376 . 10.1093/ndt/gfr496 . free .
13. Ahmed A . Use of angiotensin-converting enzyme inhibitors in patients with heart failure and renal insufficiency: how concerned should we be by the rise in serum creatinine? . Journal of the American Geriatrics Society . 50 . 7 . 1297–1300 . July 2002 . 12133029 . 10.1046/j.1532-5415.2002.50321.x . 31459410 .
14. Chrysochou C, Foley RN, Young JF, Khavandi K, Cheung CM, Kalra PA . Dispelling the myth: the use of renin-angiotensin blockade in atheromatous renovascular disease . Nephrology, Dialysis, Transplantation . 27 . 4 . 1403–1409 . April 2012 . 21993376 . 10.1093/ndt/gfr496 . free .
15. Web site: Ramipril Side Effects. eMedTV: Health Information Brought To Life.
16. Frampton JE, Peters DH . Ramipril. An updated review of its therapeutic use in essential hypertension and heart failure . Drugs . 49 . 3 . 440–466 . March 1995 . 7774515 . 10.2165/00003495-199549030-00008 . 195691742 .
17. Thomsen R, Rasmussen HB, Linnet K . In vitro drug metabolism by human carboxylesterase 1: focus on angiotensin-converting enzyme inhibitors . Drug Metabolism and Disposition . 42 . 1 . 126–133 . January 2014 . 24141856 . 10.1124/dmd.113.053512 . 206496779 .
18. McCarron D . 24-hour blood pressure profiles in hypertensive patients administered ramipril or placebo once daily: magnitude and duration of antihypertensive effects. . Ramipril Multicenter Study Group . Clinical Cardiology . 14 . 9 . 737–742 . September 1991 . 1835914 . 10.1002/clc.4960140908 . Wiley . free .
19. Web site: HOPE Trial: Main Outcomes and Serum Creatinine. Hypertension Online. 13 August 2001. https://archive.today/20120802091011/http://www.hypertensiononline.org/slides2/slide01.cfm?q=ramipril&dpg=10 . 2 August 2012. Ramipril significantly reduced the high cardiovascular risk associated with renal insufficiency.
20. Malmberg K, Rydén L . Ramipril reduced mortality and cardiovascular morbidity in high risk adults. BMJ Publishing Group Ltd . March 2000. BMJ Evidence-Based Medicine. 5. 2. 47 . 10.1136/ebm.5.2.47 . free.
21. Web site: Jafary F, Yusuf S, Nissen S . Controversies in Cardiology II . MedScape . Debate: Do ACE Inhibitors Have Unique Properties, Beyond Their Antihypertensive Effect?. 2002.
22. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators . Lancet . 342 . 8875 . 821–8 . October 1993 . 8104270 . 10.1016/0140-6736(93)92693-N . 5770772 .
23. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C . Telmisartan, ramipril, or both in patients at high risk for vascular events . The New England Journal of Medicine . 358 . 15 . 1547–59 . April 2008 . 18378520 . 10.1056/NEJMoa0801317 . free . 2437/81925 .