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.[1] 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.[2][3][4] It is a reasonable initial treatment for high blood pressure.[1] It is taken by mouth.[1]
Ramipril was patented in 1981 and approved for medical use in 1989.[6] It is available as a generic medication.[7] In 2022, it was the 187th 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 an esterase at the OCH2CH3 and form a carboxylate. This carboxylate then interacts with the positive Zn2+ ion which is located at the active site of the ACE enzyme.[10] Ramipril is similar in structure to another ACE Inhibitor, trandolapril, but it has a second cyclopentane ring instead of a cyclohexane ring.
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.[12] Randomized trial evidence suggests that a maximum tolerable dose prevents cardiovascular events and death in patients with diabetic kidney disease.
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.[1]
Ramipril can be considered in patients with bilateral or unilateral significant renal artery stenosis (RAS).[13] 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][14] 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.[15]
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.
Ramipril, a prodrug or precursor drug, is converted to the active metabolite ramiprilat by carboxylesterase 1.[17][18] 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.[19]
Synthesis
The penultimate step in the synthesis of ramipril combines an alanine derivative with a (S,S,S)-2-azabicyclo-[3.3.0]-octane-3-carboxylic acid protected as its benzyl ester.[20] In the original patented route, these components were obtained by a multi-step process.[21]
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.[21] 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.[22][23] However, the trial and the interpretation of its results have been criticised.[24]
The Acute Infarction Ramipril Efficacy (AIRE) trial[17][25] showed a 27% reduction in mortality for patients receiving ramipril for chronic heart failure following a myocardial infarction.
^Ahmed A (July 2002). "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. doi:10.1046/j.1532-5415.2002.50321.x. PMID12133029. S2CID31459410.
^Thomsen R, Rasmussen HB, Linnet K (January 2014). "In vitro drug metabolism by human carboxylesterase 1: focus on angiotensin-converting enzyme inhibitors". Drug Metabolism and Disposition. 42 (1): 126–133. doi:10.1124/dmd.113.053512. PMID24141856. S2CID206496779.
^ abUS patent 5061722, Volker Teetz, Rolf Geiger, Hansjorg Urbach, Reinhard Becker, Bernward Scholkens, "Cis, endo-2-azabicyclo-[3.3.0]-octane-3-carboxylic acids, a process for their preparation, agents containing these compounds and their use", issued 1991-10-29, assigned to Hoechst AG
^"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. doi:10.1016/0140-6736(93)92693-N. PMID8104270. S2CID5770772.
^Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. (April 2008). "Telmisartan, ramipril, or both in patients at high risk for vascular events". The New England Journal of Medicine. 358 (15): 1547–59. doi:10.1056/NEJMoa0801317. hdl:2437/81925. PMID18378520.
