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Ramipril

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Ramipril
Clinical data
Trade namesAltace, others
AHFS/Drugs.comMonograph
MedlinePlusa692027
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability28%
Protein binding73% (ramipril)
56% (ramiprilat)
MetabolismLiver, to ramiprilat
Elimination half-life13 to 17 hours
ExcretionKidney (60%) and fecal (40%)
Identifiers
  • (2S,3aS,6aS)-1-[(2S)-2-[[(2S)-1-Ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoyl]-3,3a,4,5,6,6a-hexahydro-2H-cyclopenta[b]pyrrole-2-carboxylic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.170.726 Edit this at Wikidata
Chemical and physical data
FormulaC23H32N2O5
Molar mass416.518 g·mol−1
3D model (JSmol)
Melting point109 °C (228 °F)
  • O=C(OCC)[C@@H](N[C@H](C(=O)N1[C@H](C(=O)O)C[C@@H]2CCC[C@H]12)C)CCc3ccccc3
  • InChI=1S/C23H32N2O5/c1-3-30-23(29)18(13-12-16-8-5-4-6-9-16)24-15(2)21(26)25-19-11-7-10-17(19)14-20(25)22(27)28/h4-6,8-9,15,17-20,24H,3,7,10-14H2,1-2H3,(H,27,28)/t15-,17-,18-,19-,20-/m0/s1 checkY
  • Key:HDACQVRGBOVJII-JBDAPHQKSA-N checkY
  (verify)

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]

Common side effects include headaches, dizziness, fatigue, and cough.[1] Serious side effects may include liver problems, angioedema, kidney problems, and high blood potassium.[1] Use in pregnancy and breastfeeding is not recommended.[5] It is an ACE inhibitor and works by decreasing renin-angiotensin-aldosterone system activity.[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 2 million prescriptions.[8][9]

Activation and binding

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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.

Medical uses

[edit]

Medical uses include:

  • High blood pressure (Hypertension)
  • Congestive heart failure[11]
  • 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.[12] Randomized trial evidence suggests that a maximum tolerable dose prevents cardiovascular events and death in patients with diabetic kidney disease.

Contraindications

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

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]

Adverse effects

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  • 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)[16]
  • 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

[edit]
See also: Renin–angiotensin system
Ramipril 1.25-mg oral capsule,
letter codes and icons may differ

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.[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

[edit]

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 acid chloride forms an amide bond with the amino group of the pyrrolidine ring in the presence of triethylamine and ramipril is the product after the benzyl ester has been removed by hydrogenation.[20]

Society and culture

[edit]

US patent

[edit]

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

[edit]

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

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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.

Ramipril was found to have similar results as telmisartan, an angiotensin II receptor blocker.[26]

References

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  1. ^ a b c d e f g "Ramipril Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 3 March 2019.
  2. ^ Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G (January 2000). "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. doi:10.1056/NEJM200001203420301. PMID 10639539.
  3. ^ HOPE study investigators (January 2000). "Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy". The Lancet. 355 (9200): 253–259. doi:10.1016/S0140-6736(99)12323-7. S2CID 1863533.
  4. ^ Savarese G, Costanzo P, Cleland JG, Vassallo E, Ruggiero D, Rosano G, et al. (January 2013). "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. doi:10.1016/j.jacc.2012.10.011. PMID 23219304.
  5. ^ "Ramipril Pregnancy and Breastfeeding Warnings". Drugs.com. Retrieved 3 March 2019.
  6. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 469. ISBN 9783527607495.
  7. ^ British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 172–173. ISBN 9780857113382.
  8. ^ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
  9. ^ "Ramipril Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
  10. ^ Riordan JF (2003). "Angiotensin-I-converting enzyme and its relatives". Genome Biology. 4 (8): 225. doi:10.1186/gb-2003-4-8-225. PMC 193637. PMID 12914653.
  11. ^ Pilote L, Abrahamowicz M, Eisenberg M, Humphries K, Behlouli H, Tu JV (May 2008). "Effect of different angiotensin-converting-enzyme inhibitors on mortality among elderly patients with congestive heart failure". CMAJ. 178 (10): 1303–11. doi:10.1503/cmaj.060068. PMC 2335176. PMID 18458262.
  12. ^ Remuzzi G, Macia M, Ruggenenti P (April 2006). "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. doi:10.1681/ASN.2005121324. PMID 16565256.
  13. ^ a b Chrysochou C, Foley RN, Young JF, Khavandi K, Cheung CM, Kalra PA (April 2012). "Dispelling the myth: the use of renin-angiotensin blockade in atheromatous renovascular disease". Nephrology, Dialysis, Transplantation. 27 (4): 1403–1409. doi:10.1093/ndt/gfr496. PMID 21993376.
  14. ^ 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. PMID 12133029. S2CID 31459410.
  15. ^ Chrysochou C, Foley RN, Young JF, Khavandi K, Cheung CM, Kalra PA (April 2012). "Dispelling the myth: the use of renin-angiotensin blockade in atheromatous renovascular disease". Nephrology, Dialysis, Transplantation. 27 (4): 1403–1409. doi:10.1093/ndt/gfr496. PMID 21993376.
  16. ^ "Ramipril Side Effects". eMedTV: Health Information Brought To Life.
  17. ^ a b Frampton JE, Peters DH (March 1995). "Ramipril. An updated review of its therapeutic use in essential hypertension and heart failure". Drugs. 49 (3): 440–466. doi:10.2165/00003495-199549030-00008. PMID 7774515. S2CID 195691742.
  18. ^ 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. PMID 24141856. S2CID 206496779.
  19. ^ McCarron D, et al. (Ramipril Multicenter Study Group) (September 1991). "24-hour blood pressure profiles in hypertensive patients administered ramipril or placebo once daily: magnitude and duration of antihypertensive effects". Clinical Cardiology. 14 (9). Wiley: 737–742. doi:10.1002/clc.4960140908. PMID 1835914.
  20. ^ a b Malakondaiah GC, Gurav VM, Reddy LA, Babu KS, Bhaskar BV, Reddy PP, et al. (2008). "Expeditious Synthesis of Ramipril: An Angiotensin Converting Enzyme (ACE) Inhibitor". Synthetic Communications. 38 (11): 1737–1744. doi:10.1080/00397910801989238.
  21. ^ a b US 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 
  22. ^ "HOPE Trial: Main Outcomes and Serum Creatinine". Hypertension Online. 13 August 2001. Archived from the original on 2 August 2012. Ramipril significantly reduced the high cardiovascular risk associated with renal insufficiency
  23. ^ Malmberg K, Rydén L (March 2000). "Ramipril reduced mortality and cardiovascular morbidity in high risk adults". BMJ Evidence-Based Medicine. 5 (2). BMJ Publishing Group Ltd: 47. doi:10.1136/ebm.5.2.47.
  24. ^ Jafary F, Yusuf S, Nissen S (2002). "Debate: Do ACE Inhibitors Have Unique Properties, Beyond Their Antihypertensive Effect?". MedScape. Controversies in Cardiology II.
  25. ^ "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. PMID 8104270. S2CID 5770772.
  26. ^ 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. PMID 18378520.
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