Ramipril

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Ramipril
Ramipril structure.svg
Clinical data
Trade names Altace, others
AHFS/Drugs.com Monograph
MedlinePlus a692027
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 28%
Protein binding 73% (ramipril)
56% (ramiprilat)
Metabolism Liver, to ramiprilat
Elimination half-life 13 to 17 hours
Excretion Kidney (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 InfoCard 100.170.726 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C23H32N2O5
Molar mass 416.518 g·mol−1
3D model (JSmol)
Melting point 109 °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 Yes check.svgY
  • Key:HDACQVRGBOVJII-JBDAPHQKSA-N Yes check.svgY
   (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]

Contents

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

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

Medical uses include:

Contraindications

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

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

Ramipril 1.25-mg oral capsule, letter codes and icons may differ Ramipril 1.25 MG Oral Capsule.jpg
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

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]

Ramipril synthesis.svg

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

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. [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.

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

Related Research Articles

<span class="mw-page-title-main">ACE inhibitor</span> Class of medications used primarily to treat high blood pressure

Angiotensin-converting-enzyme inhibitors are a class of medication used primarily for the treatment of high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart.

<span class="mw-page-title-main">Creatinine</span> Breakdown product of creatine phosphate

Creatinine is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body.

<span class="mw-page-title-main">Proteinuria</span> Presence of an excess of serum proteins in the urine

Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein, less than 150 mg/day; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become foamy. Severe proteinuria can cause nephrotic syndrome in which there is worsening swelling of the body.

<span class="mw-page-title-main">Renin</span> Aspartic protease protein and enzyme

Renin, also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin-angiotensin-aldosterone system (RAAS)—also known as the renin-angiotensin-aldosterone axis—that increases the volume of extracellular fluid and causes arterial vasoconstriction. Thus, it increases the body's mean arterial blood pressure.

<span class="mw-page-title-main">Captopril</span> Antihypertensive drug of the ACE inhibitor class

Captopril, sold under the brand name Capoten among others, is an angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first oral ACE inhibitor found for the treatment of hypertension. It does not cause fatigue as associated with beta-blockers. Due to the adverse drug event of causing hyperkalemia, as seen with most ACE Inhibitors, the medication is usually paired with a diuretic.

Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34% and of ischaemic heart disease by 21%, and can reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors (ACEis), angiotensin II receptor blockers or antagonists (ARBs), and beta blockers.

<span class="mw-page-title-main">Angiotensin-converting enzyme</span> Mammalian protein found in humans

Angiotensin-converting enzyme, or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconstrictor angiotensin II. Therefore, ACE indirectly increases blood pressure by causing blood vessels to constrict. ACE inhibitors are widely used as pharmaceutical drugs for treatment of cardiovascular diseases.

<span class="mw-page-title-main">Enalapril</span> ACE inhibitor medication

Enalapril, sold under the brand name Vasotec among others, is an ACE inhibitor medication used to treat high blood pressure, diabetic kidney disease, and heart failure. For heart failure, it is generally used with a diuretic, such as furosemide. It is given by mouth or by injection into a vein. Onset of effects are typically within an hour when taken by mouth and last for up to a day.

<span class="mw-page-title-main">Chronic kidney disease</span> Abnormal kidney structure or gradual loss of kidney function

Chronic kidney disease (CKD) is a type of long-term kidney disease, in which either there is a gradual loss of kidney function which occurs over a period of months to years, or an abnormal kidney structure. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, and confusion. Complications can relate to hormonal dysfunction of the kidneys and include high blood pressure, bone disease, and anemia. Additionally CKD patients have markedly increased cardiovascular complications with increased risks of death and hospitalization. CKD can lead to kidney failure requiring kidney dialysis or kidney transplantation.

<span class="mw-page-title-main">Fosinopril</span> Antihypertensive drug of the ACE inhibitor class

Fosinopril is an angiotensin converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of chronic heart failure. Fosinopril is the only phosphonate-containing ACE inhibitor marketed, by Bristol-Myers Squibb under the trade name Monopril. Fosinopril is a cascading pro-drug. The special niche for the medication that differentiates it from the other members of the ACE Inhibitor drug class is that was specifically developed for the use for patients with renal impairment. This was through manipulation of the metabolism and excretion, and is seen that fifty percent of the drug is hepatobiliary cleared, which can compensate for diminished renal clearance. The remaining fifty percent is excreted in urine. It does not need dose adjustment.

<span class="mw-page-title-main">Angiotensin II receptor blocker</span> Group of pharmaceuticals that modulate the renin–angiotensin system

Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists, also known as angiotensin receptor blockers, angiotensin II receptor antagonists, or AT1 receptor antagonists, are a group of pharmaceuticals that bind to and inhibit the angiotensin II receptor type 1 (AT1) and thereby block the arteriolar contraction and sodium retention effects of renin–angiotensin system.

<span class="mw-page-title-main">Lisinopril</span> Medication used to treat hypertension and heart failure

Lisinopril is a medication belonging to the drug class of angiotensin-converting enzyme (ACE) inhibitors and is used to treat hypertension, heart failure, and heart attacks. For high blood pressure it is usually a first-line treatment. It is also used to prevent kidney problems in people with diabetes mellitus. Lisinopril is taken orally. Full effect may take up to four weeks to occur.

<span class="mw-page-title-main">Diabetic nephropathy</span> Chronic loss of kidney function

Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally. The triad of protein leaking into the urine, rising blood pressure with hypertension and then falling renal function is common to many forms of CKD. Protein loss in the urine due to damage of the glomeruli may become massive, and cause a low serum albumin with resulting generalized body swelling (edema) so called nephrotic syndrome. Likewise, the estimated glomerular filtration rate (eGFR) may progressively fall from a normal of over 90 ml/min/1.73m2 to less than 15, at which point the patient is said to have end-stage renal disease. It usually is slowly progressive over years.

<span class="mw-page-title-main">Quinapril</span> ACE inhibitor used in the treatment of hypertension and congestive heart failure

Quinapril, sold under the brand name Accupril by the Pfizer corporation, is a medication used to treat high blood pressure (hypertension), heart failure, and diabetic kidney disease. It is a first line treatment for high blood pressure. It is taken by mouth.

<span class="mw-page-title-main">Telmisartan</span> Blood pressure lowering medication

Telmisartan, sold under the brand name Micardis among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth. Versions are available as the combination telmisartan/hydrochlorothiazide, telmisartan/cilnidipine and telmisartan/amlodipine.

<span class="mw-page-title-main">Valsartan</span> Angiotensin II receptor antagonist

Valsartan, sold under the brand name Diovan among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It belongs to a class of medications referred to as angiotensin II receptor blockers (ARBs). It is a reasonable initial treatment for high blood pressure. It is taken by mouth.

<span class="mw-page-title-main">Trandolapril</span> Antihypertensive drug of the ACE inhibitor class

Trandolapril is an ACE inhibitor used to treat high blood pressure. It may also be used to treat other conditions. It is similar in structure to another ramipril but has a cyclohexane group. It is a prodrug that must be metabolized into its active form. It has a longer half-life when compared to other agents in this class.

<span class="mw-page-title-main">Perindopril</span> High blood pressure medication

Perindopril is a medication used to treat high blood pressure, heart failure, or stable coronary artery disease. As a long-acting ACE inhibitor, it works by relaxing blood vessels and decreasing blood volume. As a prodrug, perindopril is hydrolyzed in the liver to its active metabolite, perindoprilat. It was patented in 1980 and approved for medical use in 1988.

<span class="mw-page-title-main">Fimasartan</span> Chemical compound

Fimasartan is a non-peptide angiotensin II receptor antagonist (ARB) used for the treatment of hypertension and heart failure. Through oral administration, fimasartan blocks angiotensin II receptor type 1 (AT1 receptors), reducing pro-hypertensive actions of angiotensin II, such as systemic vasoconstriction and water retention by the kidneys. Concurrent administration of fimasartan with diuretic hydrochlorothiazide has shown to be safe in clinical trials. Fimasartan was approved for use in South Korea on September 9, 2010, and is available under the brand name Kanarb through Boryung Pharmaceuticals, who are presently seeking worldwide partnership.

Cardiovascular agents are drugs used to treat diseases associated with the heart or blood vessels. These medications are available for purchase only with a physician’s prescription. They include, but are not limited to, drugs that target hypertension (antihypertensives), hyperlipidemia (antihyperlipidemics) and blood clotting (blood-thinners) to reduce the risk of cardiovascular diseases.

References

  1. 1 2 3 4 5 6 7 "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. 1 2 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. 1 2 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. 1 2 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. 1 2 USpatent 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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