Ramipril

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Ramipril
Ramipril.svg
Systematic (IUPAC) name
(2S,3aS,6aS)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]-octahydrocyclopenta[b]pyrrole-2-carboxylic acid
Clinical data
Trade names Altace
AHFS/Drugs.com monograph
MedlinePlus a692027
Pregnancy cat. D
Legal status POM (UK) -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability 28%
Protein binding 73% (ramipril)
56% (ramiprilat)
Metabolism Hepatic, to ramiprilat
Half-life 2 to 4 hours
Excretion Renal (60%) and fecal (40%)
Identifiers
CAS number 87333-19-5 YesY
ATC code C09AA05
PubChem CID 5362129
DrugBank DB00178
ChemSpider 4514937 YesY
UNII L35JN3I7SJ YesY
KEGG D00421 YesY
ChEBI CHEBI:8774 YesY
ChEMBL CHEMBL1168 YesY
Chemical data
Formula C23H32N2O5 
Mol. mass 416.511 g/mol
 YesY (what is this?)  (verify)

Ramipril is an angiotensin-converting enzyme (ACE) inhibitor, used to treat high blood pressure (hypertension) and congestive heart failure. By inhibiting an enzyme, ACE inhibitors relax the muscles around small arteries (arterioles). The arterioles expand and allow blood to flow through more easily. This reduces blood pressure.

Medical uses[edit]

Indications for its use include:

Contraindications[edit]

Renovascular disease (impaired blood flow in the kidneys), severe renal impairment (especially in patients with one kidney or with bilateral renal artery stenosis), volume-depleted patients, history of angioedema while on an ACE inhibitor, pregnancy, hypotension.

Adverse effects[edit]

  • low blood sugar (in patients taking medication for diabetes), causing sweating or shakiness
  • dry cough
  • dizziness and light-headedness due to low blood pressure
  • tiredness and fatigue, especially in the early stages
  • mouth dryness in the early stages
  • nausea, vomiting, diarrhea (persistent in rare cases)
  • fainting
  • change in amount of urine
  • signs of infection (e.g., fever, chills, persistent sore throat)
  • yellowing of eyes or skin, dark urine
  • stomach or abdominal pain
  • neutropenia (low white blood cells)
  • impotence (erectile dysfunction)[3]

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]

Ramipril 1.25mg oral capsule.
Letter codes & icons may differ.

ACE inhibitors inhibit the actions of angiotensin converting enzyme (ACE), thereby lowering the production of angiotensin II and also 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 (metabolic product) ramiprilat by liver esterase enzymes.[4] Ramiprilat is mostly excreted by the kidneys. The half-life of ramiprilat is variable (3–16 hours), and is prolonged by heart and liver failure, as well as kidney failure.

Patent[edit]

The compound was protected by U.S. Patent 5,061,722 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.

Ramipril is marketed in India under the brand names of Cardace, Zigpril, Ramistar and Zorem.

Clinical trials[edit]

The HOPE trial[5][6] seemed to show ramipril possessed cardioprotective qualities which extended beyond its qualities as an antihypertensive. However, the HOPE trial and the interpretation of the results have been criticised.[7]

The AIRE trial[4][8] 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 (ARB).[9]

Synthesis[edit]

Ramipril synthesis.[10]

Although acid used to remove acetamido protecting group, base is said to give higher % yield.[11]

See also[edit]

References[edit]

  1. ^ 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. 
  2. ^ Remuzzi, Giuseppe (April 2006). "Prevention and Treatment of Diabetic Renal Disease in Type 2 Diabetes: The BENEDICT Study". Journal of the American Society of Nephrology. 2 14 (4): 590–597. 
  3. ^ Med Tv
  4. ^ 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): 440–66. doi:10.2165/00003495-199549030-00008. PMID 7774515. 
  5. ^ Hypertension Online Slides - ramipril, mortality, kidney failure, HOPE
  6. ^ Ramipril reduced mortality and cardiovascular morbidity in high risk adults - 5 (2): 47 - Evidence-Based Medicine
  7. ^ http://www.medscape.com/viewarticle/430926 "Debate: Do ACE Inhibitors Have Unique Properties, Beyond Their Antihypertensive Effect?"
  8. ^ "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. 
  9. ^ Yusuf S, Teo KK, Pogue J, et al (April 2008). "Telmisartan, ramipril, or both in patients at high risk for vascular events". N. Engl. J. Med. 358 (15): 1547–59. doi:10.1056/NEJMoa0801317. PMID 18378520. 
  10. ^ "The synthesis of Ramipril" (in English). Retrieved 2014-07-09. 
  11. ^ "Deprotecting Acetamide: acid vs base.". 

External links[edit]