Ramipril

Ramipril (INN, BAN, USAN)

File:Ramipril structure.svg
Systematic (IUPAC) name
(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
Clinical data
Trade names	Altace
AHFS/Drugs.com	monograph
MedlinePlus	a692027
Pregnancy category	D
Legal status	UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	28%
Protein binding	73% (ramipril) 56% (ramiprilat)
Metabolism	Hepatic, to ramiprilat
Biological half-life	2 to 4 hours
Excretion	Renal (60%) and fecal (40%)
Identifiers
CAS Number	87333-19-5 Y
ATC code	C09AA05 (WHO)
PubChem	CID: 5362129
IUPHAR/BPS	6339
DrugBank	DB00178 Y
ChemSpider	4514937 Y
UNII	L35JN3I7SJ Y
KEGG	D00421 Y
ChEBI	CHEBI:8774 Y
ChEMBL	CHEMBL1168 Y
Chemical data
Formula	C23H32N2O5
Molecular mass	416.511 g/mol
SMILES 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 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 Y Key:HDACQVRGBOVJII-JBDAPHQKSA-N Y
Physical data
Melting point	109 °C (228 °F)
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Ramipril, sold under the brand name Altace among others, 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

Indications for its use include:

• High blood pressure
• Congestive heart failure
• Following heart attack in patients with clinical evidence of heart failure
• Susceptible patients over 55 years: prevention of heart attack, stroke, cardiovascular death, or need of revascularization procedures
• kidney damage due to diabetes with protein in the urine (In low doses it is used as a prophylaxis for developing nephropathy and related secondary cardiovascular events.)

Contraindications

Contraindications to its use include 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, a history of angioedema while on an ACE inhibitors, pregnancy, and hypotension.

Adverse effects

• Shakiness
• Dry cough
• Dizziness and light-headedness 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)

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

File: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. 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.

Patent

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.

Brand names

It is marketed as Prilace by Arrow Pharmaceuticals in Australia, Ramipro by Westfield Pharma in the Philippines, Tritace 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 (Sonfi) and Ramipril (Pharmascience).

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

Clinical trials

The Heart Outcomes and Prevention Evaluation trial seemed to show ramipril possessed cardioprotective qualities which extended beyond its qualities as an antihypertensive. However, the trial and the interpretation of its results have been criticised.

The AIRE trial 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.

See also

• Angiotensin-converting enzyme (ACE) inhibitor
• Hypertension
• Hypotension
• Heart failure
• Chest pain

External links

• Altace (ramipril), a registered trademark of King Pharmaceuticals, Inc.
• Data Sheet for Ramipril – ChemSpider 18 September 2008
• U.S. National Library of Medicine: Drug Information Portal - Ramipril