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targets (1) transporters (2)
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Identification
Name Ramipril
Accession Number DB00178 (APRD00009)
Type small molecule
Groups approved
Description

Ramipril is a prodrug belonging to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is metabolized to ramiprilat in the liver and, to a lesser extent, kidneys. Ramiprilat is a potent, competitive inhibitor of ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII). ATII regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system (RAAS). Ramipril may be used in the treatment of hypertension, congestive heart failure, nephropathy, and to reduce the rate of death, myocardial infarction and stroke in individuals at high risk of cardiovascular events.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Ramiprilum [Latin]
Brand names
  • Acovil (Sanofi-Aventis (Spain))
  • Altace (Sanofi-Aventis, King)
  • Carasel (Almirall (Spain))
  • Cardace (Sanofi-Aventis (Finland), Aventis (India), Aventis (Indonesia))
  • Delix (Aventis (Germany, Turkey), )
  • Hypren (AstraZeneca (Austria))
  • Hytren
  • Lostapres (Temis (Argentina))
  • Pramace (discontinued) (Astra (Ireland), AstraZeneca (Sweden))
  • Quark (Polifarma (Italy))
  • Ramace (Sanofi-Aventis (Australia), Teva (Hungary), AstraZeneca (South Africa))
  • Triatec (Sanofi-Aventis (Brazil, Chili, Denmark, France, Greece, Indonesia, Italy,Norway, Portugal, Sweden, Switzerland))
  • Tritace (Sanofi-Aventis (Argentina, Australia, Austria, Belgium, Czech Republic, Hong Kong, Hungary, Ireland, Israel, Malaysia, Mexico, Netherlands, Poland, Singapor, Thailand, United Kingdom), Aventis (New Zealand, Philippines, South Africa))
  • Unipril (AstraZeneca (Italy))
  • Vesdil (AstraZeneca (Germany), Promed (Germany))
Brand name mixtures
  • Altace HCT (ramipril + hydrochlorothiazide)
Categories
  • Antihypertensive Agents
  • Angiotensin-converting Enzyme Inhibitors
CAS number 87333-19-5
Weight Average: 416.5106
Monoisotopic: 416.231122144
Chemical Formula C23H32N2O5
InChI Key InChIKey=HDACQVRGBOVJII-JBDAPHQKSA-N
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
Plain Text
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
SMILES
[H][C@@]12CCC[C@]1([H])N([C@@H](C2)C(O)=O)C(=O)[C@H](C)N[C@@H](CCC1=CC=CC=C1)C(=O)OCC
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Polypeptides
  • Phenylpropylamines
Substructures
  • Carboxylic Acids and Derivatives
  • Hydroxy Compounds
  • Acetates
  • Aliphatic and Aryl Amines
  • Amino Ketones
  • Pyrrolidines
  • Ethers
  • Benzene and Derivatives
  • Polypeptides
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Phenylpropylamines
  • Amino Acids
Pharmacology
Indication For the management of mild to severe hypertension. May be used to reduce cardiovascular mortality following myocardial infarction in hemodynamically stable individuals who develop clinical signs of congestive heart failure within a few days following myocardial infarction. To reduce the rate of death, myocardial infarction and stroke in individuals at high risk of cardiovascular events. May be used to slow the progression of renal disease in individuals with hypertension, diabetes mellitus and microalubinuria or overt nephropathy.
Pharmacodynamics Ramipril is an ACE inhibitor similar to benazepril, fosinopril and quinapril. It is an inactive prodrug that is converted to ramiprilat in the liver, the main site of activation, and kidneys. Ramiprilat confers blood pressure lowing effects by antagonizing the effect of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain the effects of ramiprilat by causing increased vasodilation and decreased blood pressure.
Mechanism of action There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Ramiprilat, the principle active metabolite of ramipril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Ramipril also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors.
Absorption The extent of absorption is at least 50-60%. Food decreases the rate of absorption from the GI tract without affecting the extent of absorption. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when oral administration was compared to intravenous administration.
Volume of distribution Not Available
Protein binding Protein binding of ramipril is about 73% and that of ramiprilat about 56%.
Metabolism

Hepatic metabolism accounts for 75% of total ramipril metabolism. 25% of hepatic metabolism produces the active metabolite ramiprilat via liver esterase enzymes. 100% of renal metabolism converts ramipril to ramiprilat. Other metabolites, diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, are inactive.

Route of elimination Not Available
Half life Plasma concentrations of ramiprilat decline in a triphasic manner. Initial rapid decline represents distribution into tissues and has a half life of 2-4 hours. The half life of the apparent elimination phase is 9-18 hours and that of the terminal elimination phase is > 50 hours. Two elimination phases occur as a result of ramiprilat's potent binding to ACE and slow dissociation from the enzyme. The half life of ramiprilat after multiple daily doses (MDDs) is dose-dependent, ranging from 13-17 hours with 5-10 mg MDDs to 27-36 hours for 2.5 mg MDDs.
Clearance Not Available
Toxicity Symptoms of overdose may include excessive peripheral vasodilation (with marked hypotension and shock), bradycardia, electrolyte disturbances, and renal failure. The most likely adverse reactions are symptoms attributable to its blood-pressure lowing effect. May cause headache, dizziness, asthenia, chest pain, nausea, peripheral edema, somnolence, impotence, rash, arthritis, and dyspnea. LD50 = 10933 mg/kg (orally in mice).
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00154 Ramipril Pathway SMP00154
Pharmacoeconomics
Manufacturers
  • King pharmaceuticals inc
  • Actavis elizabeth llc
  • Apotex inc
  • Cipla ltd
  • Dr reddys laboratories ltd
  • Invagen pharmaceuticals inc
  • Lupin ltd
  • Ranbaxy laboratories ltd
  • Roxane laboratories inc
  • Sandoz inc
  • Teva pharmaceuticals usa
  • Watson laboratories inc
  • Zydus pharmaceuticals usa inc
  • King Pharmaceuticals, Inc.
Packagers
Dosage forms
Form Route Strength
Capsule Oral 1.25 mg
Capsule Oral 10 mg
Capsule Oral 15 mg
Capsule Oral 2.5 mg
Capsule Oral 5 mg
Prices
Unit description Cost Unit
Altace 10 mg capsule 2.87 USD capsule
Altace 2.5 mg capsule 2.54 USD capsule
Altace 5 mg capsule 2.53 USD capsule
Altace 10 mg tablet 2.37 USD tablet
Altace 1.25 mg capsule 2.2 USD capsule
Ramipril 10 mg capsule 2.19 USD capsule
Altace 5 mg tablet 2.02 USD tablet
Altace 2.5 mg tablet 1.93 USD tablet
Ramipril 5 mg capsule 1.87 USD capsule
Ramipril 2.5 mg capsule 1.78 USD capsule
Altace 1.25 mg tablet 1.63 USD tablet
Ramipril 1.25 mg capsule 1.59 USD capsule
Altace 10 mg Tablet 1.14 USD tablet
Altace 2.5 mg Tablet 0.9 USD tablet
Altace 5 mg Tablet 0.9 USD tablet
Altace 1.25 mg Tablet 0.78 USD tablet
Apo-Ramipril 10 mg Tablet 0.64 USD tablet
Co Ramipril 10 mg Tablet 0.64 USD tablet
Jamp-Ramipril 10 mg Tablet 0.64 USD tablet
Mylan-Ramipril 10 mg Tablet 0.64 USD tablet
Novo-Ramipril 10 mg Tablet 0.64 USD tablet
Pms-Ramipril 10 mg Tablet 0.64 USD tablet
Ramipril 10 mg Tablet 0.64 USD tablet
Ran-Ramipril 10 mg Tablet 0.64 USD tablet
Ratio-Ramipril 10 mg Tablet 0.64 USD tablet
Sandoz Ramipril 10 mg Tablet 0.64 USD tablet
Apo-Ramipril 2.5 mg Tablet 0.5 USD tablet
Apo-Ramipril 5 mg Tablet 0.5 USD tablet
Co Ramipril 2.5 mg Tablet 0.5 USD tablet
Co Ramipril 5 mg Tablet 0.5 USD tablet
Jamp-Ramipril 2.5 mg Tablet 0.5 USD tablet
Jamp-Ramipril 5 mg Tablet 0.5 USD tablet
Mylan-Ramipril 2.5 mg Tablet 0.5 USD tablet
Mylan-Ramipril 5 mg Tablet 0.5 USD tablet
Novo-Ramipril 2.5 mg Tablet 0.5 USD tablet
Novo-Ramipril 5 mg Tablet 0.5 USD tablet
Pms-Ramipril 2.5 mg Tablet 0.5 USD tablet
Pms-Ramipril 5 mg Tablet 0.5 USD tablet
Ramipril 2.5 mg Tablet 0.5 USD tablet
Ramipril 5 mg Tablet 0.5 USD tablet
Ran-Ramipril 2.5 mg Tablet 0.5 USD tablet
Ran-Ramipril 5 mg Tablet 0.5 USD tablet
Ratio-Ramipril 2.5 mg Tablet 0.5 USD tablet
Ratio-Ramipril 5 mg Tablet 0.5 USD tablet
Sandoz Ramipril 2.5 mg Tablet 0.5 USD tablet
Sandoz Ramipril 5 mg Tablet 0.5 USD tablet
Apo-Ramipril 1.25 mg Tablet 0.44 USD tablet
Co Ramipril 1.25 mg Tablet 0.44 USD tablet
Jamp-Ramipril 1.25 mg Tablet 0.44 USD tablet
Mylan-Ramipril 1.25 mg Tablet 0.44 USD tablet
Pms-Ramipril 1.25 mg Tablet 0.44 USD tablet
Ramipril 1.25 mg Tablet 0.44 USD tablet
Ran-Ramipril 1.25 mg Tablet 0.44 USD tablet
Ratio-Ramipril 1.25 mg Tablet 0.44 USD tablet
Sandoz Ramipril 1.25 mg Tablet 0.44 USD tablet
Patents
Country Patent Number Approved Expires
United States 7368469 2000-08-30 2020-08-30
United States 5403856 1995-04-04 2012-04-04
Canada 2382387 2005-06-21 2020-08-25
Canada 1338344 1996-05-21 2013-05-21
Properties
State solid
Melting point 109 oC
Experimental Properties
Property Value Source
water solubility 3.5mg/L PhysProp
logP 2.9 PhysProp
Predicted Properties
Property Value Source
water solubility 3.90e-02 g/l ALOGPS
logP 0.92 ALOGPS
logP 1.45 ChemAxon Molconvert
logS -4.03 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 5 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 95.94 ChemAxon Molconvert
rotatable bond count 10 ChemAxon Molconvert
refractivity 111.19 ChemAxon Molconvert
polarizability 44.78 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Cacciapuoti F, Capasso A, Mirra G, De Nicola A, Minicucci F, Gentile S: Prevention of left ventricular hypertrophy by ACE-inhibitor, ramipril in comparison with calcium-channel antagonist, felodipine. Int J Cardiol. 1998 Jan 31;63(2):175-8. Pubmed
  2. Kleinert S: HOPE for cardiovascular disease prevention with ACE-inhibitor ramipril. Heart Outcomes Prevention Evaluation. Lancet. 1999 Sep 4;354(9181):841. Pubmed
External Links
Resource Link
KEGG Drug D00421 Link_out
PubChem Compound 5362129 Link_out
PubChem Substance 46506390 Link_out
ChemSpider 4514937 Link_out
ChEBI 8774 Link_out
ChEMBL 8774 Link_out
Therapeutic Targets Database DAP000581 Link_out
PharmGKB PA451223 Link_out
Drug Product Database 2221829 Link_out
RxList http://www.rxlist.com/cgi/generic/ramipril.htm Link_out
Drugs.com http://www.drugs.com/ramipril.html Link_out
PDRhealth http://www.pdrhealth.com/drugs/rx/rx-mono.aspx?contentFileName=alt1014.html&contentName=Altace&contentId=44 Link_out
Wikipedia http://en.wikipedia.org/wiki/Ramipril Link_out
ATC Codes
  • C09AA05
AHFS Codes
  • 24:32.04
PDB Entries
FDA label Not Available
MSDS show (53.6 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Alcohol may increase the vasodilatory effects of ramipril.
  • Herbs that may attenuate the antihypertensive effect of ramipril include: bayberry, blue cohash, cayenne, ephedra, ginger, ginseng (American), kola and licorice.
  • High salt intake may attenuate the antihypertensive effect of ramipril.
  • Ramipril decreases the excretion of potassium. Salt substitutes containing potassium increase the risk of hyperkalemia.
  • Take without regard to meals.
Targets

1. Angiotensin-converting enzyme

Pharmacological action: yes
Actions: inhibitor

Converts angiotensin I to angiotensin II by release of the terminal His-Leu, this results in an increase of the vasoconstrictor activity of angiotensin. Also able to inactivate bradykinin, a potent vasodilator

Organism class: human
UniProt ID: P12821 Link_out
Gene: ACE Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Levitt DG, Schoemaker RC: Human physiologically based pharmacokinetic model for ACE inhibitors: ramipril and ramiprilat. BMC Clin Pharmacol. 2006 Jan 6;6:1. Pubmed
  3. Piepho RW: Overview of the angiotensin-converting-enzyme inhibitors. Am J Health Syst Pharm. 2000 Oct 1;57 Suppl 1:S3-7. Pubmed
  4. Song JC, White CM: Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin converting enzyme inhibitors: an update. Clin Pharmacokinet. 2002;41(3):207-24. Pubmed
Transporters

1. Oligopeptide transporter, small intestine isoform

Actions: substrate

Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides. May constitute a major route for the absorption of protein digestion end-products

UniProt ID: P46059 Link_out
Gene: SLC15A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Knutter I, Wollesky C, Kottra G, Hahn MG, Fischer W, Zebisch K, Neubert RH, Daniel H, Brandsch M: Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther. 2008 Nov;327(2):432-41. Epub 2008 Aug 19. Pubmed

2. Oligopeptide transporter, kidney isoform

Actions: substrate

Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides

UniProt ID: Q16348 Link_out
Gene: SLC15A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Knutter I, Wollesky C, Kottra G, Hahn MG, Fischer W, Zebisch K, Neubert RH, Daniel H, Brandsch M: Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther. 2008 Nov;327(2):432-41. Epub 2008 Aug 19. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:01

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.