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Identification
NameRamipril
Accession NumberDB00178  (APRD00009)
Typesmall molecule
Groupsapproved
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
Synonyms
SynonymLanguageCode
RamiprilumLatinNot Available
SaltsNot Available
Brand names
NameCompany
AcovilSanofi-Aventis (Spain)
AltaceSanofi-Aventis, King
CaraselAlmirall (Spain)
CardaceSanofi-Aventis (Finland), Aventis (India), Aventis (Indonesia)
DelixAventis (Germany, Turkey),
HyprenAstraZeneca (Austria)
LostapresTemis (Argentina)
PramaceAstra (Ireland), AstraZeneca (Sweden)
QuarkPolifarma (Italy)
RamaceSanofi-Aventis (Australia), Teva (Hungary), AstraZeneca (South Africa)
TriatecSanofi-Aventis (Brazil, Chili, Denmark, France, Greece, Indonesia, Italy,Norway, Portugal, Sweden, Switzerland)
TritaceSanofi-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)
VesdilAstraZeneca (Germany), Promed (Germany)
Brand mixtures
Brand NameIngredients
Altace HCTramipril + hydrochlorothiazide
Categories
CAS number87333-19-5
WeightAverage: 416.5106
Monoisotopic: 416.231122144
Chemical FormulaC23H32N2O5
InChI KeyInChIKey=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
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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganic Acids and Derivatives
ClassCarboxylic Acids and Derivatives
SubclassAmino Acids, Peptides, and Analogues
Direct parentPeptides
Alternative parentsN-acyl-alpha Amino Acids; Alpha Amino Acid Esters; Alpha Amino Acid Amides; Phenylpropylamines; Pyrrolidine Carboxylic Acids; Fatty Acid Esters; Dicarboxylic Acids and Derivatives; Tertiary Carboxylic Acid Amides; Cyclic Alcohols and Derivatives; Tertiary Amines; Carboxylic Acid Esters; Enolates; Carboxylic Acids; Dialkylamines; Polyamines; Ethers
Substituentsn-acyl-alpha amino acid or derivative; n-acyl-alpha-amino acid; alpha-amino acid ester; alpha-amino acid amide; phenylpropylamine; alpha-amino acid or derivative; pyrrolidine carboxylic acid or derivative; pyrrolidine carboxylic acid; fatty acid ester; dicarboxylic acid derivative; benzene; pyrrolidine; cyclic alcohol; tertiary carboxylic acid amide; carboxylic acid ester; carboxamide group; tertiary amine; secondary amine; secondary aliphatic amine; ether; enolate; carboxylic acid; polyamine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the peptides. These are compounds containing an amide derived from two or more amino carboxylic acid molecules (the same or different) by formation of a covalent bond from the carbonyl carbon of one to the nitrogen atom of another.
Pharmacology
IndicationFor 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.
PharmacodynamicsRamipril 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 actionThere 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.
AbsorptionThe 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 distributionNot Available
Protein bindingProtein 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.

SubstrateEnzymesProduct
Ramipril
    Diketopiperazine acidDetails
    Ramipril
      Diketopiperazine esterDetails
      Ramipril
      RamiprilatDetails
      Route of eliminationNot Available
      Half lifePlasma 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.
      ClearanceNot Available
      ToxicitySymptoms 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
      PathwayCategorySMPDB ID
      Ramipril Action PathwayDrug actionSMP00154
      Ramipril Metabolism PathwayDrug metabolismSMP00597
      SNP Mediated Effects
      Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeEffectReference(s)
      Angiotensin-converting enzyme
      Gene symbol: ACE
      UniProt: P12821
      rs4344 Not AvailableA Allele, homozygoteMore rapid response to drug treatment17885551
      Angiotensin-converting enzyme
      Gene symbol: ACE
      UniProt: P12821
      rs4344 Not AvailableG Allele, homozygoteMore rapid response to drug treatment17885551
      Angiotensin-converting enzyme 2
      Gene symbol: ACE2
      UniProt: Q9BYF1
      rs4344 Not AvailableG > AThose with the AA or GG gentypes respond better to treatment17885551
      SNP Mediated Adverse Drug ReactionsNot Available
      ADMET
      Predicted ADMET features
      Property Value Probability
      Human Intestinal Absorption + 0.9159
      Blood Brain Barrier - 0.8726
      Caco-2 permeable - 0.8491
      P-glycoprotein substrate Substrate 0.7263
      P-glycoprotein inhibitor I Non-inhibitor 0.7002
      P-glycoprotein inhibitor II Inhibitor 0.6295
      Renal organic cation transporter Non-inhibitor 0.8869
      CYP450 2C9 substrate Non-substrate 0.8541
      CYP450 2D6 substrate Non-substrate 0.8969
      CYP450 3A4 substrate Non-substrate 0.5082
      CYP450 1A2 substrate Non-inhibitor 0.9045
      CYP450 2C9 substrate Non-inhibitor 0.907
      CYP450 2D6 substrate Non-inhibitor 0.9304
      CYP450 2C19 substrate Non-inhibitor 0.9025
      CYP450 3A4 substrate Non-inhibitor 0.8309
      CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5691
      Ames test Non AMES toxic 0.9108
      Carcinogenicity Non-carcinogens 0.9267
      Biodegradation Not ready biodegradable 0.8903
      Rat acute toxicity 1.6732 LD50, mol/kg Not applicable
      hERG inhibition (predictor I) Weak inhibitor 0.98
      hERG inhibition (predictor II) Non-inhibitor 0.7901
      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
      FormRouteStrength
      CapsuleOral1.25 mg
      CapsuleOral10 mg
      CapsuleOral15 mg
      CapsuleOral2.5 mg
      CapsuleOral5 mg
      Prices
      Unit descriptionCostUnit
      Altace 10 mg capsule2.87USDcapsule
      Altace 2.5 mg capsule2.54USDcapsule
      Altace 5 mg capsule2.53USDcapsule
      Altace 10 mg tablet2.37USDtablet
      Altace 1.25 mg capsule2.2USDcapsule
      Ramipril 10 mg capsule2.19USDcapsule
      Altace 5 mg tablet2.02USDtablet
      Altace 2.5 mg tablet1.93USDtablet
      Ramipril 5 mg capsule1.87USDcapsule
      Ramipril 2.5 mg capsule1.78USDcapsule
      Altace 1.25 mg tablet1.63USDtablet
      Ramipril 1.25 mg capsule1.59USDcapsule
      Altace 10 mg Tablet1.14USDtablet
      Altace 2.5 mg Tablet0.9USDtablet
      Altace 5 mg Tablet0.9USDtablet
      Altace 1.25 mg Tablet0.78USDtablet
      Apo-Ramipril 10 mg Tablet0.64USDtablet
      Co Ramipril 10 mg Tablet0.64USDtablet
      Jamp-Ramipril 10 mg Tablet0.64USDtablet
      Mylan-Ramipril 10 mg Tablet0.64USDtablet
      Novo-Ramipril 10 mg Tablet0.64USDtablet
      Pms-Ramipril 10 mg Tablet0.64USDtablet
      Ramipril 10 mg Tablet0.64USDtablet
      Ran-Ramipril 10 mg Tablet0.64USDtablet
      Ratio-Ramipril 10 mg Tablet0.64USDtablet
      Sandoz Ramipril 10 mg Tablet0.64USDtablet
      Apo-Ramipril 2.5 mg Tablet0.5USDtablet
      Apo-Ramipril 5 mg Tablet0.5USDtablet
      Co Ramipril 2.5 mg Tablet0.5USDtablet
      Co Ramipril 5 mg Tablet0.5USDtablet
      Jamp-Ramipril 2.5 mg Tablet0.5USDtablet
      Jamp-Ramipril 5 mg Tablet0.5USDtablet
      Mylan-Ramipril 2.5 mg Tablet0.5USDtablet
      Mylan-Ramipril 5 mg Tablet0.5USDtablet
      Novo-Ramipril 2.5 mg Tablet0.5USDtablet
      Novo-Ramipril 5 mg Tablet0.5USDtablet
      Pms-Ramipril 2.5 mg Tablet0.5USDtablet
      Pms-Ramipril 5 mg Tablet0.5USDtablet
      Ramipril 2.5 mg Tablet0.5USDtablet
      Ramipril 5 mg Tablet0.5USDtablet
      Ran-Ramipril 2.5 mg Tablet0.5USDtablet
      Ran-Ramipril 5 mg Tablet0.5USDtablet
      Ratio-Ramipril 2.5 mg Tablet0.5USDtablet
      Ratio-Ramipril 5 mg Tablet0.5USDtablet
      Sandoz Ramipril 2.5 mg Tablet0.5USDtablet
      Sandoz Ramipril 5 mg Tablet0.5USDtablet
      Apo-Ramipril 1.25 mg Tablet0.44USDtablet
      Co Ramipril 1.25 mg Tablet0.44USDtablet
      Jamp-Ramipril 1.25 mg Tablet0.44USDtablet
      Mylan-Ramipril 1.25 mg Tablet0.44USDtablet
      Pms-Ramipril 1.25 mg Tablet0.44USDtablet
      Ramipril 1.25 mg Tablet0.44USDtablet
      Ran-Ramipril 1.25 mg Tablet0.44USDtablet
      Ratio-Ramipril 1.25 mg Tablet0.44USDtablet
      Sandoz Ramipril 1.25 mg Tablet0.44USDtablet
      DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
      Patents
      CountryPatent NumberApprovedExpires (estimated)
      United States73684692000-08-302020-08-30
      United States54038561995-04-042012-04-04
      Canada23823872005-06-212020-08-25
      Canada13383441996-05-212013-05-21
      Properties
      Statesolid
      Experimental Properties
      PropertyValueSource
      melting point109 °CPhysProp
      water solubility3.5mg/LNot Available
      logP2.9Not Available
      Predicted Properties
      PropertyValueSource
      water solubility3.90e-02 g/lALOGPS
      logP0.92ALOGPS
      logP1.47ChemAxon
      logS-4ALOGPS
      pKa (strongest acidic)3.75ChemAxon
      pKa (strongest basic)5.2ChemAxon
      physiological charge-1ChemAxon
      hydrogen acceptor count5ChemAxon
      hydrogen donor count2ChemAxon
      polar surface area95.94ChemAxon
      rotatable bond count10ChemAxon
      refractivity111.19ChemAxon
      polarizability44.78ChemAxon
      number of rings3ChemAxon
      bioavailability1ChemAxon
      rule of fiveYesChemAxon
      Ghose filterYesChemAxon
      Veber's ruleNoChemAxon
      MDDR-like ruleYesChemAxon
      Spectra
      SpectraNot Available
      References
      Synthesis Reference

      Edward Wilson, Martin Beasley, “Stabilized ramipril compositions and methods of making.” U.S. Patent US20060134213, issued June 22, 2006.

      US20060134213
      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
      ResourceLink
      KEGG DrugD00421
      PubChem Compound5362129
      PubChem Substance46506390
      ChemSpider4514937
      ChEBI8774
      ChEMBLCHEMBL1168
      Therapeutic Targets DatabaseDAP000581
      PharmGKBPA451223
      Drug Product Database2221829
      RxListhttp://www.rxlist.com/cgi/generic/ramipril.htm
      Drugs.comhttp://www.drugs.com/ramipril.html
      PDRhealthhttp://www.pdrhealth.com/drugs/rx/rx-mono.aspx?contentFileName=alt1014.html&contentName=Altace&contentId=44
      WikipediaRamipril
      ATC CodesC09AA05
      AHFS Codes
      • 24:32.04
      PDB Entries
      FDA labelNot Available
      MSDSshow(53.6 KB)
      Interactions
      Drug Interactions
      Drug
      AmilorideIncreased risk of hyperkalemia
      Azilsartan medoxomilPharmacodynamic synergism: dual blockade of renin-angiotensin system. Increases risks of hypotension, hyperkalemia, renal impairment.
      DrospirenoneIncreased risk of hyperkalemia
      IcatibantIcatibant may attenuate the antihypertensive effect of ACE inhibitors by pharmacodynamic antagonism. Monitor concomitant therapy closely.
      Insulin LisproConcomitant therapy with ACE inhibitors may increase the blood-glucose-lowering effect of insulin lispro and thus the chance of hypoglycemia should be monitored closely.
      LithiumThe ACE inhibitor increases serum levels of lithium
      PotassiumIncreased risk of hyperkalemia
      SpironolactoneIncreased risk of hyperkalemia
      TizanidineTizanidine increases the risk of hypotension with the ACE inhibitor
      TobramycinIncreased risk of nephrotoxicity
      TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
      TriamtereneIncreased risk of hyperkalemia
      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.

      1. Angiotensin-converting enzyme

      Kind: protein

      Organism: Human

      Pharmacological action: yes

      Actions: inhibitor

      Components

      Name UniProt ID Details
      Angiotensin-converting enzyme P12821 Details

      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

      1. Cholinesterase

      Kind: protein

      Organism: Human

      Pharmacological action: unknown

      Actions: inhibitor

      Components

      Name UniProt ID Details
      Cholinesterase P06276 Details

      References:

      1. Shah GB, Sharma S, Mehta AA, Goyal RK: Oculohypotensive effect of angiotensin-converting enzyme inhibitors in acute and chronic models of glaucoma. J Cardiovasc Pharmacol. 2000 Aug;36(2):169-75. Pubmed

      1. Solute carrier family 15 member 1

      Kind: protein

      Organism: Human

      Pharmacological action: unknown

      Actions: substrate

      Components

      Name UniProt ID Details
      Solute carrier family 15 member 1 P46059 Details

      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. Solute carrier family 15 member 2

      Kind: protein

      Organism: Human

      Pharmacological action: unknown

      Actions: substrate

      Components

      Name UniProt ID Details
      Solute carrier family 15 member 2 Q16348 Details

      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 September 16, 2013 17:08