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));

Ramiprilum [Latin];

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.

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Synthesis Reference

Not Available

General Reference

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 Kleinert S: HOPE for cardiovascular disease prevention with ACE-inhibitor ramipril. Heart Outcomes Prevention Evaluation. Lancet. 1999 Sep 4;354(9181):841. Pubmed

Type	small molecule

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

ANTIHYPERTENSIVES 降血压;

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. Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us. Substrate Enzymes Product Ramipril Diketopiperazine acid Details Ramipril Diketopiperazine ester Details Ramipril Ramiprilat Details
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 Ramipril Pathway SMP00154

Properties
State	solid
Experimental Properties	Property Value Source melting point 109 °C PhysProp water solubility 3.5mg/L Not Available logP 2.9 Not Available
Predicted Properties	Property Value Source water solubility 3.90e-02 g/l ALOGPS logP 0.92 ALOGPS logP 1.47 ChemAxon logS -4 ALOGPS pKa (strongest acidic) 3.75 ChemAxon pKa (strongest basic) 5.2 ChemAxon physiological charge -1 ChemAxon hydrogen acceptor count 5 ChemAxon hydrogen donor count 2 ChemAxon polar surface area 95.94 ChemAxon rotatable bond count 10 ChemAxon refractivity 111.19 ChemAxon polarizability 44.78 ChemAxon

Drug	Interaction
Amiloride	Increased risk of hyperkalemia
Azilsartan medoxomil	Pharmacodynamic synergism: dual blockade of renin-angiotensin system. Increases risks of hypotension, hyperkalemia, renal impairment.
Drospirenone	Increased risk of hyperkalemia
Icatibant	Icatibant may attenuate the antihypertensive effect of ACE inhibitors by pharmacodynamic antagonism. Monitor concomitant therapy closely.
Insulin Lispro	Concomitant therapy with ACE inhibitors may increase the blood-glucose-lowering effect of insulin lispro and thus the chance of hypoglycemia should be monitored closely.
Lithium	The ACE inhibitor increases serum levels of lithium
Potassium	Increased risk of hyperkalemia
Spironolactone	Increased risk of hyperkalemia
Tizanidine	Tizanidine increases the risk of hypotension with the ACE inhibitor
Tobramycin	Increased risk of nephrotoxicity
Treprostinil	Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Triamterene	Increased risk of hyperkalemia

• 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.