Ramipril

416.51

416.51

1312995-182-4

L35JN3I7SJ

758933

DTXSID8023551

C29411

Felty needles from ether|White crystalline solid

C09AA05|C - Cardiovascular system

2933995300

95.9

2.9

white

1.200±0.06 g/cm3(Predicted)

109 °C

616.2ºC at 760 mmHg

H2O: 3.5mg/L;DMSO: ~18mg/mL

2-8°C

3.80X10-11 mm Hg at 25 °C (est)

LD50 (14 day) in male, female mice, male, female rats (mg/kg): 1194, 1158, 687, 608 i.v.; 10933, 10048, >10000, >10000 orally (Donaubauer, Mayer)

D24 +33.2° (c = 1 in 0.1N ethanolic HCl)

Henry's Law constant = 3.44X10-16 atm-cu m/mol at 25 °C (est)

pKa1 = 3.74 (caboxylic acid); pKa2 = 5.15 (secondary amine) (est)

197 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

2

36/38

26-37/39

GY5879600

Xi

P201, P202, P281, P308+P313, P405, P501

H360

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company; Contaminated packaging: Dispose of as unused product.

Incompatible materials: Strong oxidizing agents.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ramipril, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Danger|H360 (95.95%): May damage fertility or the unborn child [Danger Reproductive toxicity]|P201, P202, P281, P308+P313, P405, and P501|Aggregated GHS information provided by 75 companies from 12 notifications to the ECHA C&L Inventory.

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).|Skin protection: Handle with gloves.|Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place.|Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.|Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains.|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.|Precautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed.|Appropriate engineering controls: General industrial hygiene practice.|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

Ramipril exhibited a 70% removal rate during wastewater treatment at a sewage treatment plant in Dresden, Germany. Influent and effluent sampling was conducted on 10 consecutive days in January/February 2015(1).

Occupational exposure to ramipril may occur through inhalation and dermal contact with this compound at workplaces where ramipril is produced or used. The general public is not likely to be exposed to ramipril unless by direct medical treatment. (SRC)

Symptoms of overdose may include excessive peripheral vasodilation (with marked hypotension and shock), bradycardia, electrolyte disturbances, and renal failure. Cases of ACE inhibitor induced hepatotoxicity have been reported in humans and presented as acute jaundice and elevated liver enzymes. Removal of the ACE inhbitor resulted in a decline in liver enzymes and re-challenge produced a subsequent increase. There were no observed tumerogenic effects at chronic doses up to 500mg/kg/day to rats for 24 months or at doses up to 1000mg/kg/day to mice for 18 months. For both species doses were administered by gavage and equivalent to 200 time the maximum recommended human exposure based on body surface area. No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites of ramipril also produced negative results in the Ames test. No effects on fertility were seen in rats at doses up to 500mg/kg/day. No teratogenicity was observed in rats and cynomolgus monkeys at doses 400 times the maximum recommended human exposure nor in rabbites at 2 times the maximum recommended human exposure. LD50 10 g/kg (rat).[MSDS] LD50 10.5 g/kg (mouse).[MSDS] LD50 1 g/kg (dog).[MSDS]|IDENTIFICATION AND USE: Ramipril is a prodrug and has little pharmacologic activity until hydrolyzed in the liver to ramiprilat. It is an angiotensin-converting enzyme (ACE) inhibitor indicated for the treatment of hypertension. It is also used for stable patients with demonstratable congestive heart failure within the first few days of sustaining acute myocardial infarction. HUMAN STUDIES: Rare ACE inhibitor-associated clinical syndrome manifested initially by cholestatic jaundice may occur. It may progress to fulminant hepatic necrosis and is potentially fatal. Patients receiving an ACE inhibitor, including ramipril, who develop jaundice or marked elevations in hepatic enzymes should discontinue the drug and receive appropriate monitoring. Sensitivity reactions, including anaphylactic reactions and angioedema (including laryngeal or tongue edema) are potentially fatal. Head and neck angioedema involving the tongue, glottis, or larynx may cause airway obstruction. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, ramipril should be discontinued and appropriate therapy (e.g., epinephrine) should be initiated immediately. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue ramipril as soon as possible. No mutagenic activity was detected in the unscheduled DNA synthesis in a human cell line. ANIMAL STUDIES: No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility. Kidney organogenesis and functional development continue well into the postnatal period in the rat. A within-litter design was used to characterize renal susceptibility to an ACE inhibitor during the third week of life in rats. There were no treatment-related effects in rats dosed on PND 21. Following dosing on PND 14, dose-related increases were noted in mean serum urea nitrogen and/or creatinine levels on PND 17, but these measures recovered by PND 28. The interim changes were accompanied by macroscopic and microscopic changes in the kidneys on PND 17, including tubular hypoplasia, renal papillary edema, cortical tubular dilatation, hydronephrosis (pelvic dilatation) and tubular basophilia; renal anatomic changes were still evident and more severe on PND 28, 14 days after dosing. No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice or a forward gene-mutation assay in a Chinese hamster ovary cell line.

Ramipril, like other ACE inhibitors, has been associated with a low rate of serum aminotransferase elevations (

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of non-ateroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, with angiotensin-converting enzyme (ACE) inhibitors, including ramipril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving ramipril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including ramipril, may be attenuated by NSAIDs.|Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium; therefore, frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.|Coadministration of ramipril with other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients.|Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with ramipril. The possibility of hypotensive effects with ramipril can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with ramipril. If this is not possible, reduce the starting dose.

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of non-ateroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, with angiotensin-converting enzyme (ACE) inhibitors, including ramipril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. ...

Protein binding of ramipril is about 73% and that of ramiprilat about 56%. Protein binding is independent of concentration over the range of 0.1μg/mL-10μg/mL

Ramipril's production and administration as a antihypertensive(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2000(SRC), determined from a structure estimation method(2), indicates that ramipril is expected to have low mobility in soil(SRC). The estimated pKa values of ramipril are 3.74 and 5.15(3), indicating that this compound will exist almost entirely exist in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as an anion and anions do not volatilize. Ramipril is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.8X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2017).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2000(SRC), determined from a structure estimation method(2), indicates that ramipril is expected to adsorb to suspended solids and sediment(SRC). Estimated pKa values of 3.74 and 5.15(3) indicate ramipril will exist almost entirely in the anion form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 3(SRC), from an estimated log Kow of 3.32(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2017).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ramipril, which has an estimated vapor pressure of 3.8X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase ramipril may be removed from the air by wet and dry deposition(SRC). Ramipril contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Particulate-phase ramipril may be removed from the air by wet and dry deposition(SRC). A base-catalyzed second-order hydrolysis rate constant of 1.7X10-3 L/mole-sec(SRC) was estimated using a structure estimation method(1); this corresponds to half-lives of 12 and 126 years at pH values of 7 and 8, respectively(1). Ramipril contains chromophores that absorb at wavelengths >290 nm(2) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 3 was calculated in fish for ramipril(SRC), using an estimated log Kow of 3.32(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low (SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of ramipril can be estimated to be 2000(SRC). According to a classification scheme(2), this estimated Koc value suggests that ramipril is expected to have low mobility in soil. The estimated pKa values of ramipril 3.74 and 5.15(3), indicating that this compound will exist almost entirely in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

Estimated pKa of values of 3.74 and 5.15(1) indicate ramipril will exist almost entirely in the anion form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). Ramipril is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.8X10-11 mm Hg(SRC), determined from a fragment constant method(2).

/MILK/ Ingestion of a single 10 mg oral dose of ramipril resulted in undetectable amounts of ramipril and its metabolites in breast milk.

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.|FDA Label|Treatment of heart failure, Treatment of hypertension|Treatment of coronary artery disease, Treatment of heart failure, Treatment of hypertension|Treatment of hypercholesterolaemia, Treatment of hypertension|Treatment of hypertension|Treatment of essential hypertension|Treatment of cardiovascular disease|Prevention of Ischaemic Heart Disease|Risk of myocardial infarction, stroke, death from cardiovascular causes, or hospitalization forcongestive heart failure in patients at high risk of developing major cardiovascular events|Prevention of cardiovascular events, Treatment of hypertension, Treatment of lipid metabolism disorders

Ramipril is an angiotensin-converting enzyme (ACE) inhibitor used in the therapy of hypertension and heart failure. Ramipril is associated with a low rate of transient serum aminotransferase elevations and has been linked to rare instances of acute liver injury.

Angiotensin-Converting Enzyme Inhibitors

Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents|/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Ramipril is included in the database.|Ramipril capsules are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug. ... Ramipril capsules may be used alone or in combination with thiazide diuretics. /Included in US product label/|Ramipril capsules are indicated in stable patients who have demonstrated clinical signs of congestive heart failure within the first few days after sustaining acute myocardial infarction. Administration of ramipril capsules to such patients have been shown to decrease the risk of death (principally cardiovascular death) and to decrease the risks of failure-related hospitalization and progression to severe/resistant heart failure. /Included in US product label/|For more Therapeutic Uses (Complete) data for Ramipril (8 total), please visit the HSDB record page.

/BOXED WARNING/ When pregnancy is detected, discontinue ramipril as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.|Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue ramipril as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.|Angiotensin-converting enzyme (ACE) inhibitors can cause fetal and neonatal morbidity and mortality when used in pregnancy during the second and third trimesters. ACE inhibitors also increase the risk of major congenital malformations when administered during the first trimester of pregnancy. Discontinue as soon as possible when pregnancy is detected, unless continued use is considered lifesaving. Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy. /Angiotensin-converting enzyme (ACE) inhibitors/|Rare angiotensin-converting enzyme (ACE) inhibitor-associated clinical syndrome manifested initially by cholestatic jaundice may occur; may progress to fulminant hepatic necrosis and is potentially fatal. Patients receiving an ACE inhibitor, including ramipril, who develop jaundice or marked elevations in hepatic enzymes should discontinue the drug and receive appropriate monitoring.|For more Drug Warnings (Complete) data for Ramipril (18 total), please visit the HSDB record page.

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.

A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. (See all compounds classified as Angiotensin-Converting Enzyme Inhibitors.)|Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS. (See all compounds classified as Antihypertensive Agents.)

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. The serum concentration of ramiprilat was unchanged when capsules were opened and the contents dissolved in water, dissolved in apple juice, or suspended in apple sauce.|60% of the parent drug and its metabolites are eliminated in the urine with the remaining 40% eliminated in the feces. The drug eliminated in the feces represents both absorbed drug and drug eliminated through biliary excretion although the proportion of these has not been determined. Less than 2% of drug is eliminated in the urine unchanged.|The renal clearance of ramipril and ramiprilat was reported to be 7.2 and 77.4 mL/min/1.73m². The mean renal clearance of ramipril and ramiprilat is reported to be 10.7 and 126.8 mL/min in healthy elderly patients with normal renal function, additionally the Cmax of ramiprilat is approximately 20% higher in this population. While the pharmacokinetics of ramipril appear unaffected by reduced renal function, the plasma concentration and half-life of ramiprilat are increased. In patient's with hepatic failure the concentration of ramipril is initially increased while the tmax of ramiprilat is prolonged due to a reduced ability to metabolize the drug. However, steady state concentrations of ramiprilat are the same in hepatic failure as in healthy patients.|/MILK/ Ingestion of a single 10 mg oral dose of ramipril resulted in undetectable amounts of ramipril and its metabolites in breast milk.|Following oral administration of ramipril, peak plasma concentrations (Cmax) of ramipril are reached within 1 hour. The extent of absorption is at least 50% to 60%, and is not significantly influenced by the presence of food in the gastrointestinal tract, although the rate of absorption is reduced.|Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2 to 4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9 to 18 hours. The terminal elimination phase has a prolonged half-life (>50 hours) and probably represents the binding/dissociation kinetics of the ramiprilat/ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of ramipril 5 mg to 10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13 to 17 hours. /Ramiprilat/|Plasma concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose-proportional. The 24-hour AUC for ramiprilat, however, is dose-proportional over the 2.5 mg to 20 mg dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg of oral ramipril was compared with the same dose of ramipril given intravenously.|For more Absorption, Distribution and Excretion (Complete) data for Ramipril (7 total), please visit the HSDB record page.

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.|Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat. Peak plasma concentrations of ramiprilat are reached 2 to 4 hours after drug intake. The serum protein binding of ramipril is about 73% and that of ramiprilat about 56%; in vitro, these percentages are independent of concentration over the range of 0.01 ug/mL to 10 mcg/mL.|After oral administration to dogs, ramipril is rapidly converted via de-esterification into ramiprilat. Bioavailability of ramiprilat after a dose of 0.25 mg/kg per day of ramipril is approximately 6.7%.|Ramipril is a prodrug and has little pharmacologic activity until hydrolyzed in the liver to ramiprilat.|Ramipril is almost completely metabolized to ramiprilat, which has about 6 times the angiotensin-converting enzyme (ACE) inhibitory activity of ramipril, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which are inactive.

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, which is thought to represent clearance of free drug. The half-life of the terminal elimination phase is > 50 hours and thought to represent clearance of drug bound to ACE due to its slow dissociation. 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.|Plasma concentrations of ramiprilat /metabolite of ramipril/ decline in a triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2 to 4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9 to 18 hours. The terminal elimination phase has a prolonged half-life (>50 hours) and probably represents the binding/dissociation kinetics of the ramiprilat/ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of ramipril 5 mg to 10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13 to 17 hours. /Ramiprilat/

Ramipril inhibits the RAAS system by binding to and inhibiting ACE thereby preventing the conversion of angiotensin I to angiotensin II. As plasma levels of angiotensin II fall, less activation of the G-protein coupled receptors angiotensin receptor I (AT₁R) and angiotensin receptor II (AT₂R) occurs. AT₁R mediates vasoconstriction, inflammation, fibrosis, and oxidative stress through a variety of signaling pathways. These include G_q coupling to the inositol triphosphate pathway, activation of phospholipases C, A₂, and D which contribute to eicosanoid production, activation of Ca²⁺-dependent and MAP kinases, G_i and G_12/13, and eventual activation of the Jak/STAT pathway leading to cell growth and production of extracellular matrix components. AT₁R activation also leads to increased activity of membrane-bound NADH/NADPH oxidase which contributes to production of reactive oxygen species. Decreased activation of this receptor mediates the renoprotective, antihypertensive, and cardioprotective effects of ramipril by reducing inflammation and vasoconstriction. AT₂R acts in opposition to the effects of AT₁R by activating phosphotyrosine phosphatases which inhibit MAP kinases, inhibiting Ca²⁺ channel opening, and stimulating cGMP and nitric oxide production leading to vasodilation. These counteracting effects are shared by the Mas receptor which is activated by Ang(1-7), a subtype of angiotensin produced by plasma esterases from AngI or by ACE2 from AngII produced through a secondary pathway by tonin and cathepsin G. Ang(1-7) also activates AT₂R although the bulk of its effect is mediated by MasR. ACE is also responsible for the breakdown of bradykinin. The resulting buildup of bradykinin due to ACE inhibition is thought to mediate the characteristic dry-cough as a side effect of ACE inhibitor medications.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|Treatment and supportive measures: Monitor blood pressure and heart rate for 6 hours after ingestion. If symptomatic or significant hypotension develops, observe for at least 24 hours. 1. If hypotension occurs, treat it with supine positioning and IV fluids. Vasopressors are rarely necessary. 2. Treat angioedema with usual measures (eg, diphenhydramine, corticosteroids) and discontinue the ACE inhibitors. Switching to an AR blocker may not be appropriate as angioedema has also been reported with these agents. 3. Treat hyperkalemia if it occurs. /Angiotensin blockers and ACE inhibitors/|For more Antidote and Emergency Treatment (Complete) data for Ramipril (6 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ Rare angiotensin-converting enzyme (ACE) inhibitor-associated clinical syndrome manifested initially by cholestatic jaundice may occur; may progress to fulminant hepatic necrosis and is potentially fatal. Patients receiving an ACE inhibitor, including ramipril, who develop jaundice or marked elevations in hepatic enzymes should discontinue the drug and receive appropriate monitoring.|/SIGNS AND SYMPTOMS/ Like other angiotensin-converting enzyme (ACE) inhibitors, ramipril rarely is associated with hypotension in patients with uncomplicated hypertension. Symptomatic hypotension may occur; patients at particular risk include those with severe volume and/or salt depletion secondary to prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before starting ramipril therapy. Marked hypotension may occur in patients with heart failure (with or without associated renal impairment), which may be associated with oliguria and/or progressive azotemia and, rarely, acute renal failure and/or death. In patients with heart failure, ramipril therapy should be started under close medical supervision, and patients should be followed closely for at least 2 weeks after initiation of ramipril or diuretic therapy or dosage adjustment of either drug.|/SIGNS AND SYMPTOMS/ Sensitivity reactions, including anaphylactic reactions and angioedema (including laryngeal or tongue edema) are potentially fatal. Head and neck angioedema involving the tongue, glottis, or larynx may cause airway obstruction. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, ramipril should be discontinued and appropriate therapy (e.g., epinephrine) should be initiated immediately.|/CASE REPORTS/ ... /The purpose of this study was/ to describe 3 patients who developed hepatitis, with or without jaundice, after receiving ramipril. Medical records and liver biopsies of the 3 patients were reviewed. Clinical, laboratory, and histologic findings were compared with findings in other cases of angiotensin-converting enzyme inhibitor-induced liver injury reported in the literature. The 3 patients were middle-aged men. In 2 patients, jaundice appeared 4 and 8 weeks after starting ramipril. Bilirubin levels peaked at 15.5 and 5 mg/dL, and alkaline phosphatase values peaked at 957 and 507 U/L. Aminotransferase levels were mildly elevated. Endoscopic retrograde cholangiopancreatography and ultrasonography showed no bile duct obstruction. Liver biopsies from the jaundiced patients were similar, with cholestasis, duct necrosis, and extravasation of bile, ductular proliferation, and portal inflammation. Cholestasis improved in 1 patient 6 weeks after stopping ramipril and was prolonged for 14 months in the other, in whom biliary cirrhosis was present on biopsy. The third patient developed hepatitis without jaundice 3 weeks after starting ramipril; symptoms resolved after stopping the drug. Ramipril-associated liver injury is similar to that seen with other angiotensin-converting enzyme inhibitors, but liver biopsy findings of duct necrosis and extravasation of bile have not been reported previously. Prolonged cholestatic hepatitis and biliary cirrhosis may result from the use of ramipril. Monitoring of liver enzymes is advisable for patients starting on ramipril.|For more Human Toxicity Excerpts (Complete) data for Ramipril (9 total), please visit the HSDB record page.

Acovil

Table: Ramipril Preparations [Table#8451]

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