Enalapril

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Antihypertensives

Pharmaceuticals -> Listed in ZINC15

log Kow = 0.07 at pH 4.9

2.1

-0.07

In water, 1.64X10+4 mg/L at 25 °C

2.13e-01 g/L

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Angiotensin-Converting Enzyme Inhibitors; ACE Inhibitors; ACEIs

Pharmaceuticals

Antihypertensive medicines

143-144.5

143 - 144.5 °C

Needles from water. MP 148-151 °C. Specific optical rotation: - 67.0 deg at 0 °C (0.1M HCl). Sparingly soluble in methanol, DMF; slightly soluble in water, isopropyl alcohol; very slightly soluble in acetone, alcodhol, hexane. Practically insoluble in acetonitrile, chlorform /Enalapril diacid dihydrate/

Stable under recommended storage conditions. /Enalapril maleate/

Following dilution of enalaprilat injection in 5% dextrose, 0.9% sodium chloride, 5% dextrose and 0.9% sodium chloride, 5% dextrose in lactated Ringer's, or Isolyte(R) E, solutions of the drug are stable for 24 hrs at room temperature. /Enalaprilat/

2.92

pKa1 = 3.0 (carboxylic acid); pKa2 = 5.5 (secondary amide)

pKa1 = 3 (carboxylic acid); pKa2 = 5.4 (secondary amine), at 25 °C

pKa1 = 2.3 (carboxylic acid); pKa2 = 3.4 (caboxylic acid); pKa3 = 8.0 (secondary amide) /Enalaprilat/

188.33 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

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

197.07 Ų [M-H]-

Enalapril is commercially available as the maleate salt and differs structurally from enalaprilat by the presence of an ethoxycarbonyl group rather than a carboxy group at position 1 of L-alanyl-L-proline and by the presence of the maleate salt. These structural modifications result in increased GI absorption of enalapril compared with enalaprilat, which is poorly absorbed from the GI tract. Enalapril is structurally and pharmacologically similar to captopril but contains a disubstituted nitrogen rather than a sulfhydryl group at position 3 of 2-methyl-1- oxopropyl-L-proline.

White to off-white crystalline powder;... slightly soluble in water and sparingly soluble in methanol. /Enalaprilat/

White to off-white crystalline powder. MP: 143-144.5 °C. pH = 2.6 (1% water). pKa 1 = 3.0; pKa2 = 5, 25 °C. Solubility in water, 0.025 g/mL at 25 °C; solubility in (g/mL): alcohol 0.08, methanol 0.20. Freely soluble in DMF; Slightly soluble in semipolar organic solvents. Practically insoluble in nonpolar organic solvents. Specific optical rotation: -42.2 deg at 25 °C/D (concentration by volume = 1 g in 100 ml methanol) /Enalapril maleate/

Warning

H317 (100%): May cause an allergic skin reaction [Warning Sensitization, Skin]

P203, P261, P272, P280, P302+P352, P318, P321, P333+P317, P362+P364, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 39 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Enalapril tablets. ... Indications for use. For treatment of mild, moderate, and severe (modified New York Heart Association Class II, III, IV) heart failure in dogs. ... Federal law restricts this drug to use by or on the order of a licensed veterinarian.

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

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

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Enalapril maleate is included on this list. /Enalapril maleate/

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Enalapril maleate/

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /Enalapril maleate/

Commercially available enalaprilat injection should be stored at a temperature less than 30 °C. /Enalaprilat/

The manufacturer recommends that enalapril maleate tablets be stored in tight containers at a temperature <30 °C and that transient exposure to temperatures warmer than 50 °C be avoided. The tablets should be protected from moisture. The tablets have an expiration date of 30 mos following the date of manufacture when stored at <30 °C. The manufacturer states that extemporaneous preparation of oral solutions of enalapril maleate should be avoided since the drug is not sufficiently stable in solution.

Keep container tightly closed in a dry and well-ventilated place. /Enalapril maleate/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Avoid breathing dust. 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. /Enalapril maleate/

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. /Enalapril maleate/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Avoid breathing dust. Environmental precautions: Do not let product enter drains. /Enalapril maleate/

Precautions for safe handling: Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection. /Enalapril maleate/

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Enalapril maleate/

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. /Enalapril maleate/

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.

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Enalapril maleate/

Skin protection: Handle with gloves. /Enalapril maleate/

Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place. /Enalapril maleate/

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). /Enalapril maleate/

When enalapril is administered with diuretics or other hypotensive drugs, the hypotensive effect of enalapril is increased. The effect is usually used to therapeutic advantage, but careful adjustment of dosage is necessary when these drugs are used concomitantly. ... Enalapril and diuretics appear to have additive hypotensive effects; however, severe hypotension and reversible renal insufficiency may occasionally occur, especially in volume and/or sodium depleted patients. Hypotensive drugs that cause release of renin (e.g., diuretics) will increase the hypotensive effect of enalapril.

Potassium sparing diuretics (eg, amiloride, spironolactone, triamterene), potassium supplements, or potassium-containing salt substitutes should be used with caution and serum potassium should be determined frequently in patients receiving enalapril, since hyperkalemia may occur.

Because ACE inhibitors may promote kinin-mediated prostaglandin synthesis and/or release, concomitant administration of drugs that inhibit prostaglandin synthesis (e.g., aspirin, ibuprofen) may reduce the blood pressure response to ACE inhibitors, including enalapril. Limited data indicate that concomitant administration of ACE inhibitors with nonsteroidal anti-inflammatory agents (NSAIAs) occasionally may result in acute reduction of renal function; however, the possibility cannot be ruled out that one drug alone may cause such an effect. ... Aspirin and other NSAIAs also can attenuate the hemodynamic actions of ACE inhibitors in patients with congestive heart failure. Because ACE inhibitors share and enhance the effects of the compensatory hemodynamic mechanisms of heart failure, with aspirin and other NSAIAs interacting with the compensatory mechanisms rather than with a given ACE inhibitor per se, these desirable mechanisms are particularly susceptible to the interaction and a subsequent potential loss of clinical benefits. As a result, the more severe the heart failure and the more prominent the compensatory mechanisms, the more appreciable the interaction between NSAIAs and ACE inhibitors. Even if optimal dosage of an ACE inhibitor is used in the treatment of congestive heart failure, the potential cardiovascular and survival benefit may not be seen if the patient is receiving an NSAIA concomitantly. In several multicenter studies, concomitant admin of a NSAIA (i.e., a single 350-mg dose of aspirin) in patients with congestive heart failure inhibited favorable hemodynamic effects associated with ACE inhibitors, attenuating the favorable effects of these drugs on survival and cardiovascular morbidity. /ACE inhibitors/

Lithium toxicity has occurred following concomitant administration of enalapril and lithium carbonate and was reversible following discontinuance of both drugs. In one patient, the toxicity was associated with elevated plasma lithium concentration and was manifested as ataxia, dysarthria, tremor, confusion, and altered electroencephalogram, bradycardia and T wave depression also occurred. Moderate renal insufficiency (serum creatinine of 2.2 mg/deciliter) or acute renal failure has also occurred in these patients. The exact mechanism of this interaction remains to be established, but it has been suggested that enalapril may decrease renal elimination of lithium, possibly by increasing sodium excretion secondary to decreased aldosterone secretion or by altering renal function secondary to angiotensin converting enzyme inhibition.

Concomitant use of enalapril and some vasodilating agents (eg, nitrates) or anesthetic agents may cause an exaggerated hypotensive response. Patients receiving enalapril concomitantly with nitrates or with anesthetic agents that produce hypotension should be observed for possible additive hypotensive effects. Fluid volume expansion can correct hypotension during surgery or anesthesia if it is thought to result from an enalapril-induced inhibition of the angiotensin II formation that occurs secondary to compensatory renin release.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 350(SRC), determined from a structure estimation method(2), indicates that enalapril is expected to have moderate mobility in soil(SRC). The pKa values of enalapril are 3.0 and 5.5(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). Volatilization from moist soil is not expected because the compound exists as a anion and cations do not volatilize. Enalapril is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.1X10-12 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 350(SRC), determined from a structure estimation method(2), indicates that enalapril is not expected to adsorb to suspended solids and sediment(SRC). Reported pKa values of 3.0 and 5.5(3) indicate enalapril 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 its log Kow of 0.07(5) 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), enalapril, which has an estimated vapor pressure of 1.1X10-12 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 enalapril may be removed from the air by wet and dry deposition(SRC). Enalapril contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

The most commonly encountered adverse drug reaction with ACE inhibitors is cough. The cough is characteristically nonproductive and resolves upon discontinuation of the drug. If dry cough persists after ruling out other potential causes, switching to ARBs is recommended. Other adverse effects associated with enalapril include hypotension, hyperkalemia, angioedema, cholestatic jaundice, and hypersensitivity reactions.

IDENTIFICATION AND USE: Enalapril is angiotensin-converting enzyme inhibitor and antihypertensive agent. HUMAN STUDIES: Overdosage of enalapril produces effects that are mainly extensions of the drug's pharmacologic effects as an angiotension converting enzyme inhibitor. Plasma angiotension enzyme activity was completely suppressed within 10-15 hr after acute ingestion of 300-440 mg of enalapril maleate in 2 patients. The most likely manifestation of enalapril overdosage is hypotension, which may be profound and also maybe accompanied by stupor. Onset and duration of the hypotensive effect may be prolonged following acute overdosage. Renal dysfunction, including acute renal failure, hyperkalemia, and hyponatremia may also occur. 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 enalapril maleate tablets as soon as possible. ANIMAL STUDIES: There was no evidence of a tumorigenic effect when enalapril was administered for 106 weeks to male and female rats at doses up to 90 mg/kg/day or for 94 weeks to male and female mice at doses up to 90 and 180 mg/kg/day, respectively. There were no adverse effects on reproductive performance of male and female rats treated with up to 90 mg/kg/day of enalapril. Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with Escherichia coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow.

Enalapril toxicity is rare, with hypotension being a major complication. Management typically involves symptomatic treatment, while fluid resuscitation can be utilized to increase intravascular volume. In neonates, peritoneal dialysis can remove enalapril from circulation, while hemodialysis is effective in general cases.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of November 16, 2017: http://actor.epa.gov/dashboard/]

Enalapril exhibited a 60% removal rate from the sewage treatment plant in Dresdin Kaditz, Germany; sampling was conducted on 10 consecutive days in January/February 2015(1). Enalapril was tested for in influent and effluent samples of treatment plants in the Mediterranean region of Valencia, Spain. During a June 2008 and January 2009 test period, 96% of 42 influent samples tested positive with detections ranging from 0.02-0.29 ug/L. During a April 2009 and October 2009 test period, 14 of 14 influent samples tested positive with detections ranging from 0.09-0.20 ug/L. It was not detected in effluent samples during both test periods(2). Enalapril was present at a concentration of 2200 ng/L in undiluted effluent samples collected from the Patancheru Enviro Tech Ltd plant in Hyderabad, India, a region that receives process water from approximately 90 bulk drug manufacturers(3).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of enalapril can be estimated to be 350(SRC). According to a classification scheme(2), this estimated Koc value suggests that enalapril is expected to have moderate mobility in soil. The pKa values of enalapril are 3.0 and 5.5(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).

/SIGNS AND SYMPTOMS/ Overdosage of enalapril produces effects that are mainly extensions of the drug's pharmacologic effects as an angiotension converting enzyme inhibitor. Plasma angiotension enzyme activity was completely suppressed within 10-15 hr after acute ingestion of 300-440 mg of enalapril maleate in 2 patients. The most likely manifestation of enalapril overdosage is hypotension, which may be profound and also maybe accompanied by stupor. Onset and duration of the hypotensive effect may be prolonged following acute overdosage. Renal dysfunction, including acute renal failure, hyperkalemia, and hyponatremia may also occur.

/CASE REPORTS/ A 35-year-old nephrotic man developed acute renal failure with serum creatinine to 1543 umol/L after a month of therapy with enalapril. Renal biopsy demonstrated minimal glomerular changes with fusion of podocytes, tubular necrosis with regeneration of tubular epithelial cells, interstitial edema with focal interstitial fibrosis, and interstitial infiltration with neutrophils, eosinophils, plasma cells and mononuclear cells. Three hemodialyses were performed in the patient during the oliguric phase of the disease. Renal function was restored after withdrawal of enalapril and initiation of steroid therapy. Steroids also contributed to the improvement of the nephrotic syndrome and proteinuria decreased from maximal ranges of 27 g/L to 2.2 g/L after six months of the follow-up. Similar cases were previously described associated with captopril treatment, but not with enalapril.

/PREGNANCY AND HUMAN REPRODUCTION/ A 34 year-old woman was given enalapril from the onset of her pregnancy because of hypertension from the age of 18 years. Oligoamnios was diagnosed in the fetus on gestational week 28; enalapril was then replaced by nifedipine but this drug was badly tolerated so that the woman was again given enalapril 8 days later. The baby (1700 g) was born by cesarean section at gestational week 34 because of acute distress syndrome; he developed hypotension, anuria, generalized edema and was placed in intensive care. Treatment included ventilation, sympathomimetic agents, and diuretics. An exchange-transfusion followed by peritoneal dialysis was performed a few hours later. Renal function returned to normal between the 3rd and 5th day. Unilateral kidney hypoplasia was diagnosed at the age of 2 years. ...

/PREGNANCY AND HUMAN REPRODUCTION/ ACE inhibitors are commonly used drugs in the management of adult hypertension. However their use in pregnant women can have serious effects on the fetus. In this manuscript we report a case of fatal neonatal renal failure associated with maternal intake of enalapril during third trimester and review the related literature. The index case was born to a mother with pregnancy-induced hypertension (PIH) which was treated with enalapril (5 mg) once a day for 21 days prior to delivery in addition to other anti-hypertensives. Temporally, use of enalapril was associated with the onset of oligohydramnios. The neonate presented with intrauterine growth retardation, hydrops and oliguric renal failure, which did not respond to furosemide, peritoneal dialysis and exchange transfusion. Autopsy showed macroscopically and microscopically normal kidneys. Use of ACE inhibitors during pregnancy should be avoided.

For more Human Toxicity Excerpts (Complete) data for Enalapril (8 total), please visit the HSDB record page.

Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)

enalapril

Vasotec®

ACE inhibitors

4

less-DILI-concern drugs

Enalapril tablets. ... Indications for use. For treatment of mild, moderate, and severe (modified New York Heart Association Class II, III, IV) heart failure in dogs. ... Federal law restricts this drug to use by or on the order of a licensed veterinarian.

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

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

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Enalapril maleate is included on this list. /Enalapril maleate/

C09AA02

C - Cardiovascular system

QC - Cardiovascular system

C09AA02

Enalapril is an antihypertensive agent that exhibits natriuretic and uricosuric properties. Enalapril lowers blood pressure in all grades of essential and renovascular hypertension, and peripheral vascular resistance without causing an increase in heart rate. Individuals with low-renin hypertensive population were still responsive to enalapril. The duration of hypertensive effect in the systolic and diastolic blood pressure persists for at least 24 hours following initial administration of a single oral dose, and repeated daily administration of enalapril confers an additional reduction in blood pressure and a steady-state antihypertensive response may take several weeks. In patients with severe congestive heart failure and inadequate clinical response to conventional antihypertensive therapies, treatment with enalapril resulted in improvements in cardiac performance as observed by a reduction in both preload and afterload, and improved clinical status long-term. Furthermore, enalapril was shown to increase cardiac output and stroke volume while decreasing pulmonary capillary wedge pressure in patients with congestive heart failure refractory to conventional treatment with digitalis and diuretics. In clinical studies, enalapril reduced left ventricular mass, and did not affect cardiac function or myocardial perfusion during exercise. Enalapril is not highly associated with the risk of bradycardia unlike most diuretics and beta-blockers and it does not produce rebound hypertension upon discontinuation of therapy. Enalapril is not reported to produce hypokalaemia, hyperglycaemia, hyperuricaemia or hypercholesterolaemia. In the kidneys, enalapril was shown to increase renal blood flow and decrease renal vascular resistance. It also augmented the glomerular filtration rate in patients with a glomerular filtration rate less than 80 mL/min. When used in combination, enalapril was shown to attenuate the extent of drug-induced hypokalemia caused by hydrochlorothiazide and the antihypertensive effects of both drugs were potentiated.

The renin-angiotensin-aldosterone system (RAAS) is a signaling pathway that works in synergism with the sympathetic system to regulate blood pressure and fluid and electrolyte homeostasis. Activation of this system upon stimulation by different factors, such as low blood pressure and nerve impulses, leads to increased release of norepinephrine (NE) from sympathetic nerve terminals and effects on the vascular growth, vasoconstriction, and salt retention in the kidneys. Renin is released from Renin acts on the precursor prottein angiotensinogen, which is a plasma globulin synthesized from the liver, to produce cleaved peptide hormone angiotensin I. Angiotensin I then can be further cleaved by ACE to produce angiotensin II, a vasoconstrictive peptide hormone. Present in different isoforms, angiotensin converting enzyme (ACE) is peptidyl dipeptidase enzyme expressed in various tissues, including the vascular tissues, such as the heart, brain, and kidneys. ACE also plays a role in inactivation of bradykinin, a potent vasodepressor peptide. Angiotensin II mediates various actions on the body by working on its G-protein coupled receptors, AT1 and AT2. It causes direct vasoconstriction of precapillary arterioles and postcapillary venules, inhibits the reuptake of NE thereby increasing available levels, stimulates the release of catecholamines from the adrenal medulla, reduces urinary excretion of sodium ions and water by promoting proximal tubular reabsorption, stimulates synthesis and release of aldosterone from the adrenal cortex, and stimulates hypertrophy of both vascular smooth muscle cells and cardiac myocytes. Enalapril is a pharmacologically inactive prodrug that requires hepatic biotransformation to form [enalaprilat], its active metabolite that works on the RAAS to inhibit ACE. Biotransformation is critial for the therapeutic actions of the drug, as enalapril itself is only a weak inhibitor of ACE. ACE inhibition results in reduced production and plasma levels of angiotensin II, increased plasma renin activity due to the loss of feedback inhibition by angiotensin II, and decreased aldosterone secretion. However, plasma aldosterone levels usually return to normal during long-term administration of enalapril. Decreased levels of angiotensin II subsequently leads to the dilatation of peripheral vessles and reduced vascular resistance which in turn lower blood pressure. While inhibition of ACE leading to suppression of RAAS is thought to be the primary mechanism of action of enalapril, the drug was shown to still exert antihypertensive effects on individuals with low-renin hypertension. It is suggested that enalapril may mediate its pharmacological actions via other modes of action that are not fully understood. As ACE is structurally similar to kininase I, which is a carboxypeptidase that degrades bradykinin, whether increased levels of bradykinin play a role in the therapeutic effects of enalapril remains to be elucidated.

Enalapril maleate is a prodrug of enalaprilat and has little pharmacologic activity until hydrolyzed in vivo to enalaprilat. ... Enalapril prevents the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor) through inhibition of angiotensin-converting enzyme (ACE). The drug competes with physiologic substrate (angiotensin I) for the active site of ACE; the affinity of enalaprilat for ACE is approximately 200,000 times greater than that of angiotensin I. In vitro on a molar basis, the affinity of enalaprilat for ACE is 300-1000 or 2-17 times that of enalapril or captopril, respectively. However, in vitro on a molar basis, the ACE-inhibitory effect of enalapril was shown to be similar to that of enalaprilat in rat plasma and kidneys, because these tissues extensively hydrolyze enalapril to form enalaprilat. The drug apparently does not inhibit brain ACE in animals.

The average terminal half life of enalaprilat is 35-38 hours. The effective half life following multiple doses is 11-14 hours. The prolonged terminal half-life is due to the binding of enalaprilat to ACE.

Following oral admin, the half-life of unchanged enalapril appears to be <2 hr in healthy individuals and in patients with normal hepatic and renal functions, but may be increased in patients with congestive heart failure. Following oral admin of a single 5 or 10 mg dose of enalapril maleate in patients with congestive heart failure, the half-life of enalapril was 3.4 or 5.8 hr, respectively.

Elimination of enalaprilat may also be prolonged in patients with congestive heart failure or impaired hepatic function compared with healthy individuals and patients with hypertension observations of serum concns of enalaprilat over long periods following oral or iv admin suggest that enalaprilat has an avg terminal half-life of about 35-38 hr (range: 30-87 hr). ...The effective half-life for accumulation of enalaprilat (determined from urinary recovery) has been reported to average about 11 hr in healthy individuals with normal renal function.

About 60% of the absorbed dose is extensively hydrolyzed to enalaprilat via de-esterification mediated by hepatic esterases. In humans, metabolism beyond bioactivation to enalaprilat is not observed.

About 60% of an absorbed dose of enalapril is extensively hydrolyzed to enalaprilat, principally in the liver via esterases. About 20% appears to be hydrolyzed on first pass through the liver; this hydrolysis does not appear to occur in plasma in humans. Enalaprilat is a more potent angiotensin converting enzyme inhibitor than enalapril. There is no evidence of other metabolites of enalapril in humans, rats, or dogs. However, a despropyl metabolite of enalaprilat was identified in urine in rhesus monkeys, accounting for 13% of an oral dose of enalapril maleate. Hydrolysis of enalapril to enalaprilat may be delayed and/or impaired in patients with severe hepatic impairment, but the pharmacodynamic effects of the drug do not appear to be significantly altered.

69PN84IO1A

ENALAPRIL

Established Pharmacologic Class [EPC] - Angiotensin Converting Enzyme Inhibitor

Mechanisms of Action [MoA] - Angiotensin-converting Enzyme Inhibitors

Physiologic Effects [PE] - Decreased Blood Pressure

Enalapril is an Angiotensin Converting Enzyme Inhibitor. The mechanism of action of enalapril is as an Angiotensin-converting Enzyme Inhibitor. The physiologic effect of enalapril is by means of 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.

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.

Following oral administration, the peak plasma concentrations (Cmax) of enalapril is achieved within 1 hour post dosing while the Cmax of enalaprilat occurs at three to four hours post dosing. The steady-state is achieved by the fourth daily dose and there is no accumulation with repeated dosing. However, accumulation of enalaprilat may occur in patients with creatinine clearance less than 30 mL/min. Food intake is reported to have a minimal effect on drug absorption. Following oral administration, about 60% of enalapril was absorbed. Bioavailability of enalapril averaged about 40% when intravenous enalaprilat was used as a reference standard.

Enalapril is mainly eliminated through renal excretion, where approximately 94% of the total dose is excreted via urine or feces as either enalaprilat or unchanged parent compound. About 61% and 33% of the total dose can be recovered in the urine and feces, respectively. In the urine, about 40% of the recovered dose is in the form of enalaprilat.

The volume of distribution of enalapril has not been established. Enalaprilat is shown to penetrate into most tissuesm, in particular the kidneys and vascular tissuem, although penetration of the blood-brain barrier has not been demonstrated after administration at therapeutic doses. In dog studies, enalapril and enalaprilat cross the blood-brain barrier poorly. Minimal penetration occurs into breast milk but significant fetal transfer occurs. The drug crosses the placental barrier in rats and hamsters.

Following oral administration in healthy male volunteers, the renal clearance was approximately 158 ± 47 mL/min. It is reported that enalapril and enalaprilat are undetectable in the plasma by 4 hours post-dosing.

Pharmacokinetic and pharmacodynamic of IV enalapril at 0.50 mg/kg, PO placebo and PO enalapril at three different doses (0.50, 1.00 and 2.00 mg/kg) were analyzed in 7 healthy horses. Serum concentrations of enalapril and enalaprilat were determined for pharmacokinetic analysis. Angiotensin-converting enzyme (ACE) activity, serum ureic nitrogen (SUN), creatinine and electrolytes were measured, and blood pressure was monitored for pharmacodynamic analysis. The elimination half-lives of enalapril and enalaprilat were 0.67 and 2.76 hr respectively after IV enalapril. Enalapril concentrations after PO administrations were below the limit of quantification (10 ng/mL) in all horses and enalaprilat concentrations were below the limit of quantification in 4 of the 7 horses. Maximum mean ACE inhibitions from baseline were 88.38, 3.24, 21.69, 26.11 and 30.19% for IV enalapril at 0.50 mg/kg, placebo and PO enalapril at 0.50, 1.00 and 2.00 mg/kg, respectively. Blood pressures, SUN, creatinine and electrolytes remained unchanged during the experiments.

Enalapril maleate, unlike enalaprilat, is well absorbed following oral administration. Although enalaprilat is a more potent angiotensin converting enzyme inhibitor than enalapril, it is poorly absorbed from the GI tract because of its high polarity, with only about 3-12% of an orally administered dose being absorbed. Approximately 55-75% of an oral dose of enalapril maleate is rapidly absorbed from the GI tract in healthy individuals and hypertensive patients. Food does not appear to substantially affect the rate or extent of absorption of enalapril maleate. Following oral administration, enalapril maleate appears to undergo first pass metabolism principally in the liver, being hydrolyzed to enalaprilat.

Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents

MEDICATION (VET)

MEDICATION

Use (kg) in Switzerland (2009): >500

Parenteral Injection, for IV use only: equivalent to 1.25 mg of anhydrous enalaprilat per mL, Enalaprilat Injection (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name). /Enalaprilat/

Table: Enalapril Maleate Preparations [Table#6038]

Table: Enalapril Maleate and Hydrochlorothiazide Combination Preparations [Table#6039]