Enalapril
(British Approved Name, rINN)
Drug Nomenclature
International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):
Enalapril Maleat
(British Approved Name Modified, rINNM)
Drug Nomenclature
Pharmacopoeias. In China, Europe, and US.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Enalapril Maleate). A white or almost white crystalline powder. Sparingly soluble in water; practically insoluble in dichloromethane; freely soluble in methyl alcohol. It dissolves in dilute solutions of alkali hydroxides. A 1% solution in water has a pH of 2.4 to 2.9. Protect from light.
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Enalapril Maleate). An off-white crystalline powder. Sparingly soluble in water; soluble in alcohol; freely soluble in dimethylformamide and in methyl alcohol; slightly soluble in semipolar organic solvents; practically insoluble in nonpolar organic solvents.
Stability. Enalapril has been reported to be stable for at least 56 days in extemporaneously compounded oral liquids containing enalapril maleate 1 mg/mL in a number of vehicles.
Enalaprilat
(British Approved Name, US Adopted Name, rINN)
Drug Nomenclature
Pharmacopoeias. In Europe and US.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Enalaprilat Dihydrate). A white or almost white, hygroscopic, crystalline powder. It exhibits pseudopolymorphism. Very slightly soluble or slightly soluble in water; sparingly soluble in methyl alcohol; practically insoluble in acetonitrile. Store in airtight containers.
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Enalaprilat). A white to nearly white, hygroscopic, crystalline powder. Soluble 1 in 200 of water, 1 in 40 of dimethylformamide, and 1 in 68 of methyl alcohol; very slightly soluble in alcohol, in acetone, and in hexane; practically insoluble in acetonitrile and in chloroform; slightly soluble in isopropyl alcohol.
Incompatibility. Enalaprilat was visually incompatible with phenytoin sodium in sodium chloride 0.9%, producing a crystalline precipitate; there was also some visual evidence of incompatibility when mixed with amphotericin B in glucose 5%.
Adverse Effects, Treatment, and Precautions
As for ACE inhibitors.
Incidence of adverse effects. Postmarketing surveillance for enalapril was carried out by prescription-event monitoring of 12 543 patients. There were 374 skin events including facial oedema or angioedema in 29 (leading to withdrawal of treatment in 10), 15 cases of photosensitivity, and urticaria in 32 (leading to withdrawal in 5). Syncope and dizziness occurred in 155 and 483 patients respectively, sometimes in association with hypotension. Hypotension occurred in 218 patients, 71 in the first month. Treatment was stopped in 121 patients with hypotension, and dosage reduced in 36. Other adverse effects reported included headache in 310 patients, paraesthesias in 126, taste disturbances in 25, conjunctivitis in 67, tachycardia in 194, cough in 360, renal failure in 82, muscle cramp in 96, diarrhoea in 236, and nausea andvomitingin 326. Of 1098 deaths only 10, due to renal failure, were thought possibly related to enalapril therapy. Dysgeusia and skin reactions appeared to be less common than has been reported for captopril, but precise comparisons were difficult; the range of adverse effects was similar
Deafness was a possible side-effect of enalapril noted earlier; it was reported in 19 of the 12 543 patients monitored, but only while they were taking enalapril, there being no record of deafness after treatment stopped.
For further reference to some of these adverse effects, see under ACE Inhibitors.
Breast feeding. After a single dose of enalapril 20 mg in 5 women enalaprilat was detected in breast milk in concentrations of 1 to 2.3 nanograms/mL (mean peak 1.72 nanograms/mL); enalapril was also present (mean peak 1.74 nanograms/mL). This compared with peak serum values of 39 to 112 nanograms/mL for enalaprilat and 92 to 151 nanograms/mL for enalapril. Another study found no detectable enalaprilat in the milk of 3 women, while in a further woman both enalapril and enalaprilat were detected, but the concentrations were low. Although enalapril and its metabolite are thus present in small amounts in breast milk it was calculated that the average total daily dose to the neonate would only be about 2 micrograms of enalaprilat. The American Academy of Pediatrics lists no reports of any clinical effect on the infant associated with the use of enalapril by breast-feeding mothers, and states that therefore it may be considered to be usually compatible with breast feeding.
Porphyria. Enalapril has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.
Interactions
As for ACE inhibitors.
Pharmacokinetics
Enalapril acts as a prodrug of the diacid enalaprilat, its active form, which is poorly absorbed orally. About 60% of an oral dose of enalapril is absorbed from the gastrointestinal tract and peak plasma concentrations are achieved within about 1 hour. Enalapril is extensively hydrolysed in the liver to enalaprilat; peak plasma concentrations of enalaprilat are achieved 3 to 4 hours after an oral dose of enalapril. Enalaprilat is 50 to 60% bound to plasma proteins. After an oral dose, enalapril is excreted in the urine and in faeces, as enalaprilat and unchanged drug, with the urinary route predominating; more than 90% of an intravenous dose of enalaprilat is excreted in the urine. The elimination of enalaprilat is multiphasic but the effective half-life for accumulation after multiple doses of enalapril is reported to be about 11 hours in patients with normal renal function. Enalaprilat is removed by haemodialysis and by peritoneal dialysis.
Renal impairment. Comparison of the pharmacokinetics of enalapril in 6 diabetics with persistent proteinuria and glomerular filtration rates (GFR) of 44.1 to 58.4 mL/minute with those in 8 age-matched controls showed that in the diabetic group the peak serum concentration of enalaprilat was higher, the time to peak concentration longer, renal clearance lower, and the areas under the concentration/time curve greater than in controls. Renal clearance of enalaprilat in the diabetics ranged from 56 to 66 mL/minute compared with 105 to 133 mL/minute in controls; clearance correlated with GFR.
Uses and Administration
Enalapril is an ACE inhibitor used in the treatment of hypertension and heart failure. It may also be given prophylactically to patients with asymptomatic left ventricular dysfunction to delay the onset of symptomatic heart failure, and has been used in patients with left ventricular dysfunction to reduce the incidence of coronary ischaemic events, including myocardial infarction.
Enalapril owes its activity to enalaprilat to which it is converted after oral doses. The haemodynamic effects are seen within 1 hour of a single oral dose and the maximum effect occurs after about 4 to 6 hours, although the full effect may not develop for several weeks during chronic dosing. The haemodynamic action lasts for about 24 hours, allowing once-daily dosing. Enalapril is given orally as the maleate. Enalaprilat is not absorbed orally but is given by intravenous injection; its haemodynamic effects develop within 15 minutes of injection and reach a peak in 1 to 4 hours. The action lasts for about 6 hours at recommended doses. Enalaprilat is given as the dihydrate, but doses are expressed in terms of the anhydrous substance. Enalaprilat 1.38 mg as the dihydrate is equivalent to about 1.25 mg of anhydrous enalaprilat.
In the treatment of hypertension, an initial oral dose of 5 mg of enalapril maleate daily may be given. Since there may be a precipitous fall in blood pressure in some patients when starting therapy with an ACE inhibitor, the first dose should preferably be given at bedtime. An initial dose of 2.5 mg daily should be given to patients with renal impairment or to those who are receiving a diuretic; if possible, the diuretic should be withdrawn 2 or 3 days before enalapril is started and resumed later if necessary. The usual maintenance dose is 10 to 20 mg given once daily, although doses of up to 40 mg daily may be required in severe hypertension. It may be given in 2 divided doses if control is inadequate with a single dose.
When oral therapy of hypertension is impractical enalaprilat may be given in a dose of 1.25 mg by slow intravenous injection or infusion over at least 5 minutes, repeated every 6 hours if necessary; the initial dose should be halved in patients with renal impairment (creatinine clearance less than 30 mL/minute) or those who are receiving a diuretic.
In the management of heart failure, severe first-dose hypotension on introduction of an ACE inhibitor is common in patients on loop diuretics, but their temporary withdrawal may cause rebound pulmonary oedema. Thus treatment should begin with a low dose under close medical supervision. In patients with heart failure or asymptomatic left ventricular dysfunction enalapril maleate is given orally in an initial dose of 2.5 mg daily. The usual maintenance dose is 20 mg daily as a single dose or in 2 divided doses although up to 40 mg daily in 2 divided doses has been given.
Administration in children. Enalapril may be used in the management of hypertension in children. The initial dose is 80 micrograms/kg once daily, with a maximum of 5 mg, adjusted according to response. Alternatively, children weighing 20 to below 50 kg may be given an initial dose of 2.5 mg once daily, increased to a maximum of 20 mg daily, while children weighing 50 kg or over may be given an initial dose of 5 mg once daily, increased to a maximum of 40 mg daily. Doses above 580 micrograms/kg or 40 mg daily have not been studied.
Enalapril has also been given to infants with severe heart failure in doses of 100 to 500 micrograms/kg daily as an oral suspension produced by suspending a crushed tablet in water. In this study one infant, with severe myocarditis, developed hypotension and the drug had to be withdrawn; the remaining 7 showed clinical improvement on a mean enalapril dose of 260 micrograms/kg daily and were able markedly to reduce the dose of concomitant diuretic required. Another study in 10 infants found that enalapril was less bioavailable and probably had a shorter duration of action in infants than in adults, and that doses of 80 micrograms/kg daily were inadequate in the treatment of infant heart failure. A larger study in 63 infants and children (median age 5.4 months) with heart failure found enalapril 360 micrograms/kg daily to be of benefit, whereas there was no improvement with a lower dose of 240 micrograms/kg daily.
Preparations
British Pharmacopoeia, 2008: Enalapril Tablets;
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Enalapril Maleate and Hydrochlorothiazide Tablets; Enalapril Maleate Tablets.
Single-ingredient Preparations
The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.
Argentina: Defluin; Ecaprilat; Enalafel; Enalapoten; Enaldun; Enatral; Enatrial; Eritril; Fabotensil; Gadopril; Glioten; Hipertan; Kinfil; Lotrial; Maxen; Nalapril; Presi Regul; Priltenk; Renitec; Sulocten; Tencas; Vapresan; Australia: Alphapril; Amprace; Auspril; Enahexal; Enalabell; Renitec; Austria: Alapril; Enac; Enalabene¤; Enapril; Enaran; Enatyrol; Mepril; Regomed¤; Renistad; Renitec; Belgium: Renitec; Brazil: Angiopril; Atens; Blootec; Co-Enaprotec; Enalabal; Enalamed; Enalaplex; Enalatec; Enalprin; Enapril¤; Enaprotec; Enatec; Enaton; Eupressin; Glioten; Hipertin; Lowpress¤; Maleapril; Multipressim; Nalaprix¤; Neolapril; Pressel; Pressotec; Prodopressin; Pryltec; Renalapril; Renipress; Renitec; Renopress; Sanvapress; Sifpryl; Vasopril; Canada: Vasotec; Chile: Bajaten; Enalten; Esalfon; Glioten; Grifopril; Hiperson; Hipoartel; Lotrial; Vasolat¤; Czech Republic: Acetensil; Berlipril; E-Cor; Ednyt; Enap; Enapirex; Enapril; Invoril; Renitec; Denmark: Aceren¤; Alacor; Alapren¤; Corodil; Enacodan; Enadil¤; Renitec; Finland: Enaloc; Enapress¤; Linatil; Renitec; France: Renitec; Germany: Benalapril; Corvo; Ena-Puren; Ena; Enabeta; enadura; Enahexal; Enal¤; Enalagamma; EnaLich; Enalind; Jutaxan; Pres; Xanef; Greece: Agioten; Analept; Antiprex; Erxetilan; Gnostocardin; Kaparlon-S; Kontic¤; Leovinezal; Megapress; Octorax; Ofnifenil; Protal¤; Rablas; Renitec; Stadelant; Supotron; Ulticadex; Virfen; Vitobel¤; Hong Kong: Anapril; Danssan; Enaldun; Lapril; Renitec; Hungary: Acepril; Ednyt; Enap; Enapril; Invoril; Renitec; India: BQL; Dilvas; EnAce; Envas; Nuril; Ireland: Ednyt¤; Enap; Innomel¤; Innovace; Israel: Convertin; Enaladex; Italy: Converten; Enapren; Naprilene; Malaysia: Acetec; Invoril; Renitec; Zynace¤; Mexico: Albec; Apo-Pyl; Bionafil¤; Blocatril; EK-3; Enaladil; Enoval; Euronal; Feliberal; Glioten; Imotoran¤; Kenopril¤; Lipraken; Nalabest; Norpril; Palane; Pulsol; Quimalan¤; Ralser; Renitec; Netherlands: Renitec; Norway: Linatil¤; Renitec; New Zealand: Enahexal; Renitec; Portugal: Balpril; Cetampril; Denapril; Hipten; Malen; Prilan; Renipril; Renitec; Tensazol; Russia: Berlipril (Берлиприл); Ednyt (Еднит); Enafarm (Енафарм); Enam (Енам); Enap (Енап); Enarenal (Енаренал); Enazil (Еназил); Invoril (Инворил); Kalpiren (Кальпирен); Myopril (Миоприл); Renitec (Ренитек); Vasopren (Вазопрен); South Africa: Alapren; Ciplatec; Enap; Hypace¤; Pharmapress; Renitec; Singapore: Anapril; Corprilor; Daren¤; Enap; Enaril; Invoril; Korandil; Renaton¤; Renitec; Spain: Acetensil; Baripril; Bitensil; Clipto; Controlvas; Corprilor; Crinoren; Dabonal; Ditensor; Herten; Hipoartel; Iecatec; Insup; Nacor; Naprilene; Neotensin; Pressitan; Presyndral¤; Reca; Renitec; Ristalen¤; Sweden: Linatil; Renitec; Switzerland: Acepril; Elpradil; ena-basan; Enasifar; Enatec; Epril; Reniten; Vasocor; Thailand: Anapril; Enam; Enapril; Enaril; Envas; Iecatec; Invoril; Istopril; Korandil; Lapril; Nalopril; Naritec; Renitec; United Arab Emirates: Narapril; United Kingdom: Ednyt¤; Enacard¤; Innovace; Pralenal¤; United States: Vasotec; Venezuela: Cosil; Dinid; Enalaprin; Enam; Enaprival; Enecal; Fibrosan; Hiperpril; Lapril; Prilace; Reminal; Renitec; Tesoren;
Multi-ingredient Preparations
Argentina: Co-Renitec; Defluin Plus; Fabotensil D; Gadopril D; Gliotenzide; Kinfil D; Lotrial D; Lotrix¤; Nikion; Presi Regul D; Vapresan Diur; Australia: Renitec Plus; Austria: Co-Enac; Co-Enalapril; Co-Enaran; Co-Enatyrol; Co-Mepril; Co-Renitec; Corenistad; Enacostad; Enalapril Comp; Enalapril/HCT; Renitec Plus; Synerpril; Belgium: Co-Enalapril; Co-Renitec; Brazil: Atens H; Co-Pressoless; Co-Pressotec; Co-Renitec; Duopril; Enatec F; Eupressin H; Gliotenzide; Pryltec-H; Sinergen; Vasopril Plus; Yrelan¤; Canada: Vaseretic; Chile: Bajaten D; Enalten D; Enalten DN; Esalfon-D; Grifopril-D; Hiperson-D; Hipoartel H; Lotrial D; Normaten Plus; Normaten; Czech Republic: Enap-H; Enap-HL; Denmark: Co-Renitec; Corodil Comp; Enacozid; Synerpril; Finland: Enalapril Comp; Enaloc Comp; Linatil Comp; Renitec Comp; Renitec Plus; France: Co-Renitec; Germany: Enabeta comp; Enahexal comp; Enalapril plus; Eneas; Pres plus; Renacor; Greece: Bumeftyl; Co-Renitec; Eneas; Iperton; Modinexil¤; Nolarmin; Penopril; Protal complex; Savosan; Siberian; Hong Kong: Co-Renitec; Hungary: Co-Renitec; Enap-HL; Renitec Plus; India: Dilvas AM; EnAce-D; Invozide; Ireland: Innozide; Israel: Naprizide; Italy: Acesistem; Condiuren; Gentipress; Neoprex; Sinertec; Vasoretic; Mexico: Co-Renitec; Gliotenzide; Netherlands: Co-Renitec; Enacostad; Renitec Plus; Norway: Renitec Comp; New Zealand: Co-Renitec; Portugal: Enatia; Laprilen; Renidur; Renipril Plus¤; Russia: Co-Renitec (Ко-Ренитек); Enap-H (Енап H); Enzix (Ензикс); South Africa: Co-Renitec; Enap-Co; Pharmapress Co; Singapore: Co-Renitec¤; Enap-HL; Spain: Acediur; Acetensil Plus; Baripril Diu; Bitensil Diu; Co-Renitec; Crinoretic; Dabonal Plus; Ditenside; Eneas; Enit; Hipoartel Plus; Neotensin Diu; Pressitan Plus; Renitecmax; Vipres; Zorail; Sweden: Enalapril Comp; Renitec Comp; Synerpril; Switzerland: Co-Acepril; Co-Enatec; Co-Epril; Co-Reniten; Co-Vasocor; Elpradil HCT; Reniten Plus; United Kingdom: Innozide; United States: Lexxel; Teczem; Vaseretic; Venezuela: Co-Renitec; Priretic; Reminalet
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