ENALAPRIL MALEATE, ENALAPRILAT

Chemistry - Angiotensin-converting enzyme (ACE) inhibitors, enalapril maleate and enalaprilat arestructurally related to captopril. Enalapril is a prodrug and is converted in vivo by the liver toenalaprilat. Enalapril maleate occurs as a white to off white crystalline powder. 25 mg are soluble inone ml of water. Enalaprilat occurs as a white to off white crystalline powder that is slightly solublein water.

Storage, Stability, Compatibility

The commercially available tablets should be stored at temperatures less than 30°C and in tight containers. When stored properly, the tablets have an expiration date of 30 months after manufacture.
Enalaprilat injection should be stored at temperatures less than 30°C. After dilution with D5W, normal saline, or D5 in lactated Ringer's it is stable for up to 24 hours at room temperature.
Enalaprilat has been documented to be incompatible with amphotericin B or phenytoin sodium.
Many other mediations have been noted to be compatible with enalaprilat at various concentrations.
Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used.
It is suggested to consult specialized references (e.g., Handbook on Injectable Drugs by Trissel; see bibliography) for more specific information.

Pharmacology - ENALAPRIL MALEATE, ENALAPRILAT

Enalapril is converted in the liver to the active compound enalaprilat. Enalaprilatprevents the formation of angiotensin II (a potent vasoconstrictor) by competing with angiotensin Ifor the enzyme angiotensin converting enzyme (ACE). ACE has a much higher affinity forenalaprilat than for angiotensin I. Because angiotensin II concentrations are decreased, aldosteronesecretion is reduced and plasma renin activity is increased.
The cardiovascular effects of enalaprilat in patients with CHF include decreased total peripheralresistance, pulmonary vascular resistance, mean arterial and right atrial pressures, and pulmonarycapillary wedge pressure, no change or decrease in heart rate, and increased cardiac index andoutput, stroke volume, and exercise tolerance. Renal blood flow can be increased with little changein hepatic blood flow.
Uses, Indications - The principle uses of enalapril/enalaprilat in veterinary medicine at present areas a vasodilator in the treatment of heart failure and in the treatment of hypertension. It may also beof benefit in treating the effects associated with valvular heart disease, and left to right shunts. It isbeing explored as adjunctive treatment in chronic renal failure and in protein losing nephropathies.

Pharmacokinetics - ENALAPRIL MALEATE, ENALAPRILAT

Enalapril/enalaprilat has different pharmacokinetic properties than captopril indogs. It has a slower onset of action (4-6 hours), but a longer duration of action (12-14 hours). Inhumans, enalapril is well absorbed after oral administration, but enalaprilat is not. Both enalapril andenalaprilat are distributed poorly into the CNS and are distributed into milk in trace amounts.
Enalaprilat crosses the placenta. In humans, the half life of enalapril is about 2 hours; enalaprilatabout 11 hours. Half lives are increased in patients with renal failure or severe CHF.

Contraindications, Precautions, Reproductive Safety

Enalaprilat is contraindicated in patientswho have demonstrated hypersensitivity to the ACE inhibitors. It should be used with caution andclose supervision, in patients with renal insufficiency and doses may need to be reduced.
Enalaprilat should also be used with caution in patients with hyponatremia or sodium depletion, coronary or cerebrovascular insufficiency, preexisting hematologic abnormalities or a collagenvascular disease (e.g., SLE). Patients with severe CHF should be monitored very closely uponinitiation of therapy.
Enalapril crosses the placenta. High doses in rodents have caused decreased fetal weights andincreases in fetal and maternal death rates; teratogenic effects have not been reported.

Adverse Effects, Warnings

Enalapril/enalaprilat's adverse effect profile in dogs is principally GIdistress (anorexia, vomiting, diarrhea). Potentially, hypotension, renal dysfunction and hyperkalemiacould occur. Because it lacks a sulfhydryl group (unlike captopril), there is less likelihood thatimmune-mediated reactions will occur, but rashes, neutropenia and agranulocytosis have beenreported in humans.

Overdosage, Acute Toxicity

In dogs, a dose of 200 mg/kg was lethal, but 100 mg/kg was not. Inoverdose situations, the primary concern is hypotension; supportive treatment with volumeexpansion with normal saline is recommended to correct blood pressure. Because of the drug'slong duration of action, prolonged monitoring and treatment may be required. Recent overdoses, should be managed using gut emptying protocols when warranted.

Drug Interactions

Concomitant diuretics or other vasodilators may cause hypotension if usedwith enalapril/enalaprilat; titrate dosages carefully. Some clinicians recommend reducingfurosemide doses (by 25 - 50%) when adding enalapril to therapy in CHF.
Hyperkalemia may develop if given with potassium or potassium sparing diuretics (e.g., spironolactone).
Non-steroidal anti-inflammatory agents (NSAIDs) may reduce the clinical efficacy ofenalapril/enalaprilat when it is being used as an antihypertensive agent. Indomethacin appears to bemost likely to evoke this problem.Laboratory Considerations - When using iodohippurate sodium I123/I134 or Technetium
Tc99 pententate renal imaging in patients with renal artery stenosis, ACE inhibitors may cause areversible decrease in localization and excretion of these agents in the affected kidney which maylead to confusion in test interpretation.