Enalapril Maleate and Hydrochlorothiazide
ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE — enalapril maleate and hydrochlorothiazide tablet
Bryant Ranch Prepack
WARNING: FETAL TOXICITY
See full prescribing information for complete boxed warning.
- When pregnancy is detected, discontinue enalapril maleate and hydrochlorothiazide tablets as soon as possible.
- Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See WARNINGS: Fetal Toxicity.
Enalapril maleate and hydrochlorothiazide tablets, USP combine an angiotensin converting enzyme inhibitor, enalapril maleate, USP and a diuretic, hydrochlorothiazide, USP.
Enalapril maleate, USP is the maleate salt of enalapril, the ethyl ester of a long-acting angiotensin converting enzyme inhibitor, enalaprilat. Enalapril maleate, USP is chemically described as (S)-1-[N — [1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline, (Z)-2-butenedioate salt (1:1). Its structural formula is:
C20 H28 N2 O5 •C4 H4 O4 M.W. 492.53
Enalapril maleate, USP is a white to off-white crystalline powder. It is sparingly soluble in water, soluble in ethanol, and freely soluble in methanol.
Enalapril is a pro-drug; following oral administration, it is bioactivated by hydrolysis of the ethyl ester to enalaprilat, which is the active angiotensin converting enzyme inhibitor.
Hydrochlorothiazide, USP is 6-chloro-3,4-dihydro-2H -1,2,4-benzo-thiadiazine-7-sulfonamide 1,1-dioxide. Its structural formula is:
C7 H8 ClN3 O4 S2 M.W. 297.74
It is a white, or practically white, crystalline powder, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.
Enalapril maleate and hydrochlorothiazide tablets, USP are available in two tablet combinations: 5 mg/12.5 mg, containing 5 mg enalapril maleate, USP and 12.5 mg hydrochlorothiazide, USP and 10 mg/25 mg, containing 10 mg enalapril maleate, USP and 25 mg hydrochlorothiazide, USP. Inactive ingredients are corn starch, lactose monohydrate, magnesium stearate, pregelatinized starch, and sodium bicarbonate. Enalapril maleate and hydrochlorothiazide tablets USP, 10 mg/25 mg also contain FD&C blue #2 aluminum lake, FD&C red #40 aluminum lake, and FD&C yellow #6 aluminum lake.
As a result of its diuretic effects, hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, and decreases serum potassium. Administration of enalapril maleate blocks the renin-angiotensin-aldosterone axis and tends to reverse the potassium loss associated with the diuretic.
In clinical studies, the extent of blood pressure reduction seen with the combination of enalapril maleate and hydrochlorothiazide was approximately additive. The antihypertensive effect of enalapril maleate and hydrochlorothiazide was usually sustained for at least 24 hours.
Concomitant administration of enalapril maleate and hydrochlorothiazide has little, or no effect on the bioavailability of either drug. The combination tablet is bioequivalent to concomitant administration of the separate entities.
Mechanism of Action
Enalapril, after hydrolysis to enalaprilat, inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. Although the latter decrease is small, it results in small increases of serum potassium. In hypertensive patients treated with enalapril maleate alone for up to 48 weeks, mean increases in serum potassium of approximately 0.2 mEq/L were observed. In patients treated with enalapril maleate plus a thiazide diuretic, there was essentially no change in serum potassium (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of enalapril remains to be elucidated.
While the mechanism through which enalapril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, enalapril is antihypertensive even in patients with low-renin hypertension. Although enalapril was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to enalapril maleate monotherapy than non-black patients. In contrast, hydrochlorothiazide was more effective in black patients than enalapril. Concomitant administration of enalapril maleate and hydrochlorothiazide was equally effective in black and non-black patients.
Pharmacokinetics and Metabolism
Following oral administration of enalapril maleate, peak serum concentrations of enalapril occur within about one hour. Based on urinary recovery, the extent of absorption of enalapril is approximately 60 percent. Enalapril absorption is not influenced by the presence of food in the gastrointestinal tract. Following absorption, enalapril is hydrolyzed to enalaprilat, which is a more potent angiotensin converting enzyme inhibitor than enalapril; enalaprilat is poorly absorbed when administered orally. Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of enalapril maleate. Excretion of enalaprilat and enalapril is primarily renal. Approximately 94 percent of the dose is recovered in the urine and feces as enalaprilat or enalapril. The principal components in urine are enalaprilat, accounting for about 40 percent of the dose, and intact enalapril. There is no evidence of metabolites of enalapril, other than enalaprilat.
The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently representing a small fraction of the administered dose that has been bound to ACE. The amount bound does not increase with dose, indicating a saturable site of binding. The effective half-life for accumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours.
The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. With glomerular filtration rate ≤ 30 mL/min, peak and trough enalaprilat levels increase, time to peak concentration increases and time to steady state may be delayed. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency. Enalaprilat is dialyzable at the rate of 62 mL/min.
Studies in dogs indicate that enalapril crosses the blood-brain barrier poorly, if at all; enalaprilat does not enter the brain. Multiple doses of enalapril maleate in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14 C enalapril maleate. Radioactivity was found to cross the placenta following administration of labeled drug to pregnant hamsters.
Administration of enalapril maleate to patients with hypertension of severity ranging from mild to severe results in a reduction of both supine and standing blood pressure usually with no orthostatic component. Symptomatic postural hypotension is infrequent with enalapril alone but it can be anticipated in volume-depleted patients, such as patients treated with diuretics. In clinical trials with enalapril and hydrochlorothiazide administered concurrently, syncope occurred in 1.3 percent of patients (see WARNINGS and DOSAGE AND ADMINISTRATION).
In most patients studied, after oral administration of a single dose of enalapril maleate, onset of antihypertensive activity was seen at one hour with peak reduction of blood pressure achieved by four to six hours.
At recommended doses, antihypertensive effects of enalapril maleate monotherapy have been maintained for at least 24 hours. In some patients the effects may diminish toward the end of the dosing interval; this was less frequently observed with concomitant administration of enalapril maleate and hydrochlorothiazide.
Achievement of optimal blood pressure reduction may require several weeks of enalapril therapy in some patients.
The antihypertensive effects of enalapril have continued during long term therapy. Abrupt withdrawal of enalapril has not been associated with a rapid increase in blood pressure.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction produced by enalapril was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of enalapril maleate, there is an increase in renal blood flow; glomerular filtration rate is usually unchanged. The effects appear to be similar in patients with renovascular hypertension.
In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalapril maleate. In this study there was no evidence of a blunting of the antihypertensive action of enalapril maleate (see PRECAUTIONS, Drug Interactions, Enalapril Maleate).
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