LISINOPRIL AND HYDROCHLOROTHIAZIDE- lisinopril and hydrochlorothiazide tablet
WARNING: FETAL TOXICITY
• When pregnancy is detected, discontinue Lisinopril 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.
Lisinopril and Hydrochlorothiazide Tablets, USP combines an angiotensin converting enzyme inhibitor, lisinopril, and a diuretic, hydrochlorothiazide.
Lisinopril, a synthetic peptide derivative, is an oral long-acting angiotensin converting enzyme inhibitor. It is chemically described as (S)-1-[N 2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline dihydrate. Its empirical formula is C21 H31 N3 O5 •2H2 O and its structural formula is:
Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.52. It is soluble in water, sparingly soluble in methanol, and practically insoluble in ethanol.
Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C7 H8 ClN3 O4 S2 and its structural formula is:
Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.73, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.
Lisinopril and Hydrochlorothiazide Tablets, USP is available for oral use in three tablet combinations of lisinopril with hydrochlorothiazide: Lisinopril and Hydrochlorothiazide Tablets, USP 10-12.5, containing 10 mg lisinopril and 12.5 mg hydrochlorothiazide USP and Lisinopril and Hydrochlorothiazide Tablets, USP 20-12.5, containing 20 mg lisinopril and 12.5 mg hydrochlorothiazide USP and Lisinopril and Hydrochlorothiazide Tablets 20-25, containing 20 mg lisinopril and 25 mg hydrochlorothiazide USP. Inactive ingredients are colloidal silicon dioxide, dibasic calcium phosphate, FD&C Blue #2 Aluminum Lake (20 mg/12.5 mg only), FD&C Red #40 Aluminum Lake (10 mg/12.5 mg, and 20 mg/25 mg), magnesium stearate, mannitol, and pregelatinized starch.
As a result of its diuretic effects, hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, and decreases serum potassium. Administration of lisinopril 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 lisinopril and hydrochlorothiazide was approximately additive. The Lisinopril and Hydrochlorothiazide Tablets 10-12.5 combination worked equally well in Black and Caucasian patients. The Lisinopril and Hydrochlorothiazide Tablets 20-12.5 and Lisinopril and Hydrochlorothiazide Tablets 20-25 (a previously — marketed strength) combinations appeared somewhat less effective in Black patients, but relatively few Black patients were studied. In most patients, the antihypertensive effect of Lisinopril and Hydrochlorothiazide Tablets was sustained for at least 24 hours.
In a randomized, controlled comparison, the mean antihypertensive effects of Lisinopril and Hydrochlorothiazide Tablets 20-12.5 and Lisinopril and Hydrochlorothiazide Tablets 20-25 were similar, suggesting that many patients who respond adequately to the latter combination may be controlled with Lisinopril and Hydrochlorothiazide Tablets 20-12.5. (See DOSAGE AND ADMINISTRATION.)
Concomitant administration of lisinopril 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
Lisinopril 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. The latter decrease may result in a small increase of serum potassium. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In hypertensive patients with normal renal function treated with lisinopril alone for up to 24 weeks, the mean increase in serum potassium was less than 0.1 mEq/L; however, approximately 15 percent of patients had increases greater than 0.5 mEq/L and approximately six percent had a decrease greater than0.5 mEq/L. In the same study, patients treated with lisinopril plus a thiazide diuretic showed essentially no change in serum potassium. (See PRECAUTIONS.)
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 lisinopril remains to be elucidated.
While the mechanism through which lisinopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril is antihypertensive even in patients with low-renin hypertension. Although lisinopril was antihypertensive in all races studied, Black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to lisinopril monotherapy than non-Black patients.
Pharmacokinetics and Metabolism
Following oral administration of lisinopril, peak serum concentrations occur within about 7 hours. Declining serum concentrations exhibit a prolonged terminal phase which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose. Lisinopril does not appear to be bound to other serum proteins.
Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25 percent, with large intersubject variability (6-60 percent) at all doses tested (5-80 mg). Lisinopril absorption is not influenced by the presence of food in the gastrointestinal tract.
Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.
Impaired renal function decreases elimination of lisinopril, which is excreted principally through the kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below
30 mL/min. Above this glomerular filtration rate, the elimination half-life is little changed. With greater impairment, however, peak and trough lisinopril levels increase, time to peak concentration increases and time to attain steady state is prolonged. Older patients, on average, have (approximately doubled) higher blood levels and area under the plasma concentration time curve (AUC) than younger patients. (See DOSAGE AND ADMINISTRATION.) Lisinopril can be removed by hemodialysis.
Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril in rats do not result in accumulation in any tissues. However, milk of lactating rats contains radioactivity following administration of 14C lisinopril. By whole body autoradiography, radioactivity was found in the placenta following administration of labeled drug to pregnant rats, but none was found in the fetuses.
Administration of lisinopril to patients with hypertension results in a reduction of supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is usually not observed although it can occur and should be anticipated in volume and/or salt-depleted patients. (See WARNINGS.)
In most patients studied, onset of antihypertensive activity was seen at one hour after oral administration of an individual dose of lisinopril, with peak reduction of blood pressure achieved by six hours.
In some patients achievement of optimal blood pressure reduction may require two to four weeks of therapy.
At recommended single daily doses, antihypertensive effects have been maintained for at least 24 hours after dosing, although the effect at 24 hours was substantially smaller than the effect six hours after dosing.
The antihypertensive effects of lisinopril have continued during long-term therapy. Abrupt withdrawal of lisinopril has not been associated with a rapid increase in blood pressure; nor with a significant overshoot of pretreatment blood pressure.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and in heart rate. In a study in nine hypertensive patients, following administration of lisinopril, there was an increase in mean renal blood flow that was not significant. Data from several small studies are inconsistent with respect to the effect of lisinopril on glomerular filtration rate in hypertensive patients with normal renal function, but suggest that changes, if any, are not large.
In patients with renovascular hypertension lisinopril has been shown to be well tolerated and effective in controlling blood pressure (see PRECAUTIONS).
The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not usually affect normal blood pressure.
Hydrochlorothiazide is a diuretic and antihypertensive. It affects the distal renal tubular mechanism of electrolyte reabsorption. Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate.
After oral use diuresis begins within two hours, peaks in about four hours and lasts about 6 to 12 hours. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have
been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier.
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