Lisinopril and Hydrochlorothiazide
LISINOPRIL AND HYDROCHLOROTHIAZIDE- hydrochlorothiazide and lisinopril tablet
Aphena Pharma Solutions — Tennessee, LLC
WARNING: FETAL TOXICITY
See full prescribing information for complete boxed warning.
- When pregnancy is detected, discontinue lisinopril and hydrochlorothiazide 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 tablet 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-[N2-(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, crystalline powder, with a molecular weight of 441.53. 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 297.72, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.
Lisinopril and hydrochlorothiazide tablets USP are available for oral use in three tablet combinations of lisinopril with hydrochlorothiazide: lisinopril and hydrochlorothiazide tablets USP, 10 mg/12.5 mg, containing 10 mg lisinopril and 12.5 mg hydrochlorothiazide; lisinopril and hydrochlorothiazide tablets USP, 20 mg/12.5 mg, containing 20 mg lisinopril and 12.5 mg hydrochlorothiazide; and lisinopril and hydrochlorothiazide tablets USP, 20 mg/25 mg, containing 20 mg lisinopril and 25 mg hydrochlorothiazide.
Inactive ingredients are dibasic calcium phosphate, magnesium stearate, mannitol, pregelatinized starch and starch (corn). Lisinopril and hydrochlorothiazide tablets USP, 10 mg/12.5 mg also contains FD&C Blue No. 2 Aluminum Lake. Lisinopril and hydrochlorothiazide tablets USP, 20 mg/12.5 mg also contains yellow iron oxide and lisinopril and hydrochlorothiazide tablets USP, 20 mg/25 mg also contain red iron oxide.
Lisinopril and Hydrochlorothiazide
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 10 mg/12.5 mg combination worked equally well in black and white patients. The lisinopril and hydrochlorothiazide 20 mg/12.5 mg and lisinopril and hydrochlorothiazide 20 mg/25 mg 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 was sustained for at least 24 hours.
In a randomized, controlled comparison, the mean antihypertensive effects of lisinopril and hydrochlorothiazide 20 mg/12.5 mg and lisinopril and hydrochlorothiazide 20 mg/25 mg were similar, suggesting that many patients who respond adequately to the latter combination may be controlled with lisinopril and hydrochlorothiazide 20 mg/12.5 mg. (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 than 0.5 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 nonblack 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% to 60 %) at all doses tested (5 mg to 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. In a multiple dose pharmacokinetic study in elderly versus young hypertensive patients using the lisinopril/hydrochlorothiazide combination, the AUC increased approximately 120% for lisinopril and approximately 80% for hydrochlorothiazide in older patients. 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 14 C 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.
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