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Quinapril and Hydrochlorothiazide Description
Quinapril HCl/hydrochlorothiazide tablets are
fixed-combination tablets that combine an angiotensin-converting
enzyme (ACE) inhibitor, quinapril hydrochloride, and a
thiazide diuretic, hydrochlorothiazide.
Quinapril hydrochloride is chemically described as
[3S-[2[R*(R*)], 3R*]] - 2 - [2 - [[1 - (ethoxycarbonyl) - 3 -
phenylpropyl]amino] - 1 - oxopropyl] - 1,2,3,4 - tetrahydro -
3 - isoquinolinecarboxylic acid, monohydrochloride. Its
empirical formula is C25H30N2O5. HCl and its structural
formula is:
Quinapril hydrochloride is a white to off-white amorphous
powder that is freely soluble in aqueous solvents.
Hydrochlorothiazide is chemically described as:
6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide
1,1-dioxide. Its empirical formula is C7H8ClN3O4S2 and its
structural formula is:
Hydrochlorothiazide is a white to off-white, crystalline
powder which is slightly soluble in water but freely soluble
in sodium hydroxide solution.
Quinapril HCl/hydrochlorothiazide tablets are available for
oral use as fixed combination tablets in three strengths of
quinapril with hydrochlorothiazide: 10 mg with 12.5 mg (quinapril
HCl/hydrochlorothiazide tablets 10/12.5), 20 mg with 12.5 mg (quinapril
HCl/hydrochlorothiazide tablets 20/12.5), and 20 mg with 25 mg
(quinapril HCl/hydrochlorothiazide tablets 20/25). Inactive
ingredients: candelilla wax, crospovidone, hydroxypropyl
cellulose, hypromellose, iron oxide red, iron oxide yellow,
lactose, magnesium carbonate, magnesium stearate, polyethylene
glycol, povidone, and titanium dioxide.
Quinapril and Hydrochlorothiazide - Clinical Pharmacology
Mechanism of Action
The principal metabolite of quinapril, quinaprilat, is an
inhibitor of ACE activity in human subjects and animals. ACE
is peptidyl dipeptidase that catalyzes the conversion of
angiotensin I to the vasoconstrictor, angiotensin II. The
effect of quinapril in hypertension appears to result
primarily from the inhibition of circulating and tissue ACE
activity, thereby reducing angiotensin II formation. Quinapril
inhibits the elevation in blood pressure caused by
intravenously administered angiotensin I, but has no effect on
the pressor response to angiotensin II, norepinephrine, or
epinephrine. Angiotensin II also stimulates the secretion of
aldosterone from the adrenal cortex, thereby facilitating
renal sodium and fluid reabsorption. Reduced aldosterone
secretion by quinapril may result in a small increase in serum
potassium. In controlled hypertension trials, treatment with
quinapril alone resulted in mean increases in potassium of
0.07 mmol/L (see PRECAUTIONS). Removal of angiotensin II
negative feedback on renin secretion leads to increased plasma
renin activity (PRA).
While the principal mechanism of antihypertensive effect is
thought to be through the renin-angiotensin-aldosterone
system, quinapril exerts antihypertensive actions even in
patients with low renin hypertension. Quinapril was an
effective antihypertensive in all races studied, although it
was somewhat less effective in blacks (usually a predominantly
low renin group) than in non-blacks. ACE is identical to
kininase II, an enzyme that degrades bradykinin, a potent
peptide vasodilator; whether increased levels of bradykinin
play a role in the therapeutic effect of quinapril remains to
be elucidated.
Hydrochlorothiazide is a thiazide diuretic. Thiazides affect
the renal tubular mechanisms of electrolyte reabsorption,
directly increasing excretion of sodium and chloride in
approximately equivalent amounts. Indirectly, the diuretic
action of hydrochlorothiazide reduces plasma volume, with
consequent increases in plasma renin activity, increases in
aldosterone secretion, increases in urinary potassium loss,
and decreases in serum potassium. The renin-aldolsterone link
is mediated by angiotensin, so coadministration of an ACE
inhibitor tends to reverse the potassium loss associated with
these diuretics.
The mechanism of the antihypertensive effect of thiazides is
unknown.
Pharmacokinetics and Metabolism
The rate and extent of absorption of quinapril and
hydrochlorothiazide from quinapril HCl/hydrochlorothiazide
tablets are not different, respectively, from the rate and
extent of absorption of quinapril and hydrochlorothiazide from
immediate-release monotherapy formulations, either
administered concurrently or separately. Following oral
administration of quinapril monotherapy tablets, peak plasma
quinapril concentrations are observed within 1 hour. Based on
recovery of quinapril and its metabolites in urine, the extent
of absorption is at least 60%. The absorption of
hydrochlorothiazide is somewhat slower (1 to 2.5 hours) and
more complete (50% to 80%).
The rate of quinapril absorption was reduced by 14% when
quinapril HCl/hydrochlorothiazide tablets were administered
with a high-fat meal as compared to fasting, while the extent
of absorption was not affected. The rate of
hydrochlorothiazide absorption was reduced by 12% when
quinapril HCl/hydrochlorothiazide tablets were administered
with a high-fat meal, while the extent of absorption was not
significantly affected. Therefore, quinapril
HCl/hydrochlorothiazide tablets may be administered without
regard to food.
Following absorption, quinapril is deesterified to its major
active metabolite, quinaprilat (about 38% of oral dose), and
to other minor inactive metabolites. Following multiple oral
dosing of quinapril, there is an effective accumulation
half-life of quinaprilat of approximately 3 hours, and peak
plasma quinaprilat concentrations are observed approximately 2
hours postdose. Approximately 97% of either quinapril or
quinaprilat circulating in plasma is bound to proteins.
Hydrochlorothiazide is not metabolized. Its apparent volume of
distribution is 3.6 to 7.8 L/kg, consistent with measured
plasma protein binding of 67.9%. The drug also accumulates in
red blood cells, so that whole blood levels are 1.6 to 1.8
times those measured in plasma.
Some placental passage occurred when quinapril was
administered to pregnant rats. Studies in rats indicate that
quinapril and its metabolites do not cross the blood-brain
barrier. Hydrochlorothiazide crosses the placenta freely but
not the blood-brain barrier.
Quinaprilat is eliminated primarily by renal excretion, up to
96% of an IV dose, and has an elimination half-life in plasma
of approximately 2 hours and a prolonged terminal phase with a
half-life of 25 hours. Hydrochlorothiazide is excreted
unchanged by the kidney. When plasma levels have been followed
for at least 24 hours, the plasma half-life has been observed
to vary between 4 to 15 hours. At least 61% of the oral dose
is eliminated unchanged within 24 hours.
In patients with renal insufficiency, the elimination
half-life of quinaprilat increases as creatinine clearance
decreases. There is a linear correlation between plasma
quinaprilat clearance and creatinine clearance. In patients
with end-stage renal disease, chronic hemodialysis or
continuous ambulatory peritoneal dialysis have little effect
on the elimination of quinapril and quinaprilat. Elimination
of quinaprilat is reduced in elderly patients (≥65 years) and
in those with heart failure; this reduction is attributable to
decrease in renal function (see DOSAGE AND ADMINISTRATION).
Quinaprilat concentrations are reduced in patients with
alcoholic cirrhosis due to impaired deesterification of
quinapril. In a study of patients with impaired renal function
(mean creatinine clearance of 19 mL/min), the half-life of
hydrochlorothiazide elimination was lengthened to 21 hours.
The pharmacokinetics of quinapril and quinaprilat are linear
over a single-dose range of 5- to 80-mg doses and 40- to
160-mg in multiple daily doses.
Pharmacodynamics and Clinical Effects
Single doses of 20 mg of quinapril provide over 80% inhibition
of plasma ACE for 24 hours. Inhibition of the pressor response
to angiotensin I is shorter-lived, with a 20-mg dose giving
75% inhibition for about 4 hours, 50% inhibition for about 8
hours, and 20% inhibition at 24 hours. With chronic dosing,
however, there is substantial inhibition of angiotensin II
levels at 24 hours by doses of 20 to 80 mg.
Administration of 10 to 80 mg of quinapril to patients with
mild to severe hypertension results in a reduction of sitting
and standing blood pressure to about the same extent with
minimal effect on heart rate. Symptomatic postural hypotension
is infrequent, although it can occur in patients who are salt-
and/or volume-depleted (see WARNINGS).
Antihypertensive activity commences within 1 hour with peak
effects usually achieved by 2 to 4 hours after dosing. During
chronic therapy, most of the blood pressure lowering effect of
a given dose is obtained in 1 to 2 weeks. In multiple-dose
studies, 10 to 80 mg per day in single or divided doses
lowered systolic and diastolic blood pressure throughout the
dosing interval, with a trough effect of about 5 to 11/3 to 7
mm Hg. The trough effect represents about 50% of the peak
effect.
While the dose-response relationship is relatively flat, doses
of 40 to 80 mg were somewhat more effective at trough than 10
to 20 mg, and twice-daily dosing tended to give a somewhat
lower trough blood pressure than once-daily dosing with the
same total dose. The antihypertensive effect of quinapril
continues during long-term therapy, with no evidence of loss
of effectiveness.
Hemodynamic assessments in patients with hypertension indicate
that blood pressure reduction produced by quinapril is
accompanied by a reduction in total peripheral resistance and
renal vascular resistance with little or no change in heart
rate, cardiac index, renal blood flow, glomerular filtration
rate, or filtration fraction.
Therapeutic effects of quinapril appear to be the same for
elderly (≥65 years of age) and younger adult patients given
the same daily dosages, with no increase in adverse events in
elderly patients. In patients with hypertension, quinapril 10
to 40 mg was similar in effectiveness to captopril, enalapril,
propranolol, and thiazide diuretics.
After oral administration of hydrochlorothiazide, diuresis
begins within 2 hours, peaks in about 4 hours, and lasts about
6 to 12 hours. Use of quinapril with a thiazide diuretic gives
blood pressure lowering effect greater than that seen with
either agent alone. In clinical trials of quinapril/hydrochlorothiazide
using quinapril doses of 2.5 to 40 mg and hydrochlorothiazide
doses of 6.25 to 25 mg, the antihypertensive effects were
sustained for at least 24 hours, and increased with increasing
dose of either component. Although quinapril monotherapy is
somewhat less effective in blacks than in non-blacks, the
efficacy of combination therapy appears to be independent of
race. By blocking the renin-angiotensin-aldosterone axis,
administration of quinapril tends to reduce the potassium loss
associated with the diuretic. In clinical trials of quinapril
HCl/hydrochlorothiazide tablets, the average change in serum
potassium was near zero when 2.5 to 40 mg of quinapril was
combined with hydrochlorothiazide 6.25 mg, and the average
subject who received 10 to 20/12.5 to 25 mg experienced a
milder reduction in serum potassium than that experienced by
the average subject receiving the same dose of
hydrochlorothiazide monotherapy.
Indications and Usage for Quinapril and Hydrochlorothiazide
Quinapril HCl/hydrochlorothiazide tablets are indicated for
the treatment of hypertension. This fixed combination is not
indicated for the initial therapy of hypertension (see DOSAGE
AND ADMINISTRATION).
In using quinapril HCl/hydrochlorothiazide tablets,
consideration should be given to the fact that another
angiotensin-converting enzyme inhibitor, captopril, has caused
agranulocytosis, particularly in patients with renal
impairment or collagen-vascular disease. Available data are
insufficient to show that quinapril does not have a similar
risk (see WARNINGS: Neutropenia/Agranulocytosis).
Contraindications
Quinapril HCl/hydrochlorothiazide tablets are contraindicated
in patients who are hypersensitive to quinapril or
hydrochlorothiazide and in patients with a history of
angioedema related to previous treatment with an ACE
inhibitor.
Because of the hydrochlorothiazide components, this product is
contraindicated in patients with anuria or hypersensitivity to
other sulfonamide-derived drugs.
Disclaimer:
Information on this page is provided for general
information purposes. You should not make a clinical treatment
decision based on information contained in this page without
consulting other references including the package insert of
the drug, textbooks and where relevant, expert opinion. We
cannot be held responsible for any errors you make in
administering drugs mentioned on this page, nor for use of any
erroneous information contained on this page.
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