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Angiotensin-converting Enzyme (ACE Inhibitors and Hydrochlorothiazide Systemic)

This monograph includes information on the following:

1) Benazepril and Hydrochlorothiazide  
2) Captopril and Hydrochlorothiazide 
3) Enalapril and Hydrochlorothiazide
4) Lisinopril and Hydrochlorothiazide
5) Moexipril and Hydrochlorothiazide  
6) Quinapril and Hydrochlorothiazide

VA CLASSIFICATION
Primary: CV408
Secondary: CV800; CV701

Commonly used brand name(s): Accuretic6; Capozide2; Lotensin HCT1; Prinzide4; Uniretic5; Vaseretic3; Zestoretic4.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antihypertensive—

vasodilator, congestive heart failure—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Hypertension (treatment)—The combination of benazepril, captopril, enalapril, lisinopril, moexipril, or quinapril and hydrochlorothiazide is indicated in the treatment of hypertension. {42} {43} {45} {49} {50} {57}{58}
—Fixed-dosage combinations generally are not recommended for initial therapy, but are utilized in maintenance therapy after the required dose is established in order to increase convenience, economy, and patient compliance.
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.

[Congestive heart failure (treatment) 1]—Captopril, enalapril, or lisinopril plus a diuretic, such as hydrochlorothiazide, and a digitalis glycoside are also used for treatment of severe congestive heart failure not responding to other measures. {51} {53} {54}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Benazepril: 460.96{42}
    Captopril: 217.28 {57}
    Chlorothiazide: 295.72
    Enalapril: 492.52 {43}
    Enalaprilat (active metabolite): 384.43 {43}
    Hydrochlorothiazide: 297.73 {42}
    Lisinopril: 441.52 {45}
    Moexipril: 535.04 {49}
    Quinapril: 474.98{58}

pKa—
    Captopril: 3.7 and 9.8 (apparent)
    Chlorothiazide: 6.7 and 9.5
    Hydrochlorothiazide: 7.9 and 9.2

Mechanism of action/Effect:


ACE inhibitors:

Activity of benazepril, enalapril, moexipril, and quinapril is due to the active metabolites benazeprilat, enalaprilat, moexiprilat, and quinaprilat respectively. {42} {43} {49} {50}

Antihypertensive: Exact mechanism of antihypertensive action is unknown but is thought to be related to competitive inhibition of angiotensin I–converting enzyme (ACE) activity, resulting in a decreased rate of conversion of angiotensin I to angiotensin II, which is a potent vasoconstrictor. Decreased angiotensin II concentrations result in a secondary increase in plasma renin activity (PRA), through removal of the negative feedback of renin release, and a direct reduction in aldosterone secretion. ACE inhibitors may be less effective in controlling blood pressure among low-renin hypertensive patients, predominantly among the black patient population, as compared to normal- or high- renin hypertensive patients. {42} {57} ACE inhibitors reduce peripheral arterial resistance. In addition, a possible effect on the kallikrein-kinin system (interference with degradation and resulting increased concentrations of bradykinin) and an increase in prostaglandin synthesis have been suggested but not proven.

Vasodilator, congestive heart failure: Decrease in peripheral vascular (afterload) resistance, pulmonary capillary wedge pressure (preload), and pulmonary vascular resistance; and improved cardiac output and exercise tolerance.



Thiazide diuretics:

Diuretic: Thiazide diuretics increase urinary excretion of sodium and water by inhibiting sodium reabsorption in the early distal tubules. They increase the rate of delivery of tubular fluid and electrolytes to the distal sites of hydrogen and potassium ion secretion, while plasma volume contraction increases aldosterone production. The increased delivery and increase in aldosterone levels promote sodium reabsorption at the distal tubules, thus increasing the loss of potassium and hydrogen ions. {25} {26}

Antihypertensive: Diuretics lower blood pressure initially by reducing plasma and extracellular fluid volume; cardiac output also decreases. Eventually, cardiac output returns to normal. Thiazide diuretics decrease peripheral resistance by a direct peripheral effect on blood vessels. {03} {04}


Absorption:

Benazepril—Approximately 37%; not affected by the presence of food. {42}

Captopril—Rapidly and at least 75% absorbed from the gastrointestinal tract. Absorption is reduced by 30 to 40% in the presence of food. {57}

Enalapril—Approximately 60%; not affected by the presence of food. {43}

Hydrochlorothiazide—Absorbed relatively rapidly after oral administration. {42}

Lisinopril—Approximately 25%, but widely variable between individuals (6 to 60%); not affected by the presence of food. {45}

Moexipril—Approximately 13%. Absorption is reduced by 40 to 50% in the presence of food. {49}

Quinapril—Approximately 60%. {50} Absorption rate is reduced by 14% when administered during a high fat meal, but extent of absorption is unchanged. {58}

Protein binding:

Benazeprilat (active metabolite)—Very high (95.3%). {42}

Captopril—Low (25 to 30%), primarily to albumin. {57}

Enalaprilat (active metabolite)—Moderate (50 to 60%).

Lisinopril—None.

Moexiprilat—Moderate (50%). {49}

Quinaprilat—Very high (97%). {50}

Biotransformation:

Benazepril—Hepatic, by de-esterification, to benazeprilat, the active metabolite. {42}

Captopril—Hepatic.

Enalapril—Hepatic, by hydrolysis, to enalaprilat, the active metabolite. {43}

Lisinopril—None. {45}

Moexipril—Rapidly converted to moexiprilat, the active metabolite in organs or tissues other than the gastrointestinal tract, in which carboxyesterases occur. {49}

Quinaprilat—De-esterified to quinalaprilat. {50}

Half-life:

Benazepril—10 to 11 hours. {42}

Captopril—Less than 3 hours; increased in renal failure (3.5 to 32 hours). {51}

Enalaprilat (active metabolite)—11 hours; increased in renal failure. {43}

Hydrochlorothiazide—5.6 to 14.8 hours.

Lisinopril—12 hours; increased in renal failure. {45}

Moexipril—Approximately 12 hours; increased in renal failure by a factor of 3 or 4. {49}

Quinaprilat—25 hours; increased in renal failure. {50}

Onset of action:


Single dose:

Benazepril: Less than 1 hour. {42}

Captopril: 15 to 60 minutes. {57}

Enalapril: 1 hour. {43}

Lisinopril: 1 hour. {45}

Moexipril: 1 hour. {49}

Quinapril: 1 hour. {50}


Time to peak serum concentration

Benazepril—30 to 60 minutes (1 to 2 hours for benazeprilat in a fasting state and 2 to 4 hours in a nonfasting state). {42}

Captopril—30 to 90 minutes. {57}

Enalapril—1 hour (3 to 4 hours for enalaprilat). {43}

Lisinopril—7 hours. {45}

Moexipril—0.8 hour (1.6 hours for moexiprilat). {49}

Quinapril—2 hours. {50}

Time to peak effect:


Single dose:

Benazepril: 2 to 4 hours. {42}

Captopril: 60 to 90 minutes. {57}

Enalapril: 4 to 6 hours. {43}

Lisinopril: 6 hours. {45}

Moexipril—3 to 6 hours. {49}

Quinapril—2 to 4 hours. {50}



Multiple doses:

The full therapeutic effect of ACE inhibitors may not be noticed until several weeks after initiation of oral therapy. {42} {43} {50} {49} The antihypertensive effects of hydrochlorothiazide may be noted after 3 to 4 days of therapy, although up to 3 to 4 weeks may be required for optimal effect.


Duration of action:


Single-dose:

Benazepril: Approximately 24 hours. {42}

Captopril: Approximately 6 to 12 hours; dose related. {57}

Enalapril: Approximately 24 hours. {43}

Hydrochlorothiazide: Antihypertensive effects persist for up to 1 week after withdrawal of therapy. {42}

Lisinopril: Approximately 24 hours. {45}

Moexipril: Approximately 24 hours. {49}

Quinapril: Approximately 24 hours. {50}


Elimination:


Benazepril—
        Renal: Approximately 90%. {42}
        Fecal: 11–12% az benazeprilat. {42}
        In dialysis: Only 6% is removed as benazeprilat. {42}



Captopril—
        Renal: More than 95%; 40 to 50% unchanged (may be less in patients with congestive heart failure); with the remainder as metabolites. {57}
        In dialysis: Captopril is removable by hemodialysis. {57}



Enalapril—
        Renal: 60% (20% as enalapril and 40% as enalaprilat).
        Fecal: 33% (6% as enalapril and 27% as enalaprilat).
        In dialysis: Enalaprilat is removable by hemodialysis, at the rate of 62 mL per minute, and by peritoneal dialysis. {43}



Hydrochlorothiazide—
        Unchanged; almost totally via the kidneys, with minute quantities in the bile. {57}



Lisinopril—
        Renal, 100% unchanged. {45}
        In dialysis: Lisinopril is removable by hemodialysis.



Moexipril—
        Renal: 13% (1% as moexipril, 7% as moexiprilat, and 5% as other metabolites). {49}
        Fecal: 53% (52% as moexiprilat and 1% as moexipril). {49}
         In dialysis: It is not known whether moexipril is dialyzable. {49}



Quinapril—
        Renal, 96% as quinaprilat. {58}
        In dialysis: Hemodialysis has little effect on the elimination of quinapril and quinaprilat. {58}



Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to one ACE inhibitor may also be sensitive to another. {57}

Patients sensitive to other sulfonamide-type medications, bumetanide, furosemide, or carbonic anhydrase inhibitors may be sensitive to hydrochlorothiazide also. {57}

Carcinogenicity

Benazepril—Two-year study in rats and mice at doses of up to 150 mg per kg of body weight per day showed no evidence of carcinogenicity. {42}

Captopril—Two-year studies in mice and rats at doses of 50 to 1350 mg per kg of body weight (mg/kg) per day showed no evidence of carcinogenicity.

Enalapril—Studies in rats for 106 weeks and in mice for 94 weeks at doses up to 150 and 300 times the maximum daily human dose (based on a patient weight of 50 kg), respectively, found no evidence of tumorigenicity or carcinogenicity.

Hydrochlorothiazide— No evidence of carcinogenicity was found in female mice given daily dietary doses of up to 600 mg per kg of body weight (mg/kg) for 2 years, or in rats given daily dietary doses of up to 100 mg/kg of hydrochlorothiazide for 2 years {49}. However, evidence of hepatocarcinogenicity occurred in male mice given the same dose as that given to the female mice. {49}

Lisinopril—Studies in male and female rats for 105 weeks at doses up to 56 times the maximum recommended human daily dose (based on a patient weight of 50 kg) and in male and female mice for 92 weeks at doses up to 84 times the maximum recommended human daily dose (based on a patient weight of 50 kg) found no evidence of tumorigenicity.

Moexipril—No evidence of carcinogenicity was found in long-term studies in mice and rats given doses of up to 14 or 27.3 times the maximum recommended human dose (MRHD) on a mg per square meter of body surface area (mg/m 2) basis. {49}

Mutagenicity

Benazepril—No evidence of mutagenicity was found in tests including the Ames test in bacteria with or without metabolic activation, in an in vitro test for forward mutations in cultured mammalian cells, or in a nucleus anomaly test. {42}

Captopril—No evidence of mutagenicity was found in tests including the Ames bacterial reverse-mutation assay with or without metabolic activation, in a forward mutation study in bacteria, and in a sister-chromatid exchange study in human lymphocytes. {57}

Enalapril—No evidence of mutagenicity was found in tests including the Ames bacterial assay with or without metabolic activation, rec-assay, reverse mutation assay with E. coli , sister chromatid exchange with cultured mammalian cells, the micronucleus test with mice, and in an in vivo cytogenic study using mouse bone marrow. {06}

Hydrochlorothiazide—No evidence of genotoxicity of hydrochlorothiazide was found in in vitro assays using multiple strains of Salmonella typhimurium (the Ames test); in the CHO test for chromosomal aberrations; or in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene {49}. Hydrochlorothiazide was found to be clastogenic in the in vitro CHO sister chromatid exchange test and mutagenic in the mouse lymphoma cell assays, using concentrations of hydrochlorothiazide of 43 to 1300 micrograms per mL (mcg/mL). {49} Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using hydrochlorothiazide at an unspecified concentration. {49}

Lisinopril—No evidence of mutagenicity was found in tests including the Ames bacterial assay with or without metabolic activation, forward mutation assay using Chinese hamster lung cells, in vitro alkaline elution rat hepatocyte assay, and chromosomal aberration studies in vitro in Chinese hamster ovary cells and in vivo in mouse bone marrow. {45}

Moexipril—No evidence of mutagenicity was found in the Ames test and microbial reverse mutation assay, with and without activation, or in an in vivo nucleus anomaly test. {49} However, under metabolic activation conditions at a 20-hour harvest time, increased frequency of chromosomal aberration was detected in Chinese hamster ovary cells. {49}

Pregnancy/Reproduction
Fertility—
Benazepril: No adverse effects were found in the reproductive performance of male and female rats. {42}

Captopril: No impairment of fertility was found in rats. {05}

Enalapril: No adverse effects on reproductive performance were found in male and female rats given enalapril in doses of 10 to 90 mg/kg per day. {06}

Hydrochlorothiazide: No evidence of impaired fertility was found in studies in mice and rats given daily dietary doses prior to mating and throughout gestation of up to 100 and 4 mg/kg of hydrochlorothiazide, respectively. {49}

Lisinopril: No adverse effects on reproductive performance were found in male and female rats given lisinopril in doses up to 300 mg/kg per day. {07}

Moexipril: No evidence of impaired fertility, reproductive toxicity, or teratogenicity was detected in studies performed in rabbits and rats given oral doses of moexipril of up to 0.7 and 90.9 times the MRHD, respectively, on a mg/m 2 basis {49}

Quinapril: No impairment of fertility were found in rats given doses up to 100 mg/kg per day. {50}

Pregnancy—
Adequate and well-controlled studies have not been done with ACE inhibitors in humans. However, ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. {57} ACE inhibitors should be discontinued as soon as possible when pregnancy is detected. {05} {07}

Fetal exposure to ACE inhibitors during the second and third trimesters can cause hypotension {08} {09} {11} {50} {57}, renal failure {08} {12}, anuria {08} {12} {50} {57}, skull hypoplasia {08} {09} {50} {57}, and even death {08} {09} {11} {12} {57} in the newborn. Maternal oligohydramnios has also been reported, probably reflecting decreasing fetal renal function. Enalapril and lisinopril have been removed from neonatal circulation by peritoneal dialysis. {43} {45} Captopril is not removable by peritoneal dialysis. {57} There is inadequate data concerning the effectiveness of hemodialysis and there is no information concerning use of exchange transfusion for removing captopril from general circulation. It is recommended that infants exposed in utero to ACE inhibitors be closely observed for hypotension, oliguria, and hyperkalemia. {45} Oliguria should be treated with support of blood pressure and renal perfusion by administration of fluids and pressors as appropriate. {45}


Benazepril

Benazepril crosses the placenta. {42}

No teratogenic effects were seen when benazepril and hydrochlorothiazide were administered to pregnant rats, mice, and rabbits administered 300 times, 90 times, and 3 times, respectively, the maximum recommended human dose on a mg per kg basis. {42}



Captopril

Captopril crosses the placenta. Several cases of intrauterine growth retardation, fetal distress and hypotension, and one case of cranial malformation have been reported in humans. {57}

Fetal deaths have occurred when rabbits were given 2 to 70 times the maximum recommended human dose and a low incidence of cranial malformations occurred in offspring. {57} Neonatal deaths have occurred in rats at up to 400 times the recommended human dose. No teratogenicity has been noted in hamsters or rats. {57}



Enalapril

Enalapril crosses the placenta.

Fetal toxicity (decrease in average fetal weight) has occurred in rats at doses of enalapril 2000 times the maximum daily human dose, and maternal and fetal toxicity has occurred in rabbits at doses almost double the maximum daily human dose. In some cases, saline supplementation prevented maternal and fetal toxicity. No teratogenicity has been noted in rabbits and neither fetal toxicity nor teratogenicity occurred in rats at doses up to 333 times the maximum daily human dose.



Hydrochlorothiazide

Thiazide diuretics cross the placenta and appear in cord blood. Although studies in humans have not been done, thiazide diuretics can cause fetal harm when given to pregnant women. Fetal or neonatal jaundice has been reported. {06} {07}

Studies in rabbits, mice, and rats at doses up to 100 mg/kg per day (50 times the maximum recommended human dose) have not shown that hydrochlorothiazide causes adverse effects on the fetus.



Lisinopril

Lisinopril was not teratogenic in mice given doses up to 625 times the maximum recommended human dose on days 6 to 15 of gestation; an increase in fetal resorptions occurred at doses of 62.5 times the maximum recommended human dose, but was prevented at doses of 625 times the maximum recommended human dose by saline supplementation. {45} No fetotoxicity or teratogenicity occurred in rats given doses up to 188 times the maximum recommended human dose on days 6 to 17 of gestation, but an increased incidence of pup deaths and a lower average birth weight (both preventable by saline supplementation) occurred postpartum in rats given lisinopril on day 15 of gestation through day 21 postpartum. {45} Lisinopril crosses the placenta in rats but has not been found in the fetus. {45} Lisinopril did not cause teratogenicity in saline-supplemented rabbits given doses up to 1 mg/kg per day, but did cause fetotoxicity (increased fetal resorptions, increased incidence of incomplete ossification). {45}



Moexipril

No embryotoxic, fetotoxic, or teratogenic effects were seen in rats or in rabbits treated with up to 90.9 and 0.7 times, respectively, the MRHD on a mg/m 2 basis. {55}

The moexipril and hydrochlorothiazide combination was not teratogenic in rats given up to the lethal dose of 800 mg/kg per day, or in rabbits given up to the maternotoxic dose of 160 mg/kg per day {49}



Quinapril

Quinapril was not teratogenic in rats given doses up to 180 times the maximum daily human dose. {50} However, offspring body weights were reduced in rats treated late in gestation and during lactation with doses of 25 mg/kg per day. {50} No teratogenicity was found in rabbits. {50} However, maternal and embryo toxicity were seen in some rabbits at doses of 0.5 to 1 mg/kg per day. {50}



Angiotensin-converting enzyme (ACE) inhibitors and hydrochlorothiazide combinations:

FDA Pregnancy Category C: First trimester. {05} {06} {07} {42} {49} {58}

FDA Pregnancy Category D: Second and third trimesters. {05} {06} {07} {42} {49} {58}


Breast-feeding

Benazepril—Benazepril is distributed into breast milk in concentrations of approximately 0.1% of the maternal dose. {42} However, problems in humans have not been documented. {42}

Captopril—Captopril is distributed into breast milk; concentrations in breast milk are approximately 1% of maternal blood concentrations. {57} However, problems in humans have not been documented. {57}

Enalapril—Enalapril is distributed into breast milk. {43} However, problems in humans have not been documented. {43}

Hydrochlorothiazide—Thiazide diuretics are distributed into breast milk. {43} However, problems in humans have not been documented. {43}

Lisinopril—It is not known whether lisinopril is distributed into human breast milk. {45} However, problems in humans have not been documented. {45} Lisinopril appears to be distributed into the milk of rats. {45}

Moexipril—It is not known whether moexipril or moexiprilat is distributed into breast milk. {49} However, problems in humans have not been documented. {49}

Quinapril—Quinapril is distributed into breast milk. {58} However, problems in humans have not been documented. {50} {58}

Pediatrics

Benazepril—Safety and efficacy in pediatric patients have not been established. {42}

Captopril, enalapril, and lisinopril—Appropriate studies on the relationship of age to the effects of ACE inhibitors have not been done in the pediatric population. However, the use of ACE inhibitors in a limited number of neonates and infants has identified some potential pediatrics-specific problems. In neonates and infants, there is a risk of oliguria and neurologic abnormalities, possibly as a result of decreased renal and cerebral blood flow secondary to marked and prolonged reductions in blood pressure caused by ACE inhibitors {13} {16}; a lower initial dose and close monitoring are recommended.

Hydrochlorothiazide—Although appropriate studies on the relationship of age to the effects of hydrochlorothiazide have not been performed in the pediatric population, pediatrics-specific problems that would limit the usefulness of this medication in children are not expected. However, caution is required in jaundiced infants because of the risk of hyperbilirubinemia.

Moexipril—Safety and efficacy in pediatric patients have not been established. {49}

Quinapril—Safety and efficacy in pediatric patients have not been established. {58}


Geriatrics


Benazepril, captopril, enalapril, lisinopril, moexipril, and quinapril—ACE inhibitors are thought to be most effective in reducing blood pressure in patients with normal or high plasma renin activity. Since plasma renin activity appears to decline with increasing age, elderly individuals may be less sensitive to the hypotensive effects of ACE inhibitors. However, elevated serum ACE inhibitor concentrations resulting from age-related decline in renal function may compensate for the lower renin dependence {18} {24}. Pharmacokinetic studies with lisinopril and moexipril have revealed higher peak serum concentrations and area under the curve (AUC) in elderly patients given doses similar to those given to younger adults. {45} {49} The net result is that no significant differences in blood pressure response or side/adverse effects have been noted in elderly patients receiving ACE inhibitors. {17} {18} {19} {20} {21} {22} {23} {42} {49} {50} Nevertheless, some elderly patients may be more sensitive to the hypotensive effects of these medications and may require caution when receiving an ACE inhibitor. {42} {45}

Hydrochlorothiazide—Although appropriate studies on the relationship of age to the effects of hydrochlorothiazide have not been performed in the geriatric population, the elderly may be more sensitive to the hypotensive and electrolyte effects. In addition, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving hydrochlorothiazide.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol or
» Diuretics or
Hypotension-producing medications,{42}{45}{49}{50} other (see Appendix II )    (hypotensive effects may be potentiated when these medications are used concurrently with ACE inhibitors and hydrochlorothiazide; although some antihypertensive and/or diuretic combinations are frequently used for therapeutic advantage, dosage adjustments may be necessary during concurrent use {42})

    (antihypertensive agents that cause renin release or affect sympathetic activity have the greatest additive effect; concurrent use of captopril with beta-adrenergic blocking agents produces an increased but less than fully additive effect; although some antihypertensive and/or diuretic combinations may be used for therapeutic advantage, dosage adjustments may be necessary during concurrent use or when one drug is discontinued {42} {49})

    (if significant systemic absorption of ophthalmic beta-blockers occurs, hypotensive effects of ACE inhibitors may be potentiated)

    (sudden and severe hypotension may occur within the first 1 to 5 hours after the initial dose of an ACE inhibitor, particularly in patients who are sodium- and volume-depleted as a result of diuretic therapy. Withdrawal of the diuretic or increase of salt intake approximately 1 week before start of captopril therapy or 2 to 3 days before start of benazepril, enalapril, lisinopril, moexipril, or quinapril therapy, or initiating ACE inhibitor therapy in lower doses, will minimize the reaction; this reaction does not usually recur with subsequent doses, although caution in increasing doses is recommended; diuretics may be reinstituted as necessary {42} {49} {50})

    (risk of renal failure may be increased in patients who are sodium- and volume-depleted as a result of diuretic therapy {42} {50})

    (ACE inhibitors may reduce the secondary aldosteronism and hypokalemia caused by diuretics {42} {49} {50})


Amantadine    (hydrochlorothiazide may reduce the renal clearance of amantadine, resulting in increased plasma concentrations and possible amantadine toxicity {30})


Amiodarone    (concurrent use of thiazide diuretics with amiodarone may lead to an increased risk of arrhythmias associated with hypokalemia {57})


Anticoagulants, coumarin- or indandione-derivative{57}    (anticoagulant effects may be decreased when used concurrently with thiazide diuretics as a result of reduction of plasma volume leading to concentration of procoagulant factors in the blood; in addition, diuretic-induced improvement of hepatic congestion may lead to improved hepatic function resulting in increased procoagulant factor synthesis; dosage adjustments may be necessary)


Antidiabetic agents, oral or
Insulin    (thiazide diuretics may raise blood glucose concentrations; for adult-onset diabetics, dosage adjustment of hypoglycemic medications may be necessary during and after thiazide diuretic therapy; insulin requirements may be increased, decreased, or unchanged {42} {49})


Anti-inflammatory drugs, nonsteroidal (NSAIDs), especially indomethacin    (concurrent use of these agents may reduce the antihypertensive effects of ACE inhibitors and hydrochlorothiazide; indomethacin, and possibly other NSAIDs, may antagonize the antihypertensive effect by inhibiting renal prostaglandin synthesis and/or causing sodium and fluid retention; the patient should be carefully monitored to confirm that the desired effect is being obtained {42} {49})

    (in addition, concurrent use of NSAIDs with a diuretic may increase the risk of renal failure secondary to a decrease in renal blood flow caused by inhibition of renal prostaglandin synthesis)


Blood from blood bank (may contain up to 30 mEq [mmol] of potassium per liter of plasma or up to 65 mEq [mmol] per liter of whole blood when stored for more than 10 days) or
Cyclosporine or
» Diuretics, potassium-sparing or
» Low-salt milk (may contain up to 60 mEq [mmol] of potassium per liter) or
» Potassium-containing medications or
» Potassium supplements or substances containing high concentrations of potassium or
» Salt substitutes (most contain substantial amounts of potassium){42}{45}{49}{57}    (concurrent administration with ACE inhibitors may result in hyperkalemia since reduction of aldosterone production induced by ACE inhibitors may lead to elevation of serum potassium; frequent determination of serum potassium concentrations is recommended if concurrent use of these agents is necessary; concurrent use is not recommended in patients with congestive heart failure {42} {49})


Bone marrow depressants (See Appendix II )    (concurrent administration with an ACE inhibitor may result in an increased risk of development of potentially fatal neutropenia and/or agranulocytosis)


Calcium-containing medications    (concurrent use of hydrochlorothiazide with large doses of calcium may result in hypercalcemia because of reduced calcium excretion)


» Cholestyramine or
» Colestipol    (may inhibit gastrointestinal absorption of hydrochlorothiazide; administration of hydrochlorothiazide 1 hour before or 4 hours after cholestyramine or colestipol is recommended {42} {49} {50})


Corticosteroids or
Adrenocorticotropic hormone (ACTH)    (concurrent use with hydrochlorothiazide may intensify electrolyte depletion, particularly hypokalemia {45})


Diazoxide    (concurrent use with thiazide diuretics may enhance hyperglycemic effects; monitoring of blood glucose levels and/or dosage adjustment of one or both agents may be necessary {43})


Diflunisal    (concurrent use of hydrochlorothiazide with diflunisal produces significantly increased plasma concentrations of hydrochlorothiazide; in addition, the hyperuricemic effect of hydrochlorothiazide is decreased)


» Digitalis glycosides    (concurrent use with hydrochlorothiazide may enhance the possibility of digitalis toxicity associated with hypokalemia {42} {49} {50})


Dopamine    (concurrent use may increase the diuretic effect of either hydrochlorothiazide or dopamine, as a result of dopamine's direct effect on dopaminergic receptors to produce vasodilation of renal vasculature and increase renal blood flow; dopamine also has a direct natriuretic effect)


» Lithium{42}{49}{50}    (concurrent use with hydrochlorothiazide is not recommended, as it may provoke lithium toxicity because of reduced renal clearance caused by thiazides; in addition, lithium has nephrotoxic effects {42})

    (reversible increases in serum lithium concentrations and toxicity have been reported during concurrent use with ACE inhibitors; caution and frequent monitoring of serum lithium concentrations are recommended during concurrent use)


Neuromuscular blocking agents, nondepolarizing    (hydrochlorothiazide may induce hypokalemia, which may enhance the blockade of nondepolarizing neuromuscular blocking agents; serum potassium determinations may be necessary prior to administration of nondepolarizing neuromuscular blocking agents; careful postoperative monitoring of the patient may be necessary following concurrent or sequential use, especially if there is a possibility of incomplete reversal of neuromuscular blockade {49} {57})


Sympathomimetics{42}{49}{50} , such as:
» Cocaine
Dobutamine
Dopamine
Ephedrine
Epinephrine
Mephentermine
Metaraminol
Methoxamine
» Norepinephrine
» Phenylephrine
Phenylpropanolamine    (may antagonize the antihypertensive effect of ACE inhibitors and hydrochlorothiazide {42}; the patient should be carefully monitored to confirm that the desired effect is being obtained; if concurrent use of cocaine, norepinephrine, or phenylephrine is indicated, caution is required, and only very small initial doses should be administered)


» Tetracycline{50}    (concurrent use with quinapril reduces the absorption of tetracycline in healthy volunteers by 28 to 37% due to the presence of magnesium carbonate as an excipient in the formulation)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Bentiromide    (administration of hydrochlorothiazide during a bentiromide test period will invalidate test results since thiazide diuretics are also metabolized to arylamines and will thus increase the percent of para-aminobenzoic acid [PABA] recovered; discontinuation of hydrochlorothiazide at least 3 days prior to the administration of bentiromide is recommended)


Iodohippurate sodium I 123/I 131 renal imaging or
Technetium Tc 99m pentetate renal imaging    (in patients with renal artery stenosis, captopril [and probably enalapril and lisinopril also] may cause a reversible decrease in localization and excretion of iodohippurate I 123/I 131 or technetium Tc 99m pentetate in the affected kidney; may cause confusion as to whether decreased renal function is drug-related)


Urinary acetone test    (captopril may produce false-positive results {57})

With physiology/laboratory test values
Alkaline phosphatase, serum and
Bilirubin, serum and
Transaminase, serum    (concentration increases have been reported with ACE inhibitors {49})

    (serum bilirubin concentrations may be increased by displacement from albumin binding by hydrochlorothiazide)


Antinuclear antibody (ANA) titer    (positive ANA has been reported {06} {07})


Blood urea nitrogen (BUN) and
Creatinine, serum    (concentrations may be transiently increased by ACE inhibitors, especially in patients with renal parenchymal and renovascular disease in patients who are volume- or sodium-depleted, or after rapid reduction of long-standing or severe high blood pressure {42} {49} {50})


Calcium, serum    (concentrations may be increased by hydrochlorothiazide; hydrochlorothiazide should be discontinued before parathyroid function tests are carried out {49})


Calcium, urinary    (concentrations may be decreased by hydrochlorothiazide)


Cholesterol, low-density lipoprotein, and triglyceride{42}{50}    (serum concentrations may be increased by hydrochlorothiazide)


Glucose, blood and urine    (concentrations may be increased by hydrochlorothiazide, usually only in patients with a predisposition to glucose intolerance {42} {49} {50})


Hematocrit or
Hemoglobin    (may rarely be slightly decreased by ACE inhibitors {43})


Magnesium    (serum concentrations may be decreased by hydrochlorothiazide; serum magnesium concentrations may increase in uremic patients {49})


Potassium    (although the effects by ACE inhibitors and hydrochlorothiazide on serum potassium may counterbalance each other, serum potassium concentrations should be monitored initially and periodically to detect imbalances; serum concentrations may be slightly increased by ACE inhibitors as a result of reduced circulating aldosterone concentrations and concomitant reduction in glomerular filtration rate [GFR], especially in patients with renal function impairment; may be decreased by hydrochlorothiazide {49})


Protein-bound iodine (PBI){42}{50}    (serum concentrations may be decreased by the ACE inhibitor and hydrochlorothiazide combination without signs of thyroid disturbances; hydrochlorothiazide should be discontinued before parathyroid function tests are carried out)


Sodium    (serum concentrations may be slightly decreased by ACE inhibitors, especially during initial therapy, and by hydrochlorothiazide {42} {49})


Uric acid    (serum concentrations may be increased by hydrochlorothiazide {42} {49} {50})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Angioedema, history of, related to previous ACE inhibitor therapy or{05}{06}{07}{42}{49}{50}
» Hereditary angioedema{31} or
» Idiopathic angioedema{32}{33}{42}    (increased risk of development of ACE inhibitor–related angioedema)


» Anuria or severe renal function impairment{42}{50}    (hydrochlorothiazide may aggravate this condition)


» Hypersensitivity to any ACE inhibitors, hydrochlorothiazide, or other sulfonamide-derived medications like hydrochlorothiazide{42}{49}{50}
Risk-benefit should be considered when the following medical problems exist
Autoimmune disease, severe, especially systemic lupus erythematosus (SLE) or scleroderma{42}{50}    (increased risk of development of neutropenia or agranulocytosis)


Bone marrow depression—for ACE inhibitors
Cerebrovascular insufficiency or
Coronary insufficiency    (ischemia may be aggravated as a result of reduced blood pressure; cerebrovascular accident or myocardial infarction could be precipitated {42} {49})


Diabetes mellitus    (increased risk of hyperkalemia with ACE inhibitors; hypoglycemic medication requirements may be altered by hydrochlorothiazide)

{42}{49}{50}
Gout, history of or
Hyperuricemia{42}{49}{50}    (serum uric acid concentrations may be elevated by hydrochlorothiazide)


Hepatic function impairment{42}{49}    (reduced breakdown of captopril and reduced conversion of enalapril to enalaprilat)

    (risk of dehydration with hydrochlorothiazide, which may precipitate hepatic coma and death; plasma half-life is unaltered)


Hypercalcemia—for hydrochlorothiazide{42}
» Hyperkalemia—for ACE inhibitors{42}{50}
Hyponatremia—for hydrochlorothiazide{42}{50}
Lupus erythematosus, history of    (exacerbation or activation by thiazide diuretics has been reported {42} {49} {50})


Pancreatitis—for hydrochlorothiazide
» Renal artery stenosis, bilateral or in a solitary kidney{50} or
» Renal transplant    (increased risk of renal function impairment caused by captopril or enalaprilat)


» Renal function impairment{42}{49}{50}    (retention of captopril, enalaprilat, or lisinopril occurs; increased risk of hyperkalemia or, for captopril, proteinuria, neutropenia, and agranulocytosis. Patients with impaired renal function may require lower or less frequent doses and smaller increments in dose. If a diuretic is also required, a loop diuretic is recommended instead of a thiazide diuretic in patients with severe renal function impairment)


Sensitivity to the ACE inhibitor prescribed or to hydrochlorothiazide{42}{50}
Sympathectomy    (antihypertensive effects of hydrochlorothiazide may be enhanced)


» Caution is required also in patients on severe dietary sodium restriction or dialysis; these patients may be volume-depleted, and sudden reduction by the initial dose of ACE inhibitor in the angiotensin II levels that have been maintaining them at a near-normotensive state may result in sudden and severe hypotension. In addition, the risk of ACE inhibitor–induced renal failure may be increased in patients who are sodium- and volume-depleted, especially those with congestive heart failure.{42}{49}{50}
» Caution is required also in jaundiced infants because of the risk of hyperbilirubinemia caused by thiazide diuretics.

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood glucose concentrations and
Blood urea nitrogen (BUN) concentrations and
Uric acid concentrations, serum{50}    (recommended prior to initiation of hydrochlorothiazide therapy and if clinical signs of a significant increase occur)


» Blood pressure measurements{42}{49}{50}    (recommended at periodic intervals in patients being treated for hypertension; selected patients may be trained to perform blood pressure measurements at home and report the results at regular physician visits)


Cholesterol, serum and
Triglycerides, serum{50}    (determinations recommended after 6 months of therapy and annually thereafter)


Electrolyte concentrations, serum{42}{49}{50}    (may be required for patients on long-term hydrochlorothiazide therapy, especially if they are also taking cardiac glycosides or systemic steroids, or when severe cirrhosis is present)


Leukocyte count determinations, total and differential{42}{49}    (recommended prior to initiation of ACE inhibitor therapy and periodically thereafter; recommended every month for the first 3 to 6 months of therapy, and at periodic intervals thereafter for a period of up to 1 year in patients at increased risk for neutropenia [i.e., those with renal function impairment or collagen vascular disease] or receiving high doses; also recommended at the first sign of infection. It is recommended that ACE inhibitor therapy be withdrawn if neutropenia [neutrophil count less than 1000 per cubic millimeter (1 × 10 9/L)] is confirmed)


Renal function determinations{42}{49}{50}    (recommended at periodic intervals in patients receiving ACE inhibitors, especially in patients who are sodium- and volume-depleted as a result of diuretic therapy or who have severe congestive heart failure)


Urinary protein estimates by means of dip-stick on first morning urine    (recommended prior to initiation of ACE inhibitor therapy and at periodic intervals thereafter for up to 1 year in patients with renal function impairment or those receiving doses of captopril greater than 150 mg per day [data with high doses of enalapril or lisinopril are not available]; if excessive or increasing proteinuria occurs, it is recommended that ACE inhibitor therapy be re-evaluated)




Side/Adverse Effects

Note: Proteinuria has occurred in about 1% of patients receiving greater than 150 mg of captopril per day. This adverse effect is thought to be due to the sulfhydryl moiety of captopril. {27} However, whether this is a true causal relationship is unknown. {27} Proteinuria usually occurs in patients with existing renal function impairment within 8 months of initiation of captopril therapy and usually reverses within 6 months even with continuation of therapy. Membranous glomerulopathy has been reported in some of these patients, especially with doses of captopril greater than 150 mg per day. Proteinuria has also been reported in patients receiving enalapril and lisinopril. {27} {29} Reported incidences range from 0% to 1.4% for enalapril and 0.7% for lisinopril. {27} {28} {29}
There have been reports of reversible renal failure during ACE inhibitor therapy, especially in patients with bilateral renal artery stenoses or renal artery stenosis in a solitary kidney. There is also evidence that renal failure may be related to sodium and volume depletion from previous diuretic therapy or severe sodium restriction, especially in patients with congestive heart failure.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Edema, peripheral {49} (swelling of ankles, feet, or legs)
    
hypotension (dizziness, lightheadedness, or fainting {49} {50})—especially following the initial dose in sodium- or volume-depleted patients or in patients receiving an ACE inhibitor for congestive heart failure
{42}    
skin rash, with or without itching, fever, or joint pain {49} {50}

Note: Maculopapular or, rarely, urticarial rash usually occurs during the first 4 weeks of the therapy with captopril and usually disappears with dosage reduction or withdrawal, or administration of an antihistamine; between 7 and 10% of these patients may show eosinophilia and/or positive antinuclear antibody (ANA) titers. The reaction may also occur, less frequently, with enalapril and lisinopril.
Rarely, a persistent lichenoid or pemphigoid reaction, possibly with a photosensitive factor, has been reported with captopril.
Skin rash or hives may also be a symptom of an allergic reaction to hydrochlorothiazide.


Incidence rare
    
Anaphylactoid reactions {49} (abnormal, high-pitched, breathing sounds; anxiety; blueness of the skin, including the lips or nail beds; confusion; generalized itching; heartbeat sensations; hives; wheezing or difficulty breathing )
    
Angioedema of the extremities, face, lips, mucous membranes, tongue, glottis, and/or larynx {42} {49} {58} ( sudden trouble in swallowing or breathing; swelling of face, mouth, hands, or feet; hoarseness)—especially following the initial dose
    
chest pain
    
cholecystitis or pancreatitis {50} (severe stomach pain with nausea and vomiting )
    
hepatic function impairment (yellow eyes or skin)
    
hyperuricemia or gout {42} {50} (joint pain; lower back or side pain)
    
neutropenia or agranulocytosis {50} (fever and chills {42})
    
thrombocytopenia (unusual bleeding or bruising )

Note: Angioedema involving the tongue, glottis, or larynx may cause airway obstruction, which could be fatal. {50}
Chest pain is usually associated with severe hypotension.
Incidence of neutropenia or agranulocytosis is much higher in patients with renal function impairment (0.2% for captopril) or collagen vascular disease (e.g., SLE or scleroderma) (3.7% for captopril). Neutropenia appears to be dose-related and may begin within 3 months after initiation of therapy, with the nadir of the leukocyte count occurring after 10 to 30 days and persisting about 2 weeks after withdrawal. Deaths from pancytopenia and sepsis have been reported with captopril in patients with and without autoimmune disease.


Signs and/or symptoms of electrolyte imbalance {42} {50}
    
Dryness of mouth
    
increased thirst
    
irregular heartbeat
    
mood or mental changes
    
muscle cramps or pain
    
numbness or tingling in hands, feet, or lips
    
weakness or heaviness of legs
    
weak pulse



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Cough, dry, persistent {49} {50}

Note: Persistent dry cough usually occurs within the first week of therapy (onset varies from 24 hours to several weeks after initiation), persists throughout therapy, and disappears within a few days after withdrawal of the ACE inhibitor. {49} Characteristically, the cough begins as a tickling sensation in the back of the throat leading to a dry, nonproductive, persistent cough; may be worse at night or in the supine position; onset can be paroxysmal and course may be episodic or intermittent; may occasionally lead to hoarseness or vomiting.


Incidence less frequent
    
Anorexia (loss of appetite)
    
diarrhea
    
headache {01}
    
photosensitivity {50} (increased sensitivity of skin to sunlight)
    
loss of taste
    
stomach upset
    
unusual tiredness

Note: Loss of taste is usually reversible after 2 to 3 months, even with continued ACE inhibitor treatment; may be associated with weight loss.






Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
Treatment of ACE inhibitor overdose consists of volume expansion for correction of hypotension with infusion of normal saline solution. {42} {49} Captopril, enalaprilat (enalapril active metabolite), and lisinopril are removable by hemodialysis. {43} {45} {57}

Thiazide diuretic overdose should be treated by immediate evacuation of the stomach with emesis and/or gastric lavage, followed by supportive, symptomatic treatment and monitoring of serum electrolyte concentrations and renal function. {49}

Monitoring renal function and serum electrolytes, including serum potassium, should be included in observing the patient. {49}


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Angiotensin-converting Enzyme (ACE) Inhibitors and Hydrochlorothiazide (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to any ACE inhibitor, thiazide diuretic, carbonic anhydrase inhibitor, or other sulfonamide-type medications

Pregnancy—ACE inhibitor-associated fetal hypotension, oliguria, and death reported in humans; and fetotoxicity found in animals; hydrochlorothiazide may cause jaundice, thrombocytopenia, hypokalemia in infant





Breast-feeding—Captopril, enalapril, quinapril, and hydrochlorothiazide are distributed into breast milk





Use in children—Caution if giving to infants with jaundice






Use in the elderly—May be more sensitive to hypotensive and electrolyte effects
Other medications, especially alcohol, cholestyramine, colestipol, diuretics (particularly potassium-sparing), potassium-containing medications, potassium supplements, low salt milk, salt substitutes, digitalis glycosides, lithium, cocaine, norepinephrine, phenylephrine, or tetracycline when quinapril is prescribed
Other medical problems, especially angioedema related to previous ACE inhibitor therapy, hereditary angioedema, idiopathic angioedema, hyperkalemia, renal artery stenosis, renal transplant, renal function impairment, or sodium and volume depletion

Proper use of this medication
Compliance with therapy; taking medication at the same time each day to maintain the therapeutic effect

Diuretic effects of the medication and timing of doses to minimize inconvenience of diuresis

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

For captopril and hydrochlorothiazide or moexipril and hydrochlorothiazide
For best results, taking on an empty stomach 1 hour before meals

For use as an antihypertensive
Possible need for control of weight and diet, especially sodium intake; risks associated with sodium depletion; not taking salt substitutes or using low-salt milk unless approved by physician

» Patient may not experience symptoms of hypertension; importance of taking medication even if feeling well

» Does not cure, but helps control hypertension; possible need for lifelong therapy; checking with physician before discontinuing medication; serious consequences of untreated hypertension

Precautions while using this medication
Making regular visits to physician to check progress

Caution when driving or doing other things requiring alertness, because of possible dizziness, especially with initial dose

To prevent dehydration and hypotension, checking with physician if severe nausea, vomiting, or diarrhea occurs and continues

Caution when exercising or during hot weather because of the risk of dehydration and hypotension due to reduced fluid volume

Caution if any kind of surgery (including dental surgery) or emergency treatment is required

Caution in using alcohol

Diabetics: May increase blood sugar levels

Possible photosensitivity; avoiding unprotected exposure to sun; using protective clothing and sun block product; avoiding use of sunlamp

Caution if any laboratory tests required; possible interference with test results

Notifying physician if there is any indication of infections, such as sore throat, fever, and/or chills, which could be a sign of neutropenia

For use as an antihypertensive
» Not taking other medications, especially nonprescription sympathomimetics, unless discussed with physician


Side/adverse effects
Signs of potential side effects, especially peripheral edema, hypotension, skin rash (with or without itching, fever, or joint pain), anaphylactic reactions, angioedema, chest pain, cholecystitis or pancreatitis, hepatic function impairment, hyperuricemia or gout, neutropenia or agranulocytosis, thrombocytopenia, and electrolyte imbalance.


General Dosing Information
Dosage must be adjusted to meet the individual requirements of each patient, on the basis of clinical response. {50}

Black hypertensive patients may be less responsive to ACE inhibitors due to having lower renin activity, and they have a greater risk of developing ACE inhibitor-induced angioedema. {49}

Fixed-dosage combinations generally are not recommended for initial therapy, but are utilized in maintenance therapy after the required dose is established in order to increase convenience, economy, and patient compliance. {42} {50}

The hypotensive effect of ACE inhibitors is the same in both standing and supine positions.

The lowest effective dosage of thiazide diuretics should be utilized to minimize potential electrolyte imbalance and the reflex increase in renin and aldosterone levels. {42} {49} {50}

If increased blood urea nitrogen (BUN) and creatinine concentrations occur, reduction in dosage of the ACE inhibitor and/or withdrawal of the diuretic may be required. {50} The possibility of renovascular hypertension should also be considered, especially in the presence of a solitary kidney, transplanted kidney, or bilateral renal artery stenosis.

Caution is recommended in initiating ACE inhibitor therapy for congestive heart failure in patients who have been receiving digitalis glycosides and/or diuretics. If the patient is sodium- and water-depleted, a lower initial dosage should be used. {50}

Concurrent administration of potassium supplements or potassium-sparing diuretics may be indicated in patients considered to be at higher risk for developing hypokalemia. Caution in administering potassium supplements is recommended, however, since loss of potassium caused by thiazide diuretics is not clinically significant in most patients and ACE inhibitors reduce diuretic-induced hypokalemia; supplementation leads to a risk of development of hyperkalemia. {50}

Recent evidence suggests that withdrawal of antihypertensive therapy prior to surgery is not necessary, but that the anesthesiologist must be aware of such therapy. If hypotension occurs during surgery, it may be corrected with volume expansion. {42}

If symptomatic hypotension occurs, dosage reduction or withdrawal of the ACE inhibitor or diuretic may be necessary.

For treatment of adverse effects
For angioedema with swelling confined to the face, mucous membranes of the mouth, lips, and extremities, treatment other than withdrawal of the medication {02} is usually not necessary, although antihistamines may relieve the symptoms {39}.
Treatment of angioedema involving the tongue, glottis, or larynx {39} {42} {50} may include the following:

   • Withdrawal of the ACE inhibitor and hospitalization of the patient.
   • Subcutaneous (or, rarely, intravenous) epinephrine.
   • Intravenous diphenhydramine hydrochloride.
   • Intravenous hydrocortisone.

BENAZEPRIL AND HYDROCHLOROTHIAZIDE

Summary of Differences


For benazepril:


Pharmacology/pharmacokinetics—
Absorption—Not affected by the presence of food.

Protein-binding—Very high (95.3%).

Elimination—Only slightly dialyzable, and dialysis is useful only in overdosed patients with severe renal impairment.




Oral Dosage Forms

BENAZEPRIL HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE TABLETS

Usual adult and adolescent dose
Antihypertensive
Oral, 1 tablet once daily as determined by titration of the individual agents.


Usual pediatric dose
Dosage has not been established

Strength(s) usually available
U.S.—


5 mg of benazepril and 6.25 mg of hydrochlorothiazide (Rx) [Lotensin HCT (scored) (lactose)]{42}


10 mg of benazepril and 12.5 mg of hydrochlorothiazide (Rx) [Lotensin HCT (scored) (lactose)]{42}


20 mg of benazepril and 12.5 mg of hydrochlorothiazide (Rx) [Lotensin HCT (scored) (lactose)]{42}


20 mg of benazepril and 25 mg of hydrochlorothiazide (Rx) [Lotensin HCT (scored) (lactose)]{42}

Canada—
Not commercially available.

Packaging and storage:
Store below 30 °C (86 °F) in a tight container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid too much sun or use of sunlamp.
   • Do not take other medicines without your doctor"s advice.

Note: Check refill frequency to determine compliance in hypertensive patients.



CAPTOPRIL AND HYDROCHLOROTHIAZIDE

Summary of Differences


For captopril:


Pharmacology/pharmacokinetics—
Absorption—Reduced by 30 to 40% in presence of food.

Half-life—Less than 3 hours (3.5–32 hours in renal failure).

Duration of action—Single dose: 6 to 12 hours.



Precautions—
Laboratory value alterations—May produce false-positive results in urinary acetone test.



Side/adverse effects—
Causes maculopapular or urticarial skin rash, sometimes with fever, joint pain, or elevated antinuclear antibody (ANA) titers.




Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

CAPTOPRIL AND HYDROCHLOROTHIAZIDE TABLETS

Usual adult and adolescent dose
Antihypertensive or
[Vasodilator, congestive heart failure]
Oral, 1 tablet two or three times a day, as determined by individual titration with the component agents, for a maximum of 150 mg captopril and 50 mg hydrochlorothiazide. {57}


Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Usual pediatric dose
Oral, as determined by individual titration with the component agents

Captopril: Oral, 300 mcg (0.3 mg) per kg of body weight three times a day, the dosage being increased if necessary in increments of 300 mcg (0.3 mg) per kg of body weight at intervals of eight to twenty-four hours to the minimum effective dose.

Hydrochlorothiazide: Oral, 1 to 2 mg per kg of body weight or 30 to 60 mg per square meter of body surface per day, as a single dose or in two divided daily doses, the dosage being adjusted according to response.

Strength(s) usually available
U.S.—


25 mg of captopril and 15 mg of hydrochlorothiazide (Rx) [Capozide (scored) (lactose)][Generic]{57}


25 mg of captopril and 25 mg of hydrochlorothiazide (Rx) [Capozide (scored) (lactose)][Generic]{57}


50 mg of captopril and 15 mg of hydrochlorothiazide (Rx) [Capozide (scored) (lactose)][Generic]{57}


50 mg of captopril and 25 mg of hydrochlorothiazide (Rx) [Capozide (scored) (lactose)][Generic]{57}

Canada—
Not commercially available.

Packaging and storage:
Store below 30 °C (86 °F), in a tight container, unless otherwise specified by manufacturer. {57}

Auxiliary labeling:
   • Take on an empty stomach, 1 hour before meals.
   • Avoid too much sun or use of sunlamp.
   • Do not take other medicines without your doctor"s advice.

Note: Check refill frequency to determine compliance in hypertensive patients.



ENALAPRIL AND HYDROCHLOROTHIAZIDE

Summary of Differences


For enalapril:


Pharmacology/pharmacokinetics—
Mechanism of action/effect—Activity due to active metabolite, enalaprilat.

Absorption—Not affected by presence of food.

Half-life—11 hours (increased in renal failure).

Duration of action—Single dose: Approximately 24 hours.




Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE TABLETS

Usual adult and adolescent dose
Antihypertensive {43} or
[Vasodilator, congestive heart failure]
Oral, 1 tablet once or twice per day, as determined by individual titration with the component agents, for a maximum of 20 mg of enalapril and 50 mg of hydrochlorothiazide. {43}


Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Usual pediatric dose
Oral, as determined by individual titration with the component agents

Enalapril: Oral, initially 100 mcg (0.1 mg) per kg of body weight per day, the dosage being adjusted as needed and tolerated, up to a maximum of 500 mcg (0.5 mg) per kg of body weight per day.

Hydrochlorothiazide: Oral, 1 to 2 mg per kg of body weight or 30 to 60 mg per square meter of body surface per day, as a single dose or in two divided doses, the dosage being adjusted according to response.

Strength(s) usually available
U.S.—


5 mg of enalapril maleate and 12.5 mg of hydrochlorothiazide (Rx) [Vaseretic (lactose)]{43}


10 mg of enalapril maleate and 25 mg of hydrochlorothiazide (Rx) [Vaseretic (lactose)]{43}

Canada—


10 mg of enalapril maleate and 25 mg of hydrochlorothiazide (Rx) [Vaseretic]{44}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a tight container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid too much sun or use of sunlamp.
   • Do not take other medicines without your doctor"s advice.

Note: Check refill frequency to determine compliance in hypertensive patients.



LISINOPRIL AND HYDROCHLOROTHIAZIDE

Summary of Differences


For lisinopril:


Pharmacology/pharmacokinetics—
Absorption—Not affected by presence of food.

Protein-binding—None.

Half-life—12 hours.

Duration of action—Approximately 24 hours.




Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

LISINOPRIL AND HYDROCHLOROTHIAZIDE TABLETS

Usual adult and adolescent dose
Antihypertensive or
[Vasodilator, congestive heart failure]
Oral, 1 or 2 tablets once a day, as determined by individual titration with the component agents, up to a maximum of 40 mg lisinopril and 50 mg hydrochlorothiazide. {45}


Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


10 mg of lisinopril and 12.5 mg of hydrochlorothiazide (Rx) [Prinzide]{45} [Zestoretic]{46}


20 mg of lisinopril and 12.5 mg of hydrochlorothiazide (Rx) [Prinzide]{45} [Zestoretic]{46}


20 mg of lisinopril and 25 mg of hydrochlorothiazide (Rx) [Prinzide]{45} [Zestoretic]{46}

Canada—


10 mg of lisinopril and 12.5 mg of hydrochlorothiazide (Rx) [Prinzide]{47} [Zestoretic]{48}


20 mg of lisinopril and 12.5 mg of hydrochlorothiazide (Rx) [Prinzide]{47} [Zestoretic]{48}


20 mg of lisinopril and 25 mg of hydrochlorothiazide (Rx) [Prinzide]{47} [Zestoretic]{48}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid too much sun or use of sunlamp.
   • Do not take other medicines without your doctor"s advice.

Note: Check refill frequency to determine compliance in hypertensive patients.



MOEXIPRIL AND HYDROCHLOROTHIAZIDE

Summary of Differences


For moexipril:


Pharmacology/pharmacokinetics—
Mechanism of action/effect—Activity due to active metabolite, moexiprilat.

Absorption—Affected significantly by the presence of food.

Half-life—12 hours (increased in renal failure).

Duration of action—Single dose: approximately 24 hours.




Oral Dosage Forms

MOEXIPRIL HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE TABLETS

Usual adult dose
Antihypertensive
Oral, 1 to 2 tablets daily, one hour before a meal, as determined by individual titration with the component agents and according to clinical response, usually not to exceed 30 mg moexipril and 50 mg hydrochlorothiazide {49}. The hydrochlorothiazide dose should not be increased until two or three weeks after initiation of treatment {49}.

One-half tablet may be used in patients who experience excessive reduction in blood pressure with the 7.5/12.5 mg tablet {49}.


Usual pediatric dose
Safety and efficacy have not been established {49}.

Strength(s) usually available
U.S.—


7.5 mg of moexipril hydrochloride and 12.5 mg of hydrochlorothiazide (Rx) [Uniretic (scored) (lactose )]{49}


15 mg of moexipril hydrochloride and 25 mg of hydrochlorothiazide (Rx) [Uniretic (scored) (lactose )]{49}

Canada—
Not commercially available.

Packaging and storage:
Store at controlled room temperature, between 20 and 25 ºC (68 and 77 ºF) in a tightly-closed container {49}. Protect from excessive moisture {49}.

Auxiliary labeling:
   • Take on an empty stomach, one hour before meals.
   • Avoid too much sun or use of sunlamp.
   • Do not take other medicines without your doctor"s advice {49}.

Note: Check refill frequency to determine compliance in hypertensive patients.



QUINAPRIL AND HYDROCHLOROTHIAZIDE

Summary of Differences


For quinapril:


Pharmacology/pharmacokinetics—
Mechanism of action/effect—Activity due to active metabolite, quinaprilat.

Absorption—Affected by the presence of high-fat foods.

Protein-binding—97% protein bound.

Half-life—25 hours.

Duration of action—Approximately 24 hours.



Precautions—
Drug interaction—Reduced absorption of tetracycline.




Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

QUINAPRIL HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE TABLETS

Usual adult and adolescent dose
Antihypertensive
Oral, 1 tablet once or twice a day, as determined by individual titration with the component agents for a maximum of 40 mg quinapril and 25 mg hydrochlorothiazide daily. {50}{58}


Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Usual pediatric dose
Safety and efficacy have not been established. {50}{58}

Strength(s) usually available
U.S.—


10 mg of quinapril and 12.5 mg of hydrochlorothiazide (Rx) [Accuretic]{58}


20 mg of quinapril and 12.5 mg of hydrochlorothiazide (Rx) [Accuretic]{58}


20 mg of quinapril and 25 mg of hydrochlorothiazide (Rx) [Accuretic]{58}

Canada—


10 mg of quinapril and 12.5 mg of hydrochlorothiazide (Rx) [Accuretic]{50}


20 mg of quinapril and 12.5 mg of hydrochlorothiazide (Rx) [Accuretic]{50}

Packaging and storage:
Store between 20 and 25 °C (68 and 77 °F), in a well-closed container.{58}

Auxiliary labeling:
   • Avoid too much sun or use of sunlamp.
   • Do not take other medicines without your doctor"s advice.

Note: Check refill frequency to determine compliance in hypertensive patients.




Revised: 06/20/2000



References

Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

  1. Capozide package insert (Squibb), 9/85.
  1. Reviewers" consensus on monograph revision of 1989.
  1. Aranda P, Novales E. Diuretics and the treatment of systemic hypertension. Am J of Cardiol 1990; 65: 72H-76H.
  1. Lant A. Diuretic drugs. Drugs 1986; 31(Suppl 4): 40-55.
  1. Capozide package insert (Squibb—US), Rev 3/92, Rec 4/92.
  1. Vaseretic package insert (MSD—US), Rev 2/92, Rec 4/92.
  1. Prinzide package insert (MSD—US), Rev 2/92, Rec 4/92.
  1. Hanssens M, Keirse MJ, Vankelecom F, Van Assche FA. Fetal and neonatal effects of treatment with angiotensin-converting enzyme inhibitors in pregnancy. Obstet Gynecol 1991; 78(1): 128-35.
  1. Rothberg AD, Lorenz R. Can captopril cause fetal and neonatal renal failure? Pediatr Pharmacol 1984; 4: 189-92.
  1. Schubiger G, Flury G, Nussberger J. Enalapril for pregnancy-induced hypertension: acute renal failure in a neonate. Ann Intern Med 1988; 108(2): 215-6.
  1. Rosa FW, Bosco LA, Graham CF, Milstien JB, Dreis M, Creamer J. Neonatal anuria with maternal angiotensin-converting enzyme inhibition. Obstet Gynecol 1989; 74(3 Part 1): 371-4.
  1. Scott AA, Purohit DM. Neonatal renal failure: A complication of maternal antihypertensive therapy. Am J Obstet Gynecol 1989; 160: 1223-4.
  1. Tack ED, Perlman JM. Renal failure in sick hypertensive premature infants receiving captopril therapy. J Pediatr 1988; 112: 805-10.
  1. O"Dea RF, Mirkin BL, Alward CT, Sinaiko AR. Treatment of neonatal hypertension with captopril. J Pediatr 1988; 113(2): 403-6.
  1. Perlman JM, Volpe JJ. Neurologic complications of captopril treatment of neonatal hypertension. Pediatrics 1989; 83(1): 47-52.
  1. Wood EG, Bunchman TE, Lynch RE. Captopril-induced reversible acute renal failure in an infant with coarctation of the aorta. Pediatrics 1991; 88(4): 816-8.
  1. Pool JL, Nelson EB, Taylor AA. Clinical experience and rationale for angiotensin-converting enzyme inhibition with lisinopril as the initial treatment for hypertension in older patients. Am J Med 1988; 85(Suppl 3B): 19-24.
  1. Gomez HJ, Smith SG, et al. Efficacy and safety of lisinopril in older patients with essential hypertension. Am J Med 1988; 85(Suppl 3B): 35-7.
  1. Laher MS, Donohoe JF, Kelly JG, Doyle GD. Antihypertensive and renal effects of lisinopril in older patients with hypertension. Am J Med 1988; 85(Suppl 3B): 38-43.
  1. Mulinari R, Gavras I, Gavras H. Efficacy and tolerability of enalapril monotherapy in mild-to-moderate hypertension in older patients compared to younger patients. Clin Ther 1987; 9(6): 678-89.
  1. Weir MR, Lavin PT. Comparison of the efficacy and tolerability of lisinopril and sustained-release verapamil in older patients with hypertension. Clin Ther 1991; 13(3): 401-8.
  1. Posvar EL, Sedman AJ. ACE inhibitors in the elderly. Angiology 1991; 42: 387-96.
  1. Canter D, Frank G. ACE inhibitors in the treatment of hypertension in the older patient. European Heart J 1990; 11(Suppl D): 33-43.
  1. Reid JL, Macdonald NJ, Lees KR, Elliott HL. Angiotensin-converting enzyme inhibitors in the elderly. Am Heart J 1989; 117: 7515.
  1. AMA-DE 1990 edition.
  1. Reviewers" consensus on thiazide diuretics monograph revision of 1990.
  1. Mason NA. Angiotensin-converting enzyme inhibitors and renal function. DICP 1990; 24: 496-505.
  1. Irvin JD, Viau JM. Safety profiles of the angiotensin converting enzyme inhibitors captopril and enalapril. Am J Med 1986; 81(suppl 4C): 46-50.
  1. Armayor GM, Lopez LM. Lisinopril: A new angiotensin-converting enzyme inhibitor. Drug Intell Clin Pharm 1988 May; 22: 365-72.
  1. Wilson TW, Rajput AH. Amantadine-dyazide interaction. Can Med Assoc J 1983; 129(9): 974-5.
  1. Shepherd GM. Possible contraindication of angiotensin converting enzyme inhibitors in patients with hereditary angioedema. Am J Med 1990; 88: 446.
  1. Girard M. The safety of angiotensin-converting enzyme (ACE) inhibitors in moderate hypertension. Adv Drug React Toxicol Rev 1991; 10(3): 169-85.
  1. Orfan N, Patterson R, Dykewicz MS. Severe angioedema related to ACE inhibitors in patients with a history of idiopathic angioedema. JAMA 1990; 264(10): 1287-9.
  1. International Olympic Committee (IOC) Medical Commission Doping classes, Methods and Restrictions, 1991.
  1. United States Olympic Committee, Drug Education Handbook 1989 to 1992.
  1. The National Collegiate Athletic Association (NCAA) Drug Testing/Education Programs 1990/1991.
  1. The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med 1993; 153(2): 154-83.
  1. Prinzide package insert (MSD—US), 1/89.
  1. Vaseretic package insert (MSD), 11/86.
  1. Health Canada Drug Product Database (DPD) [online database]. Cited June 22, 1998. Available from: URL: http://www.hc-sc.gc.ca/english/search.htm.
  1. Red book 1998. Montvale, NJ: Medical Economics Company; 1998. p. 497, 585, 601.
  1. Benazepril hydrochloride and hydrochlorothiazide (Lotensin HCT, Novartis). In: PDR Physicians" desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 2049-53.
  1. Enalapril maleate and hydrochlorothiazide (Vaseretic, Merck). In: PDR Physicians" desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 1911-4.
  1. Enalapril maleate and hydrochlorothiazide (Vaseretic, Frosst). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 34th ed. 1999. Ottawa: Canadian Pharmacists Association; 1999. p. 1899-1901.
  1. Lisinopril and hydrochlorothiazide (Prinzide, Merck). In: PDR Physicians" desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 1874-7.
  1. Lisinopril and hydrochlorothiazide (Zestoretic, Zeneca). In: PDR Physicians" desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 3441-4.
  1. Lisinopril and hydrochlorothiazide (Prinzide, Merck). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 34th ed. 1999. Ottawa: Canadian Pharmacists Association; 1999. p. 1449-52.
  1. Lisinopril and hydrochlorothiazide (Zestoretic, Zeneca). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 34th ed. 1999. Ottawa: Canadian Pharmacists Association; 1999. p. 2017-20.
  1. Moexipril hydrochloride and hydrochlorothiazide (Uniretic, Schwarz Pharma). In: PDR Physicians" desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 2919-22.
  1. Quinapril hydrochloride and hydrochlorothiazide (Accuretic, Parke-Davis). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 34th ed. 1999. Ottawa: Canadian Pharmacists Association; 1999. p. 17-19.
  1. Captopril (Captopril Tablets, Mylan). In: PDR Physicians" desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 1958-61.
  1. Benazepril hydrochloride (Lotensin, Novartis). In: PDR Physicians" desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 2047-9.
  1. Enalapril maleate (Vasotec, Merck). In: PDR Physicians" desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 1916-20.
  1. Lisinopril (Prinivil, Merck). In: PDR Physicians" desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p.1869-73.
  1. Moexipril hydrochloride (Univasc, Schwarz Pharma). In: PDR Physicians" desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company Inc; 1999. p. 2922-5.
  1. Not used.
  1. Captopril-hydrochlorothiazide package insert (Capozide, BMS—US), Rev 2/98, Rec 4/6/99.
  1. Product Information: Accuretic(R) quinapril HCl and hydrochlorothiazide. Parke-Davis, Morris Plains, NJ, (PI revised 12/99) reviewed 1/2000.
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