Side Effects of Capozide (captopril and hydrochlorothiazide/HCTZ)

Capozide (captopril and hydrochlorothiazide/HCTZ) is a combination of an angiotensin converting enzyme (ACE) inhibitor and a diuretic (water pill), used to treat high blood pressure (hypertension). 

ACE is an enzyme in the body that causes the formation of angiotensin II. Angiotensin II causes the arteries in the body to narrow, thereby elevating blood pressure. ACE inhibitors, such as captopril, lower blood pressure by preventing the formation of angiotensin II thereby relaxing the arteries. HCTZ is a diuretic used to treat high blood pressure and accumulation of fluid. It works by blocking salt and fluid reabsorption in the kidneys, causing increased urine output (diuresis). 

The mechanism of its action in lowering high blood pressure is not well understood. The combination of captopril and HCTZ reduces blood pressure better than either drug alone. 

Captopril increases potassium levels while HCTZ reduces potassium levels; the combination of both drugs has less effect on potassium levels. 

Common side effects of Capozide include

• dry and persistent cough,
• diarrhea,
• rash,
• itching,
• dizziness,
• loss of taste,
• weight loss,
• low blood pressure, and
• sexual dysfunction.

Increased blood glucose and potassium levels also may occur.

Serious side effects of Capozide are uncommon and include

• liver failure,
• angioedema (swelling of lips and throat that can obstruct breathing),
• reduced kidney function,
• muscle breakdown (rhabdomyolysis),
• reduced number of platelets, and
• pancreatitis.

Drug interactions of Capozide include potassium supplements or drugs that increase potassium levels (for example, spironolactone) because captopril may increase potassium levels (hyperkalemia) in blood.

• There have been reports of increased lithium levels when lithium is used in combination with ACE inhibitors. The reason for this interaction is not known, but the increased levels may lead to toxicity from lithium.
• There have been reports that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, indomethacin, and naproxen may reduce the effects of ACE inhibitors.
• Combining captopril or other ACE inhibitors with NSAIDs in patients who are elderly, volume-depleted (including those on diuretic therapy), or with poor kidney function may result in reduced kidney function, including kidney failure. These effects usually are reversible. Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension or low blood pressure) may occur when injectable gold (sodium aurothiomalate), used in the treatment of rheumatoid arthritis, is combined with ACE inhibitors, including captopril.
• Hydrochlorothiazide reduces the elimination of lithium by the kidneys and can lead to lithium toxicity. NSAIDs may reduce the blood pressure lowering effects of hydrochlorothiazide.
• Blood sugar levels can be elevated by HCTZ, necessitating adjustment in the doses of medications that are used for treating diabetes.
• Combining HCTZ with corticosteroids may increase the risk for low levels of blood potassium and other electrolytes. Low blood potassium can increase the toxicity of digoxin.
• Cholestyramine and colestipol bind to hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by 43%-85%.

When used in the second or third trimester of pregnancy ACE inhibitors can cause injury and even death to the fetus. Capozide should not be used during pregnancy.

Both captopril and HCTZ are excreted in breast milk and may potentially affect nursing infants. Consult your doctor before breastfeeding.

A dry, persistent cough has been reported commonly with the use of ACE inhibitors. Coughing resolves after discontinuing the drug.

Other common side effects include:

• diarrhea,
• rash,
• itching,
• dizziness,
• loss of taste,
• weight loss,
• low blood pressure, and
• sexual dysfunction.

Increased blood glucose and potassium levels also may occur.

Serious but, fortunately, very rare side effects are liver failure angioedema (swelling of lips and throat that can obstruct breathing).

Capozide may reduce kidney function in some patients and should not be used by patients who have bilateral renal artery stenosis (narrowing of both arteries going to the kidneys).

Rare cases of rhabdomyolysis (muscle breakdown), reduced number of platelets, and pancreatitis have been reported.

Reported incidences are based on clinical trials involving approximately 7000 patients.

• Renal: About one of 100 patients developed proteinuria.
• Each of the following has been reported in approximately 1 to 2 of 1000 patients and are of uncertain relationship to drug use: renal insufficiency, renal failure, nephrotic syndrome, polyuria, oliguria, and urinary frequency.
• Hematologic: Neutropenia/agranulocytosis has occurred. Cases of anemia, thrombocytopenia, and pancytopenia have been reported.
• Dermatologic: Rash, often with pruritus, and sometimes with fever, arthralgia, and eosinophilia, occurred in about 4 to 7 (depending on renal status and dose) of 100 patients, usually during the first four weeks of therapy. It is usually maculopapular, and rarely urticarial. The rash is usually mild and disappears within a few days of dosage reduction, short-term treatment with an antihistaminic agent, and/or discontinuing therapy; remission may occur even if captopril is continued. Pruritus, without rash, occurs in about 2 of 100 patients. Between 7 and 10 percent of patients with skin rash have shown eosinophilia and/or positive ANA titers. A reversible associated pemphigoid-like lesion, and photosensitivity, have also been reported.
• Flushing or pallor has been reported in 2 to 5 of 1000 patients.
• Cardiovascular: Hypotension may occur; see prescribing information for discussion of hypotension with captopril therapy.
• Tachycardia, chest pain, and palpitations have each been observed in approximately 1 of 100 patients.
• Angina pectoris, myocardial infarction, Raynaud†s syndrome, and congestive heart failure have each occurred in 2 to 3 of 1000 patients.
• Dysgeusia: Approximately 2 to 4 (depending on renal status and dose) of 100 patients developed a diminution or loss of taste perception. Taste impairment is reversible and usually self-limited (2 to 3 months) even with continued drug administration. Weight loss may be associated with the loss of taste.
• Angioedema: Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported in approximately one in 1000 patients. Angioedema involving the upper airways has caused fatal airway obstruction.
• Cough: Cough has been reported in 0.5-2% of patients treated with captopril in clinical trials.
• The following have been reported in about 0.5 -2% of patients but did not appear at increased frequency compared to placebo or other treatments used in controlled trials: gastric irritation, abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation, aphthous ulcers, peptic ulcer, dizziness, headache, malaise, fatigue, insomnia, dry mouth, dyspnea, alopecia, paresthesias.
• Other clinical adverse effects reported since the drug was marketed are listed below by body system. In this setting, an incidence or causal relationship cannot be accurately determined.
• Body as a whole: anaphylactoid reactions.
• General: asthenia, gynecomastia.
• Cardiovascular: cardiac arrest, cerebrovascular accident/insufficiency, rhythm disturbances, orthostatic hypotension, syncope.
• Dermatologic: bullous pemphigus, erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis.
• Gastrointestinal: pancreatitis, glossitis, dyspepsia.
• Hematologic: anemia, including aplastic and hemolytic.
• Hepatobiliary: jaundice, hepatitis, including rare cases of necrosis, cholestasis.
• Metabolic: symptomatic hyponatremia.
• Musculoskeletal: myalgia, myasthenia. Nervous/Psychiatric: ataxia, confusion, depression, nervousness, somnolence.
• Respiratory: bronchospasm, eosinophilic pneumonitis, rhinitis.
• Special Senses: blurred vision.
• Urogenital: impotence.
• As with other ACE inhibitors, a syndrome has been reported which may include: fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash or other dermatologic manifestations, eosinophilia and an elevated ESR.
• Fetal/Neonatal Morbidity and Mortality
• See prescribing information.
• Hydrochlorothiazide
• Gastrointestinal System: anorexia, gastric irritation, nausea, vomiting, cramping, diarrhea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, and sialadenitis.
• Central Nervous System: dizziness, vertigo, paresthesias, headache, and xanthopsia.
• Hematologic: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, and hemolytic anemia.
• Cardiovascular: orthostatic hypotension.
• Hypersensitivity: purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis; cutaneous vasculitis), fever, respiratory distress including pneumonitis, and anaphylactic reactions.
• Other: hyperglycemia, glycosuria, hyperuricemia, muscle spasm, weakness, restlessness, and transient blurred vision.
• Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.
• Altered Laboratory Findings
• Serum Electrolytes: Hyperkalemia: small increases in serum potassium, especially in patients with renal impairment.
• Hyponatremia: particularly in patients receiving a low sodium diet or concomitant diuretics.
• BUN/Serum Creatinine: Transient elevations of BUN or serum creatinine especially in volume or salt depleted patients or those with renovascular hypertension may occur. Rapid reduction of longstanding or markedly elevated blood pressure can result in decreases in the glomerular filtration rate and, in turn, lead to increases in BUN or serum creatinine.
• Hematologic: A positive ANA has been reported.
• Liver Function Tests: Elevations of liver transaminases, alkaline phosphatase, and serum bilirubin have occurred.

Captopril

• Hypotension Patients on Diuretic Therapy: Patients on diuretics and especially those in whom diuretic therapy was recently instituted, as well as those on severe dietary salt restriction or dialysis, may occasionally experience a precipitous reduction of blood pressure usually within the first hour after receiving the initial dose of captopril.
• The possibility of hypotensive effects with captopril can be minimized by either discontinuing the diuretic or increasing the salt intake approximately one week prior to initiation of treatment with captopril or initiating therapy with small doses (6.25 or 12.5 mg). Alternatively, provide medical supervision for at least one hour after the initial dose. If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of normal saline. This transient hypotensive response is not a contraindication to further doses which can be given without difficulty once the blood pressure has increased after volume expansion.
• Agents Having Vasodilator Activity: Data on the effect of concomitant use of other vasodilators in patients receiving captopril for heart failure are not available; therefore, nitroglycerin or other nitrates (as used for management of angina) or other drugs having vasodilator activity should, if possible, be discontinued before starting captopril. If resumed during captopril therapy, such agents should be administered cautiously, and perhaps at lower dosage.
• Agents Causing Renin Release: Captopril's effect will be augmented by antihypertensive agents that cause renin release. For example, diuretics (e.g., thiazides) may activate the renin-angiotensin-aldosterone system.
• Agents Affecting Sympathetic Activity: The sympathetic nervous system may be especially important in supporting blood pressure in patients receiving captopril alone or with diuretics. Therefore, agents affecting sympathetic activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents) should be used with caution. Beta-adrenergic blocking drugs add some further antihypertensive effect to captopril, but the overall response is less than additive.
• Agents Increasing Serum Potassium: Since captopril decreases aldosterone production, elevation of serum potassium may occur. Potassium-sparing diuretics such as spironolactone, triamterene, or amiloride, or potassium supplements, should be given only for documented hypokalemia, and then with caution, since they may lead to a significant increase of serum potassium. Salt substitutes containing potassium should also be used with caution.
• Inhibitors Of Endogenous Prostaglandin Synthesis: It has been reported that indomethacin may reduce the antihypertensive effect of captopril, especially in cases of low renin hypertension. Other nonsteroidal anti-inflammatory agents (e.g., aspirin) may also have this effect.
• Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity.

Hydrochlorothiazide

When administered concurrently the following drugs may interact with thiazide diuretics:

• Alcohol, barbiturates, or narcotics†potentiation of orthostatic hypotension may occur.
• Amphotericin B, corticosteroids, or corticotropin (ACTH) may intensify electrolyte imbalance, particularly hypokalemia. Monitor potassium levels; use potassium replacements if necessary.
• Anticoagulants (oral) dosage adjustments of anticoagulant medication may be necessary since hydrochlorothiazide may decrease their effects.
• Antigout medications dosage adjustments of antigout medication may be necessary since hydrochlorothiazide may raise the level of blood uric acid.
• Other antihypertensive medications (e.g., ganglionic or peripheral adrenergic blocking agents) dosage adjustments may be necessary since hydrochlorothiazide may potentiate their effects.
• Antidiabetic drugs (oral agents and insulin) since thiazides may elevate blood glucose levels, dosage adjustments of antidiabetic agents may be necessary.
• Calcium salts increased serum calcium levels due to decreased excretion may occur. If calcium must be prescribed monitor serum calcium levels and adjust calcium dosage accordingly.
• Cardiac glycosides enhanced possibility of digitalis toxicity associated with hypokalemia. Monitor potassium levels.
• Cholestyramine and colestipol resins Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.
• Diazoxide enhanced hyperglycemic, hyperuricemic, and antihypertensive effects. Be cognizant of possible interaction; monitor blood glucose and serum uric acid levels.
• Lithium diuretic agents reduce the renal clearance of lithium and increase the risk of lithium toxicity. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended.
• MAO inhibitors dosage adjustments of one or both agents may be necessary since hypotensive effects are enhanced.
• Nondepolarizing muscle relaxants, preanesthetics and anesthetics used in surgery (e.g., tubocurarine chloride and gallamine triethiodide) effects of these agents may be potentiated; dosage adjustments may be required. Monitor and correct any fluid and electrolyte imbalances prior to surgery if feasible.
• Nonsteroidal anti-inflammatory agents†in some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effect of loop, potassium-sparing or thiazide diuretics. Therefore, when hydrochlorothiazide and nonsteroidal antiinflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.
• Methenamine possible decreased effectiveness due to alkalinization of the urine.
• Pressor amines (e.g., norepinephrine)†decreased arterial responsiveness, but not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Use caution in patients taking both medications who undergo surgery. Administer preanesthetic and anesthetic agents in reduced dosage, and if possible, discontinue hydrochlorothiazide therapy one week prior to surgery.
• Probenecid or sulfinpyrazone†increased dosage of these agents may be necessary since hydrochlorothiazide may have hyperuricemic effects.
• Captopril may cause a false-positive urine test for acetone.
• Hydrochlorothiazide may cause diagnostic interference of the bentiromide test.

Drug/Laboratory Test Interactions

Captopril

• Captopril may cause a false-positive urine test for acetone.

Hydrochlorothiazide

• Hydrochlorothiazide may cause diagnostic interference of the bentiromide test.