Angiotensin Converting Enzyme Inhibitor
Action And Clinical Pharmacology: Captopril is an angiotensin converting enzyme inhibitor which is used in the treatment of hypertension and heart failure.
The mechanism of action of captopril has not yet been fully elucidated. It appears to lower blood pressure and be an adjunct in the therapy of congestive heart failure primarily through suppression of the renin-angiotensin-aldosterone system; however, there is no consistent correlation between renin levels and response to the drug. Renin, an enzyme synthesized by the kidneys, is released into the circulation where it acts on a plasma globulin substrate to produce angiotensin I, a relatively inactive decapeptide. Angiotensin I is then converted by angiotensin converting enzyme (ACE) to angiotensin II, a potent endogenous vasoconstrictor substance. Angiotensin II also stimulates aldosterone secretion from the adrenal cortex, thereby contributing to sodium and fluid retention.
Captopril prevents the conversion of angiotensin I to angiotensin II by inhibition of ACE, a peptidyldipeptide carboxy hydrolase.
ACE is identical to “bradykininase”, and captopril may also interfere with the degradation of the vasopressor peptide, bradykinin. However, the effectiveness of captopril in therapeutic doses appears to be unrelated to potentiation of the actions of bradykinin. Increased concentrations of bradykinin or prostaglandin E2 may also have a role in the therapeutic effect of captopril, especially in low-renin hypertension.
Inhibition of ACE results in decreased plasma angiotensin II and increased plasma renin activity (PRA), the latter resulting from loss of negative feedback on renin release caused by reduction in angiotensin II. The reduction of angiotensin II leads to decreased aldosterone secretion, and, as a result, small increases in serum potassium may occur along with sodium and fluid loss.
The antihypertensive effects persist for a longer period of time than does demonstrable inhibition of circulating ACE. It is not known whether the ACE present in vascular endothelium is inhibited longer than the ACE in circulating blood.
Administration of captopril results in a reduction of peripheral arterial resistance in hypertensive patients with either no change, or an increase, in cardiac output. There is an increase in renal blood flow following administration of captopril and glomerular filtration rate is usually unchanged. In instances of rapid reduction of long-standing or severely elevated blood pressure, the glomerular filtration rate may decrease transiently.
Peak reductions of blood pressure usually occur within 60 to 90 minutes after oral administration of a single dose of captopril. The duration of effect appears to be dose related. The reduction in blood pressure may be progressive, so to achieve maximal therapeutic effects, several weeks of therapy may be required. The blood pressure lowering effects of captopril and thiazide-type diuretics appear to be additive. In contrast, captopril and beta-blockers have a less than additive effect.
Blood pressure is lowered to about the same extent in both standing and supine positions. Orthostatic effects and tachycardia are infrequent but may occur in volume-depleted patients. Abrupt withdrawal of captopril has not been associated with a rapid increase in blood pressure.
The antihypertensive effect of angiotensin converting enzyme inhibitors is generally lower in black patients than in non-blacks.
In patients with heart failure, captopril significantly decreased systemic vascular resistance (afterload), reduced pulmonary capillary wedge pressure (preload) and pulmonary vascular resistance, increased cardiac output (stroke index), and increased exercise tolerance time (ETT). Clinical improvement has been observed in some patients where acute hemodynamic effects were minimal.
Captopril has been studied in patients with diabetic nephropathy, most of whom had hypertension, with type I insulin-dependent diabetes mellitus, retinopathy and proteinuria Â³500 mg/day, in a multicenter, double-blind, placebo controlled trial. In this study, captopril has shown to decrease the rate of progression of renal insufficiency and to reduce associated clinical sequelae for the combined end-point of end-stage renal disease (dialysis or renal transplantation) or death (from all causes). The effect on reduction of all-cause mortality alone was not statistically significant. No dosage adjustment was made according to creatinine clearance. Patients who had already progressed to severe renal failure were not included in the clinical trial.
Studies in rats and cats indicate that captopril does not cross the blood-brain barrier to any significant extent.
Pharmacokinetics: Following oral administration of therapeutic doses of captopril, rapid absorption occurs with peak blood levels at about 1 hour. The presence of food in the gastrointestinal tract reduces absorption by about 30 to 40%. Based on C-14 labeling, average minimal absorption is approximately 70 to 75%. In a 24-hour period, over 95% of the absorbed dose is eliminated in the urine; 40 to 50% is unchanged drug although it appears this percentage may be smaller in patients with congestive heart failure; most of the remainder is the disulfide dimer of captopril and captopril-cysteine disulfide.
Approximately 25 to 30% of the circulating drug is bound to plasma proteins. The apparent elimination half-life for total radioactivity in blood is about 4 hours. The half-life of unchanged captopril is approximately 2 hours.
In patients with normal renal function, absorption and disposition of a labeled dose are not altered after 7 days of captopril administration. In patients with renal impairment, however, retention of captopril occurs (see Dosage).
Indications And Clinical Uses: For the treatment of essential or renovascular hypertension. It is usually administered in association with other drugs, particularly thiazide diuretics. The blood pressure lowering effects of captopril and thiazides are approximately additive.
In using captopril, consideration should be given to the risk of neutropenia/agranulocytosis (see Warnings).
Patients with Normal Renal Function: Captopril should normally be used in those patients in whom treatment with diuretics or beta-blockers was found ineffective or has been associated with unacceptable adverse effects.
Captopril can be tried as an initial agent in those patients with severe hypertension or in those in whom the use of diuretics and/or beta-blockers is contraindicated or in patients with medical conditions in which those drugs frequently cause serious adverse effects.
Patients with Impaired Renal Function: In these patients, particularly those with collagen vascular disease, captopril should be reserved for hypertensives who have either developed unacceptable side effects on other drugs, or have failed to respond satisfactorily to drug combinations (see Precautions).
Captopril is indicated in the treatment of congestive heart failure as concomitant therapy with a diuretic in patients who have not responded adequately to digitalis and diuretics or in whom the administration of digitalis is contraindicated or has been associated with unacceptable side effects. Captopril therapy must be initiated under close medical supervision.
Captopril is indicated to improve survival, delay the onset of symptomatic heart failure and reduce hospitalizations for heart failure following myocardial infarction in clinically stable patients with left ventricular dysfunction manifested as an ejection fraction of 40%.
Captopril is indicated for the treatment of diabetic nephropathy (proteinuria 500 mg/day) in patients with type I insulin-dependent diabetes mellitus and retinopathy.
Pregnancy: When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury or even death of the developing fetus. When pregnancy is detected, captopril should be discontinued as soon as possible (see Warnings, Pregnancy, and Precautions, Information for the Patient).
Contra-Indications: Patients with a history of hypersensitivity to the drug and in patients with a history of angioedema related to previous treatment with an ACE inhibitor.
Manufacturers’ Warnings In Clinical States: Angioedema: Angioedema has been reported in patients treated with ACE inhibitors, including captopril. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, captopril should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment, although antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy (including but not limited to 0.3 to 0.5 mL of s.c. epinephrine solution 1:1 000) should be administered promptly (see Adverse Effects).
The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black than in non-black patients.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see Contraindications).
Proteinuria: Total urinary proteins greater than 1 g/day were seen in less than 1% of patients receiving captopril. These have been predominantly in those who had prior renal disease, or in those receiving relatively high doses (in excess of 150 mg/day), or both. In patients without prior evidence of renal disease, the incidence of proteinuria was 0.5%. In those patients without prior evidence of renal disease receiving 150 mg or less per day, the incidence was 0.2%. Parameters of renal function, such as BUN and serum creatinine, were seldom altered in the patients with proteinuria. In most cases, proteinuria subsided or cleared within 6 months whether or not captopril was continued, but some patients had persistent proteinuria. Nephrotic syndrome occurred in about one-fifth of the proteinuric patients.
Membranous glomerulopathy was found in biopsies taken from proteinuric patients. A causal relationship to captopril has not been established since pretreatment biopsies were not taken and membranous glomerulopathy has been shown to occur in hypertensive patients not receiving captopril.
Since most cases of proteinuria occurred by the eighth month of therapy, patients with prior renal disease or those receiving captopril at doses greater than 150 mg/day should have urinary protein estimations (dipstick on first morning urine, or quantitative 24-hour urine) prior to therapy, at approximately monthly intervals for the first 9 months of treatment, and periodically thereafter. When proteinuria is persistent, 24-hour quantitative determinations provide greater precision. For patients who develop proteinuria exceeding 1 g/day, or proteinuria that is increasing, the benefits and risks of continuing captopril should be evaluated.
Neutropenia/Agranulocytosis: The risk of neutropenia is dependent on the clinical status of the patient: In clinical trials in patients with hypertension who have normal renal function (serum creatinine less than 1.6 mg/dL and no collagen disease), neutropenia has been seen in 1 patient out of over 8 600 exposed.
In patients with some degree of renal failure (serum creatinine at least 1.6 mg/dL) but no collagen vascular disease, the risk of neutropenia in clinical trials was about 1 per 500, a frequency over 15 times that for uncomplicated hypertension. Daily doses of captopril were relatively high in these patients, particularly in view of their diminished renal function. In patients with renal failure, use of allopurinol concomitantly with captopril has been associated with neutropenia.
In patients with collagen vascular disease (e.g., systemic lupus erythematosus, scleroderma) and impaired renal function, neutropenia occurred in 3.7% of patients in clinical trials.
While none of the over 750 patients in formal clinical trials of heart failure developed neutropenia, it has occurred during the subsequent clinical experience. About half of the reported cases had serum creatinine>1.6 mg/dL and more than 75% were in patients also receiving procainamide. In heart failure, it appears that the same risk factors for neutropenia are present.
Neutropenia has been detected within 3 months after captopril was started. Bone marrow examinations in patients with neutropenia consistently showed myeloid hypoplasia, frequently accompanied by erythroid hypoplasia and decreased numbers of megakaryocytes (e.g., hypoplastic bone marrow and pancytopenia); anemia and thrombocytopenia were sometimes seen.
In general, neutrophils returned to normal in about 2 weeks after captopril was discontinued, and serious infections were limited to clinically complex patients. About 13% of the cases of neutropenia have ended fatally, but almost all fatalities were in patients with serious illness, having collagen vascular disease, renal failure, heart failure or immunosuppressant therapy, or a combination of these complicating factors.
Evaluation of the hypertensive or heart failure patient should always include assessment of renal function.
If captopril is used in patients with impaired renal function, white blood cell and differential counts should be evaluated prior to starting treatment and at approximately 2-week intervals for about 3 months, then periodically.
In patients with collagen vascular disease or who are exposed to other drugs known to affect the white cells or immune response, particularly when there is impaired renal function, captopril should be used only after an assessment of benefit and risk, and then with caution.
All patients treated with captopril should be told to report any signs of infection (e.g., sore throat, fever). If infection is suspected, white cell counts should be performed without delay.
Since discontinuation of captopril and other drugs has generally led to prompt return of the white count to normal, upon confirmation of neutropenia (neutrophil count
Since captopril decreases aldosterone production, elevation of serum potassium may occur rarely, especially in patients with renal failure (see Precautions, Drug Interactions).
Hypotension: Excessive hypotension was seen in hypertensive patients but is a possible consequence of captopril use in severely salt/volume-depleted persons such as those treated vigorously with diuretics, for example patients with severe congestive heart failure (see Precautions, Drug Interactions).
In heart failure, where the blood pressure was either normal or low, decreases in mean blood pressure greater than 20% were recorded in about half of the patients. This transient hypotension may occur after any of the first several doses and produces either no symptoms or brief mild lightheadedness, although in rare instances, it has been associated with arrhythmia or conduction defects. Hypotension was the reason for discontinuation of drug in 3.6% of patients with heart failure.
Because of the potential fall in blood pressure in these patients, therapy should be started under close medical supervision. A low starting dose may minimize the hypotensive effect (see Dosage). Patients should be followed closely for the first 2 weeks of treatment and whenever the dose of captopril, or diuretic, is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident. Hypotension in itself is not a reason to discontinue captopril. If associated symptoms are troublesome or persist, they are usually relieved by a reduction in the dose of either captopril or diuretic.
Pregnancy: ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, captopril should be discontinued as soon as possible.
In rare cases (probably less than once in every thousand pregnancies) in which no alternative to ACE inhibitors therapy will be found, the mothers should be apprised of the potential hazards to their fetuses. Serial ultrasound examinations should be performed to assess fetal development and well-being and the volume of amniotic fluid.
If oligohydramnios is observed, captopril should be discontinued unless it is considered life-saving for the mother. A non-stress test (NST), and/or a biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. If concerns regarding fetal well-being still persist, a contraction stress testing (CST) should be considered. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function, however, limited experience with those procedures has not been associated with significant clinical benefit. Captopril may be removed from the general circulation by hemodialysis.
Human Data: It is not known whether exposure limited to the first trimester of pregnancy can adversely affect fetal outcome. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure.
Animal Data: Captopril was embryocidal in rabbits when given in doses 2 to 70 times (on a mg/kg basis) the maximum recommended human dose, and low incidences of craniofacial malformations were seen. These effects in rabbits were most probably due to the particularly marked decrease in blood pressure caused by the drug in this species. Captopril was also embryocidal in sheep when given in doses similar to those given in humans. Captopril given to pregnant rats at 400 times the recommended human dose continuously during gestation and lactation caused a reduction in neonatal survival.
No teratogenic effects have been observed after large doses of captopril were administered to hamsters and rats.
Precautions: Renal Impairment: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.
Use of captopril should include appropriate assessment of renal function.
Hyperkalemia: Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including captopril. When treated with ACE inhibitors, patients at risk for the development of hyperkalemia include those with: renal insufficiency; diabetes mellitus; and those using concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes; or other drugs associated with increases in serum potassium (e.g., heparin). The incidence of hyperkalemia related or possibly related to therapy in the diabetic patients studied with nephropathy and proteinuria was 3.6% and was a reason for discontinuation of the drug in 1% of the patients. Hyperkalemia was defined as persistent elevation of serum potassium to 6.0 mg/dL or more in the absence of a remediable cause, such as other drugs, volume depletion, exogenous potassium supplements, etc.
Impaired Liver Function: Elevations of liver enzymes and/or serum bilirubin, cases of cholestatic jaundice, and of hepatocellular injury with or without secondary cholestasis, have occurred during therapy with captopril in patients without pre-existing liver abnormalities. In most cases the changes were reversible on discontinuation of the drug. Should the patient receiving captopril experience any unexplained symptoms (see Information for the Patient), particularly during the first weeks or months of treatment, it is recommended that a full set of liver enzyme tests and other necessary investigations be carried out. Discontinuation of captopril should be considered when appropriate.
There are no adequate studies in patients with cirrhosis and/or liver dysfunction. Captopril should be used with particular caution in patients with pre-existent liver abnormalities. Such patients should have their baseline liver function tests obtained before administration of the drug. Close monitoring of response and metabolic effects should apply to these patients.
Cough: Cough has been reported with the use of captopril. Characteristically, ACE inhibitor-induced cough is nonproductive, persistent and resolves after discontinuation of therapy or lowering of the dose. Captopril-induced cough should be considered as part of the differential diagnosis of the cough.
Valvular Stenosis: There is concern, on theoretical grounds, that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, captopril will block angiotensin II formation secondary to compensatory renin release. This may lead to hypotension which can be corrected by volume expansion.
Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes (e.g., polyacrylonitrile [PAN] and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agents.
Anaphylactoid Reactions During Desensitization: There have been isolated reports of patients experiencing sustained life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitizing treatment with hymenoptera (bees, wasps) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge.
Lactation: Following oral administration, concentrations of unchanged captopril in human milk are approximately 1% of those in maternal blood. The effect of low levels of captopril on the nursing infant has not been determined. Caution should be exercised when captopril is administered to a nursing woman, and, in general, nursing should be interrupted.
Children: Safety and effectiveness in children have not been established although there is limited experience with the use of captopril in children from 2 months to 15 years of age with secondary hypertension and varying degrees of renal insufficiency. Dosage, on a weight basis, was comparable to that used in adults. Captopril should be used in children only if other measures for controlling blood pressure have not been effective.
Information for the Patient: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever), which may be a sign of neutropenia, or of progressive edema, which might be related to proteinuria and nephrotic syndrome.
All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with the physician.
Patients should be advised to return to the physician if he/she experiences any symptoms possibly related to liver dysfunction. This would include viral like symptoms in the first weeks to months of therapy (such as fever, malaise, muscle pain, rash or adenopathy which are possible indicators of hypersensitivity reactions), or if abdominal pain, nausea or vomiting, loss of appetite, jaundice, itching or any other unexplained symptoms occur during therapy.
Patients should be warned against interruption or discontinuation of antihypertensive medications without the physician’s advice.
Patients treated for severe congestive heart failure should be cautioned to increase their physical activity slowly.
Pregnancy: Since the use of captopril during pregnancy can cause injury and even death of the developing fetus, patients should be advised to report promptly to their physician if they become pregnant.
Drug Interactions: 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 (see Warnings).
When feasible the hypotensive effects may be minimized by either discontinuing the diuretic or increasing the salt intake approximately 1 week prior to initiation of treatment with captopril. Alternatively, provide medical supervision for at least 1 hour after the initial dose. If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an i.v. 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.
In heart failure, special caution is necessary since sympathetic stimulation is a vital component supporting circulatory function and inhibition with beta-blockade always carries a potential hazard of further depressing myocardial contractility.
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 which contain 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., ASA) may also have this effect.
The blood pressure lowering effects of captopril and beta-blockers are less than additive.
In patients with renal failure, the use of allopurinol concomitantly with captopril has been associated with neutropenia.
In patients with heart failure, the use of procainamide concomitantly with captopril has been associated with neutropenia.
Drug/Laboratory Test Interaction: Captopril may cause false-positive reactions for urinary acetone and for dipstick tests for urinary ketones.
Adverse Reactions: Reported incidences are based on clinical trials involving approximately 7 000 patients treated with captopril.
Renal: Approximately 1 of every 100 patients developed proteinuria (see Warnings).
Each of the following has been reported in approximately 1 to 2 of 1 000 patients and are of uncertain relationship to drug use: renal insufficiency, renal failure, polyuria, oliguria and urinary frequency.
Hematologic: Neutropenia/agranulocytosis has occurred (see Warnings). Cases of anemia, thrombocytopenia and pancytopenia have been reported.
Dermatologic: A rash occurred in 8.5% of patients with normal renal function and 13% of patients with evidence of prior renal functional impairment. It was dose related, having occurred in 7% of patients at doses of 150 mg or less per day. The rash is usually maculopapular, but rarely urticarial, and generally occurs during the first 4 weeks of therapy. 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% of patients with skin rash have shown an eosinophilia and/or positive ANA titers. A reversible associated pemphigoid-like lesion, and photosensitivity, have also been reported.
Allergic: Angioedema of the face, mucous membranes of the mouth, or of the extremities has been observed in approximately 1 of 1 000 patients and is reversible on discontinuance of captopril therapy. Serum sickness and bronchospasm have been reported. One case of laryngeal edema has been reported.
Cardiovascular: Hypotension may occur; see Warnings and Precautions (Drug Interactions) for discussion of hypotension on initiation of 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 1 000 patients.
Flushing or pallor has been reported in 2 to 5 of 1 000 patients.
Alterations in Taste: 2% of patients receiving 150 mg or less per day of captopril developed a diminution or loss of taste perception. At doses in excess of 150 mg/day, 7% of patients experienced this effect. 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.
The following have been reported in about 0.5 to 2% of patients:
Gastrointestinal: gastric irritation, abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation, aphthous ulcers and peptic ulcer.
CNS: dizziness, headache, malaise, fatigue, insomnia and paresthesia.
Others: dry mouth, dyspnea, cough, alopecia, impotence, loss of libido, disturbed vision, and itching and/or dry eyes.
Other clinical adverse effects reported since the drug was marketed are listed below by body system. In many cases, an incidence or causal relationship cannot be accurately determined.
General: asthenia, gynecomastia.
Cardiovascular: cardiac arrest, cerebrovascular accident, syncope.
Dermatologic: bullous pemphigus, Stevens-Johnson syndrome.
Gastrointestinal: pancreatitis, glossitis.
Hematologic: anemia, including aplastic and hemolytic.
Hepatobiliary: hepatitis, including rare cases of necrosis, cholestasis (see Precautions).
Metabolic: symptomatic hyponatremia.
Musculoskeletal: myalgia, myasthenia.
Nervous/Psychiatric: ataxia, confusion, depression, nervousness, somnolence.
Respiratory: bronchospasm, eosinophilic pneumonitis, rhinitis.
Special Senses: blurred vision.
As with other ACE inhibitors, a syndrome has been reported which includes: fever, myalgia, arthralgia, rash or other dermatologic manifestations, eosinophilia and an elevated ESR. Findings have usually resolved with discontinuation of treatment.
Altered Laboratory Findings: Elevations of liver enzymes and/or serum bilirubin have occurred (see Precautions). Rare cases of cholestatic jaundice and hepatocellular injury with or without secondary cholestasis, have been reported in association with captopril administration.
Elevation of BUN and serum creatinine may occur, especially in patients who are volume-depleted or who have renovascular hypertension. In instances of rapid reduction of long-standing or severely elevated blood pressure, the glomerular filtration rate may decrease transiently, also resulting in transient rises in serum creatinine and BUN.
Small increases in the serum potassium concentration frequently occur, especially in patients with renal impairment (see Precautions).
Diabetic Nephropathy: In 400 patients treated with captopril, the overall adverse reactions profile appeared to be similar to the above. However, the following adverse reactions have occurred more frequently in women than in men: dizziness (31% vs 20%), cough (23% vs 17%) and pharyngitis (20% vs 14%). In 395 patients treated with placebo, the incidences were: dizziness (22%), cough (15%) and pharyngitis (11%) in women and men combined.
The incidence of hypotension or orthostatic hypotension was 5.3% and was a reason for discontinuation of the drug in 1.8% of the patients.
The incidence of hyperkalemia related or possibly related to therapy in the diabetic patients studied with nephropathy and proteinuria was 3.6% and was a reason of discontinuation of the drug in 1% of the patients.
Hyperkalemia was defined as persistent elevation of serum potassium to 6.0 mg/dL or more in the absence of a remediable cause, such as other drugs, volume depletion, exogenous potassium supplements, etc.
In patients with serum creatinine Â³1.5 mg/dL, the incidence of a marked abnormality in hemoglobin (a drop >3 g/dL) was 6% in patients treated with captopril versus 0% in those on placebo.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: In the event of overdosage, correction of hypotension would be of primary concern. Volume expansion with an i.v. infusion of normal saline is the treatment of choice for restoration of blood pressure.
Captopril may be removed from the general circulation by hemodialysis.
Dosage And Administration: Captopril should be taken 1 hour before meals. Dosage must be individualized.
Hypertension: Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation, salt restriction, and other clinical circumstances. If possible, discontinue the patient’s previous antihypertensive drug regimen for 1 week before starting captopril. If this is impossible, especially in severe hypertension, the diuretic should be continued.
Initial dose: 25 mg 2 or 3 times a day. If a satisfactory reduction of blood pressure has not been achieved after 1 or 2 weeks, the dose may be increased to 50 mg 2 or 3 times a day. The dose of captopril in hypertension usually does not exceed 150 mg daily. Therefore, if the blood pressure has not been satisfactorily controlled after 1 to 2 weeks at this dose (and the patient is not already receiving a diuretic), a modest dose of thiazide-type diuretic (e.g., hydrochlorothiazide 25 mg daily) should be added. The diuretic dose may be increased at 1 to 2 week intervals until its highest usual antihypertensive dose is reached.
If captopril is being started in a patient already receiving a diuretic, therapy should be initiated under close medical supervision (see Warnings and Precautions, Drug Interactions regarding hypotension), with dosage and titration of captopril as noted above.
In severe hypertension, if further blood pressure reduction is required, the dose of captopril may be increased to 100 mg 2 or 3 times a day, and then, if necessary, to 150 mg 2 or 3 times a day, while continuing the diuretic. The usual dose range is 25 to 150 mg 2 or 3 times a day. A maximum daily dose of 450 mg given in 3 equally divided doses should not be exceeded.
For patients with accelerated or malignant hypertension, when temporary discontinuation of current antihypertensive therapy is not practical or desirable, or when prompt titration to more normotensive blood pressure levels is indicated, the diuretic should be continued but other concurrent antihypertensive medication stopped and captopril dosage promptly initiated at 25 mg 3 times a day, under close medical supervision. When necessitated by the patient’s clinical condition, the daily dose of captopril may be increased every 24 hours under continuous medical supervision until a satisfactory blood pressure response is obtained or the maximum dose of captopril is reached. In this regimen, addition of a more potent diuretic, e.g., furosemide, may also be indicated.
Beta-blockers may also be used in conjunction with captopril therapy (see Precautions, Drug Interactions), but the effects of the 2 drugs are less than additive.
Heart Failure: Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/volume depletion. In patients with either normal or low blood pressure, who have been vigorously treated with diuretics and who may be hyponatremic and/or hypovolemic, a starting dose of 6.25 or 12.5 mg 3 times a day may minimize the magnitude or duration of the hypotensive effect (see Warnings, Hypotension). For these patients, titration to the usual daily dosage can then occur within the next several days.
For most patients the usual initial daily dosage is 25 mg 3 times daily. After a dose of 50 mg 3 times daily is reached, further increases in dosage should be delayed, where possible, for at least 2 weeks to determine if a satisfactory response occurs. Most patients studied have had a satisfactory clinical improvement at 50 or 100 mg 3 times daily. A maximum daily dose of 450 mg of captopril should not be exceeded.
Captopril is to be used in conjunction with a diuretic. Therapy must be initiated under very close medical supervision.
Left Ventricular Dysfunction after Myocardial Infarction: The recommended dose for long-term use in patients following a myocardial infarction is a target maintenance dose of 50 mg 3 times daily.
Therapy may be initiated as early as 3 days following a myocardial infarction. After a single dose of 6.25 mg, captopril therapy should be initiated at 12.5 mg 3 times daily. Captopril should then be increased to 25 mg 3 times daily during the next several days and to a target dose of 50 mg 3 times daily over the next several weeks as tolerated (see Pharmacology).
Captopril may be used in patients treated with other post-myocardial infarction therapies, e.g., thrombolytics, ASA, beta-blockers.
Diabetic Nephropathy: The recommended daily dose of captopril for long-term use to treat diabetic nephropathy is 25 mg 3 times daily.
If further blood pressure reduction is required, other antihypertensive agents such as diuretics, beta-adrenoceptor-blockers, centrally-acting agents or vasodilators may be used in conjunction with captopril.
Dosage Adjustment in Renal Impairment: Because captopril is excreted primarily by the kidneys, excretion rates are reduced in patients with impaired renal function. These patients will take longer to reach steady-state levels of captopril and will reach higher steady-state levels for a given daily dose than patients with normal renal function. Therefore, these patients may respond to smaller or less frequent doses.
Captopril is removed by hemodialysis.
Renal Impairment Due to Diabetic Nephropathy (With or Without Hypertension): Captopril at doses of 25 mg 3 times daily was well-tolerated in patients with diabetic nephropathy and mild to moderate renal impairment (see Precautions, Hyperkalemia). Accordingly, no dose adjustment based on creatinine clearance is recommended for these patients.
Captopril has not been studied in patients with diabetic nephropathy and severe renal impairment (creatinine clearance 30 mL/min/1.73m. These patients can be expected to have a higher steady-state concentration for a given daily dose than those with normal or mild-moderate renal impairment, and therefore may respond to smaller or less frequent doses. Doses may be adjusted based on clinical observation.
Renal Impairment Not Due to Diabetic Nephropathy: For patients with significant renal impairment not due to diabetic nephropathy, initial daily dosage of captopril should be reduced, and smaller increments utilized for titration, which should be quite slow (1- to 2-week intervals). After the desired therapeutic effect has been achieved, the dose should be slowly back-titrated to determine the minimal effective dose. When concomitant diuretic therapy is required, a loop diuretic (e.g., furosemide), rather than a thiazide diuretic, is preferred in these patients with impaired renal function (see Precautions, Anaphylactoid Reactions During Membrane Exposure).
SuppliedSupplied: 12.5 mg: Each white, capsule-shaped tablet with beveled edge, slightly mottled flat-faced, with partial bisect bars on both sides, engraved with CAPOTEN on one side and 12.5 on the other, contains: captopril 12.5 mg. Nonmedicinal ingredients: cornstarch, lactose, microcrystalline cellulose and stearic acid. May contain hydroxypropylcellulose and hydroxypropyl methylcellulose. Bottles of 100 and 500.
25 mg: Each white, square tablet, quadrisect scored on one side and imprinted CAPOTEN 25 on the other, contains: captopril 25 mg. Nonmedicinal ingredients: cornstarch, lactose, microcrystalline cellulose and stearic acid. May contain hydroxypropylcellulose and hydroxypropyl methylcellulose. Bottles of 1 000.
50 mg: Each white, oval tablet, biconvex with a full bisecting score on one side and imprinted CAPOTEN 50 on the other, contains: captopril 50 mg. Nonmedicinal ingredients: cornstarch, lactose, microcrystalline cellulose and stearic acid. May contain hydroxypropylcellulose and hydroxypropyl methylcellulose. Bottles of 100 and 500.
100 mg: Each white, oval tablet, biconvex with a full bisecting score on one side and imprinted CAPOTEN 100 on the other, contains: captopril 100 mg. Nonmedicinal ingredients: cornstarch, lactose, microcrystalline cellulose and stearic acid. May contain hydroxypropylcellulose and hydroxypropyl methylcellulose. Bottles of 100.
Store at room temperature (15 to 30°C). Protect from moisture. Keep bottles tightly closed. (Shown in Product Recognition Section)
CAPOTEN Squibb Captopril Angiotensin Converting Enzyme Inhibitor
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