"What are ACE inhibitors and how do they work?
The class of drugs called angiotensin converting enzyme (ACE) inhibitors, as the class name suggests, reduces the activity of angiotensin converting enzyme. ACE converts angiotensin I pr"...
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Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including CAPOTEN) may be subject to a variety of adverse reactions, some of them serious.
Head and Neck Angioedema
Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been seen in patients treated with ACE inhibitors, including captopril. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Emergency therapy, including but not necessarily limited to, subcutaneous administration of a 1:1000 solution of epinephrine should be promptly instituted.
Swelling confined to the face, mucous membranes of the mouth, lips and extremities has usually resolved with discontinuation of captopril; some cases required medical therapy. (See : PATIENT INFORMATION and ADVERSE REACTIONS.)
Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Anaphylactoid reactions during desensitization
Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid reactions during membrane exposure
Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
Neutropenia (<1000/mm³) with myeloid hypoplasia has resulted from use of captopril. About half of the neutropenic patients developed systemic or oral cavity infections or other features of the syndrome of 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 vascular disease), neutropenia has been seen in one 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 foreign marketing experience in patients with renal failure, use of allopurinol concomitantly with captopril has been associated with neutropenia but this association has not appeared in U.S. reports.
In patients with collagen vascular diseases (e.g., systemic lupus erythematosus, scleroderma) and impaired renal function, neutropenia occurred in 3.7 percent 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 percent were in patients also receiving procainamide. In heart failure, it appears that the same risk factors for neutropenia are present.
The neutropenia has usually been detected within three 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 two weeks after captopril was discontinued, and serious infections were limited to clinically complex patients. About 13 percent 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 two-week intervals for about three 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 <1000/mm3) the physician should withdraw captopril and closely follow the patient's course.
Total urinary proteins greater than 1 g per day were seen in about 0.7 percent of patients receiving captopril. About 90 percent of affected patients had evidence of prior renal disease or received relatively high doses of captopril (in excess of 150 mg/day), or both. The nephrotic syndrome occurred in about one-fifth of proteinuric patients. In most cases, proteinuria subsided or cleared within six months whether or not captopril was continued. Parameters of renal function, such as BUN and creatinine, were seldom altered in the patients with proteinuria.
Excessive hypotension was rarely seen in hypertensive patients but is a possible consequence of captopril use in salt/volume depleted persons (such as those treated vigorously with diuretics), patients with heart failure or those patients undergoing renal dialysis. (See PRECAUTIONS: DRUG INTERACTIONS.)
In heart failure, where the blood pressure was either normal or low, transient decreases in mean blood pressure greater than 20 percent were recorded in about half of the patients. This transient hypotension is more likely to occur after any of the first several doses and is usually well tolerated, producing 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 percent of patients with heart failure.
BECAUSE OF THE POTENTIAL FALL IN BLOOD PRESSURE IN THESE PATIENTS, THERAPY SHOULD BE STARTED UNDER VERY CLOSE MEDICAL SUPERVISION.
A starting dose of 6.25 or 12.5 mg t.i.d. may minimize the hypotensive effect. Patients should be followed closely for the first two weeks of treatment and whenever the dose of captopril and/or diuretic is increased. In patients with heart failure, reducing the dose of diuretic, if feasible, may minimize the fall in blood pressure.
Hypotension is not per se a reason to discontinue captopril. Some decrease of systemic blood pressure is a common and desirable observation upon initiation of CAPOTEN (captopril tablets, USP) treatment in heart failure. The magnitude of the decrease is greatest early in the course of treatment; this effect stabilizes within a week or two, and generally returns to pretreatment levels, without a decrease in therapeutic efficacy, within two months.
Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Capoten as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the reninangiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mothers and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Capoten, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Capoten for hypotension, oliguria, and hyperkalemia. [See PRECAUTIONS, Pediatric Use].
When captopril was given to rabbits at doses about 0.8 to 70 times (on a mg/kg basis) the maximum recommended human dose, low incidences of craniofacial malformations were seen. No teratogenic effects of captopril were seen in studies of pregnant rats and hamsters. On a mg/kg basis, the doses used were up to 150 times (in hamsters) and 625 times (in rats) the maximum recommended human dose.
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
Impaired Renal Function
Hypertension - Some patients with renal disease, particularly those with severe renal artery stenosis, have developed increases in BUN and serum creatinine after reduction of blood pressure with captopril. Captopril dosage reduction and/or discontinuation of diuretic may be required. For some of these patients, it may not be possible to normalize blood pressure and maintain adequate renal perfusion.
Heart Failure - About 20 percent of patients develop stable elevations of BUN and serum creatinine greater than 20 percent above normal or baseline upon long-term treatment with captopril. Less than 5 percent of patients, generally those with severe preexisting renal disease, required discontinuation of treatment due to progressively increasing creatinine; subsequent improvement probably depends upon the severity of the underlying renal disease.
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 in a trial of type I diabetic patients with proteinuria, the incidence of withdrawal of treatment with captopril for hyperkalemia was 2% (4/207). In two trials of normotensive type I diabetic patients with microalbuminuria, no captopril group subjects had hyperkalemia (0/116). (See: PATIENT INFORMATION and DRUG INTERACTIONS; ADVERSE REACTIONS: Altered Laboratory Findings.)
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of 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 as others.
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. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
Recent clinical observations have shown an association of hypersensitivity-like (anaphylactoid) reactions during hemodialysis with high-flux dialysis membranes (e.g., AN69) in patients receiving ACE inhibitors. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of medication. (See WARNINGS: Anaphylactoid reactions during membrane exposure.)
Carcinogenesis, Mutagenesis, Impairment of Fertility
Two-year studies with doses of 50 to 1350 mg/kg/day in mice and rats failed to show any evidence of carcinogenic potential. The high dose in these studies is 150 times the maximum recommended human dose of 450 mg, assuming a 50-kg subject. On a body-surface-area basis, the high doses for mice and rats are 13 and 26 times the maximum recommended human dose, respectively.
Studies in rats have revealed no impairment of fertility.
Concentrations of captopril in human milk are approximately one percent of those in maternal blood. Because of the potential for serious adverse reactions in nursing infants from captopril, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of CAPOTEN to the mother. (See PRECAUTIONS: Pediatric Use.)
Neonates with a history of in utero exposure to Capoten.
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. While captopril may be removed from the adult circulation by hemodialysis, there is inadequate data concerning the effectiveness of hemodialysis for removing it from the circulation of neonates or children. Peritoneal dialysis is not effective for removing captopril; there is no information concerning exchange transfusion for removing captopril form the general circulation.
Safety and effectiveness in pediatric patients have not been established. There is limited experience reported in the literature with the use of captopril in the pediatric population; dosage, on a weight basis, was generally reported to be comparable to or less than that used in adults.
Infants, especially newborns, may be more susceptible to the adverse hemodynamic effects of captopril. Excessive, prolonged and unpredictable decreases in blood pressure and associated complications, including oliguria and seizures, have been reported.
CAPOTEN should be used in pediatric patients only if other measures for controlling blood pressure have not been effective.
Last reviewed on RxList: 10/9/2012
This monograph has been modified to include the generic and brand name in many instances.
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