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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(KAP toe pril)
Generic Available (U.S.)
Yes
Index Terms
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Management of hypertension; treatment of heart failure, left ventricular dysfunction after myocardial infarction, diabetic nephropathy
Use: Unlabeled
To delay the progression of nephropathy and reduce risks of cardiovascular events in hypertensive patients with type 1 or 2 diabetes mellitus; treatment of hypertensive crisis, rheumatoid arthritis; diagnosis of anatomic renal artery stenosis, hypertension secondary to scleroderma renal crisis; diagnosis of aldosteronism, idiopathic edema, Bartter's syndrome, postmyocardial infarction for prevention of ventricular failure; increase circulation in Raynaud's phenomenon, hypertension secondary to Takayasu's disease
Pregnancy Risk Factor
D
Pregnancy Considerations
[U.S. Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected. Captopril crosses the placenta; teratogenic effects may occur following maternal use during pregnancy. Drugs that act on the renin-angiotensin system are associated with oligohydramnios. Oligohydramnios, due to decreased fetal renal function, may lead to fetal lung hypoplasia and skeletal malformations. Their use in pregnancy is also associated with anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate. Chronic maternal hypertension itself is also associated with adverse events in the fetus/infant. ACE inhibitors are not recommended during pregnancy to treat maternal hypertension or heart failure. Use of an ACE inhibitor should also be avoided in any woman of reproductive age. Women who are planning a pregnancy should be considered for other medication options if an ACE inhibitor is currently prescribed or the ACE inhibitor should be discontinued as soon as possible once pregnancy is detected. The exposed fetus should be monitored for fetal growth, amniotic fluid volume, and organ formation. Infants exposed to an ACE inhibitor in utero should be monitored for hyperkalemia, hypotension, and oliguria.
Lactation
Enters breast milk/not recommended (AAP rates “compatible”; AAP 2001 update pending)
Breast-Feeding Considerations
Captopril is excreted in breast milk. Breast-feeding is not recommended by the manufacturer.
Contraindications
Hypersensitivity to captopril, any other ACE inhibitor, or any component of the formulation; angioedema related to previous treatment with an ACE inhibitor
Warnings/Precautions
Boxed warnings:
• Pregnancy: See “Special populations” below.
Concerns related to adverse effects:
• Angioedema: At any time during treatment (especially following first dose) angioedema may occur rarely with ACE inhibitors; it may involve the head and neck (potentially compromising airway) or the intestine (presenting with abdominal pain). African-Americans and patients with idiopathic or hereditary angioedema may be at an increased risk. Prolonged frequent monitoring may be required especially if tongue, glottis, or larynx are involved as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Aggressive early and appropriate management is critical. Use in patients with previous angioedema associated with ACE inhibitor therapy is contraindicated.
• Cholestatic jaundice: A rare toxicity associated with ACE inhibitors includes cholestatic jaundice, which may progress to fulminant hepatic necrosis; discontinue if marked elevation of hepatic transaminases or jaundice occurs.
• Cough: An ACE inhibitor cough is a dry, hacking, nonproductive one that usually occurs within the first few months of treatment and should generally resolve within 1-4 weeks after discontinuation of the ACE inhibitor. Other causes of cough should be considered (eg, pulmonary congestion in patients with heart failure) and excluded prior to discontinuation.
• Hyperkalemia: May occur with ACE inhibitors; risk factors include renal dysfunction, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salts. Use cautiously, if at all, with these agents and monitor potassium closely.
• Hypersensitivity reactions: Anaphylactic/anaphylactoid reactions can occur with ACE inhibitors. Severe anaphylactoid reactions may be seen during hemodialysis (eg, CVVHD) with high-flux dialysis membranes (eg, AN69), and rarely, during low density lipoprotein apheresis with dextran sulfate cellulose. Rare cases of anaphylactoid reactions have been reported in patients undergoing sensitization treatment with hymenoptera (bee, wasp) venom while receiving ACE inhibitors.
• Hypotension/syncope: Symptomatic hypotension with or without syncope can occur with ACE inhibitors (usually with the first several doses); effects are most often observed in volume-depleted patients; correct volume depletion prior to initiation; close monitoring of patient is required especially with initial dosing and dosing increases; blood pressure must be lowered at a rate appropriate for the patient's clinical condition. Although dose reduction may be necessary, hypotension is not a reason for discontinuation of future ACE inhibitor use especially in patients with heart failure where a reduction in systolic blood pressure is a desirable observation.
• Neutropenia/agranulocytosis: Captopril has been associated with rare cases of agranulocytosis, neutropenia, or leukopenia with myeloid hypoplasia. Patients with renal impairment are at high risk of developing neutropenia. Patients with both renal impairment and collagen vascular disease (eg, systemic lupus erythematosus) are at an even higher risk of developing neutropenia. Closely monitor CBC with differential for the first 3 months of therapy and periodically thereafter in these patients. Onset of neutropenia is usually within 3 months of captopril initiation. Neutrophil count generally returns to baseline within 2 weeks of discontinuation.
• Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose glomerular filtration rate (GFR) is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function.
Disease-related concerns:
• Aortic stenosis: Use with caution in patients with severe aortic stenosis; may reduce coronary perfusion resulting in ischemia.
• Cardiovascular disease: Initiation of therapy in patients with ischemic heart disease or cerebrovascular disease warrants close observation due to the potential consequences posed by falling blood pressure (eg, MI, stroke). Fluid replacement, if needed, may restore blood pressure; therapy may then be resumed. Discontinue therapy in patients whose hypotension recurs.
• Collagen vascular disease: Use with caution in patients with collagen vascular disease especially with concomitant renal impairment; may be at increased risk for hematologic toxicity.
• Hypertrophic cardiomyopathy (HCM) with outflow tract obstruction: Use with caution in patients with HCM and outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition.
• Renal artery stenosis: Use with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks.
• Renal impairment: Use with caution in pre-existing renal insufficiency; dosage adjustment may be needed. Avoid rapid dosage escalation which may lead to further renal impairment.
Concurrent drug therapy issues:
• Angiotensin receptor blockers: Concurrent use of angiotensin receptor blockers may increase the risk of clinically-significant adverse events (eg, renal dysfunction, hyperkalemia).
Special populations:
• Pregnancy: [U.S. Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.
Other warnings/precautions:
• Surgery: Use with caution before, during, or immediately after major surgery. Cardiopulmonary bypass, intraoperative blood loss or vasodilating anesthesia increases endogenous renin release. Use of ACE inhibitors perioperatively will blunt angiotensin II formation and may result in hypotension.
Adverse Reactions
Frequency not defined:
Cardiovascular: Angioedema, cardiac arrest, cerebrovascular insufficiency, rhythm disturbances, orthostatic hypotension, syncope, flushing, pallor, angina, MI, Raynaud's syndrome, CHF
Central nervous system: Ataxia, confusion, depression, nervousness, somnolence
Dermatologic: Bullous pemphigus, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis
Endocrine & metabolic: Alkaline phosphatase increased, bilirubin increased, gynecomastia
Gastrointestinal: Pancreatitis, glossitis, dyspepsia
Genitourinary: Urinary frequency, impotence
Hematologic: Anemia, thrombocytopenia, pancytopenia, agranulocytosis, anemia
Hepatic: Jaundice, hepatitis, hepatic necrosis (rare), cholestasis, hyponatremia (symptomatic), transaminases increased
Neuromuscular & skeletal: Asthenia, myalgia, myasthenia
Ocular: Blurred vision
Renal: Renal insufficiency, renal failure, nephrotic syndrome, polyuria, oliguria
Respiratory: Bronchospasm, eosinophilic pneumonitis, rhinitis
Miscellaneous: Anaphylactoid reactions
1% to 10%:
Cardiovascular: Hypotension (1% to 3%), tachycardia (1%), chest pain (1%), palpitation (1%)
Dermatologic: Rash (maculopapular or urticarial) (4% to 7%), pruritus (2%); in patients with rash, a positive ANA and/or eosinophilia has been noted in 7% to 10%.
Endocrine & metabolic: Hyperkalemia (1% to 11%)
Hematologic: Neutropenia may occur in up to 4% of patients with renal insufficiency or collagen-vascular disease.
Renal: Proteinuria (1%), serum creatinine increased, worsening of renal function (may occur in patients with bilateral renal artery stenosis or hypovolemia)
Respiratory: Cough (<1% to 2%)
Miscellaneous: Hypersensitivity reactions (rash, pruritus, fever, arthralgia, and eosinophilia) have occurred in 4% to 7% of patients (depending on dose and renal function); dysgeusia - loss of taste or diminished perception (2% to 4%)
<1% (Limited to important or life-threatening; frequency ≤ to placebo): Gastric irritation, abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation, aphthous ulcers, peptic ulcer, dizziness, headache, malaise, fatigue, insomnia, xerostomia, dyspnea, alopecia, paresthesia, angina, glomerulonephritis, cholestatic jaundice, psoriasis, hyperthermia, myalgia, arthralgia
Postmarketing and/or case reports: Aplastic anemia, hemolytic anemia, bronchospasm, alopecia, systemic lupus erythematosus, Kaposi's sarcoma, pericarditis, exacerbations of Huntington's disease, Guillain-Barré syndrome, seizure (in premature infants). A syndrome which may include fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash, eosinophilia, and elevated ESR has been reported for captopril and other ACE inhibitors.
Metabolism/Transport Effects
Substrate of CYP2D6 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Drug Interactions
Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Risk D: Consider therapy modification
Alfuzosin: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Allopurinol: ACE Inhibitors may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Risk D: Consider therapy modification
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy
Antacids: May decrease the serum concentration of ACE Inhibitors. Management: Separate fosinopril administration from antacids by at least 2 hours. US and Canadian recommendations for use of other ACE- inhibitors with antacids may vary. Consult appropriate labeling. Monitor for decreased therapeutic effects of ACE-inhibitors. Risk D: Consider therapy modification
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Aprotinin: May diminish the antihypertensive effect of ACE Inhibitors. Risk C: Monitor therapy
AzaTHIOprine: ACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine. Risk C: Monitor therapy
CycloSPORINE: ACE Inhibitors may enhance the nephrotoxic effect of CycloSPORINE. Risk D: Consider therapy modification
CycloSPORINE (Systemic): ACE Inhibitors may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Risk D: Consider therapy modification
CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification
Darunavir: May increase the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
DPP-IV Inhibitors: May enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Eplerenone: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Everolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy
Ferric Gluconate: ACE Inhibitors may enhance the adverse/toxic effect of Ferric Gluconate. Risk C: Monitor therapy
Gold Sodium Thiomalate: ACE Inhibitors may enhance the adverse/toxic effect of Gold Sodium Thiomalate. An increased risk of nitritoid reactions has been appreciated. Risk C: Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy
Icatibant: May diminish the antihypertensive effect of ACE Inhibitors. Risk C: Monitor therapy
Iron Dextran Complex: ACE Inhibitors may enhance the adverse/toxic effect of Iron Dextran Complex. Specifically, patients receiving an ACE inhibitor may be at an increased risk for anaphylactic-type reactions. Management: Follow iron dextran recommendations closely regarding both having resuscitation equipment and trained personnel on-hand prior to iron dextran administration and the use of a test dose prior to the first therapeutic dose. Risk D: Consider therapy modification
Lanthanum: May decrease the serum concentration of ACE Inhibitors. Management: Administer angiotensin-converting enzyme inhibitors at least two hours before or after lanthanum. Risk D: Consider therapy modification
Lithium: ACE Inhibitors may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an ACE inhibitor. Monitor patient response to lithium closely following addition or discontinuation of concurrent ACE inhibitor treatment. Risk D: Consider therapy modification
Loop Diuretics: May enhance the hypotensive effect of ACE Inhibitors. Specifically, postural hypotension which can accompany ACE Inhibitor initiation. Loop Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Risk C: Monitor therapy
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: ACE Inhibitors may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of ACE Inhibitors. Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Potassium Salts: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Salicylates: May diminish the antihypertensive effect of ACE Inhibitors. They may also diminish other beneficial pharmacodynamic effects desired for the treatment of CHF. The effects are likely dose-related. 100 mg doses aspirin appear to cause no problems, whereas 300 mg doses appear to significantly affect ACE Inhibitor efficacy. Risk C: Monitor therapy
Sirolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy
Sodium Phosphates: ACE Inhibitors may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with ACEIs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Risk D: Consider therapy modification
Temsirolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy
Thiazide Diuretics: May enhance the hypotensive effect of ACE Inhibitors. Specifically, postural hypotension which can accompany ACE Inhibitor initiation. Thiazide Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Risk C: Monitor therapy
TiZANidine: May enhance the hypotensive effect of ACE Inhibitors. Risk C: Monitor therapy
Tolvaptan: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Trimethoprim: May enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Food: Captopril serum concentrations may be decreased if taken with food. Long-term use of captopril may lead to a zinc deficiency which can result in altered taste perception. Potassium supplements and/or potassium-containing salts may cause or worsen hyperkalemia. Management: Take on an empty stomach 1 hour before or 2 hours after meals. Consult prescriber before consuming a potassium-rich diet, potassium supplements, or salt substitutes.
Herb/Nutraceutical: Some herbal medications may worsen hypertension (eg, licorice); others may increase the antihypertensive effect of captopril (eg, shepherd's purse). Management: Avoid bayberry, blue cohosh, cayenne, ephedra, ginger, ginseng (American), kola, yohimbe, and licorice. Avoid black cohosh, california poppy, coleus, golden seal, hawthorn, mistletoe, periwinkle, quinine, and shepherd's purse.
Mechanism of Action
Competitive inhibitor of angiotensin-converting enzyme (ACE); prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor; results in lower levels of angiotensin II which causes an increase in plasma renin activity and a reduction in aldosterone secretion
Pharmacodynamics/Kinetics
Onset of action: Peak effect: Blood pressure reduction: 1-1.5 hours after dose
Duration: Dose related, may require several weeks of therapy before full hypotensive effect
Absorption: 60% to 75%; reduced 30% to 40% by food
Protein binding: 25% to 30%
Metabolism: 50%
Half-life elimination (renal and cardiac function dependent):
Adults, healthy volunteers: 1.9 hours; Heart failure: 2.06 hours; Anuria: 20-40 hours
Time to peak: 1 hour
Excretion: Urine (>95%) within 24 hours (40% to 50% as unchanged drug)
Dosage
Note: Titrate dose according to patient's response; use lowest effective dose. Oral:
Infants: Initial: 0.15-0.3 mg/kg/dose; titrate dose upward to maximum of 6 mg/kg/day in 1-4 divided doses
Children: Initial: 0.3-0.5 mg/kg/dose; titrate upward to maximum of 6 mg/kg/day in 2-4 divided doses (NHBPEP, 2004)
Older Children: Initial: 6.25-12.5 mg/dose every 12-24 hours; titrate upward to maximum of 6 mg/kg/day
Adolescents: Initial: 12.5-25 mg/dose; titrate to a maximum of 450 mg/day
Adults:
Acute hypertension (urgency/emergency): 12.5-25 mg, may repeat as needed (may be given sublingually, but no therapeutic advantage demonstrated)
Heart failure:
Initial dose: 6.25-12.5 mg 3 times/day in conjunction with cardiac glycoside and diuretic therapy; initial dose depends upon patient's fluid/electrolyte status
Target dose: 50 mg 3 times/day
Hypertension:
Initial dose: 25 mg 2-3 times/day (a lower initial dose of 12.5 mg 3 times/day may also be considered [VA Cooperative Study Group, 1984]); may increase by 12.5-25 mg/dose at 1- to 2-week intervals up to 50 mg 3 times/day; add thiazide diuretic, unless severe renal impairment coexists then consider loop diuretic, before further dosage increases or consider other treatment options; maximum dose: 150 mg 3 times/day
Usual dose range (JNC 7): 25-100 mg/day in 2 divided doses
LV dysfunction after MI: Initial: 6.25 mg; if tolerated, follow with 12.5 mg 3 times/day; then increase to 25 mg 3 times/day during next several days and then gradually increase over next several weeks to target dose of 50 mg 3 times/day (some dose schedules are more aggressive to achieve an increased goal dose within the first few days of initiation.)
Diabetic nephropathy: Initial: 25 mg 3 times/day. May be taken with other antihypertensive therapy if required to further lower blood pressure.
Elderly: Hypertension: Consider lower initial doses and titrate to response (Aronow, 2011)
Dosing adjustment in renal impairment:
Manufacturers recommendations: Reduce initial daily dose and titrate slowly (1- to 2-week intervals) with smaller increments. Slowly back titrate to determine the minimum effective dose once the desired therapeutic effect has been reached.
Alternative recommendations (Aronoff 2007): Adults:
Clcr 10-50 mL/minute: Administer at 75% of normal dose every 12-18 hours.
Clcr <10 mL/minute: Administer at 50% of normal dose every 24 hours.
Intermittent hemodialysis (IHD): Administer after hemodialysis on dialysis days
Peritoneal dialysis: Dose for Clcr 10-50 mL/minute; supplemental dose is not necessary
Administration: Oral
Unstable in aqueous solutions; to prepare solution for oral administration, mix prior to administration and use within 10 minutes.
Monitoring Parameters
BUN, electrolytes, serum creatinine; blood pressure. In patients with renal impairment and/or collagen vascular disease, closely monitor CBC with differential for the first 3 months of therapy and periodically thereafter.
Test Interactions
Positive Coombs' [direct]; may cause false-positive results in urine acetone determinations using sodium nitroprusside reagent
Dietary Considerations
Should be taken at least 1 hour before or 2 hours after eating.
Patient Education
Do not use potassium supplement or salt substitutes without consulting prescriber. Take first dose at bedtime. Take all doses on an empty stomach, 1 hour before or 2 hours after meals. This drug does not eliminate need for diet or exercise regimen as recommended by prescriber. May cause dizziness, fainting, lightheadedness, postural hypotension, nausea, vomiting, abdominal pain, dry mouth, or transient loss of appetite. Report immediately swelling or numbness of face, mouth, or throat; unusual chest pain or palpitations; decreased urinary output; fever or chills; swelling of extremities; skin rash; numbness, tingling, or pain in muscles; or respiratory difficulty or unusual cough.
Geriatric Considerations
Due to frequent decreases in glomerular filtration (also Clcr) with aging, elderly patients may have exaggerated responses to ACE inhibitors; differences in clinical response due to hepatic changes are not observed. ACE inhibitors may be preferred agents in elderly patients with congestive heart failure and diabetes mellitus. Diabetic proteinuria is reduced and insulin sensitivity is enhanced. In general, the side effect profile is favorable in the elderly and causes little or no CNS confusion; use lowest dose recommendations initially. Many elderly may be volume depleted due to diuretic use and/or blunted thirst reflex resulting in inadequate fluid intake.
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: In patients on chronic ACE inhibitor therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; however, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent. Episodes of intraoperative hypotension may be managed by fluid administration and/or modest doses of alpha-adrenergic agents. Patients who have undergone coronary artery bypass graft (CABG) surgery should have therapy reinstituted once the patient is stable or initiated in those who were not receiving ACE inhibition prior to CABG surgery; continue indefinitely (Hillis, 2011).
Cardiovascular Considerations
Heart Failure (HF): The ACC/AHA 2009 Heart Failure Guidelines recommend that ACE inhibitors be used in patients with a reduced EF (with or without HF symptoms) unless contraindicated. ACE inhibitors decrease morbidity and mortality in patients with asymptomatic and symptomatic left ventricular dysfunction. In this situation, they decrease hospitalizations for, and retard progression to, HF. When used in patients with HF, the target dose should be achieved, if possible. Lower daily doses of ACE inhibitors have demonstrated the same mortality effects as high doses, but have not decreased hospitalizations to the extent that high-dose ACE inhibitors have, as demonstrated in the ATLAS study (Packer, 1999).
Hypertension: The ALLHAT study (ALLHAT Collaborative Research Group, 2002) compared CV outcomes of lisinopril, amlodipine, or chlorthalidone in hypertensive patients having at least one other risk factor for coronary heart disease. Investigators found no difference between the groups on the primary outcome of fatal coronary disease or nonfatal MI. The ACC/AHA 2009 Heart Failure Guidelines suggest that ACE inhibitors or angiotensin receptor blockers (ARBs) can be beneficial in patients with hypertension and LVH without symptoms of HF. JNC 7 suggests that patients can benefit from treatment with an ACE inhibitor if they have hypertension and HF, acute myocardial infarction, high coronary disease risk, diabetes, chronic kidney disease, history of stroke.
Vascular Disease: The ACC/AHA 2009 Heart Failure Guidelines suggest that ACE inhibitors can be useful in preventing HF in patients who have a history of atherosclerotic vascular disease, diabetes, or hypertension with associated cardiovascular risk factors. The HOPE trial (Yusuf, 2000) investigated the value of an ACE inhibitor (ramipril 5-10 mg daily) versus placebo in patients who had evidence of vascular disease or diabetes (one other cardiovascular risk factor) and were at least 55 years of age. Patients were excluded if they had a low ejection fraction, HF, or were on an ACE inhibitor. The primary outcome was a composite of death from cardiovascular cause, myocardial infarction, or stroke; 9297 patients were enrolled and randomized. Ramipril significantly reduced the risk of death from CV causes, MI, or stroke over placebo. New cases of diabetes were also reduced in the ramipril group. In the EUROPA trial, patients with stable coronary artery disease (at low risk for cardiovascular events) received perindopril or placebo and were evaluated for incidence of cardiovascular events after 4 years of treatment. In this randomized, placebo-controlled, prospective study, 12,218 patients received either perindopril (8 mg/day, n=6110) or placebo (n=6108) and were assessed for the primary endpoint of a cardiovascular event, defined as cardiovascular death, myocardial infarction, or cardiac arrest. The study population was well balanced with respect to baseline demographics and concomitant medication use (including beta-blockers, platelet inhibitors, antihyperlipidemics, calcium channel blockers, nitrates, and diuretics). Intent-to-treat analysis revealed that 603 (10%) of placebo patients experienced the primary endpoint of a cardiovascular event compared to 488 (8%) of perindopril-receiving patients, for a 20% relative risk reduction (p=0.0003). This result was not influenced by presence of other comorbidities (eg, diabetes, hypertension) or concomitant beta-blocker, calcium channel blocker, or lipid-lowering therapies. Withdrawal from the study (postrandomization) due to adverse reactions was similar between treatment groups. Number needed to treat analysis suggests that treatment of 50 patients over a 4-year period will prevent one major cardiovascular event.
Acute Coronary Syndromes: In the treatment of unstable angina/non-ST-segment elevation MI, ACE inhibitors are recommended when hypertension persists despite treatment with nitroglycerin and a beta-blocker in patients with LV systolic dysfunction or HF and in ischemic patients with diabetes (Class I). ACE inhibitors are also recommended for all post-ACS individuals (Class IIa). According to 2004 ACC/AHA STEMI guidelines, an ACE inhibitor should be administered orally within the first 24 hours of STEMI to patients with anterior infarction, pulmonary congestion, or LVEF <0.4, in the absence of hypotension or known contraindications to this class of medicines. In the emergency management of complicated STEMI, a short-acting ACEI (eg, captopril 1-6.25 mg) may be added once the patient's systolic blood pressure is >100 mm Hg and not <30 mm Hg below baseline. The VALIANT trial evaluated the effects of valsartan (target dose: 160 mg twice daily), captopril (target dose: 50 mg twice daily), and the combination (target doses: valsartan 80 mg twice daily and captopril 150 mg once daily) in a randomized, double-blind trial of patients with acute MI (0.5-10 days post-MI) complicated by left ventricular systolic dysfunction, HF, or both. Enrollment in the study numbered 14,703 patients and followed for a median of 24.7 months. There was no difference in the primary endpoint (all cause mortality) among the 3 groups. There was no difference in incidence of CV death, recurrent MI, or hospitalization for HF either. Hypotension and renal dysfunction occurred significantly more often in the valsartan group than captopril alone. Cough, rash, and taste disturbances occurred more often in the captopril group. The authors (Pfeffer, 2003) concluded that valsartan is as effective as captopril in patients who are at high risk for cardiovascular events after MI. Combining valsartan with captopril increased the rate of adverse events without improving survival.
Potential Adverse Events: ACE inhibitor therapy may elicit rapid increases in potassium and creatinine, especially when used in patients with bilateral renal artery stenosis. Severe hypotension may occur in patients who are sodium- and/or volume-depleted; initiate lower doses and monitor closely when starting therapy in these patients. Aging patients with a decrease in glomerular filtration (also creatinine clearance), severe HF, and renal failure may experience an exaggerated response with administration of ACE inhibitors. In those patients experiencing cough on an ACE inhibitor, the ACE inhibitor may be discontinued and, if necessary, ARB therapy instituted. Because of the potent teratogenic effects of ACE inhibitors, these drugs should be avoided, if possible, when treating women of childbearing potential not on effective birth control measures.
Drug Interactions: Concomitant indomethacin therapy may blunt the reduction in sitting and 24-hour ambulatory diastolic blood pressure. Use of NSAIDs should be avoided or limited, with monitoring of blood pressure control in this setting. In patients with HF, NSAID use may be associated with an increased risk for fluid accumulation and edema.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Loss or diminished perception of taste and orthostatic hypotension.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause drowsiness or insomnia
Mental Health: Effects on Psychiatric Treatment
May rarely cause agranulocytosis; use caution with clozapine and carbamazepine; may decrease lithium clearance resulting in an increase in serum lithium levels and potential lithium toxicity; monitor serum lithium levels
Nursing: Physical Assessment/Monitoring
Assess other pharmacological or herbal products patient may be taking that may impact renal function. When beginning therapy, patient should be closely monitored for anaphylactic reaction or severe angioedema. Assess results of renal function tests. Monitor blood pressure. Monitor for hypovolemia, angioedema, and postural hypotension when beginning therapy, adjusting dosage, and on a regular basis throughout.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral: 12.5 mg, 25 mg, 50 mg, 100 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Captopril)
12.5 mg (100): $11.99
25 mg (90): $13.99
50 mg (100): $15.67
100 mg (90): $19.99
Extemporaneously Prepared
A 1 mg/mL oral solution may be made by allowing two 50 mg tablets to dissolve in 50 mL of distilled water. Add the contents of one 500 mg sodium ascorbate injection ampul or one 500 mg ascorbic acid tablet and allow to dissolve. Add quantity of distilled water sufficient to make 100 mL. Label “shake well” and “refrigerate”. Stable for 56 days refrigerated.
Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.
References
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International Brand Names
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Last full review/revision March 2012
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