Continuing Education Activity

Captopril is an FDA-approved medication used in the management of hypertension, left ventricular dysfunction after myocardial infarction, and diabetic nephropathy. Off-label indications include acute hypertensive crisis and Raynaud phenomenon. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of captopril, pertinent for clinicians and other interprofessional team members to be familiar with to ensure appropriate administration of captopril.

Objectives:

• Describe the mechanism of action of captopril.
• Identify the FDA and off-label indications for captopril.
• Review the potential adverse effects of captopril.
• Summarize the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients receiving treatment with captopril.

Indications

FDA-approved Indications

Hypertension

• Initial therapy for patients with normal renal function.
• In patients with impaired renal function, captopril should be reserved for those patients that have developed unacceptable side effects or failed to respond to other drug therapy.[1]
• Effective alone and in combination with other antihypertensive agents.

Left Ventricular Dysfunction after Myocardial Infarction

• Improves survival following myocardial infarction in clinically stable patients with left ventricular ejection fraction less than 40% and reduces the incidence of hospitalization.[1]
• It prevents remodeling and reduces cardiovascular mortality in patients with heart failure.

Diabetic Nephropathy

• Diabetic nephropathy is the leading cause of end-stage kidney disease (ESKD) in developed countries. It is due to microvessel disease and can occur in Type I diabetes mellitus and diabetes mellitus type 2. Early treatment can prevent or slow the onset of diabetic nephropathy.[2]
• Hyperglycemia leads to the production of reactive oxygen species and leads to the production of advanced glycation end products (AGE) and cytokines (IL-6, MCP-1, TGF-beta, VEGF), which cause inflammation and fibrosis, leading to increased vascular permeability and albuminuria. Kimmelstiel-Wilson nodules, glomerular basement membrane thickening, and glomerular sclerosis are the pathological manifestations seen in diabetic nephropathy. The duration of diabetes, poor glycemic control, uncontrolled hypertension, obesity, smoking, and hyperlipidemia are major risk factors for developing diabetic nephropathy (DN).[2]
• It can be diagnosed by constant albuminuria on two or more occasions separated by three months. Persistent albuminuria is defined as greater than 300 mg over 24 hours or greater than 200 micrograms per minute, while moderately increased albuminuria is when the urine albumin is 30 to 300 mg over 24 hours and is a sign of early diabetic nephropathy. Other important criteria to diagnose include elevated blood pressure, the decline in GFR, and persistent albuminuria (greater than 300 mg/d) on at least two occasions 3 to 6 months apart.[2]
• Treatment of diabetic nephropathy (proteinuria greater than 500 mg per day) in patients with type I insulin-dependent diabetes mellitus and retinopathy.[2]
• Decreases the rate of progression of renal insufficiency by controlling blood pressure. With chronic renal failure, ACE inhibitor or ARBs needs to be dose adjusted for patients with renal impairment.[1]
• Treatment involves smoking cessation, good glycemic control, good blood pressure control (130/80 or less in diabetic patients), inhibition of the renin-angiotensin-aldosterone system with ARBs or ACE inhibitors.
• An angiotensin-converting enzyme (ACE) inhibitor, captopril, is FDA-approved to treat diabetic nephropathy. Enalapril is not FDA-approved to treat diabetic nephropathy.[2]

Off-labeled Uses

Acute Hypertensive Crisis

• Maybe given sublingually, but the therapeutic advantage has not been demonstrated over oral administration.[3]
• Consider alternative therapy if blood pressure does not normalize within 20 to 30 minutes.[4]

Raynaud Phenomenon

• Clinically, it is characterized by discoloration of the fingers due to stressors like cold or emotion. Raynaud disease is when this phenomenon occurs without any underlying condition, while Raynaud syndrome occurs due to an underlying condition. This disease most commonly affects females with an age of onset less than 30 years old. Fingers are more commonly affected than toes. Some common risk factors include family history, history of autoimmune diseases, and exposure to beta-blockers[5]
• This occurs due to the vasospasm of blood vessels to the skin, which causes impaired vasodilation and vasoconstriction. Most patients have all three phases with white (suggesting ischemic process), blue (indicating hypoxia and cyanosis), and pink (indicating reperfusion), while some have only a few phases. Patients can also present with ulcers and gangrene due to reduced perfusion.[5]
• It is diagnosed clinically, and a cold stimulation test can be used to precipitate an attack. Labs are needed only if another condition is suspected. Treatment involves avoiding cold and smoking cessation. Medical management consists of the use of dihydropyridine-type calcium channel blockers (nifedipine, nimodipine), phosphodiesterase inhibitors, and some studies have highlighted that captopril decreases the frequency and the severity of ischaemic attacks in patients with Raynaud disease but not in patients with scleroderma. However, more definitive studies are needed to elucidate its effects.[5]
• A clinical trial evaluated patients for up to three months; additional studies are necessary to determine full effectiveness.[6]

Mechanism of Action

The benefits of captopril in hypertension and heart failure result primarily from suppressing the renin-angiotensin-aldosterone system (RAAS).[7] An angiotensin-converting enzyme (ACE) inhibitor inhibits ACE, converting angiotensin I to angiotensin II. Angiotensin II binds to AT1 receptors on smooth muscles to produce vasoconstriction of precapillary arterioles and postcapillary venules, inhibits the reuptake of norepinephrine, and release of catecholamines from the adrenal medulla, which all increases blood pressure. Angiotensin II also stimulates the adrenal cortex to secrete aldosterone. Aldosterone causes the distal tubules and collecting ducts of the kidneys to reabsorb water and sodium in exchange for potassium, which results in an expansion in extracellular volume and an increase in blood pressure.[8]

ACE inhibition leads to decreased plasma angiotensin II, leading to vasodilation and decreased aldosterone secretion. Small increases in serum potassium and sodium and fluid loss may occur due to decreased aldosterone secretion.[1] Administration of captopril results in a reduction of peripheral arterial resistance in hypertensive patients. Regarding the cardiovascular system, ACE inhibitors reduce preload by causing vasodilation and natriuresis, reduce afterload by inhibiting the formation of angiotensin II. The overall effect is the improvement of cardiac output and reduced blood pressure.[9] ACE also metabolizes bradykinin, a peptide that causes vasodilation. ACE inhibitors impede the breakdown of bradykinin, resulting in vasodilation and a bradykinin-evoked cough. The only two ACE inhibitors that do not have to be activated in the body to be effective are lisinopril and captopril while others need to be activated to be effective.[9]

Administration

Captopril should be taken 1 hour before meals. Therapy initiation requires analysis of recent antihypertensive drug treatment, the extent of blood pressure elevation, and salt restriction. If possible, the previous antihypertensive drug regimen should be stopped one week before starting captopril. The daily dose of captopril may be increased every 24 hours under continuous medical supervision. For patients with significant renal impairment, the initial daily dosage should be reduced and smaller increments utilized for titration. 

Hypertension

• Initial dose: 25 mg twice per day (BID) or three times per day (TID)
• Unsatisfactory reduction of blood pressure after one to two weeks: Increase the dose to 50 mg BID or TID.
• The dose of captopril may increase to 100 mg BID or TID and, if necessary, to 150 mg BID or TID if further blood pressure reduction is required.
• The usual dose range is 25 to 150 mg BID or TID. The maximum daily dose of 450 mg should not be exceeded.[10]

Heart Failure

• Initial dose in patients vigorously treated with diuretics, hyponatremic and hypovolemic patients: 6.25 or 12.5 mg TID with titration to the usual daily dosage within several days.[11]
• The initial dose in most patients: 25 mg TID
  • After a dose of 50 mg TID, further increases in dosage should delay for at least two weeks.[11]

Left Ventricular Dysfunction after Myocardial Infarction

• After a single dose of 6.25 mg, captopril therapy should be initiated at 12.5 mg TID and then increased to 25 mg TID during several days
• Long-term use: target maintenance dose of 50 mg TID
• Therapy can be initiated as early as three days following myocardial infarction.[12] 

Diabetic Nephropathy

• Long-term use: 25 mg TID[13]

Acute Hypertensive Crisis

• Dosed orally, sublingually 25 mg; consider alternative therapy if blood pressure is nonresponsive within 20 to 30 minutes.[4]

Raynaud Phenomenon

• Initial dose 12.5 mg twice daily; may be gradually increased to 25 mg TID.[6] The starting dose may be gradually increased to 25 mg three times daily
• Neutropenia is a common adverse event with captopril administration in patients with the Raynaud phenomenon.

Specific Patient Population

• Pregnancy: Category D
  • Drug use that acts 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.[14]
  • Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.[14]
  • Captopril must be discontinued as soon as possible when pregnancy is confirmed.
• Breastfeeding Patients
  • Present in breast milk at an approximate concentration of 1% of those in maternal blood.
  • It may consider acceptable for use in breastfeeding.
  • Monitor the weight of the breastfeeding child for the first four weeks.[15]

Adverse Effects

Adverse Effects

• Paroxysmal cough (1% to 10%)[9]
• Proteinuria (1 of 100 patients), which subsides or clears within six months even when captopril therapy is continued[16]
• Renal insufficiency, renal failure, nephrotic syndrome, polyuria, oliguria, and urinary frequency (1 to 2 of 1000 patients)[14]
• Neutropenia (less than 1000/mm3) or agranulocytosis with myeloid hypoplasia
• Rash with pruritus and occasionally with fever, arthralgia, and eosinophilia (4 to 7 of 100 patients)[16]
• Angina pectoris, myocardial infarction, Raynaud syndrome, and congestive heart failure (2 to 3 of 1000 patients)[17]
• Dysgeusia (diminution or loss of taste perception) reversible and usually self-limited (2 to 4 of 100 patients).[17]
• Anaphylactoid and other related reactions due to the inhibition of the metabolism of eicosanoids and polypeptides, including bradykinin
• In terms of angioedema, it can occur in any region such as the intestine but angioedema of the tongue, glottis, or larynx cause obstruction of the airway. The prevalence of angioedema is higher in the African-American population. Treatment for angioedema involving the airways involves immediate stabilization with an endotracheal tube until the swelling resolves. Many pharmacological agents like diphenhydramine, methylprednisolone, epinephrine, or bradykinin blocking agents have been tried as treatment without a definitive answer[9] 
• Intestinal angioedema- abdominal pain with or without nausea vomiting[16]
• Flushing or pallor 
• Tachycardia, chest pain, and palpitations
• Hypotension[9]
• ACE inhibitors may cause hyperkalemia. Individuals who are more prone to developing hyperkalemia have a history of renal impairment and/or diabetes, concurrent use of potassium-sparing diuretics, and/or potassium supplements. Treatment planning should also consider factors such as potassium levels, EKG changes, and the patient’s renal function and urine production.[9] There has been one case of sudden death in a patient who was taking an ACE inhibitor and trimoxazole at the same time. Hyperkalemia was assumed to be the cause since it can trigger lethal arrhythmias.[9] Symptoms of hyperkalemia can range from nausea, palpitations, muscle pain, or paresthesia. Electrocardiography (ECG) monitoring is required in patients with serum potassium >6.5 mmol/l. ECG changes may present as non-specific repolarization abnormalities, peaked T-waves, widening of QRS, and ST-segment depression. Treatment involves immediate stabilization of cardiac myocytes with calcium gluconate, dextrose, and insulin infusion or the use of beta-agonists. The last step consists of removing total body potassium using loop diuretics, polystyrene sulfonate, or hemodialysis.[18]

Precautions

• Hypertension: Increases in BUN and serum creatinine have been observed in some patients with renal disease.[14]
• Heart failure: Elevations of BUN and serum creatinine greater than 20% above normal or baseline with long-term treatment[11]
• Hyperkalemia: Elevations in serum potassium
• Surgery/Anesthesia: In patients undergoing major surgery with anesthesia with agents that produce hypotension, captopril will block angiotensin II formation, and hypotension may result.
• Captopril should not be coadministered with aliskiren in patients with diabetes mellitus.[2]

Contraindications

• Hypersensitivity to captopril, any component of the formulation, or any other ACEI
• Angioedema related to previous treatment with ACEI
• Concomitant aliskiren use in patients with diabetes mellitus[2]
• Coadministration with or within 36 hours of switching to or from a neprilysin inhibitor (sacubitril)

Monitoring

In general, the patient's BUN, electrolytes, serum creatinine, and blood pressure require routine monitoring. 

If captopril is initiated in patients with impaired renal function and/or collagen vascular disease, the complete blood count with differential should be evaluated before starting treatment and at two-week intervals for about three months, then periodically after that.[14]

All patients treated with captopril receive counsel to report any signs of infection, including sore throat or fever. Patients with heart failure should be followed closely for the first two weeks of treatment and whenever the dose of captopril is titrated, especially in patients with preexisting hypotension, hyponatremia, diabetes, azotemia, or those taking potassium supplements due to the potential for excessive hypotension, arrhythmia and conduction defects.[19] 

According to the latest hypertension guidelines, patients with or without CVD or increased ASVD risk should maintain a blood pressure of less than 130/80 mm Hg while on therapy. On the other hand, according to the diabetes guidelines, adult patients (18 to 65 years) with both diabetes and hypertension have a goal blood pressure of less than 140/90 mm Hg.[20]

Toxicity

Correction of hypotension is the primary concern through volume expansion with an intravenous infusion of normal saline. Excessive hypotension has been rarely seen in hypertensive patients but is a possible consequence of captopril use in salt/volume depleted persons. ACE inhibitors have rarely shown an association with a syndrome that begins with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death.[1] If a marked elevation of hepatic transaminases or jaundice occurs, captopril should be discontinued. A persistent, dry, hacking, nonproductive cough that occurs within the first few months of treatment can also occur with captopril therapy. ACE inhibitor-induced cough results from the inhibition of the degradation of bradykinin and generally resolve within 1 to 4 weeks after discontinuation.

Enhancing Healthcare Team Outcomes

Captopril is a widely prescribed drug in clinical medicine. All interprofessional healthcare team members need to work collaboratively and communicate openly to maximize therapeutic results. Clinicians (physicians, physician assistants, and nurse practitioners) who prescribe this medication for hypertension should be aware of its side effects and the need to monitor electrolytes and renal function. In some patients, captopril may produce a chronic cough, and in such scenarios, the drug should be discontinued, and another class of antihypertensive medication should be used. Nursing can provide patient counseling and answer questions. The pharmacist should keep track of the patient's medications to avoid polypharmacy and drug interactions and counsel the patient. This interprofessional approach will optimize patient outcomes. [Level 5]