Captopril

Captopril is an antihypertensive agent belonging to angiotensin-converting enzyme (ACE) inhibitors.

Captopril is approved for the treatment of Hypertension, left ventricular dysfunction after myocardial infarction, and diabetic nephropathy. It is also used to treat acute hypertensive crises and the Raynaud phenomenon.

The mean oral bioavailability of Captopril is 60-65%. The average volume of distribution (Vd) was 0.2 l/kg for the central compartment and two l/kg for the elimination (beta) phase. The Vd at steady-state was 0.7 l/kg. The total body clearance of Captopril averaged 0.8 l/kg/hr, and the mean blood half-life during the beta phase was 1.9 hr. In the 0- to 96-hr urine, after intravenous and oral drugs, excretion of radioactivity accounted for 87% and 61% of doses.

The more common side effect that can occur with Captopril includes dry cough and dizziness. Skin rash, fast heartbeat, decreased ability to taste, etc.

Captopril is available in the form of dosage forms as tablets

Captopril is available in India, France, Japan, and the USA.

Captopril is an antihypertensive agent belonging to angiotensin-converting enzyme (ACE) inhibitors.

Captopril blocks the conversion of angiotensin I to angiotensin II by inhibition of ACE, a peptidyldipeptide carboxy hydrolase. Angiotensin I is then converted by the angiotensin-converting enzyme (ACE) to angiotensin II, which is a potent endogenous vasoconstricting substance. Angiotensin II also stimulates the aldosterone secretion from the adrenal cortex, thereby contributing to sodium and fluid retention.

The onset of action of Captopril occurs within 15-30 minutes.

The duration of action of Captopril in the body is 12-24 hours.

The Tmax was found within 1-2 hours following the administration of Captopril, and Cmax was about 1.31 +/- 0.20 mg.

Captopril is available in the form of tablets.

Captopril tablets are to be swallowed whole with water. Captopril comes as a tablet to be taken by mouth. It is usually taken two times a day.

Captopril is approved for the treatment of Hypertension, left ventricular dysfunction after myocardial infarction, and diabetic nephropathy. It is also used to treat acute hypertensive crises and the Raynaud phenomenon.

Captopril works by blocking a substance (ACE) in the body that causes blood vessels to tighten. As a result, the blood vessels relax. This decreases blood pressure and increases the supply of blood and oxygen to the heart. Captopril is also used to help treat heart failure.

Captopril is approved for use in the following clinical indication.

• Hypertension

Angiotensin-converting enzyme inhibitors effectively lower mean arterial blood pressure as well as systolic and diastolic blood pressure both in hypertensive and normotensive subjects. Angiotensin-converting enzyme inhibitors have been evaluated as antihypertensive drugs in multiple randomized controlled trials. The three classes of drugs are calcium channel blockers, thiazide diuretics, and angiotensin receptor blockers, which are useful as initial therapy for the general population. Recent guidelines released by the American Heart Association/American College of Cardiology (AHA/ACC) and the European Society of Cardiology also recommend ACE inhibitors as the first-line antihypertensive therapy, especially in patients with diabetes mellitus and cardiovascular diseases.

• Left Ventricular Dysfunction after Myocardial Infarction

Angiotensin-converting enzyme inhibitors (ACEIs) improve heart failure by reducing afterload, preload, and systolic wall stress, which results in increased cardiac output without any increase in heart rate. ACE inhibitors play an important role in promoting salt excretion by augmenting renal blood flow and reducing aldosterone and antidiuretic hormone production. Apart from decreasing the afterload, ACEI also reduces cardiac myocyte hypertrophy.

• Diabetes Nephropathy

The Renin-Angiotensin-Aldosterone system and increased glomerular capillary pressure have been reported to increase the progression of renal dysfunction due to diabetes mellitus-related nephropathy. A large, prospective, randomized, placebo-controlled has demonstrated that ACE inhibitors slow down the progression of nephropathy in patients with insulin-dependent diabetes mellitus and significantly reduce combined endpoints of dialysis, transplantation, and death.

• Although not approved, there have been certain off-label uses documented for Captopril. These include :

Acute Hypertensive Crisis

● Maybe given sublingually, but the therapeutic advantage has not been demonstrated over oral administration.

● Consider alternative therapy if blood pressure does not normalize within 20 to 30 minutes.

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.

● 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 an 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.

● 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 colds and smoking cessation. Medical management consists of the use of dihydropyridine-type calcium channel blockers (nifedipine, nimodipine), and 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.

● A clinical trial evaluated patients for up to three months; additional studies are necessary to determine full effectiveness.

Captopril is available in the form of tablets in potencies of 12.5 mg, 25 mg, 50 mg, and 100 mg.

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 one week before starting Captopril.
• In most patients, a starting dose of 12.5mg may be used. The dose may then be increased to 25 mg twice daily. If a satisfactory reduction of blood pressure has not been achieved after 2-4 weeks, the dose of captopril may be increased to 50 mg twice daily. Concomitant sodium restriction may be beneficial when Captopril is used alone. In patients in whom a satisfactory reduction in blood pressure is not achieved after a further two weeks at this dosage, it is likely that hypertension may have a substantial volume-dependent component. In these patients, it may be appropriate to add a thiazide diuretic. The diuretic dose may be increased at one to two-week intervals until its highest usual antihypertensive dose is reached.
• The usual effective dose of Captopril in mild to moderate hypertension does not exceed 50mg twice daily.

Left Ventricular Dysfunction after Myocardial Infarction

• Therapy may be initiated as early as 3 days following myocardial infarction. After an initial dose of 6.25mg, Captopril therapy should be increased as tolerated to 25mg three times daily during the next several days and to a final target dose of 50mg three times daily over the next several weeks. If symptomatic hypotension occurs, a dosage reduction may be required. Subsequent attempts at achieving the target dose of 150mg should be based on the patient's tolerance to Captopril.
• Captopril may be used in patients treated with other post-myocardial infarction therapies, e.g., thrombolytics, aspirin, and beta blockers.

Diabetes Nephropathy

• In patients with diabetic nephropathy, the recommended dose of Captopril is 75 to 100 mg daily, in divided doses. Clinical trials in normotensive type 1 diabetic patients with microalbuminuria ( albumin excretion rate between 30 - 300mg/day) showed that Captopril at a dose of 50mg twice daily attenuated the progression of the disease. Clinical trials in normotensive and controlled hypertensive type 1 diabetic patients with overt proteinuria (total protein excretion >500mg/day) demonstrated that Captopril at a dose of 25 mg three times daily had significant beneficial effects by reducing the need for dialysis and transplantation or the occurrence of death.
• The effects of Captopril were independent of and addition to, its antihypertensive activity. 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.

Captopril can be administered orally after meals. The dosage and the duration of treatment should be as per the clinical judgment of the treating physician

Captopril is available in various dosage strengths as 12.5 mg, 25 mg, 50 mg, and 100 mg.

Captopril is available in the form of tablets.

Dose Adjustment in Kidney Patients:

1. GFR 10 to 50 mL/minute/1.73 m2: Administer 75% of dose
2. GFR <10 mL/minute/1.73 m2: Administer 50% of dose
3. Intermittent hemodialysis: Administer 50% of the dose
4. Peritoneal dialysis (PD): Administer 50% of the dose
5. Continuous renal replacement therapy (CRRT): Administer 75% of the dose

Dose Adjustment in the pediatric patient:

Heart failure (afterload reduction):

Infants: Oral: Initial: 0.1 to 0.3 mg/kg/dose every 6 to 24 hours; titrate as needed; reported daily dose range: 0.3 to 3.5 mg/kg/day divided every 6 to 12 hours; maximum daily dose: 6 mg/kg/day .

Children and Adolescents: Oral: Initial: 0.3 to 0.5 mg/kg/dose every 8 to 12 hours; titrate as needed; in clinical trials, usual reported dosage range was 0.9 to 3.9 mg/kg/day in divided doses; maximum daily dose: 6 mg/kg/day.

Hypertension:

Infants: Oral: Initial: 0.05 mg/kg/dose every 6 to 24 hours (AAP) higher initial doses of 0.15 to 0.3 mg/kg/dose every 6 to 24 hours have been recommended by some experts and may be needed in patients with severe hypertension; titrate dose carefully upward as necessary to a maximum of 6 mg/kg/day; monitor for hypotension (AAP [Flynn 2017]; Park 2014).

• Children and Adolescents: Oral: Initial: 0.3 to 0.5 mg/kg/dose every 8 hours; may titrate as needed up to maximum daily dose: 6 mg/kg/day in 3 divided doses; in adults, the amount is titrated as needed up to 150 mg/day (usual dose).

Captopril is approved for the treatment of Hypertension, left ventricular dysfunction after myocardial infarction, and diabetic nephropathy. It is also used to treat acute hypertensive crises and the Raynaud phenomenon.

Hypertension: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

Myocardial Infarction: No more than 25 to 35 percent of your daily calories should come from total fat (including saturated fat). Less than 7 % of your daily calories should come from saturated fat. Avoid trans fats and Consume less than 200 milligrams a day of dietary cholesterol.

Diabetic Nephropathy: Limit carbohydrates with added sugars or with refined grains, such as white bread and white rice. Instead, eat carbohydrates from fruit, vegetables, whole grains, beans, and low-fat or nonfat milk.

The dietary restriction should be individualized as per patient requirements.

Captopril may be contraindicated in the following

● Abrupt discontinuation

Abrupt discontinuation of any ACE Inhibitors, including Captopril, can result in the development of myocardial ischemia, myocardial infarction, ventricular arrhythmias, or severe Hypertension, particularly in patients with preexisting cardiac disease.

● These drugs should not be given to patients already taking a direct renin inhibitor such as Aliskiren.

The risk or severity of hypotension, hyperkalemia, and nephrotoxicity can be increased when Aliskiren is combined with Captopril.

● Contraindicated In Pregnancy.

ACE inhibitors should be avoided pregnancy. They were Category D in pregnancy under old FDA system because it causes skull hypoplasia, anuria, hypotension, renal failure, lung hypoplasia, skeletal deformations, oligohydramnios, and death.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

• 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 may be subject to a variety of adverse reactions, some of them serious

• Hypotension

Excess hypotension was rarely seen in hypertensive patients, but it is a possible consequence of captopril use in salt/volume depleted persons, patients with heart failure or those patients undergoing renal dialysis.

In heart failure, where blood pressure was either normal or low, transient decreases in mean blood pressure greater than twenty 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 main reason for discontinuation of drug in 3.6 percent of patients with heart failure.

• Fetal toxicity

The 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 Captopril as soon as possible. These adverse outcomes are usually associated with the 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 renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal Hypertension during pregnancy is important to optimize outcomes for both mothers and fetus

PRECAUTIONS

• Impaired Renal or Hepatic Function

ACE inhibitors should be used with caution in patients with impaired hepatic or renal function. Poor renal function has minor effects on Captopril clearance, but poor hepatic function may cause blood levels of Captopril to increase substantially

Drinking alcohol while taking the Captopril can increase drowsiness and dizziness, which in turn increases the risk of accidental injury.

Captopril use in breastfeeding patients is not recommended.

Pregnancy Category (FDA): D

The 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. The 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 Captopril as soon as possible. These adverse outcomes are usually associated with the use of these drugs in the second and third trimester of pregnancy.

Potassium-Rich Foods: Bananas, sweet potatoes, nuts, and other foods rich in potassium when taken along with Captopril, can be led to an increase in blood potassium levels.

Pleurisy Root: Pleurisy roots are not recommended with most heart medications due to the cardiac glycoside content of the root.

The adverse reactions related to molecule Captopril can be categorized as

• Common Adverse effects:

Insomnia, Muscle pain, Dizziness, fatigue etc.

• Less Common adverse effect:

Nervousness, Elevated liver enzymes, joint paint, edema, vivid dreams, abdominal discomfort, nausea, muscle cramps, paresthesias, bradycardia, cold extremities, hypotension, palpitations, syncope, Tachycardia, Anxiety, lethargy, diarrhea, vomiting, Impotence/reduced libido.

• Rare adverse effects:

Heart failure, tachyarrhythmia, bronchospasm, depression, decreased exercise tolerance, etc.

The clinically relevant drug interactions of Captopril is briefly summarized here

● Interactions involving specific ACE inhibitors include captopril-digoxin, resulting in decreased clearance of digoxin from plasma in patients with heart failure, and captopril-probenecid, causing a decrease in captopril clearance. Tissue kinins, such as bradykinin, are metabolized by ACE inhibitors.

● Interactions involving bradykinin include captopril-indomethacin, in which an attenuation of the antihypertensive effects of Captopril is manifest. Interestingly, neither enalapril nor lisinopril appear to show this interaction with indomethacin. Kinin-based interactions may also be important in the genesis of ACE inhibitor-induced cough and skin rash.

● Renal dysfunction affects the pharmacokinetics and pharmacodynamics of all ACE inhibitors, necessitating dosage reduction. Hepatic impairment is of less clinical importance, causing a delay in the onset of action of enalapril with initial doses, but probably having little relevance to long-term therapy.

The common side of Captopril include the following

Cold hands or feet, Eye irritation, upset stomach, headache, depression, dizziness, nausea, cough etc.

The use of Captopril should be prudent in the following group of special populations:

Pregnancy

Pregnancy Category (FDA): D

The 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 Captopril as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy

Nursing Mothers

Since Captopril is secreted in human milk, nursing should not be undertaken by mothers receiving this drug.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

There is no FDA guidance on the use of Captopril in geriatric settings.

Symptoms:

Severe hypotension, shock, stupor, bradycardia, electrolyte disturbances, and renal failure.

Management:

Correction of hypotension would be of primary concern. Volume expansion with an intravenous infusion of normal saline is the treatment of choice for restoration of blood pressure.

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.

Pharmacodynamics:

Captopril is a sulfhydryl-containing ACE inhibitor which competitively inhibits ACE to prevent conversion of angiotensin I to angiotensin II, thereby increasing plasma renin activity and reducing aldosterone secretion.Captopril works by blocking a substance in the body that causes blood vessels to tighten. As a result, the blood vessels relax. This lowers blood pressure and increases the supply of blood and oxygen to the heart.

Captopril is also used to help treat heart failure. It is also used in some patients after a heart attack. After a heart attack, some of the heart muscle becomes damaged and weak. The heart muscle may continue to weaken as time goes by. This makes it more difficult for the heart to pump blood. Captopril may be started within the first few days after a heart attack to increase survival rate.

Captopril is also used to treat kidney problems caused by diabetes (diabetic nephropathy).

Pharmacokinetics:

• Absorption: Rapidly absorbed from the gastrointestinal tract (approx. 60-75%). Decreased serum concentration with food. Bioavailability: Approx 60-75%. Time to peak plasma concentration: Within 1-2 hours.

• Distribution: Crosses placenta and enters breast milk (small amounts). Volume of distribution at steady state: 0.7 L/kg. Plasma protein binding: 25%-30%.

• Excretion: Via urine (>95%; 40-50% as unchanged drug). Elimination half-life: 2-3 hours.

1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018343s084lbl.pdf
2. https://pubmed.ncbi.nlm.nih.gov/7037265/#:~:text=In the 0- to 24,bioavailability of captopril was 62%.
3. https://www.ncbi.nlm.nih.gov/books/NBK431051/
4. https://www.rxlist.com/Captopril-drug.htm#warnings
5. https://go.drugbank.com/drugs/DB01197