Enalaprilat

Usage

• Medical Conditions: Enalaprilat is primarily used to treat hypertensive emergencies, a severe form of high blood pressure requiring immediate intervention. It is the active metabolite of enalapril and provides rapid blood pressure control when oral administration is not feasible. It is also used for short-term management of severe hypertension, including cases associated with acute coronary syndromes (e.g., unstable angina, non-ST-elevation myocardial infarction), acute pulmonary edema, or acute left ventricular dysfunction.

• Pharmacological Classification: Enalaprilat is classified as an angiotensin-converting enzyme (ACE) inhibitor, and specifically as an antihypertensive agent.

• Mechanism of Action: Enalaprilat works by inhibiting the ACE enzyme, which is responsible for converting angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor (narrows blood vessels) and also stimulates the release of aldosterone, a hormone that promotes sodium and water retention. By blocking the formation of angiotensin II, enalaprilat promotes vasodilation (widening of blood vessels), reduces blood volume, and lowers blood pressure.

Alternate Names

• Enalaprilat is the active form of enalapril. Enalapril itself is marketed under several brand names, most notably Vasotec. It is primarily known by its generic name internationally.

How It Works

• Pharmacodynamics: Enalaprilat’s primary effect is a reduction in blood pressure through vasodilation and reduced blood volume. It also has beneficial effects on cardiac remodeling (structural changes in the heart) in heart failure, reducing cardiac workload and improving cardiac output.

• Pharmacokinetics: Enalaprilat is administered intravenously. It has a rapid onset of action (usually within 15 minutes) and a short half-life of about 3 to 6 hours. It is primarily excreted unchanged by the kidneys.

• Mode of Action: Enalaprilat competitively binds to and inhibits the active site of ACE. It thereby blocks the conversion of angiotensin I to angiotensin II, reducing angiotensin II-mediated vasoconstriction and aldosterone secretion.

• Receptor Binding/Enzyme Inhibition: Enalaprilat specifically inhibits ACE.

• Elimination Pathways: Enalaprilat is eliminated predominantly through renal excretion, with a small portion possibly metabolized in the liver.

Dosage

Standard Dosage

Adults:

• The standard dosage for hypertensive emergencies is 1.25 mg administered intravenously over 5 minutes every 6 hours. Doses up to 5 mg every 6 hours have been used in controlled clinical trials, but higher doses beyond this range haven’t been thoroughly studied for safety and efficacy. The duration of treatment depends on the patient’s clinical response.

Children:

• The safety and effectiveness of enalaprilat in children have not been established, and it’s generally not recommended for pediatric use. In certain very limited situations, a pediatric cardiologist may consider off-label usage under close monitoring, and the dose is carefully titrated based on weight and clinical response. The starting dose is typically much lower than the adult dose.

Special Cases:

• Elderly Patients: Initiate therapy at a low dose (e.g., 0.625 mg) due to potential age-related decline in renal function and increased sensitivity to side effects. Closely monitor blood pressure and renal function.
• Patients with Renal Impairment: For patients with creatinine clearance (CrCl) ≤ 30 mL/min, the initial dose is 0.625 mg IV over 5 minutes. If there’s an inadequate response after one hour, repeat the 0.625mg dose; administer subsequent 1.25 mg doses at six-hour intervals if there is a positive response.
• Patients with Hepatic Dysfunction: No dosage adjustment is typically needed in patients with hepatic impairment.
• Patients with Comorbid Conditions: In heart failure patients with hyponatremia (low sodium) or renal impairment, start with a lower dose (0.625 mg) and titrate cautiously based on clinical response and renal function.

Clinical Use Cases

• Intubation: Enalaprilat can be administered during intubation for blood pressure control, especially in hypertensive emergencies.
• Surgical Procedures: Its use is limited in surgical settings, as it is primarily meant for managing hypertensive crises.
• Mechanical Ventilation: Enalaprilat is suitable for blood pressure management in ventilated patients, particularly those experiencing hypertension.
• Intensive Care Unit (ICU) Use: It is often used in ICU for short-term control of severe hypertension.
• Emergency Situations: The primary clinical use of enalaprilat is for hypertensive emergencies in the ER setting.

Dosage Adjustments

• Renal dysfunction necessitates significant dose reduction. Monitor closely.
• Dose titration is vital in heart failure with renal/hepatic issues.
• Consider genetic polymorphisms impacting drug metabolism and monitor effects.

Side Effects

Common Side Effects

• Hypotension (low blood pressure)
• Dizziness
• Headache
• Nausea
• Fatigue
• Cough

Rare but Serious Side Effects

• Angioedema (swelling of face, lips, tongue, throat)
• Renal failure
• Hyperkalemia (high potassium)
• Neutropenia (low white blood cell count)

Long-Term Effects

• Renal impairment (with chronic use)
• Electrolyte imbalances

Adverse Drug Reactions (ADR)

• Angioedema requiring immediate medical intervention.
• Severe hypotension leading to syncope or shock.

Contraindications

• Hypersensitivity to enalaprilat or any ACE inhibitor
• History of angioedema related to ACE inhibitor use
• Hereditary or idiopathic angioedema
• Pregnancy (especially second and third trimesters)
• Concomitant use with sacubitril/valsartan or aliskiren (in patients with diabetes or renal impairment)

Drug Interactions

• Diuretics: Enhanced hypotensive effect, monitor for excessive blood pressure drop.
• Potassium supplements/Salt substitutes: Increased risk of hyperkalemia.
• NSAIDs (Nonsteroidal anti-inflammatory drugs): Reduced antihypertensive effect and possible renal impairment.
• Lithium: Increased lithium levels.
• Aliskiren: Contraindicated, especially in patients with diabetes or renal impairment.
• Sacubitril/Valsartan: Contraindicated due to increased angioedema risk.
• Alcohol: May enhance hypotensive effect.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C (first trimester), D (second and third trimesters) — contraindicated. ACE inhibitors can cause fetal harm and death, especially during the second and third trimesters.
• Fetal Risks: Renal failure, oligohydramnios, skull hypoplasia, neonatal hypotension.
• Breastfeeding: Not recommended due to potential for adverse effects in infants.

Drug Profile Summary

• Mechanism of Action: ACE inhibitor, reducing angiotensin II and aldosterone.
• Side Effects: Hypotension, dizziness, cough, angioedema, renal failure, hyperkalemia.
• Contraindications: Hypersensitivity, history of angioedema, pregnancy, sacubitril/valsartan, aliskiren.
• Drug Interactions: Diuretics, potassium supplements, NSAIDs, lithium, aliskiren.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy, not recommended during breastfeeding.
• Dosage: 1.25 mg IV every 6 hrs for hypertensive emergencies; adjust for renal impairment.
• Monitoring Parameters: Blood pressure, renal function, electrolytes (potassium).

Popular Combinations

• Enalaprilat is rarely used in combinations due to its intravenous administration and use primarily in emergency situations. When switching to oral therapy, combinations with other antihypertensives like thiazide diuretics or beta-blockers may be used for long-term blood pressure control.

Precautions

• General Precautions: Monitor renal function, electrolytes, especially potassium.
• Specific Populations: Avoid in pregnancy, use cautiously during breastfeeding and in patients with renal impairment. Start low and go slow with the elderly.
• Lifestyle Considerations: Limit alcohol intake.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Enalaprilat?

A: The standard adult dosage for hypertensive emergencies is 1.25 mg IV over 5 minutes every 6 hours. Doses up to 5mg every six hours have been administered. Titrate cautiously in patients with renal impairment, starting at 0.625mg. It is not recommended for children.

Q2: How quickly does Enalaprilat lower blood pressure?

A: Enalaprilat typically lowers blood pressure within 15 minutes of intravenous administration, with peak effects occurring within 1-4 hours.

Q3: Can Enalaprilat be given orally?

A: No, enalaprilat is formulated for intravenous administration only. Enalapril maleate is the oral prodrug form.

Q4: What are the most serious side effects of Enalaprilat?

A: Angioedema (swelling of the face, lips, tongue, or throat, potentially obstructing the airway), severe hypotension, acute renal failure, and hyperkalemia are the most serious potential side effects.

Q5: What should I do if a patient develops angioedema after Enalaprilat administration?

A: Discontinue enalaprilat immediately and provide supportive care, including airway management if necessary. Administer subcutaneous epinephrine (1:1000, 0.3 to 0.5 mL (0.01 mg/kg)) if the airway is compromised. Patients with a history of angioedema related to ACE inhibitor use are contraindicated from receiving enalaprilat.

Q6: Can Enalaprilat be used in pregnancy?

A: Enalaprilat is contraindicated during pregnancy, especially in the second and third trimesters. It can cause serious fetal harm, including renal failure and death.

Q7: How is Enalaprilat metabolized and eliminated?

A: Enalaprilat is primarily excreted unchanged by the kidneys. A small amount may be metabolized in the liver.

Q8: What are the key drug interactions with Enalaprilat?

A: Significant interactions can occur with diuretics (additive hypotensive effect), potassium supplements (increased risk of hyperkalemia), NSAIDs (reduced antihypertensive effect and renal impairment risk), lithium (increased lithium levels), and sacubitril/valsartan (contraindicated due to risk of angioedema). Coadministration with aliskiren is also contraindicated, especially in patients with diabetes or renal impairment.

Q9: What monitoring is required for patients receiving Enalaprilat?

A: Closely monitor blood pressure, renal function (serum creatinine, blood urea nitrogen), and serum electrolyte levels, especially potassium, before and during treatment. Monitor for signs and symptoms of angioedema.

Q10: What is the difference between Enalaprilat and Enalapril?

A: Enalaprilat is the active metabolite of enalapril. Enalapril is administered orally (as Vasotec or its generic equivalent), and is converted to enalaprilat in the liver. Enalaprilat is administered intravenously, usually for acute hypertensive crisis.