Usage
- Ambrisentan is prescribed for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity and delay clinical worsening. It’s also used in combination with tadalafil for PAH to reduce the risks of disease progression and hospitalization, as well as to improve exercise ability.
- Pharmacological Classification: Endothelin Receptor Antagonist (ERA).
- Mechanism of Action: Ambrisentan competitively binds to endothelin type A receptors, blocking the effects of endothelin-1, a potent vasoconstrictor that plays a key role in the development of PAH. This receptor blockade leads to vasodilation and reduced pulmonary vascular resistance, ultimately improving blood flow and reducing strain on the heart.
Alternate Names
- International Nonproprietary Name (INN): Ambrisentan
- Brand Name: Letairis (and generic versions)
How It Works
- Pharmacodynamics: Ambrisentan lowers pulmonary arterial pressure and improves cardiac output by selectively inhibiting the endothelin A receptor, leading to pulmonary vasodilation.
- Pharmacokinetics:
- Absorption: Ambrisentan is readily absorbed after oral administration, reaching peak plasma concentrations in about 1 to 2 hours. Food does not significantly affect absorption.
- Metabolism: Primarily metabolized in the liver via glucuronidation and oxidation by CYP3A4, with a minor contribution from CYP2C19.
- Elimination: Excreted mainly in the bile and feces, with a small amount in urine. The elimination half-life is around 15 hours.
- Mode of Action: Ambrisentan competitively antagonizes endothelin-1 at the endothelin type A receptor located on vascular smooth muscle cells. This antagonism prevents endothelin-1-mediated vasoconstriction, thereby promoting vasodilation in the pulmonary arteries.
- Receptor Binding: Selective for endothelin type A receptor.
- Elimination Pathways: Primarily hepatic metabolism and biliary/fecal excretion.
Dosage
Standard Dosage
Adults:
- Initial: 5 mg orally once daily.
- Maintenance: May be increased to 10 mg orally once daily, as needed and tolerated, after 4 weeks.
- With Tadalafil: Initial: Ambrisentan 5 mg once daily and Tadalafil 20 mg once daily. Either drug may be uptitrated at 4-week intervals (Ambrisentan to max 10 mg and Tadalafil to max 40 mg daily) as needed and tolerated.
Children:
- Not recommended for use in patients under 18 years of age due to limited safety and efficacy data.
Special Cases:
- Elderly Patients: No dose adjustment is required.
- Patients with Renal Impairment: No dose adjustment is required. Caution is advised for severe renal impairment (creatinine clearance < 30 mL/min).
- Patients with Hepatic Dysfunction:
- Mild impairment: Dose adjustment may be needed, but no specific guidelines. Caution recommended.
- Moderate or severe impairment: Use is not recommended.
- Patients with Comorbid Conditions:
- Concomitant cyclosporine A: Limit ambrisentan dose to 5 mg once daily.
Clinical Use Cases
- Ambrisentan is specifically indicated for pulmonary arterial hypertension. Its use in other clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations is not established.
Dosage Adjustments
- Adjust dose based on individual patient response and tolerability, as well as comorbid conditions and concomitant medications (e.g., cyclosporine A). Monitor for adverse effects, particularly liver function abnormalities.
Side Effects
Common Side Effects:
- Peripheral edema
- Nasal congestion
- Sinusitis
- Headache
- Flushing
Rare but Serious Side Effects:
- Hepatotoxicity (liver damage)
- Anemia
- Pulmonary edema
Long-Term Effects:
- Potential for chronic liver dysfunction with prolonged use.
Adverse Drug Reactions (ADR):
- Angioedema (rare)
- Hypersensitivity reactions (rare)
Contraindications
- Pregnancy (absolute contraindication).
- Idiopathic pulmonary fibrosis (IPF).
- Hypersensitivity to ambrisentan.
- Severe hepatic impairment (with or without cirrhosis).
- Baseline hepatic aminotransferases (AST and/or ALT) greater than 3 times the upper limit of normal.
Drug Interactions
- CYP3A4 Inhibitors (e.g., ketoconazole): May increase ambrisentan concentrations. Monitor closely.
- CYP3A4 Inducers (e.g., rifampicin): May decrease ambrisentan concentrations. Monitor closely.
- Cyclosporine A: Increases ambrisentan exposure; limit ambrisentan dose to 5 mg once daily.
- Tadalafil: May be used concomitantly; adjust doses as needed based on tolerability and efficacy.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: X (Contraindicated)
- Fetal Risks: Ambrisentan is teratogenic and can cause serious birth defects. Strict contraception is mandatory during treatment and for one month after discontinuation. Monthly pregnancy tests are required.
- Breastfeeding: Ambrisentan may pass into breast milk. Breastfeeding is not recommended.
Drug Profile Summary
- Mechanism of Action: Endothelin receptor antagonist, selectively targeting the endothelin A receptor, leading to pulmonary vasodilation.
- Side Effects: Peripheral edema, nasal congestion, sinusitis, headache, flushing, hepatotoxicity, anemia.
- Contraindications: Pregnancy, IPF, severe hepatic impairment, hypersensitivity.
- Drug Interactions: CYP3A4 inhibitors/inducers, cyclosporine A, tadalafil.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy; breastfeeding not recommended.
- Dosage: Adults: 5 mg once daily, may increase to 10 mg daily; adjustments needed for concomitant cyclosporine A.
- Monitoring Parameters: Liver function tests (ALT, AST, bilirubin), hemoglobin/hematocrit, signs of fluid retention, pregnancy tests (in females of reproductive potential).
Popular Combinations
- Tadalafil: Co-administration with ambrisentan has shown synergistic effects in improving exercise capacity and delaying clinical worsening in PAH patients.
Precautions
- General Precautions: Assess liver function and hemoglobin/hematocrit before initiating therapy and periodically during treatment. Monitor for fluid retention and peripheral edema.
- Specific Populations: See dosage section for considerations in pregnant women, breastfeeding mothers, children, elderly patients, and individuals with renal/hepatic impairment.
- Lifestyle Considerations: Counsel patients regarding the importance of adhering to contraception guidelines, avoiding alcohol if liver function is impaired, and promptly reporting any signs of hepatic dysfunction or fluid overload.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Ambrisentan?
A: Adults: Initial dose is 5 mg orally once daily. May increase to 10 mg daily after 4 weeks if tolerated. Children: Use is not recommended.
Q2: How does Ambrisentan work?
A: It blocks the endothelin type A receptor, which causes pulmonary vasodilation and reduces pulmonary artery pressure.
Q3: What are the major side effects of Ambrisentan?
A: Common side effects include peripheral edema, nasal congestion, sinusitis, headache, and flushing. More serious but less frequent adverse effects include liver dysfunction and anemia.
Q4: Can Ambrisentan be used during pregnancy?
A: No, Ambrisentan is contraindicated during pregnancy as it can cause serious birth defects. Effective contraception must be used during treatment and for one month after stopping the medication. Monthly pregnancy tests are required.
Q5: What are the potential drug interactions with Ambrisentan?
A: Drugs that may interact with Ambrisentan include strong CYP3A4 inhibitors and inducers and cyclosporine A. The dose of ambrisentan should be limited to 5 mg once daily when co-administered with cyclosporine. Tadalafil may be used concomitantly, however close monitoring and dose adjustments are needed.
Q6: Are there any contraindications for using Ambrisentan?
A: Contraindications for Ambrisentan include pregnancy, idiopathic pulmonary fibrosis (IPF), severe hepatic impairment, and markedly elevated liver enzymes.
Q7: What should be monitored during treatment with Ambrisentan?
A: Liver function tests (ALT, AST, bilirubin), hemoglobin and hematocrit levels, signs of fluid retention and edema, and monthly pregnancy tests in women of childbearing potential.
Q8: How should Ambrisentan be administered?
A: Ambrisentan is given orally once daily, with or without food. Tablets should be swallowed whole and not crushed, chewed or split.
Q9: Can Ambrisentan be used in patients with renal impairment?
A: Yes, no dose adjustment is necessary for mild or moderate renal impairment. Caution is advised in patients with severe renal impairment.
Q10: What is the role of Ambrisentan in combination therapy for PAH?
A: Ambrisentan is frequently combined with tadalafil in the treatment of PAH. This combination therapy targets multiple pathways involved in PAH pathogenesis, potentially providing greater efficacy compared to monotherapy.
