Ambrisentan - Uses, Dosage, Warnings, and Mechanism of Action

Overview:

Ambrisentan is an orally administered drug and an active, selective type A endothelin receptor antagonist approved in various countries to treat pulmonary arterial hypertension. Studies suggest that they improve exercise ability and delay the worsening of the condition. In addition, the United States has approved a combination of Ambrisentan and Tadalafil for retarding the disease progress. Various research has successfully proven the efficacy of Ambrisentan against pulmonary arterial hypertension, both idiopathic and heritable types.

How Does Ambrisentan Work?

Ambrisentan, an endothelin receptor antagonist, helps to relax the muscles around the blood vessels, thereby reducing blood pressure. Hence, it is prescribed for pulmonary hypertension.

Uses:

Ambrisentan is used in the following conditions.

• Treating patients with idiopathic or primary pulmonary arterial hypertension.

• Treating patients with pulmonary arterial associated with connective tissue diseases.

• Helps patients improve their exercise ability and retards the disease progress in combination with Tadalafil.

Dosage:

The treatment is started with a dosage of Ambrisentan 5 mg with or without Tadalafil 20 mg once daily. Then, for every four-week interval, the dosage of any of the two drugs is increased if needed. For example, Ambrisentan is increased to 10 mg and Tadalafil to 40 mg.

Warnings:

• Embryo-Fetal Toxicity: Ambrisentan can harm the fetus when administered to a pregnant woman. Hence, it is contraindicated during pregnancy.

• Fluid Retention: Ambrisentan can cause fluid retention if administered in combination with Tadalafil than when administered alone.

• Pulmonary Edema with Pulmonary Veno-Occlusive Disease: Ambrisentan can develop pulmonary edema during initial therapy, which increases the risk of pulmonary veno-occlusive disease. Hence, the drug has to be discontinued.

• Decreases Sperm Counts: Ambrisentan can reduce sperm counts by disturbing spermatogenesis.

• Hematologic Changes: Ambrisentan can reduce hemoglobin levels. Hence the drug is contraindicated in anemic patients.

For Patients:-

Things to Know About Pulmonary Hypertension:

Pulmonary hypertension is the increase in blood pressure affecting the arteries in the lungs. Pulmonary arterial hypertension is due to the narrowing or blockage of blood vessels in the lungs, obstructing blood flow through the lungs, thereby increasing blood pressure. In chronic cases, the heart muscles weaken and fail as the heart pumps hard for blood flow. It can be life-threatening in some cases; however, providing treatment can control the symptoms and improve life.

Learn More About Ambrisentan:-

When and How Often to Take Ambrisentan?

Ambrisentan should be taken once daily. The initial treatment starts with 5 mg. After that, the drug can be taken with Tadalafil 10 mg as per the doctor’s advice. Then, in a four-week interval, the drug dosage may be increased to Ambrisentan 10 mg and Tadalafil 20 mg, if needed.

How Effective Is Ambrisentan?

Ambrisentan is effective after regular administration for around one to three months. During this period, the physician can alter the drug dosage and combination. Studies reveal that Ambrisentan administered in one-year follow-up improves exercise ability by 94 % and reduces clinical worsening contributing to around 83 %.

Things to Inform the Doctor Before They Prescribe Ambrisentan:

The following history must be provided to the doctor before prescribing Ambrisentan.

• Anemia.

• Liver disease.

• Previous medical conditions.

• Medications taken for the medical issues.

Starting Ambrisentan:-

How to Take Ambrisentan?

• Take the prescribed dosage of the drug regularly unless the doctor tells to stop it.

• Take Ambrisentan orally with or without food.

• Take the drug once daily with water, and avoid chewing or crushing the tablet.

Things to Do After TakingAmbrisentan:

After initiation of treatment with Ambrisentan, it is better to take the drug at the same time every day to avoid missing the dose. In addition, a regular checkup must be scheduled to determine the effectiveness of Ambrisentan and the alteration of the drug dose, if required.

Look Out for Side Effects:

The side effects of Ambrisentan include

• Flushing.

• Pale skin.

• Fast heartbeat.

• Headache.

• Swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs.

• Hoarseness.

• Difficulty swallowing or breathing.

• Rash.

• Weight gain.

• Tiredness.

• Loss of appetite.

• Lack of energy

• Nausea.

• Vomiting.

• Pain in the upper right stomach area.

• Yellowing of the skin or eyes.

• Flu-like symptoms.

• Itching.

• Dark-colored urine.

The individual should report to the doctor immediately if the symptoms worsen.

Dietary Alterations:

As Ambrisentan is unaffected by food, a regular diet can be followed until the doctor advises any diet modifications.

What Should Be Done When a Dose Is Missed?

Ambrisentan can be taken as soon in the day as possible if missed. The next dose can be taken regularly. However, combining two doses at the same time must be avoided.

What Should Be Done to Treat Ambrisentan Overdose?

If an overdose of Ambrisentan is taken, it is better to consult a physician immediately. However, research shows that there are rare cases where Ambrisentan overdoses and causes complications.

How to Store Ambrisentan?

The medication should be stored in a tightly sealed container at room temperature. It should be out of reach for pets and children.

How to Handle Ambrisentan?

The drug has to be taken with neat and clean hands. The caretaker can wear a glove while handling the medicine.

How to Dispose Ambrisentan?

The medicine should not be flushed in the toilet. Instead, it can be disposed of by contacting a local garbage disposal department. They are done specifically to avoid the consumption of drugs by pets, children, or other people.

Avoid Self-Medication:

Avoid taking Ambrisentan if the doctor has not prescribed the drug for the condition. In addition, do not recommend the drug to an individual with the same symptoms.

Staying On Ambrisentan:-

Tips to Stay On Track:

The common tips to stay on track with the medication are

• Take the drug as prescribed by the physician.

• Do not alter the drug dose without the physician’s consent.

• Avoid missing the dose by setting the alarm or taking the drug at the same time of the day to remember it.

• Avoid overdosing on the drug to compensate for the missed dose.

• Go for a regular checkup with the physician to monitor the disease progression.

For Doctors:-

Indication:

Ambrisentan is used in the following conditions.

• Treating patients with idiopathic or primary pulmonary arterial hypertension.

• Treating patients with pulmonary arterial associated with connective tissue diseases.

• Helps patients improve their exercise ability and retards the disease progress in combination with Tadalafil.

Pharmacology:-

Mechanism of Action:

The endothelin-1 receptor is autocrine and paracrine with two subtypes:

• Endothelin-1A (ETA): ETA causes vasoconstriction and cell proliferation.

• Endothelin-1B (ETB): The action of ETB are vasodilation, antiproliferation, and ET-1 clearance.

The plasma concentrations of ET-1 are generally high in patients with pulmonary arterial hypertension.

Ambrisentan is an endothelin receptor antagonist, showing a high affinity for ETA, relaxing the muscles around blood vessels, and reducing blood pressure.

Pharmacodynamics:

The QTc interval assesses the heart's electrical activity by recording it in the electrocardiogram. A study was conducted where the QT interval was assessed in patients who received 10 mg Ambrisentan, which did not show a significant effect on QTc interval; however, a 40 mg dose showed an increased mean QTc interval.

Chemical Taxonomy:

• Kingdom - Organic compounds.
• Superclass - Benzenoids.
• Class - Benzene and substituted derivatives.
• Subclass - Diphenylmethanes.
• Direct Parent - Diphenylmethanes.

Ingredients:

Active Ingredient: Ambrisentan.

Inactive Ingredients: Inactive ingredients include lactose monohydrate, magnesium stearate, croscarmellose sodium, and microcrystalline cellulose. The film-coating of the tablet contains talc, polyvinyl alcohol, lecithin, polyethylene glycol, and titanium dioxide.

Absorption:

The peak plasma concentration of Ambrisentan after oral administration is around two hours. The exact bioavailability of the drug is unknown. No food affects Ambrisentan absorption.

Distribution:

Ambrisentan has a high affinity towards plasma protein and is 99 % plasma protein bound, mainly albumin contributing to 96.5 % binding affinity. It is minimally distributed in the red blood cells, with the blood: plasma ratio of 0.57 in males and 0.61 in females.

Metabolism:

Ambrisentan undergoes metabolism to form Ambrisentan glucuronide. The enzyme involved in the process is uridine 5’-diphosphate glucuronosyltransferases (UGTs).

Elimination:

Ambrisentan is not excreted renally. Instead, it is found in the feces undergoing a hepatic or extra-hepatic metabolism. Oral administration of Ambrisentan shows approximately 22 % in urine, of which 3 % is an unchanged form of the drug.

What Are the Toxicities Related to Ambrisentan Therapy?

Ambrisentan is toxic to the embryo or the fetus. However, a study in rats did not show evidence of carcinogenicity.

Warning and Precaution:

• Embryo-Fetal Toxicity: Ambrisentan can harm the fetus when administered to a pregnant woman. Hence, it is contraindicated during pregnancy. In addition, contraceptives are recommended to prevent pregnancy during and one month after Ambrisentan administration.

• Fluid Retention: Ambrisentan can cause fluid retention if administered in combination with Tadalafil than when administered alone. Studies suggest that most patients experience fluid retention after starting Ambrisentan for pulmonary hypertension. These patients require diuretics and fluid management.

• Pulmonary Edema with Pulmonary Veno-Occlusive Disease: Ambrisentan can develop pulmonary edema during initial therapy, which increases the risk of pulmonary veno-occlusive disease, and the drug has to be discontinued.

• Decreases Sperm Counts: Ambrisentan can reduce sperm counts by disturbing spermatogenesis. Animal fertility tests prove this, so the patients must be counseled about infertility due to Ambrisentan administration.

• Hematologic Changes: Ambrisentan can reduce hemoglobin levels. Hence the drug is contraindicated in anemic patients. The exact cause is unknown. However, it is not due to bleeding. In some cases, after the initial therapy, hemoglobin levels fall when the drug has to be discontinued.

Dosage and Forms:

Ambrisentan is a film-coated tablet available in two dosage forms: 5 mg and 10 mg.

Administration of the Drug:

• Ambrisentan should be taken once daily.

• The drug can be taken orally.

• The recommended doses are 5 mg and 10 mg.

• The drug can be taken with or without food.

• The dose should be taken regularly and not skipped.

• If missed, overdosing should be avoided.

Considerations for Administration:

• The coadministration of Cyclosporine and Ambrisentan can increase exposure to Ambrisentan; hence the drug dose is limited to 5 mg.

• Ambrisentan, when administered with conjugated estrogens, can increase the effect of estrogens by affecting enzyme metabolism. Hence they must be administered cautiously and monitored regularly.

• The coadministration of Ambrinsentan and Rifampin can decrease the effectiveness of Ambrisentan by affecting the enzyme. Therefore, they are administered cautiously and monitored.

Contraindications:

The individuals with the following conditions are contraindicated from taking Ambrisentan.

• Anemia.

• Pulmonary fibrosis.

• Chronic heart failure.

• Liver disease.

• Abnormal liver function tests.

• Pregnancy.

• Breastfeeding.

• Water retention.

Clinical Studies for Ambrisentan:

A randomized controlled trial was conducted to compare the administration of Ambrisentan and Tadalafil alone and in combination for 605 patients with pulmonary arterial hypertension.

Dosage Administered: The patients were administered Ambrisentan 2.5 mg, 5 mg, or 10 mg once daily and a placebo.

Adverse Reactions: The common adverse effects were peripheral edema, sinusitis, flushing, and nasal congestion.

Significant Differences: Peripheral edema was more remarkable in elderly patients than in younger adults. However, there were no differences between those receiving Ambrisentan and placebo in the same age group.

Discontinuation of the Drug: Adverse events led to drug discontinuation in various groups.

• Combination of Ambrisentan and Tadalafil - 16 %.

• Tadalafil alone - 14 %.

• Tadalafil alone - 13 %.

Drug Interactions:

The dose of Ambrisentan should be limited to 5 mg once daily when administered with Cyclosporine because the combination administration results in increased exposure to Ambrisentan in healthy individuals. However, no dose adjustment was required when combined with Ketoconazole, Rifampin, Tacrolimus, Ritonavir, Tadalafil, and Warfarin.

Other Specifications:-

• Ambrisentan in Pregnant Women:

Ambrisentan can harm the fetus when administered to pregnant women. Animal studies reveal that they are teratogenic. Hence, the drug is contraindicated during pregnancy. In addition, contraceptive methods are recommended to prevent pregnancy during and one month after Ambrisentan administration.

• Ambrisentan in Lactating Women:

The administration of Ambrisentan in lactating women is not yet established. However, considering the significant side effects of the drug, either lactation or the drug administration must be discontinued.

• Ambrisentan in Pediatric Patients:

The effectiveness and dosage of Ambrisentan still need to be established in pediatric populations.

• Ambrisentan in Geriatric Patients:

The effectiveness of Ambrisentan was evaluated in geriatric patients, where there was less improvement in walking ability in the elderly than in younger adults. In addition, peripheral edema was more common in elderly patients.

• Ambrisentan in Renal Impairment Patients:

Studies were conducted to examine the impact of renal impairment on the administration of Ambrisentan, in which no significant impact was observed. Hence, no drug dose adjustment is required for patients with mild to moderate renal impairment. However, the impact on severe renal impairment patients is not yet established.

• Ambrisentan in Hepatic Impairment Patients:

Ambrisentan is not recommended for patients with moderate to severe hepatic impairment as they are expected to cause significant effects on the pharmacokinetics of Ambrisentan.

If an individual develops hepatic impairment after administration of Ambrisentan, the exact cause must be determined, and the drug must be discontinued.