Ambrisentan

Ambrisentan is a medicine that is used to treat pulmonary arterial hypertension. It is an endothelin receptor antagonist that targets specifically endothelin receptor type A (ETA). In 2007, the US FDA approved ambrisentan to treat primary PAH (WHO group 1) and PAH with functional class Ⅱ or Ⅲ symptoms. The approval was based on phase Ⅱ and two randomized, double-blind, placebo-controlled phase Ⅲ studies. Pulmonary arterial hypertension can be treated with Ambrisentan, an orally active selective type A endothelin receptor antagonist. It has not yet been linked to instances of acute liver injury that is clinically evident but it has been linked to a low rate of blood enzyme increases throughout the medication.

BRAND NAME: 

Letairis: It is available in the form of Letairis Ambisartan 5mg /10mg, prescribed in the treatment of pulmonary arterial hypertension.

MECHANISM OF ACTION:

Ambrisentan has minimal effect against ETB at the levels administered to humans since it is a selective inhibitor of the endothelin receptor type A (ETA). Vasodilation results from inhibition of the ETA receptor, which upsets the intracellular pathways responsible for vasoconstriction.

An endogenous peptide called endothelin-1 (ET-1) works on the endothelin type A (ETA) and type B (ETB) receptors in the endothelium and smooth muscle of blood vessels. Vasoconstriction and cell proliferation are among the effects that ETA mediates; on the other hand, ETB primarily mediates vasodilation, anti-proliferation, and ET-1 clearance. ET-1 levels are elevated in pulmonary arterial hypertension patients, and they are correlated with elevated right arterial pressure and disease severity. Among the several recently created vasodilator medications, Ambrisentan specifically targets the endothelin type A (ETA) receptor, reducing vasoconstriction by blocking its function.

PHARMACOKINETICS:

Absorption:

Ambrisentan is quickly absorbed, and two hours after oral dosing, peak plasma concentrations occur. Throughout the therapeutic dose range, Cmax and AUC arise in proportion to the dose. It is uncertain how bioavailable Ambrisentan is when taken orally.

Distribution:

Ambrisentan's mean blood plasma ratio in males is 0.57, while in females it is 0.61. This indicates that ambrisentan is poorly distributed red blood cells. Metabolism:

The main enzymes that break down ambrisentan into ambrisentan glucuronide are urine 5'-diphosphate glucuronosyl transferases (UGTs) 1A9S, 2B7S, and 1A3S. To a lesser extent, CYP3A4, CYP3A5, and CYP2C19 also metabolize ambrisentan to produce 4-hydroxymethyl ambrisentan, which is then glucuronidated to produce 4-hydroxymethyl ambrisentan glucuronide.

Excretion:

The majority of ambrisentan elimination happens outside of the kidneys. After hepatic or extra-hepatic metabolism, ambrisentan and its metabolites are primarily found in the feces. Following oral administration, approximately 22% of the dosage is recovered in the urine, with 3.3% remaining as Ambrisentan.

PHARMACODYNAMICS:

The QTC interval was not significantly affected by 10 mg daily; however, 40 mg daily of ambrisentan raised the mean QTC at tmax by 5 ms with a 95% confidence limit of 9 ms. Patients who take Ambrisentan without other metabolic inhibitors are unlikely to develop severe QTc prolongation. Patients treated with Ambrisentan for 12 weeks exhibited considerably lower plasma levels of B-type natriuretic peptide (BNP). 

DOSAGE AND ADMINISTRATION:

It is an orally administered medication. Avoid splitting, chewing, or crushing pills. Do not take two doses simultaneously to compensate for a missing one. Adults are first administered 5 mg per day. The physician increases the dose based on the patient's needs. 

CONTRAINDICATIONS:

When given to a pregnant woman, ambrisentan tablets may harm the fetus.

Ambrisentan tablets are not recommended for those with idiopathic pulmonary hypertension, including those with IPF.

DRUG INTERACTIONS:

Certain pharmaceuticals should never be combined; nevertheless, in some cases, two distinct medications may be provided concurrently even if an interaction occurs. In this case, your doctor may want to alter the dosage or take additional steps. It is not recommended to take this drug with any of the following medications. The doctor may decide not to treat you with this treatment or to change some of the other medications you take.

Combining this drug with Cyclosporine, Levo ketoconazole, Methotrexate, or Simeprevir is generally not suggested; however, it may be necessary in specific cases. If both medications are administered concurrently, your doctor may change the dose or frequency with which you take one or both.

ADVERSE EFFECTS:

•        Bloating or swelling of the face, arms, hands, lower legs, or feet

•        Rapid weight gain

•        Itching on hands or feet

•        Unusual weight gain or loss

•        Fever

•        Headache

•        Muscle aches

•        Irregular heartbeat

OVERDOSE :

Overdosage can cause hypotension, necessitating medical attention.

•        Blurred vision

•        Confusion

•        Dizziness

•        Sweating abnormalities.

TOXICITY:

Ambrisentan has a significant risk of high risk of embryo-fetal toxicity and abnormalities.

STORAGE:

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Maintain a temperature above freezing.