Work and Uses of Ambrisentan

Generic Name
Anti-hypertensive, Endothelin receptor antagonist

Pharmacology :
Endothelin-1 (ET-1) may be a potent autocrine and paracrine peptide. Two receptor subtypes, ETA and ETB, mediate the consequences of ET-1 within the vascular smooth muscle and endothelium. the first actions of ETA are vasoconstriction and cell proliferation, while the predominant actions of ETB are vasodilation, antiproliferation, and ET-1 clearance.
In patients with PAH, plasma ET-1 concentrations are increased the maximum amount as 10-fold and correlate with increased mean right atrial pressure and disease severity. ET-1 and ET-1 mRNA concentrations are increased the maximum amount as 9-fold within the lung tissue of patients with PAH, primarily within the endothelium of pulmonary arteries. These findings suggest that ET-1 may play a critical role in the pathogenesis and progression of PAH.
Ambrisentan may be a high-affinity (Ki=0.011 nM) ETA receptor antagonist with high selectivity for the ETA versus ETB receptor ( > 4000-fold). The clinical impact of high selectivity for ETA isn't known.

Indications :
Ambrisentan is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1):
  • To improve exercise ability and delay clinical worsening.

  • In combination with tadalafil to scale back the risks of disease progression and hospitalization for worsening PAH, and to enhance exercise ability.
Studies establishing effectiveness included predominantly patients with WHO Functional Class II–III symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH related to animal tissue diseases (34%).

Dosage & Administration :
Initial treatment is 5 mg once daily and may be increased to 10 mg once daily if 5 mg is tolerated. Ambrisentan could also be administered with or without food.

Interaction :
Multiple-dose co-administration of Ambrisentan and Cyclosporine resulted in an approximately 2-fold increase in Ambrisentan exposure in healthy volunteers; therefore, limit the dose of Ambrisentan to five mg once daily when co-administered with Cyclosporine.

Contraindications :
Ambrisentan may cause fetal harm when administered to a pregnant woman. Ambrisentan is contraindicated in women who are or may become pregnant. If this drug is employed during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Pregnancy must be excluded before the initiation of treatment with Ambrisentan and prevented during treatment and for one month after stopping treatment. Ambrisentan is contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF) including IPF patients with pulmonary hypertension (WHO Group 3).

Side Effects :
Decreases in haemoglobin concentration and hematocrit have followed the administration of other endothelin receptor antagonists and were observed in clinical studies with Ambrisentan.

Pregnancy & Lactation :
Pregnancy Category X. it's not known whether Ambrisentan is excreted in human milk. Breastfeeding while receiving Ambrisentan isn't recommended.

Precautions & Warnings :
Fluid Retention: Peripheral edema may be a known class effect of endothelin receptor antagonists, and is additionally a clinical consequence of PAH and worsening PAH.

Pulmonary Veno-occlusive Disease: If patients develop acute pulmonary edema during initiation of therapy with vasodilating agents like Ambrisentan, the likelihood of pulmonary venous-occlusive disease should be considered, and if con_rmed. Ambrisentan should be discontinued.

Haematological Changes: Decreases in haemoglobin concentration and hematocrit have followed the administration of other endothelin receptor antagonists and were observed in clinical studies with Ambrisentan.

Storage :
Store in a cool and dry place, below 30° C. Protect from light and moisture.

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