Endobloc

Endobloc Uses, Dosage, Side Effects, Food Interaction and all others data.

Endothelin-1 (ET-1) is a potent autocrine and paracrine peptide. Two receptor subtypes, ETA and ETB, mediate the effects of ET-1 in the vascular smooth muscle and endothelium. The primary 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 as much as 10-fold and correlate with increased mean right atrial pressure and disease severity. ET-1 and ET-1 mRNA concentrations are increased as much as 9-fold in the lung tissue of patients with PAH, primarily in the endothelium of pulmonary arteries. These findings suggest that ET-1 may play a critical role in the pathogenesis and progression of PAH.

Endobloc is a high-affinity (Ki=0.011 nM) ETA receptor antagonist with a high selectivity for the ETA versus ETB receptor ( > 4000-fold). The clinical impact of high selectivity for ETA is not known.

Endobloc 10 mg daily had no significant effect on the QTc interval, whereas a 40 mg daily dose of ambrisentan increased mean QTc at tmax by 5 ms with an upper 95% confidence limit of 9 ms. Significant QTc prolongation is not expected in patients taking ambrisentan without concomitant metabolic inhibitors.Plasma concentrations of B-type natriuretic peptide (BNP) in patients who received ambrisentan for 12 weeks were significantly decreased. Two Phase III placebo-controlled studies demonstrated a decrease in BNP plasma concentrations by 29% in the 2.5 mg group, 30% in the 5 mg group, and 45% in the 10 mg group (p < 0.001 for each dose group) and an increase by 11% in the placebo group.

Endobloc
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Endobloc
Availability	Prescription only
Generic	Ambrisentan
Ambrisentan Other Names	Ambrisentan
Related Drugs	sildenafil, tadalafil, Revatio, Adempas, Opsumit, bosentan
Type	Tablet
Formula	C₂₂H₂₂N₂O₄
Weight	Average: 378.428 Monoisotopic: 378.157957196
Protein binding	Ambrisentan is 99% plasma protein bound, primarily to albumin (96.5%) and to a lesser degree alpha1-acid glycoprotein.
Groups	Approved, Investigational
Therapeutic Class	Anti-hypertensive, Endothelin receptor antagonist
Manufacturer	Cipla Limited
Available Country	India,
Last Updated:	September 19, 2023 at 7:00 am

Uses

Endobloc is used for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1):

To improve exercise ability and delay clinical worsening.
In combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve 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 associated with connective tissue diseases (34%).

Endobloc is also used to associated treatment for these conditions: Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH)

How Endobloc works

Endothelin-1 (ET-1) is an endogenous peptide that acts on the endothelin type A (ETA) and endothelin type B (ETB) receptors in vascular smooth muscle and endothelium. ETA-mediated actions include vasoconstriction and cell proliferation, whereas ETB predominantly mediates vasodilation, anti-proliferation, and ET-1 clearance. In patients with pulmonary arterial hypertension, ET-1 levels are increased and correlate with increased right arterial pressure and severity of disease. Endobloc is one of several newly developed vasodilator drugs that selectively target the endothelin type A (ETA) receptor, inhibiting its action and preventing vasoconstriction. Selective inhibition of the ETA receptor prevents phospholipase C-mediated vasoconstriction and protein kinase C-mediated cell proliferation. Endothelin type B (ETB) receptor function is not significantly inhibited, and nitric oxide and prostacyclin production, cyclic GMP- and cyclic AMP-mediated vasodilation, and endothelin-1 (ET-1) clearance is preserved.

Dosage

Endobloc dosage

Initial treatment is 5 mg once daily, and can be increased to 10 mg once daily if 5 mg is tolerated. Endobloc may be administered with or without food.

Side Effects

Decreases in hemoglobin concentration and hematocrit have followed administration of other endothelin receptor antagonists and were observed in clinical studies with Endobloc.

Toxicity

Endobloc is teratogenic and has a high risk of embryo-fetal toxicity. LD50 was found to be greater than or equal to 3160 mg/kg when studied in rats. There was no evidence of carcinogenic potential in 2 year oral daily dosing studies in rats and mice.

Precaution

Fluid Retention: Peripheral edema is a known class effect of endothelin receptor antagonists, and is also 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 such as Endobloc, the possibility of pulmonary veno-occlusive disease should be considered, and if con_rmed. Endobloc should be discontinued.

Hematological Changes: Decreases in hemoglobin concentration and hematocrit have followed administration of other endothelin receptor antagonists and were observed in clinical studies with Endobloc.

Interaction

Multiple dose co-administration of Endobloc and Cyclosporine resulted in an approximately 2-fold increase in Endobloc exposure in healthy volunteers; therefore, limit the dose of Endobloc to 5 mg once daily when co-administered with Cyclosporine.

Food Interaction

No interactions found.

Endobloc Drug Interaction

Minor: tadalafil, tadalafilUnknown: charcoal, charcoal, aspirin, aspirin, carvedilol, carvedilol, apixaban, apixaban, sodium iodide, sodium iodide, furosemide, furosemide, selexipag, selexipag, cyanocobalamin, cyanocobalamin, cholecalciferol, cholecalciferol

Endobloc Disease Interaction

Major: hepatotoxicity/liver impairmentModerate: renal impairment, anemia, fluid retention

Volume of Distribution

Endobloc has a low distribution into red blow cells, with a mean blood:plasma ratio of 0.57 and 0.61 in males and females, respectively.

Elimination Route

Endobloc is rapidly absorbed with peak plasma concentrations occuring around 2 hours after oral administration. Cmax and AUC increase proportionally with dose across the therapeutic dosing range. Absolute oral bioavailability of ambrisentan is unknown. Absorption is not affected by food.

Half Life

Endobloc has a terminal half-life of 15 hours. It is thought that steady state is achieved after around 4 days of repeat-dosing.

Clearance

The mean oral clearance of ambrisentan was found to be 38 mL/min in healthy subjects and 19 mL/min in patients with pulmonary artery hypertension.

Elimination Route

Endobloc is primarily cleared by non-renal pathways. Along with its metabolites, ambrisentan is primarily found in the feces following hepatic and/or extra-hepatic metabolism. Approximately 22% of the administered dose is recovered in the urine following oral administration with 3.3% being unchanged ambrisentan.

Pregnancy & Breastfeeding use

Pregnancy Category X. It is not known whether Endobloc is excreted in human milk. Breastfeeding while receiving Endobloc is not recommended.

Contraindication

Endobloc may cause fetal harm when administered to a pregnant woman. Endobloc is contraindicated in women who are or may become pregnant. If this drug is used 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 Endobloc and prevented during treatment and for one month after stopping treatment. Endobloc is contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF) including IPF patients with pulmonary hypertension (WHO Group 3).