Bosentan Monohydrates: Uses, Interactions, Mechanism of Action:

INDICATIONS:

It is recommended that patients with WHO or IV symptoms take the Bosentan tablet for the treatment of idiopathic or familial pulmonary arterial hypertension, pulmonary arterial hypertension (PAH) associated with scleroderma, or pulmonary arterial hypertension associated with congenital systemic to pulmonary shunts. In order to lessen the frequency of new digital ulcers, the bosentan tablet is indicated for the treatment of systemic sclerosis with active digital ulcer disease.

Clinical pharmacy:

Mechanism of action.

A neurohormone called endothelin-1 (ET-1) exerts its effects by attaching to ETA and ETB receptors in vascular smooth muscle and endothelium, respectively. Patients with pulmonary arterial hypertension have elevated levels of ET-1 in their plasma and lung tissues, which may indicate that ET-1 plays a pathogenic role in this condition. Bosentan is a selective and competitive antagonist at the endothelin receptor types ETA and ETB. It has a slightly higher affinity for ETA receptors than for EB receptors.

Pharmacokinetics:

It is unknown if age, race, gender, or body weight have an impact on Bosentan's pharmacokinetics.

Absorption:

Bosentan's absolute bioavailability in healthy subjects is about 50%, and food has no impact on this number. Within three to five hours, the highest plasma concentrations are reached.

Distribution:

Bosentan is very tightly bound (> 98%) to plasma proteins, primarily albumin. Erythrocytes are not penetrated by bosentan. Following a 250mg intravenous dose, a volume of distribution (Vss) of roughly 18 litres was found.

Biotransformation and elimination:

A single 250mg intravenous dose resulted in a clearance of 8 points 2 L/h. 54 hours make up the terminal elimination half-life. Plasma concentrations of bosentan gradually drop after multiple doses, reaching 50–65 percent of those after a single dose. The liver enzymes that help with metabolism are probably to blame for this decrease. Within 3 to 5 days, steady-state conditions are attained. Bosentan is broken down in the liver by the cytochrome P450 enzymes CYP2C9 and CYP3A4 before being excreted by the bile. Less than 3% of an oral dose is excreted in the urine. Only one of the three metabolites formed by bosentan is pharmacologically useful. The bile is primarily used to excrete this metabolite in its unchanged form. Compared to healthy subjects, adult patients have a higher exposure to the active metabolite. The exposure to the active metabolite may be increased in patients who have cholestasis symptoms.

CONTRAINDICATIONS:

Patients who have are not advised to take this medication.

Hypersensitivity to any excipient or the active ingredient.
Moderate to severe liver damage, i.e. B or C Chid-Pugh class.
Baseline liver aminotransferase values, i.e., aspartate aminotransferases (AST) and/or alanine aminotransferases (ALT), more than three times the upper limit of normal.
concurrent use of cyclosporine.
Pregnancy.
Potential mothers who don't use safe forms of birth control.

DOSE AND ADMINISTRATION:

The initial dose of bosentant ablet should be 62.5mg twice daily for 4 weeks, and then the dose should be increased to the maintenance dose of 125mg twice daily. The extra benefit from doses above 125mg twice a day does not seem to outweigh the increased risk of liver damage. With or without food, tablets should be taken in the morning and evening.

Use in Women of Child-bearing Potential:

Following a negative pregnancy test and only in those who use effective contraception, bosentan tablet therapy should be started in women of childbearing potential.

OVERDOSAGE:

Mild to moderate headaches were by far the most frequent adverse reaction. Massive overdosage may cause pronounced hypotension that necessitates active cardiovascular support.

PRECAUTIONS:

Haematologic Changes: Bosentan therapy led to a dose-related decline in hemoglobin and hemocrit. Following the first and third months of treatment, along with every third month after that, hemoglobin levels should be checked. For patients taking Bosentan, the overall mean decrease in hemoglobin concentration was 0. 9g/di (change to treatment's conclusion). In order to identify the cause and the requirement for a particular course of treatment, additional testing should be done if there is a significant drop in hasmoglobin concentration. Patients with decompensating heart failure who experienced fluid retention needed to be treated with a dureud, huid managerbell, or luspicasion. Bosentan causes pulmonary edoma in patients with pulmonary arterial hypertension; as a result, Bosentan should be stopped. Pulmonary Veno-Occlusive Disease (POD): When Bosentan is administered to patients with pulmonary arterial hypertension, it may be associated with POD. Bosentan is not recommended for use during pregnancy or lactation because it can cause teratogenicity, a class effect of these medications. Bosentan should not be taken while breast-feeding.

Drug Interactions:

By CYP2C9 and CYP3A4, bosentan is metabolized. The plasma concentration of Bosentan may rise as a result of the inhibition of these enzymes. Large increases in plasma concentrations of Bosentan are likely to occur when it is administered concurrently with a CYP2C9 inhibitor (like fluconazole or amiodarone) and a CYP3A4 inhibitor (like ketoconazole, itraconazole, or ritonavir). Bosentan shouldn't be administered with such mixtures of a strong CYP2C9 inhibitor and a CYP3A4 inhibitor. Bosentan is a CYP3A4 and CYP2C9 inducer. As a result, when Bosentan is also administered, the plasma concentrations of drugs metabolized by these two isozymes will drop. Any CYP isozyme (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) in vitro had no detectable inhibitory effect from bosentan. Since these drugs are metabolized by these enzymes, Bosentan is not anticipated to raise their plasma concentrations.

Adverse Effects:

decrease in hemoglobin due to anemia.
Red blood cell transfusions are necessary when anaemia or hemoglobin levels fall.
Thrombocytopenia.
"Neutropenia" and "leukopenia.".
Reactions due to hypersensitivity, such as dermatitis, pruritus, and rash.
Angioedema and/or anaphylaxis.
Headache.
Syncope.
Palpitations.
Flushing.
Hypotension.
congestion in the nose.
diarrhea caused by gastroesophageal reflux disease.
abnormal liver function test results.
Elevated aminotransferases that are related to jaundice, hepatitis, and/or possible underlying hepatitis flare-ups.
liver failure and cirrhosis.
skin as well as subcutaneous.
Erythema.
disorders.
fluid retention, edema.

WARNINGS:

Potential Liver Injury: Elevations of AST and/or ALT linked to Bosentan are dose-dependent, present early and late in treatment, typically progress slowly, are frequently asymptomatic, and typically have been reversible after treatment interruption or cessation. Elevations of aminotransferases may also spontaneously reverse while receiving Bosentan treatment. If increased levels of aminotransferase are detected, treatment and monitoring must be adjusted. If liver aminotransferase elevations are accompanied by clinical signs of liver injury (such as nausea and vomiting), the combination of hepatocellular injury (increases in aminotransferases of >3 ULN) and increase in total bilirubin (23* ULN) is a marker for potential serious liver injury. Treatment should be discontinued if there are any changes in bilirubin 22 ULN (fever, abdominal pain, jaundice, or unusual lethargy or fatigue). In these conditions, there is no experience with the reintroduction of Bosentan.

Liver impairment from a previous condition:

Prior to starting a course of treatment, and then on a monthly basis, liver aminotransferase levels must be checked. Patients with mild to severe liver impairment should generally avoid taking bosentan. Bosentan should also generally be avoided in patients with elevated aminotransferases (>3 ULN), as it may be more difficult to monitor liver damage in these patients.