Bostentan

Question.

218. Bostentan is a:

1. Serotonin uptake injibitor.

2. Endothelin receptor antagonist.

3. Leukotriene modifier.

4. Calciuim sensitizer.

Answer

2. Endothelin receptor antagonist.

Reference

CMDT 2002 Page 450

http://www.pharmacist.com/new_drug/tracleer.cfm

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Discussion

• It is endothelin receptor antagosnist
• Generic name: Bosentan
• Manufacturer: Actelion
• Drug Class:
• PROSTACYCLIN
• Dual endothelin receptor antagonist
• Indications: Treatment of pulmonary arterial hypertension.
• Dosage: Initiate treatment at an oral dosage of 62.5 mg twice daily for 4 weeks and then increase to a maintenance dosage of 125 mg twice daily.
• Evidence of liver damage present in 14% of patients in Bosentan: Randomized Trial of Endothelin Receptor Antagonist Therapy trial, but no evidence suggests agent can cause irreversible liver damage.
• It has been made available to patients at the University of Pittsburgh Medical Center as part of a clinical trial. Bosentan works by blocking the action of a hormone called endothelin. Endothelin exists in higher levels in people with PH is a hormone that is harmful to the lung and pulmonary arteries. The damaged lung and pulmonary arteries create the blood flow resistance that results in hypertension. Bosentan was designed to offset endothelin, lowers the endothelin levels, reversing its effects, resulting in lower artery pressure.
• Tracleer blocks the action of endothelin, a substance made by the body. Endothelin narrows blood vessels and elevates blood pressure. Although endothelin is present in healthy people, high concentrations of the hormone have been found in the plasma and lungs of patients with PAH suggesting it is capable of causing the disease.
• Liver function tests are needed
• Because of its potential to cause birth defects, Tracleer must not be prescribed to pregnant women. Female patients of childbearing potential must therefore take measures to prevent pregnancy, and monthly pregnancy testing will be required.

Explanation

1. Serotonin uptake injibitors are Fluoxetine, Fluvoxamine, Paroxetine.

2. Endothelin receptor antagonist.

3. Leukotriene modifiers are Montelukast and Zafirlukast.

4. Calcium sensitizer is Levosimendan.

Comments

Myocardial stunning refers to the phenomenon of transient myocardial dysfunction after brief periods of coronary ischaemia and reperfusion. During stunning there is less myocardial fibre shortening and myocardial oxygen consumption is near normal, indicating a low efficiency of the contractile apparatus. Depressed responsiveness of the myofilaments to Ca ions is regarded as an important factor in the process of stunning. Levosimendan (Levo) increases the sensitivity of troponin C in a Ca-dependent way.

STRUCTURE AND DYNAMICS OF CARDIAC TROPONIN C

Cardiac Troponin C (cTnC) plays a pivotal role in the function of heart. The heart contraction is induced by a conformational change of cTnC triggered by the binding of calcium ions which are released from the sarcoplasmic reticulum. The conformational change of cTnC allows myosin to interact with actin filaments. Subsequently, the heart contracts as the filaments glide past each other. Knowledge of the three-dimensional structure of cTnC and its induced conformational changes at atomic resolution provide new means for understanding the basic events in the heart contraction. This knowledge is also of applied importance. In a number of cases impaired heart functions can be alleviated by drug molecules designed to make troponin C more prone to a conformational change. These drugs which increase the calcium sensitivity are designated calcium sensitizers. It would be most useful for further development of these pharmaceuticals to be able to demonstrate the drug binding and its consequences to the conformation and dynamics of cTnC.

Considering the fundamental role of cardiac troponin C in the heart function and the possibilities to modulate the function by pharmaceuticals a study of cTnC by methods of structural biology is most interesting and useful. The three-dimensional structure of cTnC should be determined in complex with relevant motifs of TnI. In addition deeper insight into the structure-function relationship should be gained by a molecular dynamics study.

A new calcium sensitizer drug levosimendan was discovered by calcium dependent affinity chromatography on a troponin complex column (Haikala et al., 1992). The screening was based on a hypothesis that calcium sensitizers bind in the hydrophobic patch formed in the regulatory domain of TnC following a calcium induced conformational change (Ovaska and Taskinen, 1991). It was recently shown that the new calcium sensitizer drug levosimendan binds to human cardiac troponin C (Pollesello et al., 1994).

Tips

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