Treatment of Pulmonary Hypertension

alpha blockers [Ref- Harrison 17^th/e p 1577, 1578] Pulmonary hypertension

General management

• Diuretic therapy may be useful as it relieves pulmonary edema.
• Anticoagulant therapy is advocated for all patients.

Specific management

Calcium channel blockers

• Patients who have substantial reductions in pulmonary arterial pressure in response to short acting vasodilators at the time of cardiac catheterization should he initially treated with calcium channel blockers.

Endothelin receptor antagonist

• Bostenan is a non-selective endothelium receptor antagonist, is an approved t/t _,for patients who are NYHA .functional classes III and IV.

Phosphodiesterase-5 inhibitors

• Slidenafil is used for patients who are NYHA functional classes II and

Prostacyclins

• Iloprost is a prostacyclin analogue used in PAH patients who are NYHA functional classes III and IV.
• Pulmonary circulation is unique in that it accommodates a blood flow that is almost equal to that of all the other organs of body but still maintains low pressure.
• The factors responsible for low pressure in pulmonary circulation (even with large volume of blood) are:- – Larger diameter of pulmonary vessels due to thin wall of pulmonary artery and arterioles.

– Greater compliance (distensibility) of pulmonary vessels.

numoral factors responsible for maintaining pulmonary circulation:?

Normally

• NO causes vosodilation and proliferation of smooth muscles by r in the conc. of cGMP —) this increases the diameter of pulmonary vessels.
• causes vosodilation and decreased proliferation of smooth muscles by increasing the conc. of cAMPincrease in the diameter of pulmonary vessels. Prostaglandin also decreases coagulation.

Endothelin causes vasoconstriction and increase smooth muscle proliferation si lumen of pulmonary vessels. – Normally the vasodilators and antiprolifeave effects of NO and PGI₇ dominate 

In Pulmonary hypertension

• There is l production of NO (and cGMP) and PGI₂ (and cAMP), t vasoconstriction and proliferation of smooth

muscles, st lumen of pulmonary vessel. Decreased production of PGI₂ also causes increased coagulation.

• There is T production of endothelin, /vasoconstriction and smooth muscle proliferation, .1 lumen.

Beta blockers [Ref Harrison 17^th/e p 1577, 1578] Repeat _.from May10 Q no.69

Phosphodiesterase III inhibitors (Milrinone) acts via a non-beta receptor pathway to effect a decrease in pulmonary vascular resistance while improving left and right contractility. Such interventions are the treatment of choice in conditions of Right Heart Failure secondary to high pulmonary vascular resistance (pulmonary hypertension).

Ref: Review of Clinical Anesthesia By Neil Roy Connelly, Page 218.

Primary pulmonary hypertension

Ans. is ‘d’ i.e., For reducing pulmonary hypertension

According to Goodman Gilman

“Inhaled nitric oxide has been approved by FDA for use in newborns with persistent pulmonary hypertension and has become the first line therapy for this disease. In this disease state NO inhalation has been shown to reduce, significantly, the necessity for extracorporeal oxygenation”

Ans. is ‘b’ i.e., Newborn with pulmonary hypertension

Ans. is ‘b’ i.e., Phosphodiesterase -5

o Sildenafil inhibits phosphodiesterase-5 and is used for erectile dysfuction.

Ans. is ‘c’ i.e., Tadalafil

o Tadalafil is the longest acting phosphodiesterase inhibitor used for erectile dysfunction. Its half life is 17.5 hours.

Ans. is ‘c’ i.e., Alpha blockers

Drug for pulmonary hypertension

1.  By increasing the effect of NO/cGMP

o This can done by increasing the concentration of cGMP by preventing its degradation.

o This can be achieved by inhibiting phosphodiesterase-5 by phosphodiesterase -5 inhibitors like sildenafil, Tadalofil.

2.  By increasing the effect of Prostacyclin (cAMP)

o This can be achieved by using prostacyclins like epoprostenol, Treprostinil, Iloprost.

3.  By decreasing the effect of endothelin

o This can be acheived by using endothelin receptor antagonists like Bosentan, ambrisentan.

By having direct vasodilatory effect on pulmonary vessels. o Calcium channel blockers like nifedipine dilate both systemic and pulmonary vascular bed.

Answer is D (Inhalation):

Iloprost is a Prostacyclin analogue approved via inhalation for treatment of Pulmonary Arterial Hypertension (PAH).

Ans: C i.e. Phosphodiesterase-5 inhibitor

Drugs and mechanism of action

• Finsateride is a competitive inhibitor of the enzyme 5 alpha reductase (which converts testosterone into more active dihydrotestosterone)
• Flutamide is a non-steroidal drug having specific anti-androgenic, but no other hormonal activity
• Sildenafil acts by selectively inhibiting PDE-5 and enhancing nitric oxide action in corpus cavernosum
• Danazol is an orally active ethisterone derivative having weak androgenic, anabolic and progestational activities.

Ans. is ‘b’ i.e., cGMP

Ans. is ‘b’ i.e., used in malignant hepatitis

Endothein receptor antagonists

• There are two endothelin receptor subtypes – ET_A and and ETB.
• Bosentan is a nonselective endothelin antagonist – blocks both ET_A and ETB.
• Bosentan is active intravenously and orally.
• Bosentan is currently approved for use in pulmonary hypertension.
• Tezosentan another nonselective antagonist is used investigation for the treatment of acute heart failure.
• Sitaxentan and ambrisentan are selective ET_A antagonists.
• Phosphoramidon inhibits formation of endothelin by inhibiting endothelin converting enzyme. Remember
• Bosentan can cause severe hepatotoxicity – monthly liver function tests should be done.
• It is contraindicated in pregnancy.