In the past, several vasodilators (i.e. hydralazine, diazoxide, isosorbide dinitrate, Alpha blockers, Beta agonists like Isoprenaline) etc. have been tried without much success. Currently, Calcium Channel Blockers and PGI2 analogues are the only effective vasodilators.

CALCIUM CHANNEL BLOCKERS (CCBs): Calcium channel blockers are vasodilators of systemic and pulmonary circulations. Among the various CCBs, long acting vasoselective dihydropyridines and slow release, heart rate regulating CCBs are preferred. Before starting long term CCBs, “Responders” should be identified by measuring Pulmonary artery pressure (PAP) and Pulmonary venous resistance (PVR) in response to short acting vasodilators (e.g. inhaled NO, intravenously Adenosine or intravenously. PGI2) (₃). A positive response is 10mm Hg or more fall in Mean Pulmonary artery pressure (MPAP) with either no change or an increase in Cardiac output and or decrease in PVR of approx. 25%. Rich et al (₄) have shown that high doses of CCBs resulted in a 5-year survival of more than 90% in “responders” i.e. in patients who showed an acute response to vasodilators. It should be noted that only 10-15% of patients come under this “responder” category. The patients who respond to CCBs need large doses (eg. Nifedipine upto 300mg/day, Diltiazem upto 720mg/day).

The adverse affects are due to their negative inotropic effect and fall in systemic blood pressure, which may be an important limiting factor in their use. Hence CCBs should not be used in patients with overt right ventricular failure and those with systemic hypotension.

PROSTAGLANDINS: The prostacyclins act through an increase in Cyclic AMP, which produces vasodilatation.

EPOPROSTENOL: Epoprostenol is a potent pulmonary vasodilator. Its other mechanisms of benefit are unclear. It may also result in a positive inotropic effect, has some amount of systemic vasodilatation and antiplatelet effect by which it may reverse vascular damage (₅)

Prospective randomized trials by Barst et al (₆) and McLaughlin et al (₇) have demonstrated improved exercise tolerance and survival in patients with primary pulmonary hypertension treated with Epoprostenol. The survival benefit was seen in patients with NYHA class 3 & 4 heart failure. The optimal dose is yet to be clearly defined. However, starting Epoprostenol at a dose of 2-4ng/kg/min intravenously is recommended followed by increments of 1-2ng/kg/min until either clinical improvement is seen or further increment is not possible due to side effects.

Epoprostenol has a very short half life (t½). Therefore, a permanent central venous access is needed for administration and hence a risk of potentially serious complications thereof. Common side effects are flushing, headache, diarrhoea, nausea, jaw pain, leg pain. Sudden withdrawal may result in rebound rise in PAP leading to Acute RV failure. Epoprostenol is unstable in aqueous solution and has a t½ of 1-2 minutes. Hence any interruption of the infusion may lead to sudden life threatening loss of its effect. Therefore, a more stable PGI2 analogue like Iloprost offers theoretical advantages.

ILOPROST: Iloprost is a stable prostacyclin analogue with a t½ of 20-30min. given intravenously; its effects are similar to intravenous epoprostenol. Dosing of intravenous iloprost is lower than that of intravenous epoprostenol. The normal starting dose is 0.5–1 ng/kg/min and maintenance dose is 2-4 ng/kg/min. Iloprost can be given by inhalation also. By inhalation route, less of the drug reaches systemic circulation thus making it a “pseudoselective pulmonary vasodilator”.

Currently, intravenously prostaglandins are the first line of treatment for patients in New York Heart Association (NYHA) class III & IV. However, in the future, patients with less severe disease (NYHA II, III) may be initially treated with one of the novel prostaglandins.

The propensity for serious central venous catheter related infections in case of intravenous epoprostenol led to the development of Trepostinil, a stable prostacyclin analog for subcutaneous infusion. It is given as a continuous subcutaneous infusion by a mini pump that has been used for insulin. It has a t½ of 3-4 hours.

A 12-week, double blind, randomized placebo controlled multicenter trial (in 470 patients with PH either primary or associated with connective tissue disease, congenital systemic to pulmonary shunts) showed that continuous subcutaneous Trepostinil improved indices of dyspnea, signs and symptoms of pulmonary hypertension and hemodynamics (₈). It was given through a micro infusion pump with catheter placed in the subcutaneous tissue of abdominal wall at an initial dose of 1.25ng/kg/min. During the course of this study, the drug was increased to a maximum dose at which PH signs and symptoms were improved. The maximum allowed dose was 22.5ng/kg/min. The most common side effect was infusion site pain (85%). 3 patients had gastrointestinal (GI) bleed.

Oral Beraprost another prostacyclin analogue appears to be beneficial in the treatment of PPH (₉,₁₀). A study of oral Beraprost in 13 patients with severe PH (given treatment for 1 year) concluded that oral Beraprost might result in long-lasting clinical and hemodynamic improvement (₉).A placebo controlled multicenter trial (ALPHABET) of 130 patients showed that oral Beraprost decreased mean pulmonary artery pressure in many patients. This study included patients with primary PH, PH associated with collagen vascular disease, congenital systemic to pulmonary shunts, portal hypertension and HIV. A median dose of 80ug was given 4 times/day.

Inhaled Iloprost also appears to be beneficial (₁₁,₁₂). In a study involving 203 patients with severe pulmonary hypertension (including PH with scleroderma and chronic thrombo embolic PH) inhaled Iloprost was found to be useful (₁₂). 2.5–5 ug of Iloprost (6-9 times/day – median inhaled dose 30 ug/d) was compared with placebo and was found to be effective in decreasing the signs and symptoms of PH. Inhaled Iloprost has the disadvantage of short duration of action and hence requires frequent (₆,₇,₈,₉,₁₀,₁₁,₁₂) inhalations per day. It may hence disturb patient’s lifestyle and may be cumbersome.

Endothelin – 1 mediates vasoconstriction and smooth muscle cell proliferation through ETA receptor. It also induces vasodilatation through ETB receptor.

BOSENTAN: Bosentan is an oral, dual endothelin receptor antagonist. It blocks both Endothelium A and Endothelium B receptors (and hence it is non selective). It is thus an antiproliferative agent and may be most useful in PPH. A double blind randomized placebo-controlled study showed that oral Bosentan increases exercise capacity and improves hemodynamics in patients with PH (₁₃). The results of BREATHE-1 (Bosentan: Randomized trial of Endothelin receptor Antagonist Therapy for Pulmonary Hypertension) concluded that Bosentan is beneficial in patients with PH and is well tolerated at a dose of 125mg twice daily (₁₄). Elevation of liver enzymes was observed in 14% patients (transient in most cases and necessitated discontinuation of treatment in only 3 patients). The mechanism responsible for this is not clear. An accumulation of bile acids in hepatocytes due to competitive inhibition of bile salt-export pump may be the reason.

SITAXSENTAN: It is an oral, selective ETA receptor blocker. A 12-week open label trial by Barst et al showed that Sitaxsentan is beneficial in PH (₁₅). It was given orally at a dose of 100-500mg bd. It also resulted in elevated liver enzymes in some patients.

NITIRIC OXIDE (NO) & L – ARGININE: Vasodilators including inhaled NO act through Cyclic GMP

NO: Inhaled NO is an effective acute pulmonary vasodilator in PH. It requires a continuous inhalation device. Though NO is a potent and selective pulmonary vasodilator, its long-term use is limited by its short half-life. Inhaled NO is currently used to identify “responders” (who respond to CCBs). 80ppm of NO is usually the maximum dose used in acute vasodilator setting (₁₆). Long-term therapy with NO is not practical or viable at present.

L.ARGININE: NO is synthesized from the amino acid L-Arginine. Hence L-Arginine supplementation may be beneficial in PH. The first ever randomized placebo controlled study to examine the effects of short term oral administration of L-Arginine (₁₇) showed that oral L-Arginine significantly decreased mean PAP and PVR associated with significant increase in citrulline and improved exercise capacity. It was used at a dose of 0.5g/kg body weight

PHOSPHODIESTERASE INHIBITOR – SILDENAFIL: PH is associated with a defect in endothelial nitric oxide production and hence nitric oxide dependent pulmonary artery dilation. Therapeutic approaches have been devised to reverse this relative deficiency of nitric oxide. This has been tried using L-Arginine, the substrate required for nitric oxide synthesis and administration of nitric oxide as mentioned earlier. An alternative approach for enhancing the endogenous nitric oxide in PH is to increase nitric oxide – dependent, cGMP mediate pulmonary artery vasodilatation by inhibiting the breakdown of cGMP by PDE5 (Phosphodiesterase5). Sildenafil increases cGMP level by inhibiting PDE5, an enzyme that hydrolyses cGMP.

There are few data on long term Siladenafil treatment barring a few case reports. Michelakis et al (₁₆) have demonstrated that Sildenafil is as effective and selective a pulmonary vasodilator as inhaled Nitric Oxide. Studies that have been done so far are in a small number of patients.

Kothari and Duggal (₁₈) have demonstrated that oral Sildenafil is effective in PH. They studied 14 patients with severe PH (9 patients with primary PH & 5 patients were operated Congenital heart disease patients). Oral Sildenafil was started at low dose and then increased. It was used at a dose of 87.5mg/day in children < 30kgs and at a dose of 150mg/day in patients > 30kgs. They observed remarkable improvement in 6 min walk test, NYHA class and Mean pulmonary artery pressure (MPAP)

Bharani et al (₁₉) studied 10 patients with PH of varied etiology (PPH, left to right shunts, pulmonary thromboembolism and interstitial lung disease) They used Sildenafil at a dose of 25mg Q8H in their randomized double blind placebo controlled cross over study, and showed that Siladenafil was useful in PH of varied etiology.

Ghofrani et al (₂₀), in a randomized controlled open label trial showed that Sildenafil causes preferential pulmonary vasodilation and improves gas exchange in patients with severe lung fibrosis and secondary pulmonary HT.

Sastry et al (₂₁) studied the efficacy of sildenafil in 29 patients with PPH.Sildenafil was started at a dose of 25mg tid & increased upto 100mg tid. There was a significant improvement in functional class, 6min walk test and MPAP.

However, the experience with Sildenafil is limited and remains preliminary and more studies are required to establish its efficacy and safety.

The most commonly reported side effects of Sildenafil are due to vasodilatation. It can cause flushing, nasal congestion, headache, dizziness, hypotension. It can cause relaxation of lower esophageal sphincter resulting in dyspepsia and reflux related symptoms and transient visual abnormalities such as blurred vision and increased light perception due to inhibition of PDE6 in rods and cones in retina (₂₂) It is contraindicated in patients with ischemic heart disease (IHD) who are on nitrates.

A current option for treatment of Pulmonary Hypertension has been summarized in Table 3.

Table 3: Current Options for Treatment of Pulmonary Hypertension

Vasodilators:

Other Adjunctive Therapies: