INTRODUCTION
Pulmonary arterial hypertension (PAH) includes primary pulmonary hypertension (PPH) with no apparent cause, PAH secondary to congenital shunt lesions, connective tissue disorders, portal hypertension, drug-induced PAH, and human immunodeficiency virus (HIV)-related PAH. Severe PAH, whether primary or secondary, causes management problems.
PPH is a progressive disease with no cure, and if untreated, results in a life expectancy of less than an year.
The structural abnormalities of the pulmonary vasculature in Eisenmenger’s syndrome are similar to patients with PPH, and it would be logical to use a similar therapeutic approach in these patients.
The current therapeutic options available for PPH include anticoagulants, calcium-channel blockers, epoprostenol (prostacyclin), iloprost, beraprost, the endothelin-receptor antagonist bosentan, and sildenafil, a selective phosphodi-esterase-5 (PDE-5) inhibitor.2 Sildenafil citrate is a potent pulmonary vasodilator.It has been found to be clinically effective in patients of moderate-to-severe pulmonary hypertension.3,4 Tadalafil, an analog of sildenafil, also has similar properties. We report our experience in two patients with severe PAH. Both patients gave their informed written consent to receive tadalafil.
Dyspnea and a 3-month history of being unable to cycle for 100 yards without dyspnea (NYHA class III). Evidence of collagen vascular and HIV status were negative. His electrocardiogram (ECG) showed sinus tachycardia with features of P-pulmonale and chest X-ray showed cardiomegaly with prominent pulmonary conus. Echocardiogram revealed dilated right-sided chambers and proximal pulmonary artery.
Pulmonary artery systolic pressure was 131mmHg. Left ventricular systolic function was preserved. Pulmonary function tests showed only mild airflow limitation. The patient could not afford treatment with continuous epoprostenol infusion or bosentan. Subsequently, treatment with tadalafil was started, based on reports that another PDE-5 inhibitor, sildenafil was effective in treatment of PPH. The initial dose of 10mg once daily was initially associated with transient side effect of flushing, which disappeared after few days.The dose was then adjusted until a maintenance dose of 30mg once daily was reached, and no further side effects were reported. The patient’s only other medication was the anticoagulant war-farin. An improvement was noted within three weeks of treatment and the patient showed progressive improvement over the next three months. On a follow-up at three months he was able to cycle 200 yards (NYHA class II) comfortably. The echocardiogram showed an estimated pulmonary artery systolic pressure of 92mmHg.
REPORT
Case 1
A 35-year-old male, who is a nonsmoker, and a hawker by profession, presented with a 1-year history of worsening
Case 2
The second patient was a 32-year-old female complaining of worsening exertional dyspnea (NYHA class III) and increasing fatigue. Echocardiography showed features of
Eisenmenger’s complex with estimated right ventricular systolic pressure of 130mmHg. Both ventricular systolic functions were normal. Blood examination revealed a hema-tocrit of 58% with normal red blood cell morphology. She was not receiving any drugs at the time of examination and she could not afford invasive treatment.
Tadalafil was then started at an initial dose of 10mg once daily, which was well tolerated along with an improvement in her symptoms. Over the next two weeks, the dose was gradually increased to 20mg once daily and the patient showed substantial symptomatic improvement. Over a follow-up of three months at the same dose, the patient’s symptoms improved to NYHA class II. Echocardiography showed a significant reduction of estimated pulmonary artery systolic pressure (a reduction of 45mmHg from 130 to 85mmHg).
DISCUSSION
Primary pulmonary hypertension is characterized by progressive elevation of the PAH, which eventually leads to right ventricular failure and death.5 Calcium-channel antagonists are the mainstay of therapy, but only 25–30% of patients respond.Other treatment options include continuous prostacyclin infusion and heart–lung transplantation, which are limited by nonavailability in many parts of the world, clinical difficulties, complications, and costs involved.
Thus, a form of treatment without these shortcomings, but which achieves a sustained decrease in PAH, is required.
Sildenafil citrate, a selective inhibitor of cyclic guanosine monophosphate PDE-5 has been found to induce smooth muscle relaxation via a nitric oxide-dependent increase of GMP.7 Inhibition of PDE-5, found in high concentration in lung tissue by sildenafil, has been found to decrease PAH in recent clinical studies in both primary and secondary PAH.8,9 Subsequent to sildenafil, two additional agents in this class (PDE-5 inhibitors), tadalafil and vardenafil have been developed.
Tadalafil is a long-acting PDE-5 inhibitor,which is effective for up to 36h in the majority of men. This drug also appears to be generally safe and well tolerated, with a side effect profile similar to sildenafil.10 From these two cases of severe PAH, we conclude that tadalafil, like sildenafil, may be beneficial as a selective pulmonary vasodilator in patients with severe PAH, and because of its long effective half life, it may offer the advantage of once daily dosing. We recommend that the role of tadalafil in PAH be further evaluated.
REFERENCES
1. British cardiac society guidelines and medical practice committee, and approved by the British Thoracic Society and the British Society of Rheumatology. Recommendation on the management of pulmonary hypertension in clinical practice. Heart 2001; 86: i1–i3.
2. Kothari SS, Bahl VK. Primary pulmonary hypertension—an update. Indian Heart J 2002; 54: 255–60.
3. Watanable H, Ohasi K, Takeuchi K, Yamashita K, Yokoyama T, Tran QK, et al. Sildenafil for primary and secondary pulmonary hypertension. Clin Pharmacol 2002; 71: 398–402.
4. Bharani A, Mathew V, Sahu A, Lunia B. The efficiency and tolerability of sildenafil in patients with moderate-to-severe pulmonary hypertension. Indian Heart J 2003; 55: 55–59.
5. D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991; 115: 343–49.
6. Higgenbotam TW, Spiegelhaltor D, Scott JP, Fuster V, Dinh-Xuan AT, Caine N, et al. Prostacyclin (epoprostenol) and heart-lung transplantation as treatments for severe pulmonary hypertension. Br Heart J 1993; 70: 366–70.
7. Turko IV, Ballard SA, Francis SH, Corbin JD. Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. Mol Pharmacol 1999; 56: 124–30.
8. Kothari SS, Duggal B. Chronic oral sildenafil in severe pulmonary artery hypertension. Indian Heart J 2002; 54: 404–09.
9. Sastry BKS, Narasemhan C, Reddy NK, Anand B, Prakash GS, Raju PR, et al. A study of sildenafil in patients with primary pulmonary hypertension. Indian Heart J 2002; 54: 410–14.
10. Eardley I, Cartledge J. Tadalafil (Cialis) for men with erectile dysfunction. Int J Clin Pract 2002; 56: 300–04.
Correspondence: Dr Thokchom Sachin Deba Singh, Sagolband Meinoleirak, Imphal-795001, India.
E-mail: sukacm@yahoo.com
|
