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About pulmonary hypertension and how it can be managed


Pulmonary hypertension is a progressive condition that can shorten patients’ lives considerably. Targeted medicines are used to dilate the pulmonary vasculature, improve quality of life and prolong survival

Pulmonary hypertension is the result of constriction or blockage of the pulmonary vasculature, which causes a reduction in blood flow from the right side of the heart to the lungs. As the condition develops, there is an increased strain on the right side of the heart.

With progressive difficulty in pumping blood to the lungs, the right side may become enlarged. In severe cases of right-sided dilation, the volume and function of the left atrium and ventricle become compromised. This can result in arrythmias, renal impairment, syncope and other complications associated with reduced cardiac output.

Constriction of the pulmonary vascular bed can occur for a number reasons, some of which are progressive and have no known cure. The different types of pulmonary hypertension are[1]:

  • Pulmonary arterial hypertension (PAH)
  • Pulmonary hypertension in association with left heart disease
  • Pulmonary hypertension associated with lung diseases (eg, chronic obstructive pulmonary disease)
  • Chronic thromboembolic pulmonary hypertension (CTEPH)
  • Pulmonary hypertension that is multifactorial or of unclear origin

Shortness of breath is the most common presenting symptom[2] and fatigue, weakness, chest pain and syncope — all at various degrees of severity — can also occur[3]. Because symptoms can be vague and non-specific, the presence of pulmonary hypertension is often overlooked by clinicians and referral to a specialist centre delayed[4].

Before specific treatments became available, the mean survival of patients with PAH was just 2.8 years. Although survival has doubled over the past decade, PAH continues to be a life-shortening disease.

Greater awareness of the condition, the evolution of specialist care and the increasing number of treatment options that are becoming available have the potential to improve quality of life for those affected.

Diagnosis and classification

The disease progression and response to treatment for each type of pulmonary hypertension differ[5]. There are defined treatments for PAH and CTEPH, whereas the optimal treatment for the other types is unclear. Detailed and systematic phenotyping is needed to ensure that patients are being managed in the most appropriate way for the specific nature of their condition.1

Referral to a specialist centre is vital for determining the cause of pulmonary hypertension and accurately classifying its severity[6]. There are seven specialist centres in the UK for adult pulmonary hypertension: one in Newcastle, one in Sheffield, one near Cambridge, one in Glasgow and three in London. All paediatric patients are treated at Great Ormond Street Hospital in London.

Assessment is complex and involves a combination of cardiothoracic imaging, pulmonary function testing, exercise tolerance testing and the measurement of blood pressure in the pulmonary artery. A diagnosis of pulmonary hypertension can only be confirmed if the mean blood pressure in the pulmonary artery is 25mmHg or higher.

Once a formal diagnosis of pulmonary hypertension has been made, the clinical severity of the condition is graded using the World Health Organization functional classification system. The four functional classes (with associated untreated median survival) are[7]:

  • Class I — No limitation of physical activity. No symptoms at rest or with exercise (median survival six years)
  • Class II — Slight limitation of physical activity. No symptoms at rest, but ordinary activity causes undue shortness of breath or fatigue, chest pain or near syncope (median survival six years)
  • Class III — Marked limitation of physical activity. No symptoms at rest, but less than ordinary activity causes undue shortness of breath or fatigue, chest pain or near syncope (median survival 2.5 years)
  • Class IV — Inability to carry out any physical activity. Symptoms may be present at rest. Patients manifest signs of right heart failure (median survival six months)

Patients are reassessed at follow-up along with assessment of exercise capacity and right heart function to determine if treatment has been successful.

Pharmacological management

If the cause of pulmonary hypertension is unknown, patients are given a vasodilator challenge using pulsed, inhaled nitric oxide to see if the pressure in the pulmonary artery falls. Approximately 10% of patients with idiopathic PAH are vasoreactive and half of these patients may benefit from long-term treatment with high doses of calcium channel blockers, namely nifedipine, diltiazem or amlodipine.[7]

Patients with operable CTEPH may be suitable for a potentially curable surgical intervention — pulmonary endarterectomy.

Treatment is started as soon as a diagnosis is made and continues for life assuming patients tolerate and benefit from therapy. The majority of patients will find benefit from monotherapy. However, some patients do require dual therapy.

All patients in England with PAH or CTEPH who are in WHO functional classes III or IV are eligible to receive treatment in line with a national commissioning policy by NHS England[8]. Patients in WHO functional class II must meet additional criteria before they can be treated on the NHS. All Welsh patients require prior approval from Health Commission Wales. The specialist centre must ensure that funding is available before initiating treatment.

Phosphodiesterase-5 inhibitors

The phosphodiesterase-5 inhibitors (PDE5Is) sildenafil (Revatio) and tadalafil (Adcirca) are the most commonly prescribed treatment option for PAH (last year over half of patients requiring treatment for pulmonary hypertension in the UK were prescribed sildenafil)[9].  They exert their action though preventing the breakdown of cyclic guanosine monophosphate (cGMP). An accumulation of cGMP then causes vasodilation.

They are administered orally and can be used alone first line and in combination with other treatments for patients who demonstrate a sub-optimal response to monotherapy. Although generic sildenafil products are available, these are only licensed for erectile dysfunction (the sildenafil product licensed for PAH is Revatio).

Sildenafil is usually prescribed at a dose of 20mg or 25mg three times a day. However, there is evidence to support the use of off-licence doses up to 100mg three times a day. Tadalafil is prescribed at 40mg once daily, offering patients a more convenient dosing regimen.

PDE5Is can precipitate the hypotensive effects of nitrates, resulting in potentially serious hypotension[10]; concomitant use is therefore contraindicated.

Endothelin receptor antagonists

Endothelin receptor antagonists block the vasoconstrictive and proliferative effect of the protein endothelin.[11] Proliferation of the smooth muscle tissue contributes substantially to narrowing the vessel lumen and increasing pulmonary pressures. Endothelin receptors are abundant in the pulmonary vasculature.

Bosentan, ambrisentan and macitentan are oral treatments that have been shown to be safe, tolerable and effective in the treatment of patients with PAH.[12],[13],[14]

Macitentan became available in the UK in February 2014 and is currently being considered by NHS England for incorporation into the national commissioning policy.

Regular blood monitoring is needed during treatment because of the potential for these medicines to cause abnormal liver transaminases and affect haemoglobin. The incidence of abnormal liver function tests is low (around 5–10% for bosentan[15] and less than 2% for ambrisentan and macitentan).[14]

However, the endothelin receptor antagonist sitaxentan has already been withdrawn from the market because it was found to cause idiosyncratic life-threatening liver toxicity; therefore, strict pharmacovigilance with these medicines is essential. It is important to note that bosentan interacts with progestogen-containing contraceptives, making prevention of pregnancy — which can be life-threatening for patients with pulmonary hypertension — more complex.


Prostacyclin is produced by endothelial cells and induces potent vasodilation in blood vessels. Epoprostenol (Flolan), a synthetic prostacyclin, was the first treatment for pulmonary hypertension to be licensed in the UK. It has a short half-life (3–5 minutes) and when prepared for intravenous administration is stable at room temperature for around eight hours, requiring continuous intravenous infusion through a central Hickman line.

Patients need to be fully independent and be able to reconstitute and administer the medicine appropriately. A new thermodynamically stable formulation of epoprostenol, Veletri, has recently become available, which offers another alternative to twice daily infusions.

Iloprost, an unlicensed alternative, is favoured by some specialist centres. It is more stable in solution than epoprostenol, meaning that patients only need to change their pump once every 24 hours rather than 8–12-hourly.

Iloprost can also be nebulised: patients are required to do so six to nine times a day. Although this method of administration avoids the risks associated with inserting intravenous lines, managing to comply with nebulising every three hours may be a challenge for some patients.

Treprostinil is licensed in many European countries, but not in the UK. It is used in a small number of patients through named-patient schemes.

Future developments

Riociguat, a soluble guanylate cyclase stimulator, has received a European Medicines Agency positive opinion for a licence to treat PAH and CTEPH. Selexipag, an oral prostacyclin analogue, is undergoing phase III clinical investigation.


Studying this article will help you gain a better understanding of:
  • The different causes of pulmonary hypertension
  • How the severity of pulmonary hypertension is classified
  • The treatment options available for patients with pulmonary hypertension

For Discussion 

  • What supportive treatments should patients with pulmonary hypertension receive?
  • What practical considerations should be made when deciding how to treat patients with pulmonary hypertension?
  • How would you counsel a patient using nebulised iloprost?



At the time of writing, Alia Nizam was a rotational clinical pharmacist at Barts Health NHS Trust.

Citation: Clinical Pharmacist DOI: 10.1211/CP.2014.11134795

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