Drug Class Overview and Guidelines
Pulmonary arterial hypertension (PAH) is a rare, heterogenous family of disease states marked by pathologic remodeling of the pulmonary vascular system, leading to increased pulmonary artery pressure and ultimately right ventricular failure, hypoxia, and death. Unlike the majority of pulmonary hypertension in the United States, which is secondary to either chronic lung disease or chronic left ventricular dysfunction, PAH is thought to be a primary disease of the vasculature itself, triggered by an array of etiologic agents, including connective tissue disease, drugs or toxins, infections, genetic triggers among others, or is idiopathic in approximately 40% of cases.
Pathobiology of Pulmonary Arterial Hypertension
Historically neglected due to its relatively rare prevalence, insights into the pathophysiology of PAH have led to a steady influx therapies for patients over the past two decades. Most of these therapies that primarily work by specific pulmonary vasodilation have been developed based on a now classical view of PAH characterized by a mismatch between vasodilatory and vasoconstrictive molecules in the pulmonary arteriolar tree. An important vasodilator, nitric oxide (NO), has long been identified as a key regulatory molecule in PAH. NO is decreased in the pulmonary artery endothelial cells (PAECs) of diseased patients. A lack of NO triggers both loss of vasorelaxation mediated by cyclic guanosine monophosphate (cGMP) as well as smooth muscle cell proliferation. Endothelin-1 (ET-1), a vasoconstricting small peptide is a second molecule implicated in PAH pathobiology. ET-1 has been shown to be overexpressed in PAECs of PAH patients. Prostacyclin, a potent vasodilatory prostanoid, is a third important vasoactive small molecule. Prostacyclin, via cyclic adenosine monophosphate (cAMP), normally vasodilates smooth muscle cells but is decreased in afflicted patients.
Most of the mainstays of modern PAH pharmacologic therapy operate via one of the pathways previously discussed. More recently, discoveries in the basic science of the disease are driving interest in new drug classes aimed at targeting the disordered and proliferative aspects of diseased arterioles in PAH. Development of these drugs are in various stages of implementation.
Updates in the Clinical Classification of PAH
The World Health Organization (WHO) organized the first World Symposium on Pulmonary Hypertension (WSPH) in 1973. Since that time, pulmonary hypertension has been invariably defined as a mean pulmonary artery pressure (mPAP) ≥ 25 mmHg. PAH, or WHO group 1 disease, requires not only mPAP ≥ 25 mmHg but also the presence of precapillary pulmonary hypertension with pulmonary vascular resistance > 3 Wood units in the absence of alternative causes of precapillary disease such as chronic thromboembolic disease, lung disease, or select rare other causes not considered to be group 1 etiologic agents. At the sixth WSPH in 2018, however, the definition of pulmonary hypertension and PAH was changed. It is now recommended that a lower mPAP cutoff of > 20 mmHg now be used to define pulmonary hypertension and PAH. This change was made to better reflect the understanding that the typical upper limit of normal for mPAP is lower than the traditional 25 mmHg as endorsed by the older definition and mPAP > 20 mmHg is associated with worse clinical outcomes. As of this writing, the American Heart Association and American College of Cardiology PAH guidelines have not been revised to reflect the new WHO-endorsed position. It is also unclear whether this new definition should drive the use of pulmonary vasodilator drugs in this population of formerly “borderline” PAH patients.
In addition to the change in PAH definition, three new oral agents have become available for treatment of PAH since 2013. Riociguat is a first-in-class soluble guanylate cyclase (sGC) stimulator that was approved in 2013. Riociguat achieves its augmented vasodilation via the NO-cGMP pathway. Later that same year, the United States Food and Drug Administration (FDA) approved an oral form of the prostanoid treprostinil (treprostinil diolamine) for use in PAH patients. Finally, in 2015, selexipag, a nonprostanoid oral prostacyclin (PGI 2 ) receptor (IP receptor) agonist, was approved for use to delay disease progression and reduce risk of hospitalization in PAH.
Currently Available/Approved Drug Classes
History and the Modern Era of PAH Therapy
“I would comment now upon the clinical picture of pure right ventricular failure. Usually one sees it secondary to failure of the left side, or the case is one of mitral disease with embarrassment of the pulmonary circulation… It is rare in my experience to witness such a pure and rapidly progressive failure of the right ventricle.” Dr. Terence East, London, 1940, describing a series of three young women with rapidly fatal PAH.
PAH was traditionally an invariably progressive and often fatal condition. Although it remains incurable (except by lung transplantation), PAH has become viewed in more recent years a more manageable chronic condition that can be marked by long periods of clinical stability. This is in large part due to the number of agents now available for patients with PAH and the expansion of dedicated PAH comprehensive care centers with expert multidisciplinary teams dedicated to this disease.
The modern era of PAH therapy began in the mid-1990s with the remarkable success of intravenous prostacyclin. In a landmark 1996 study including 81 patients with PAH followed for only 12 weeks, intravenous epoprostenol was associated with a reduction in pulmonary vascular resistance, 6-minute walk test (6MWT) distance, and mortality—100% of epoprostenol patients were alive at study end versus 80% in the control group. Prior to the epoprostenol era, registry data of patients with idiopathic PAH showed a 1-year and 5-year survival of 68% and 34%, respectively. These figures have slowly improved over the years. Over a decade later, results from the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry) showed that the 1- and 5-year survival for idiopathic PAH patients had improved to 91% and 65%, respectively.
Prostanoids
The first truly efficacious therapy in PAH, the prostanoid class of medications has now grown to include medications available in four routes of administration: intravenous, subcutaneous, inhaled, and oral.
Approved in 1996 on the basis of the randomized trial described previously, epoprostenol is the prototypical example of a vasodilatory agent used in PAH. Available only in intravenous formulation, epoprostenol has two available preparations: Flolan and Veletri, the latter designed to have enhanced room temperature stability.
Treprostinil is a synthetic prostanoid that is now available for use intravenously or subcutaneously (Remodulin), via inhalation (Tyvaso), or orally (Orenitram). Like epoprostenol, treprostinil is a potent pulmonary vasodilator. It is distinguished from epoprostenol by its much longer half-life (4 hours versus 2.7 minutes for epoprostenol) and greater flexibility with respect to route of administration.
Approved in 2004, and only available in inhaled formation, Iloprost is the third currently available prostanoid for the treatment of PAH. It is marketed under the trade name Ventavis.
While not a true prostanoid by molecular structure, Selexipag (Uptravi) is an IP receptor antagonist, administered orally, and approved for use since 2015.
Endothelin Receptor Antagonists (ERAs)
With action against the ET-1 receptor, there are three ERAs currently available for use: bosentan (Tracleer), ambrisentan (Letaris), and macitentan (Opsumit). All are oral agents and have been proven efficacious in improving hemodynamics and symptoms in PAH.
Phosphodiesterase Type 5 Inhibitors (PDE-5is)
Orally taken, the PDE-5is vasodilate the pulmonary circulation via augmentation of the cGMP pathway. Two agents are available for use in the US, sildenafil (Revatio) and tadalafil (Adcirca). Vardenafil has been studied for use in a PAH population but is not approved for use in PAH by the FDA.
Closely related to PDE-5is are the sGC stimulators, of which the recently approved oral agent riociguat (Adempas) is the only approved agent.
Calcium Channel Blockers (CCBs)
Off-label use of CCBs, particularly diltiazem and nifedipine , and occasionally amlodipine , has long had a role in PAH, specifically in those with a positive vasoreactivity study on right heart catheterization. To perform such a study, an operator with experience in PAH would place a pulmonary artery catheter in position, then administer a vasodilator, typically inhaled NO, intravenous epoprostenol, adenosine, or sodium nitroprusside. A drop in mPAP of ≥ 10 mmHg to a mPAP of ≤ 40 mmHg with stable cardiac output is defined as a positive vasoreactivity test. Approximately 5%–10% of treatment naïve patients will have a positive vasoreactivity test—a figure that may be higher in idiopathic PAH patients. A 2010 analysis of approximately 2400 registry patients showed that 8.7% took CCBs specifically for PAH, a number that is consistent with the expected prevalence of positive vasoreactivity studies.
Guidelines
Rationale and General Principles
In general, more aggressive therapy, including parental medications, is reserved for patients with more advanced and higher-risk disease. Correctly matching PAH therapy to a patient requires a careful and complete physiologic and historical assessment. Diligent evaluation of PAH patients, both at index presentation and longitudinally, is essential. The most important historical element is the patient’s level of functioning. Often referred to as the WHO functional class (FC), it is modeled on the frequently used New York Heart Association functional status. Briefly, FC I patients have no functional limitation. FC II patients have a slight impairment in physical activity, where ordinary causes symptoms such as dyspnea, chest pain, fatigue, or presyncope. FC III patients recall symptoms with less than ordinary daily activity, and FC IV patients are either symptomatic at rest, often with signs of overt right heart failure.
Patients with PAH often suffer from delayed diagnosis, meaning it is not unusual for PAH patients to first present with severe disease and advanced symptoms. In one study, a series of retrospective interviews with PAH patients revealed that patients averaged 5.3 general practitioner visits and 3.0 specialist visits prior to being seen in a PAH referral center—a process that took 47 months on average. In REVEAL, 61% of patients were FC III at the time of diagnostic right heart catheterization and 12% suffered from FC IV.
Initial workup of PAH will include detailed history and physical examination to determine the WHO functional class and assess for signs of right ventricular failure, including syncope, ascites, and edema. An electrocardiogram and echocardiogram are included in the initial evaluation of all patients. At times, cardiac magnetic resonance imaging (MRI) can be helpful in quantifying the level of right ventricular dysfunction. In patients in whom initial evaluation raises concern for PAH, and in patients with established disease but a change in clinical status, a right heart catheterization is required.
Risk Stratification
The evaluation of the PAH patient should allow for risk stratification. Patients with more significant functional limitation are higher risk. In addition, patients with so-called “sentinel events” such as hospital admission, intensification of PAH therapy, decrease in 6MWT distance by 15%, or worsening WHO FC should be given heightened scrutiny, as these morbidity events have been shown to be predictive of incident mortality.
The 2015 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines proposed a simple low/moderate/high risk framework based on history, laboratory, and hemodynamic assessment ( Table 11.1 ). Patients in the highest risk category should be considered for aggressive escalation of therapy.
| Risk category est. 1-year mortality | Low < 5% | Moderate 5%–10% | High > 10% |
|---|---|---|---|
| Clinical signs of right heart failure a | Absent | Absent | Present |
| Progression of symptoms | Stable symptoms | Slow | Rapid |
| Syncope | Absent | Occasional; orthostatic or with heavy exercise | Frequent; especially with minimal activity |
| Functional class b | I, II | III | IV |
| 6-minute walk test distance | > 440 m | 165-440 m | < 165 m |
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| BNP level NT-pro BNP level | < 50 ng/L < 300 ng/L | 50–300 ng/L 300–1400 ng/L | > 300 ng/L > 1400 ng/L |
| Imaging | RA area < 18 cm 2 No pericardial effusion | RA area 18–26 cm 2 Trivial pericardial effusion | RA area > 26 cm 2 Pericardial effusion |
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a Signs of right heart failure include peripheral edema, hepatic congestion, decreased urine output, and ascites.
b Functional class I: no limitations; II: symptoms with ordinary activity; III: symptoms with less than ordinary activity; IV: symptoms with any activity or at rest.
Patients With Positive Vasoreactivity Studies
Guidelines support vasoreactivity testing during right heart catheterization in select patients with an initial diagnosis of PAH. Contraindications include low blood pressure, reduced cardiac output, a diagnosis of pulmonary vasoocclusive disease, or pulmonary capillary hemangiomatosis (PVOD or PCH), as these patients may not tolerate an acute vasodilator challenge. Patients with FC IV would not be candidates for a trial of CCB even if vasoreactivity test were positive; therefore, it is of questionable utility to proceed with such testing in these patients.
For the 5%–10% of patients who do respond to vasodilator challenge and have FC II or III symptoms, current guidelines suggest a trial of CCB as initial therapy, with early repeat catheterization in 3 months to assess for response. Required doses are typically high; up to 240 mg for nifedipine, 20 mg for amlodipine, and 720 mg for diltiazem. Verapamil is not typically used or recommended for use in this indication, mostly over concern (perhaps based more on experience than data ) that verapamil is more potent negative inotrope than the other CCBs, including diltiazem.
Multiple concerns have been voiced for the use of long-term CCB in the PAH population. Most acutely, there is concern for the lack of direct evidence of benefit in the modern vasodilator therapy era, along with the theoretical risk of worsening inotropy on high-dose CCBs.
Asymptomatic Patients
Patients without symptoms (WHO FC I) at diagnosis represent a rare clinical scenario. Current guidelines suggest close monitoring for the development of symptoms while withholding active therapy. In such cases, careful examination, history, and functional testing may be required to determine if patients are truly asymptomatic. Occasionally, cardiopulmonary exercise testing, either invasive or noninvasive, may be considered to provide an objective assessment of severity of functional limitation and may be of use in borderline cases.
Initial Combination Therapy
From the early 1990s until 2004, all PAH clinical drug trials tested single drug regimens against placebo or alternatives. It was not until the BREATHE-2 trial, which compared epoprostenol plus bosentan to epoprostenol plus placebo in patients with WHO FC III or IV, that initial combination therapy was rigorously tested. Although it did not show significant difference in hemodynamics or clinical status, BREATHE-2 was an important first step toward initial combination therapy in treatment naïve individuals, and led the way for the AMBITION trial, published in 2015. Comprised of patients with WHO FC II and III on no current PAH therapy, AMBITION was a three-armed protocol that randomized patients to ambrisentan plus tadalafil combination therapy or to each drug (plus placebo) alone. In contrast to BREATHE-2, AMBITION showed a marked reduction in a combined clinical endpoint of all-cause mortality, PAH hospitalization, and disease progression.
The 2015 ESC/ERS guidelines make no value judgment on starting combination therapy versus monotherapy in treatment naïve patients presenting with FC II or III, citing the possible benefit of combination therapy seen in AMBITION but also the potential for increased drug interactions and side effects with upfront combination therapy. In contrast, the 2019 update to the American College of Chest Physicians (ACCP) guideline now recommends initial combination ambrisentan plus tadalafil for patients with FC II and III, reflecting the advancing acceptance of the overall benefit profile of upfront combination therapy. This represents a change from the 2014 guidelines and is given a grade of weak recommendation with moderate quality of evidence. Tables 11.2 and 11.3 outline selected regimens for initial combination therapy as supported by current guidelines and expert consensus.
| European Society of Cardiology/European Respiratory Society (ESC/ERS) | |||
| Strength of recommendation | Level of evidence | ||
| Class I | Is recommended. Evidence or general agreement of benefit. | A | Data from multiple randomized controlled trials. |
| Class IIa | Should be considered. Weight of evidence or opinion is in favor of usefulness. | B | Data from a single randomized controlled trial or from high-quality observational studies. |
| Class IIb | May be considered. Usefulness/efficacy is less well established | C | Consensus opinion and/or evidence from small studies, registries, and other nonrandomized studies. |
| Class III | Not recommended. Evidence or agreement of lack of efficacy or harm | ||
| American College of Chest Physicians (ACCP) | |||
| 1A | Strong recommendation, high-quality evidence: Benefits clearly outweigh risks, evidence from multiple randomized trials or overwhelming evidence from nonrandomized studies. | ||
| 1B | Strong recommendation, moderate quality evidence: Benefits clearly outweigh risks, evidence from randomized trials with limitations or high-quality nonrandomized studies. | ||
| 1C | Strong recommendation, low-quality evidence: Benefits clearly outweigh risks, evidence from observational studies or case series only. | ||
| 2A | Weak recommendation, high-quality evidence: Benefits closely balanced with risks, evidence from multiple randomized trials or overwhelming evidence from nonrandomized studies. | ||
| 2B | Weak recommendation, moderate quality evidence: Benefits closely balanced with risks, evidence from randomized trials with limitations or high-quality nonrandomized studies. | ||
| 2C | Weak recommendation, low-quality evidence: Benefits closely balanced with risks, evidence from observational studies or case series only. | ||
| UC | Ungraded, consensus-based statement of recommendation | ||
| Therapy | WHO FC | ESC/ERS, 2015 1 class/level of evidence | ACCP, 2019 update grade |
|---|---|---|---|
| Ambrisentan + tadalafil | II | 1/B | 2B |
| III | 1/B | 2B | |
| IV | IIb/C | — | |
| Other ERA + other PDE-5i | II | IIa/C | — |
| III | IIa/C | — | |
| IV | IIb/C | — | |
| Bosentan + sildenafil + IV epoprostenol | III | IIa/C | — |
| IV | IIa/C | — | |
| Bosentan + IV epoprostenol | III | IIa/C | — |
| IV | IIa/C | — | |
| Inhaled prostanoid + PDE-5i + ERA | IV | — | UC a |
a For patients unable or unwilling to manage parenteral prostanoids.
Initial Monotherapy
Starting monotherapy in treatment naïve PAH patients, then adding additional agents sequentially based on patient response and tolerability is the more traditional approach to the management of PAH—albeit a decreasingly popular choice in light of the AMBITION trial data. In general, patients presenting with WHO FC II or III symptoms are recommended to begin with oral therapy; parenteral therapy is reserved for WHO functional class IV patients and those with high-risk features ( Table 11.4 ). In the 2019 ACCP guidelines, the same therapy might have several different recommendation grades for a particular WHO FC, as the guidelines’ authors may provide a separate recommendation grade for multiple outcomes. For example, there may be two recommendations provided for one particular drug: one for the endpoint of improving 6MWT and one for improving functional class. The summary information in Table 11.4 records the strongest recommendation given for each drug.
| Therapy | WHO FC | ESC/ERS, 2015 Class/Level of evidence | ACCP, 2019 Update Grade |
|---|---|---|---|
| Calcium channel blockers a | II | 1/C | UC |
| III | 1/C | UC | |
| Ambrisentan | II | 1/A | 1C |
| III | 1/A | 1C | |
| IV | IIb/C | — | |
| Bosentan | II | 1/A | UC |
| III | 1/A | 1B | |
| IV | IIb/C | — | |
| Macitentan | II | 1/B | UC |
| III | 1/B | UC | |
| IV | IIb/C | — | |
| Sildenafil | II | I/A | 1C |
| III | I/A | 1C | |
| IV | IIb/C | — | |
| Tadalafil | II | I/B | UC |
| III | I/B | UC | |
| IV | IIb/C | — | |
| Riociguat | II | I/B | UC |
| III | I/B | UC | |
| IV | IIb/C | — | |
| Epoprostenol, IV | III | 1A | UC b |
| IV | 1A | UC | |
| Treprostinil, IV | III | IIa/C | UC b |
| IV | IIb/C | UC | |
| Treprostinil, SC | III | I/B | UC b |
| IV | IIb/C | UC | |
| Treprostinil, oral | III | IIb/B | — |
| Selexipag | II | I/B | — |
| III | I/B | — |
a Only for use in patients with a positive vasoreactivity test
b In patients with WHO FC III symptoms but with rapid progression or other markers of poor prognosis
Several key differences exist among the presently offered expert guidelines. The ACCP currently recommends starting an intravenous or subcutaneous prostanoid (epoprostenol or treprostinil) in patients with FC IV and issue no recommendation for oral agents in this scenario. The ESC/ERS guidelines do issue recommendations for specific oral agents as monotherapy in FC IV; however, these guidelines also make a statement recommending upfront combination therapy that includes an intravenous or subcutaneous prostanoid in such patients.
Sequential Therapy
For patients already started on initial monotherapy, a common strategy for treatment of PAH consists of short interval reassessment of symptoms and risk ( Table 11.1 ) with consideration of sequential addition of therapies. This has been the approach often taken in the trial literature as well, where novel agents are often tested when added to established medications.
In patients who continue to be symptomatic on stable doses of an ERA or PDE-5i, the addition of inhaled iloprost or inhaled treprostinil is guideline-supported. Riociguat is recommended as an addition to bosentan, ambrisentan, or inhaled prostanoid. Macitentan receives a recommendation as an addition to symptomatic patients on stable doses of a PDE-5i or inhaled prostanoid, and tadalafil as add-on therapy to ambrisentan.
In practice, drugs within a class are often substituted for each other, based on side effect profiles, availability or formulary access, and cost. This is done with the presumption that class effects may be interchangeable to varying degrees, but evidence does exist regarding the specific nature of activity of single drugs independent of drug class as well.
Mechanisms of Action
A mechanistic overview for important pathways of action for PAH drugs is shown in Fig. 11.1 .
Prostanoids
Prostanoids were first indirectly described in the 1960s upon the discovery of a vasoactive substance that was downregulated by administration of aspirin. Prostanoids were subsequently characterized as a family of 20-carbon eicosanoids (from the Greek ɛίκοσι—“twenty”) derived from arachidonic acid via oxygenation by cyclooxygenase (COX). The prostanoid family includes PGI 2 , thromboxane A 2 , and the prostaglandins, among other molecules. Most prostanoids share a five-carbon ring base with attached fatty-acid derived chains. In the pulmonary hypertension literature, the term “prostanoid” refers almost exclusively to PGI 2 , or epoprostenol, and a number of synthetic stable PGI 2 analogues, including treprostinil and iloprost. PGI 2 was discovered in 1976, and within 5 years its use was described in a patient with idiopathic PAH. The potent vasodilatory properties of PGI 2 were recognized early on, but a wealth of evidence now exists suggesting that beyond providing vasodilation to improve pulmonary vascular resistance, prostanoids have a wide array of other disease modifying effects.
PGI 2 and its analogues bind the IP receptor on the cell surface membrane. Once engaged, the IP receptor couples the G-protein Gs and activates adenylyl cyclase, producing cyclic adenosine monophosphate (cAMP) and leading to relaxation in smooth muscle cells and antithrombosis in platelets. Like PGI 2 , treprostinil engages the IP receptor, but also demonstrates strong affinity to the EP 2 and DP 1 cell surface receptors. Ex vivo study indicates that the latter may have an increased role in dilation of pulmonary veins in addition to arteries; the clinical relevance of this finding is unclear. Iloprost has also been shown to have action at the EP 4 receptor, an additional pathway of vasodilation. Such a finding may be important therapeutically, as there is some evidence that patients with PAH have downregulated IP receptors, perhaps reducing their susceptibility to treatment with prostacyclin/epoprostenol.
Beyond vasodilation, PGI 2 also has proapoptotic properties via the IP receptor. This is particularly important given the recent attention given to the “cancer theory” of PAH. BMPR2 , the most important gene identified in hereditary PAH, has been implicated in dysregulation and proliferation (antiapoptosis) in diseased pulmonary artery endothelial cells. Important activities are also held by the growth factors PDGF and VEGF, as well as a shift from oxidative metabolism to glycolysis in processes mirroring cancer pathogenesis. There is evidence that prostanoids may directly interrupt some of these processes and may enhance apoptosis. Treprostinil, for example, has been shown to reduce PDGF-related proliferative signaling.
While not a prostanoid, selexipag also exerts its effects via the IP receptor. Selexipag is an orally available prodrug of MRE-269, a highly selective IP receptor agonist with a half-life of approximately 8 hours. Unlike epoprostenol, treprostinil, and iloprost, selexipag does not appear to engage prostanoid receptors other than the IP receptor.
Phosphodiesterase Type 5 Inhibitors
Selective PDE-5is leverage the action of endogenous NO in the cells of smooth muscle and other tissues. NO is produced in endothelial cells from L-arginine via NO synthase. A small molecule, NO diffuses into smooth muscle adjacent to endothelial cells where it binds to sGC, stimulating production of cGMP from guanosine triphosphate. cGMP has potent vasodilatory effects by decreasing intracellular calcium concentration, leading to lower smooth muscle tone. It is rapidly hydrolyzed by PDE-5. The two currently approved PDE-5is for the treatment of PAH, sildenafil and tadalafil, both function to selectively inhibit PDE-5, thus augmenting the availability of cGMP and leading to vasorelaxation.
PDE-5is can cause a certain degree of nondiscriminate vasodilation in both arterial and venous systems in healthy subjects. However, affinity for the pulmonary circulation has been described in patients with PAH. An early hemodynamic study found, for example, that pulmonary systolic pressures decreased over twice as much as systemic systolic pressures (14 mmHg versus 5.9 mmHg) after 3 months of sildenafil treatment in PAH patients. The underlying reason for this is only partially clear. It has been proposed that atrial natriuretic peptide, found in increased concentration in PAH patients, may act synergistically with the NO-cGMP pathway to selective vasodilate the pulmonary circulation.
Like prostanoids, there is evidence that PDE-5is have important disease-modifying effects outside of vasodilation. One intriguing possibility is that PDE-5is may improve dysfunctional signaling in PAH patients with abnormal bone morphogenetic protein (BMP). Pulmonary artery smooth muscle cells carrying loss-of-function mutations in BMPR2 tend to become proproliferative via decreased and/or altered BMP and SMAD 1/5/8 signalling. In a BMPR2 knockout animal model, sildenafil has been shown to prevent development of PAH and partially restore SMAD signaling.
Riociguat, the only available sGC stimulator, has a mechanism closely related to PDE-5is, in that it is active directly via the NO-cGMP pathway. The original synthesis of riociguat was propelled by the discovery in the 1990s that YC-1, a related compound originally discovered as a synthetic benzylindazole antiplatelet agent, had sGC stimulatory properties. Riociguat binds sGC and increases production of cGMP from GTP in a NO-independent manner. Synergism with NO is also possible. In vitro , sGC activity is increased 122-fold by riociguat in the presence of NO, and 73-fold when riociguat acts alone.
Endothelin Receptor Antagonists
A potent vasoconstrictor, ET-1 is a 21-amino-acid peptide overexpressed in patients with PAH. ET-1 is produced mainly in endothelial cells—it is not stored and both transcription its mRNA and ET-1 itself have relative short half-lives (10–20 minutes), meaning that ET-1 levels may fluctuate in response to a myriad stimulators. Notable stimuli include hypoxia, ischemia, shear stress. ET-1 has two cellular targets relevant to PAH therapeutics. Endothelin receptor A (ET A ) is found on the surface of pulmonary artery smooth muscle cells, while endothelin receptor B (ET B ) is found both on pulmonary artery smooth muscle cells and endothelial cells.
ET-1 has mitogenic properties via both ET A and ET B ; the overall effect is to increase extracellular matrix proliferation as well as potentiation of growth factors such as TGF-β. On the smooth muscle cell, the binding of ET-1 to both ET A and ET B activates phospholipase C and promotes vasoconstriction via production of inositol triphosphate, which raises intracellular calcium. The vasoactive effects of ET B on endothelial cells are more complex. ET-1 binding endothelial cells may increase NO production, leading to vasorelaxation. However, the vasodilatory properties of ET-1, acting at the ET B receptor, appear to be impaired in PAH-afflicted patients. In sum, the net effect of ET-1 on the pulmonary circulation is vasoconstriction and cellular proliferation.
Differences Among Drugs in Class
The full list of currently available PAH-specific drug therapies approved for use in the United States is presented in Table 11.5 . Specific and important intraclass differences between agents are discussed later.
