Pulmonary arterial hypertension (PAH) is a group of malignant diseases that seriously threaten human life and health. In the past, it has been neglected due to insufficient understanding of the disease and the lack of effective vasodilating drugs in China. With the advent of bosentan, subcutaneous and oral prostacyclin analogs abroad, the prognosis of PAH has been improved and the quality of life has been significantly improved. The pharmacological treatment of PAH includes
Treatment of the underlying disease.
Other underlying diseases that cause PAH, such as thromboembolism, intracardiac shunts, immune disorders, etc., should be actively treated. The prognosis can be improved by short-term immunosuppressive therapy in SLE combined with PAH; glucocorticoid enzyme replacement therapy in Gaucher syndrome; praziquantel, an antiparasitic drug, in schistosomiasis; and treatment of obstructive pulmonary disease in PAH caused by chronic obstructive pulmonary disease.
General treatment
1. Lifestyle changes: PAH does not mean that the patient completely loses the ability to live, but excessive physical activities should be avoided. Appropriate adjustment of daily activities is generally appropriate to avoid symptoms such as dyspnea and chest pain.
2 . Prevention and treatment of respiratory infections: Influenza and pneumococcal pneumonia must be routinely prevented because of the potentially catastrophic consequences for the patient. Once respiratory infections occur, they should be treated actively.
3 . Psychological treatment: Due to various reasons such as limited physical activity, changes in lifestyle and economic sources, family and social pressure, psychological treatment needs attention. The care of the doctor, the affection of the family and the confidence of the patient are the keys to successful treatment.
4. Diet and medication: All patients with PAH should limit salt intake to reduce fluid retention, to help prevent hypertension and reduce the risk of osteoporosis and kidney stones. Modify diet carefully, e.g. weight loss in dieting patients can affect INR. take medications with attention to interactions and avoid drugs that elevate pulmonary artery pressure such as beta-blockers and drugs that increase the risk of gastrointestinal bleeding. Use drugs that affect warfarin metabolism such as non-steroidal anti-inflammatory drugs with caution.
Traditional drug therapy.
1 , cardiotonic drugs.
There are few studies of digitalis for PAH, and there are no reliable studies to support that long-term use of digoxin for PAH extends the life of patients. Some studies suggest that digoxin improves right ventricular insufficiency in patients with PAH, increases right heart output at rest by about 10%, and improves the state of left heart extrusion, and is often used for Idiopathic Pulmonary Arterial Hypertension (IPAH) combined with right heart failure and/or atrial arrhythmias. Blood levels need to be monitored closely during application.
The combination of digoxin with antacids, laxatives, some antibiotics, anti-gastric ulcer drugs, and anti-anxiety drugs requires attention to drug interactions. Some drugs used to treat PAH such as nifedipine, diltiazem, and potassium-depleting diuretics can lead to increased toxicity of digoxin. The use of dopamine in patients with end-stage PAH can improve the clinical symptoms and maintain the patient’s vital signs for a period of time.
2. Diuretics.
Diuretics can significantly reduce symptoms, but the mechanism of why patients breathe and feel relaxed with diuretics is not clear; it may be that they reduce right heart failure and venous congestion in the body circulation. Diuretics can only be used as a maintenance therapy and do not slow down the progression of PAH. The use of diuretics to maintain blood volume at near normal levels and careful restriction of water and sodium intake is generally considered critical.
Care should be taken to avoid prolonged use as well as avoiding the use of strong diuretics and to closely monitor electrolyte balance and renal function. In patients with Eisenmenger syndrome, diuretics need to be used with caution.
Drugs such as Antiseptic can partially reverse pulmonary vascular fibrosis and can be used as appropriate.
3 .Oxygen therapy.
Hypoxia is a strong pulmonary vasoconstrictor that can lead to the development and/or progression of PAH. Sometimes PAH itself also leads to lower blood oxygen levels further aggravating PAH, but most patients with PAH do not have low blood oxygen. Some patients require oxygen only at certain stages of the treatment process; some may require continuous oxygen; and a small percentage require oxygen only when walking, sleeping, at high altitude, or traveling by air.
It is generally accepted that oxygen saturation should be >92% in the quiet state and between 88% and 90% in the active state. Continuous low-flow oxygenation can improve hypoxia and reduce pulmonary artery pressure. Maintaining oxygen saturation above 90% is important in patients with severe right heart failure and hypoxia at rest, but is difficult to achieve in patients with underlying lung disease and Eisenmenger’s syndrome. Patients with Eisenmenger’s syndrome do not benefit from long-term oxygen therapy.
It is important to note: when the blood is already saturated with oxygen, excess oxygen is not beneficial to the patient. If the oxygen level in the blood is too high, it can lead to dangerous excessive accumulation of carbon dioxide in the blood and in the body, and excessive oxygen flow often dries out the patient’s mucosal tissues.
4 , Anticoagulants.
Intravascular in situ thrombosis is seen microscopically in the pulmonary arteries of some patients with IPAH. A large number of patients with PAH have been found to have thrombotic damage in the small pulmonary arteries. damaged pulmonary vessels in patients with PAH are much less resistant to the coagulation process. Studies have confirmed that anticoagulant drugs make the blood less likely to clot and prolong the life of the patient, although they do not directly improve symptoms.
The oral anticoagulant warfarin is generally preferred to keep the INR under control at 1.5 to 2.5. PAH experts are not uniform in their target INR values for anticoagulation in PAH patients, with most agreeing that between 1.5 and 2.0 is appropriate, and some requiring higher. Taking a higher dose of warfarin does not mean being sicker or having a higher INR requirement; it may be metabolized more rapidly by the liver, or a different diet, or it may be the effect of other medications. A number of clinical factors determine higher or lower doses. There are currently foreign recommendations for the use of low molecular weight heparin once daily without dose adjustment and INR monitoring.
Anticoagulation for secondary PAH requires consideration of the risk/benefit ratio. In scleroderma PAH, anticoagulation increases the risk of gastrointestinal bleeding; in congenital heart disease PAH, anticoagulation increases the risk of hemoptysis; in patients with portal hypertensive PAH, anticoagulation increases the risk of gastrointestinal bleeding. Anticoagulation is not recommended in the following conditions: mild PAH (defined as pulmonary artery systolic pressure around 40 mmHg at the time of diagnosis and almost asymptomatic); tendency to fall; engagement in vigorous exercise; history of major bleeding (including gastric ulcer or cerebral hemorrhage).
Vasodilator therapy
The ideal vasodilator should meet the following requirements: it can effectively reduce pulmonary artery pressure and pulmonary vascular resistance; increase cardiac output; have little effect on body circulation; be inexpensive and easy to use; and be used for a long time without drug resistance and significant side effects. The current vasodilators basically do not meet the above criteria.
1.Calcium ion antagonist (CCB).
Only patients with PAH who are sensitive to acute vasodilation test (about 10%) can take CCB. these patients can improve hemodynamics, slow down the progress of disease and prolong life after taking CCB. Patients with PAH who are not sensitive to acute vasodilator testing (>80%) may be made worse with CCB.
The acute vasodilator test is an important component in the evaluation of every patient with PAH. criteria for a positive IPAH acute vasodilator test: 10 to 40 mmHg decrease in pulmonary artery pressure with unchanged or increased cardiac output after application of vasodilator (European Society of Cardiology criteria).
In patients with IPAH without combined right heart failure and sensitive to the acute vasodilator test, the preferred treatment with CCB improves symptoms and decreases mean pulmonary artery pressure while cardiac output remains unchanged or improves. Long-term application of CCB improves survival. Patients rarely cease to be sensitive after a short period of good response to CCB, and many remain sensitive after 10 years, some for life, but no year-to-year improvement in treatment effect has been reported. Those caused by weight-loss drugs can also be used if they respond well.
The most commonly used CCBs are nifedipine and Hersinol. In principle, patients with a fast heart rate should start with a small dose of 60 mg tid and increase to the maximum tolerated dose within a few weeks, with an effective dose of about 240 to 720 mg/d. Patients with a slow heart rate should choose nifedipine, starting with a small dose of 30 mg tid and increasing to the maximum tolerated dose within a few weeks, with an effective dose of about 120 to 240 mg/d. The dose should be follow the principle of individualization. Effective judgement: improvement of sensory symptoms and shortness of breath. Side effects: swelling of feet, condyles and lower extremities, headache, gingival hyperplasia, heartburn sensation.
In portal hypertensive PAH, CCB should not be used because it aggravates lower extremity edema. Michael McGoon recommends that CCB should not be tried or used in patients with PAH with a mean right atrial pressure > 15 mmHg, or a cardiac output < 2 L/min, as it can lead to right heart failure. It should be contraindicated in patients with severe PH (with reduced LV or ventricular wall depression or biventricular chambers) and in patients with severe hypotension.
Prostacyclin and its analogs.
Prostacyclin is an arachidonic acid metabolite that is produced primarily by the vascular endothelium. Prostacyclin not only has potent pulmonary vasodilating and vascular effects in the body circulation, but also has anti-platelet aggregation effects. Studies have shown that patients with IPAH have a deficiency of prostacyclin and an excess of thromboxane. Prostacyclin deficiency can lead to PAH, and microscopic in situ thrombosis is sometimes found during pathological examination of IPAH.
Epoprostenol (Flolan)
Continuous intravenous administration of epoprostenol not only improves survival in patients with severe IPAH compared to conventional therapy, but also improves clinical symptoms and hemodynamic status, and remains the most effective prostacyclin drug. Long-term intravenous epoprostenol improves exercise tolerance and hemodynamics in scleroderma-associated PAH.
Epoprostenol is unstable at room temperature and requires cryopreservation prior to infusion; has a very short blood half-life (<6< span="">minutes); and is unstable under acidic conditions, so it cannot be given orally and requires continuous intravenous input. Epoprostenol therapy is generally started at a small dose (1 to 2 ng/kg/min), followed by a gradual upward adjustment of the drug dose at a rate of 1 to 2 ng/kg/min depending on drug side effects and patient tolerability. Because of the large individual differences, the range of steady-state doses is also large. Most patients have a steady-state dose of 20-40 ng/kg/min, and no further upward adjustment is needed once a steady-state dose is reached.
Common side effects of epoprostenol include headache, facial flushing, jaw pain during chewing, diarrhea, nausea, hemorrhagic herpes of the skin, and musculoskeletal pain (mainly involving the lower extremities and both feet). The side effects are dose-dependent and diminish or disappear when the drug is carefully reduced. Overdose can cause serious side effects. Other complications include cannulation-related infections (possibly puncture site confined infection, vasculitis, cellulitis, or septicemia), venous thrombosis associated with cannulation, thrombocytopenia, and ascites. Occasionally, central venous cannulation can lead to pneumothorax or hemothorax.
Abrupt discontinuation of epoprostenol should be avoided as it can lead to rebound in pulmonary artery pressure, worsening the patient’s symptoms and even death. Patients on long-term use need to be supervised by a nurse and internist with extensive clinical experience. In patients with severe PAH who are highly dependent on Iloprostol, even a short discontinuation (20-30 minutes) can lead to worsening of the condition.
Inhaled Iloprost
Inhaled iloprost is a chemically stable endogenous prostacyclin analogue that improves exercise tolerance, relieves symptoms and improves hemodynamics primarily by antagonizing abnormal vasoconstriction, vessel wall remodeling and in situ thrombosis. Its inhaled formulation, vantave, was first approved for domestic marketing in China in April 2006 for the indication of moderate primary pulmonary hypertension.
Iloprost is administered intravenously or by nebulized inhalation, with a short half-life of about 20-25 min, but the time to effect exceeds its own half-life in serum, making it popular for inhalation therapy. It is lung-selective and has little effect on the body circulation. The median number of nebulized inhalations per day is 6 to 9, with each inhalation lasting about 5 to 10 minutes. Patients inhale vantave during the day and usually do not need to inhale again at night, allowing them to rest adequately. Patients with higher inhalation volumes are recommended to inhale before bedtime, in the morning before waking up, or when waking up. Studies have confirmed that NYHA class III-IV PAH (including IPAH and connective tissue disease, thromboembolic pulmonary hypertension that is intolerant to surgery), inhalation of iloprost 2.5 μg to 5 μg/d, 6 to 9 times/d (maximum dose 45 μg/d, mean dose 30 μg/d), resulted in significant improvement in patient symptoms, hemodynamic parameters, and six-minute walking distance.
Contraindications: hypersensitivity to iloprost; presence of conditions that may increase the risk of bleeding (e.g., active peptic ulcer, trauma, or intracranial hemorrhage); severe coronary heart disease, or unstable angina, myocardial infarction within the last 6 months, severe arrhythmias; uncontrolled and untreated or closely monitored decompensated heart failure; cerebrovascular events within the last 3 months (e.g. Transient ischemic attack, stroke); PAH due to pulmonary vein occlusion; congenital or acquired heart valve disease with clinically relevant myocardial abnormalities not due to PAH; pregnancy or lactation.
Adverse reactions include cough, headache, and jaw pain. Patients who discontinued inhalation did not experience rapid cardiac failure triggered by hemodynamic rebound from, for example, discontinuation of inhaled NO and abrupt discontinuation of intravenous administration of iloprost, but still cannot be excluded from the technical aspects.
The efficacy of intravenous Iloprost (Ilomedin) is comparable to that of epoprostenol, with the benefit of being stable at room temperature and eliminating the need for temporary preparation and freezing.
Treprostinil
Treprostacyclin is a triple-phenylene ring analog of prostacyclin that has similar hemodynamic effects to those of epoprostenol in animal studies. It is stable at room temperature, has a half-life of up to 3 hours, and can be administered subcutaneously. Continuous subcutaneous administration reduces clinical events and improves exercise tolerance and hemodynamic parameters in patients. The starting dose is 1.25 ng/kg/min and is gradually increased to a maximum dose of 22.5 ng/kg/min. Improvement in maximum exercise tolerance is more likely to be seen in patients who can tolerate a dose of 13.8 ng/kg/min.
Common side effects included headache, diarrhea, flushing, jaw pain and foot pain, and pain at the subcutaneous dosing site, occasionally severe pain with erythema and nodules. Almost all patients with subcutaneous administration experience pain at the injection site, which can be treated with local hot and cold compresses, topical pain relievers and anti-inflammatory drugs. Some patients do well with a change in injection site every 3 days, with the abdomen where there is a lot of subcutaneous fat being the most commonly chosen site, but also the buttocks or outer thighs and the inner upper arms. Because of the long half-life of travoprost, there are no serious consequences if catheter displacement or infusion pump dysfunction causes interruption of dosing.
Beprostacycline
Beprostacyclin sodium has a preventive effect on pulmonary vascular injury in the wild lily base induced PAH model, and high doses of beprostacyclin appear to have positive inotropic and negative frequency effects on isolated guinea pig myocardium. Beprostacyclin is the first chemically stable, orally available active prostacyclin analogue. It is rapidly absorbed on an empty stomach, with peak blood concentrations after 30 minutes of oral administration and a plasma half-life of 35-40 min. The main adverse effect after 12 weeks of oral administration of beraprost (80 μg/dose, 4 times/d) in NYHA class II-III PAH (idiopathic and secondary) was systemic vasodilation during the initial dosing period. In addition, beraprost has been used for the treatment of peripheral vascular diseases (e.g., intermittent claudication, Raynaud’s phenomenon due to systemic sclerosis, and gangrene of finger/toe ends), but the results have been mixed.
Endothelin receptor antagonists
Endothelin-1 (ET-1) is mainly produced by vascular endothelial cells and, in addition to direct vasoconstriction, stimulates vascular smooth muscle cell proliferation and fibrosis, and acts as an inflammatory mediator promoting the expression of adhesion molecules that increase PAH vascular tension and pulmonary vascular hyperplasia. et-1 is mediated by ETA and ETB endothelin receptors. eta receptors are present in smooth muscle cells and activation causes sustained vascular ETB receptors are found in endothelial cells and smooth muscle cells, and their activation regulates the clearance of pulmonary vascular endothelin and induces NO and prostacyclin production by endothelial cells.
Bosentan
Bosentan is a non-selective, dual (ETA and ETB) active endothelin receptor antagonist that has been shown to prevent and even reverse the development of PAH, pulmonary vascular remodeling, and right ventricular hypertrophy in studies of PAH models and does not have an intrinsic trigger mechanism. Bosentan is convenient to take orally and is now included as a first-line agent for PAH up to class III cardiac function abroad.
Patients with PAH treated with oral bosentan (62.5 mg Bid, changed to 125 mg Bid after 4 weeks for at least 12 weeks) showed an increase in 6-minute walk distance and cardiac index, a significant decrease in cardiac output and pulmonary vascular resistance, and a decrease in mean right atrial pressure, mean pulmonary artery pressure, and pulmonary capillary wedge pressure compared to the placebo group. Some studies have shown that bosentan 250 mg bid and 125 mg bid both produce significant therapeutic effects, and that the former improves exercise tolerance more significantly than the latter. It is not certain that the efficacy of bosentan is dose-dependent.
Bosentan is metabolized by the liver and may cause an increase in hepatic transaminases, with a dose-dependent incidence of hepatic abnormalities, 14% and 5% in the high-dose group (250 mg bid) compared to the low-dose group (125 mg bid). It is generally accepted that a reasonable dose of bosentan is 125 mg Bid, which can cause fetal malformations when taken during pregnancy and should not be taken with glibenclamide (eugenol) or cyclosporine. Oral bosentan 125 mg Bid was approved in North America in 2001 and in Europe in 2002 for the treatment of PAH, but liver function must be monitored monthly.
Sitaxsentan and Ambrisentan
Sitaxsentan and Ambrisentan are both long-acting, potent endothelin receptor antagonists administered orally with high bioavailability, selective antagonism of ETA receptors approximately 6,000 times greater than antagonism of ETB receptors, and few side effects on body circulatory pressure or heart rate.
A study of sitaxsentan enrolled 178 patients with NYHA class II, III, or IV IPAH and PAH associated with connective tissue disease or congenital body-pulmonary shunts, randomized to a placebo control group, a sitaxsentan 100 mg qd treatment group, and a 300 mg qd treatment group. The improvements in 6-minute walk distance, cardiac function class, and hemodynamic parameters were similar between the two dose groups after 12 weeks of treatment, indicating that 100 mg of sitaxsentan essentially completely antagonized the ETA receptor with a lower incidence of hepatic abnormalities, whereas 300 mg produced effects at or near the apex of the dose-effect curve.
High doses of sitaxsentan can lead to fatal hepatitis. The most common adverse effects include headache, peripheral edema, nausea, nasal congestion, and vertigo. The most common abnormalities in laboratory tests are elevated INR and prolonged PT, associated with sitaxsentan inhibition of CYP2C9 P450 enzyme, the most important hepatic enzyme for warfarin metabolism.
In PAH treatment, the choice of blocking both ETA and ETB receptors or blocking ETA receptors alone is controversial. Some experts believe that selective ETA receptor antagonists may be more beneficial in the treatment of PAH because the vasodilatory and ET scavenging effects of ETB receptors may be preserved.
Phosphodiesterase (PDE) inhibitors
Inhibitors (PDE5 inhibitors) are able to increase the sensitivity of the pulmonary vasculature to endogenous or inhaled NO in PAH models. PDE5 is expressed mainly in the lung and penis, and the expression and activity of the PDE5 gene is increased in patients with chronic PAH.
Sildenafil is a highly selective PDE5 inhibitor. Studies have shown that sildenafil blocks the acute hypoxic pulmonary vasoconstriction response in healthy adult volunteers and significantly reduces the mean pulmonary artery pressure (PAPm) in PAH patients. In combination with inhaled NO, sildenafil enhances and prolongs the effect of NO, reduces pulmonary capillary pressure, improves cardiac index, and reduces pulmonary vascular resistance more strongly than when administered alone.
Sildenafil is rarely used due to its weaker action and poor selectivity. Because of the ease of oral administration, it is effective in the treatment of chronic pulmonary hypertension when used in conjunction with other first-line drugs. Evidence is needed for the efficacy of the drug alone. 25mg tid to 75mg tid appear to improve cardiopulmonary hemodynamic status and exercise tolerance. 20mg tid, 40mg tid and 80mg tid have been used to treat PAH with significant therapeutic effects. sildenafil treatment may be considered for PAH if other available treatments are unsuitable or ineffective.
Side effects (e.g., headache, nasal congestion, and visual disturbances) are mild and of low incidence. sildenafil 20mg tid was approved by the US FDA in 2005 for the treatment of PAH.
and Arginine
Reduced NO synthesis is an important pathogenesis of PAH, and reduced NO production is an important factor in persistent pulmonary hypertension in neonates; NO also has a role in regulating pulmonary vascular tension and structure in adults; in addition, NO has anti-platelet activity, anti-inflammatory and antioxidant effects. The effectiveness of inhaled NO in the treatment of PAH has been demonstrated. Because L-arginine is a substrate for NO synthesis by NO synthase, supplementation with L-arginine increases NO synthesis and reduces pulmonary arterial pressure. It has outstanding efficacy for short-term use and is particularly suitable for conducting acute drug trials, or for the treatment of persistent pulmonary hypertension in newborns.
Combination therapy
The mechanism of action of each drug class is different, and the combination can enhance the efficacy and also reduce the dose of a single drug and reduce the side effects of the drug. As more and more drugs for the treatment of PAH are available in China, how to choose effective, inexpensive drugs with few side effects will be one of the goals we need to care about.
Future treatment outlook.
Due to the discovery of BMPR2 gene mutation as an important cause of IPAH, gene therapy has received much attention in recent years and become one of the most promising treatments for IPAH. Some of the transforming growth factor-β superfamily has also been shown to have some association with IPAH, and there are many unknowns. As research into the pathogenesis of PAH progresses, the next step should target newly identified changes in endothelin and smooth muscle cell function, including PDE5 and angiotensin activity, abnormal synthesis and activity of vasoactive intestinal peptides, changes in 5-hydroxytryptamine receptors, etc. Confirmation of these processes will allow us to identify potent pharmacological targets.