Pulmonary Hypertension Managment

Pulmonary hypertension (PH) is a disease characterized by elevated pulmonary artery pressure (mean pulmonary artery pressure ≥20 mmHg at rest with a pulmonary vascular resistance ≥3 Wood units).

Risk factor:

Drug- and toxin like appetite suppressants, toxic rapeseed oil, and benfluorex and possibly cocaine, phenylpropanolamine, St. John's Wort, dasatinib, and interferon.

Heart failure (preserved LVEF or reduced LVEF)

Restrictive lung disease Obstructive lung disease

Hypoxia without lung disease

Developmental lung disorders

Chronic thromboembolic PH

Sign and Symptoms:

Dyspnea and fatigue ●Symptoms of right ventricular (RV) failure like

•Exertional chest pain

•Exertional syncope

•Weight gain from edema

•Anorexia and/or abdominal pain and swelling.

•exertion intolerance

Diagnostic tests:

 Echocardiography

 Doppler echocardiography

 pulmonary function testing: Full PFTs (spirometry, lung volumes, diffusing capacity)

 Chest radiography

 Arterial blood oxygenation

Treatment

The goals of treatment are to alleviate symptoms, improve the quality of life, slow the progression of the disease, and improve survival

Nonpharmacologic Therapy:

Oxygen therapy: Continuous oxygen administration remains the cornerstone of therapy in patients with group 3 PH Oxygen should be considered for all patients with PH plus hypoxemia, the goal of oxygen therapy to maintain the O2 sat above 90 % at rest. Vaccinations: Pulmonary hypertension is considered a chronic disease and as such, patients should be immunized with all age-appropriate as well as influenza and pneumococcal pneumonia vaccines. Exercise, training was consistently associated with improved exercise capacity, muscular function, quality of life, and possibly right ventricular function and pulmonary hemodynamics, resulted in improved exercise capacity, and health-related quality of life Pharmacologic Therapy: PRIMARY THERAPY FOR PH Primary therapy refers to treatment that is directed at the underlying cause of the PH. It is warranted in nearly all patients with PH. The disease severity should be reassessed following primary therapy, in order to determine whether advanced therapy is indicated. Group 1 PAH: Patients with group 1 pulmonary arterial hypertension (PAH): There are no effective primary therapies for most types of group 1 PAH. As a result, PH-specific therapy is often needed Group 2 PH: Patients with group 2 PH have PH secondary to left heart disease with chronic left atrial and pulmonary venous hypertension: rimary therapy for group 2 PH consists of treatment of the underlying heart disease Group 3 PH: Patients with group 3 PH have PH secondary to various causes of hypoxemia: Primary therapy for group 3 PH consists of treatment of the underlying cause of hypoxemia and correction of the hypoxemia with supplemental oxygen Group 4 PH: Patients with group 4 PH have PH due to thromboembolic or other occlusion of the proximal or distal pulmonary vasculature: Anticoagulation is primary medical therapy for patients with group 4 PH. The value of anticoagulant therapy for group 4 PH is an extrapolation of the clinical evidence that anticoagulation prevents recurrent pulmonary embolism. Data suggesting that anticoagulation is beneficial in patients with group 4 PH are lacking. Surgical thromboendarterectomy is primary surgical therapy for selected patients with thromboembolic obstruction of the proximal pulmonary arteries . Prior to proceeding with this invasive approach, a three-month period of anticoagulation is required and patients must remain severely incapacitated due to PH Balloon angioplasty of the pulmonary artery is also a consideration in patients who are not suitable candidates for surgery. Group 5 PH: Group 5 PH includes PH with unclear multifactorial mechanisms. 1-Diuretics Patients with fluid retention from PH-related right ventricle failure (RV) may benefit from diuretics. Diuretics diminish hepatic congestion, peripheral edema, and pleural effusions and may be of particular benefit in those in whom interventricular sepal deviation from elevated RV pressure impairs left ventricle output. However, diuretics should be administered with caution. Since patients with PH are pre-load dependent, over-diuresis may result in under-filling of the RV, and a decline in RV stroke volume, thereby reducing left ventricle (LV) stroke volume resulting in systemic hypotension and sometimes shock. In addition, diuretics can be associated with arrhythmias induced by hypokalemia, and metabolic alkalosis (which can depress ventilation). Most diuretic is administered orally in the chronic setting. However, intravenous diuresis may be more effective in the acute setting, when it can be given as a bolus dose or a continuous infusion (which may be better tolerated hemodynamically in those with borderline blood pressure). Occasionally, the increased right ventricular pressure is so severe that diuretics are ineffective; in such cases, ultrafiltration may be beneficial.

2-Oxygen therapy: Continuous oxygen administration remains the cornerstone of therapy in patients with group 3 PH Oxygen is generally administered at 1 to 4 L/min via nasal prongs and adjusted to maintain the oxygen saturation above 90 percent at rest and, if possible, with exercise and sleep

3-Anticoagulation: Anticoagulation is indicated in patients with group 4 PH and not typically administered to those with group 2, 3, or 5. However, anticoagulation in patients with group 1 PAH is controversial; in general anticoagulation has fallen out of favor in this population and we suggest that anticoagulant therapy be administered on a case-by- case basis according to the clinician's assessment of the risks and benefits Limited experience was with direct oral anticoagulants (eg, direct thrombin or factor . Xa inhibitors) makes warfarin the anticoagulant of choice, with a therapeutic goal of an international normalized ratio (INR) of approximately 2.0. Many centers in the US target a range of 1.5 to 2.5 with no bridging for temporary interruptions. The risk of bleeding on anticoagulation (warfarin) may differ among patients with different types of PH. Patients with PH frequently have other risk factors for thromboembolism (eg, atrial fibrillation, severe left heart failure) that may warrant anticoagulation. Anticoagulation for these conditions should be assessed independently

4-Digoxin: Digoxin therapy has been shown to have both beneficial effects and drawbacks: Digoxin improves the left ventricular EF of patients with group 3 PH due to COPD and biventricular failure However, these patients may be more sensitive than most patients to digitalis toxicity and require close monitoring. Digoxin helps control the heart rate of patients who have supraventricular tachycardias associated with right ventricular dysfunction Verapamil is preferred for multifocal atrial tachycardia, unless there is concurrent left ventricular failure. No data are available on the long-term effects of digoxin in patients with group 1 PAH. 5- Exercise 6- Vaccinations PULMONARY HYPERTENSION-SPECIFIC THERAPY Pulmonary hypertension (PH)-specific therapy is directed at the pulmonary hypertension (PH) itself (PH-targeted therapy), rather than the underlying cause of the PH. PH-specific therapy should not be administered unless a diagnostic right heart catheterization (RHC) and extensive investigations for the etiology of PH have been performed. Additionally, most patients with group 1 PAH, in particular, those with idiopathic PAH, heritable PAH, and anorexigen-induced PAH, should also undergo vasoreactivity testing during RHC which facilitates agent selection PH-specific therapy is widely accepted for many patients with group 1 pulmonary arterial hypertension (PAH). In contrast, it should only be administered on a case-by- case basis for patients with group 3 PH, group 4 PH, or group 5 PH, after carefully weighing the risks versus the benefits. Advanced therapy should NOT be administered to most patients with group 2 PH. After initiating therapy, most patients are followed up within four to six weeks to evaluate the clinical and hemodynamic response. Patients with refractory PAH may require alternate or combination therapy For those who are refractory to all medical interventions, lung transplantation or creation of a right to left shunt by atrial septostomy are options 1-Calcium channel blockers: Some patients who are vasoreactive and receive CCB therapy with a Amlodipine or diltiazem can achieve prolonged survival, sustained functional improvement, and hemodynamic improvement. CCB therapy can be initiated with either long- acting nifedipine (30 mg/day) or diltiazem (120 mg/day), then increased to the maximal tolerated dose. Short-acting nifedipine should NOT be used. 2- Prostacyclin pathway agonists: Epoprostenol: Intravenous epoprostenol (prostacyclin; PGI2) improves hemodynamic parameters, functional capacity, and survival in patients with IPAH Delivered continuously through a permanently implanted central venous catheter using a portable infusion pump. It is usually initiated at doses of 1 to 2 ng/kg per min and increased by 1 to 2 ng/kg per min every one to two days as tolerated. Treprostinil can be given intravenously or subcutaneously or inhaled Iloprost: Inhaled iloprost has theoretical advantages in targeting the lung vasculature and does not require intravenous administration the main disadvantage is the need for frequent administration (six to nine times per day) Selexipag is an oral selective non-prostanoid prostacyclin receptor (IP receptor) agonist that results in vasodilation of the pulmonary vascular bed.

3- Endothelin receptor antagonists:

There are two receptors (endothelin receptor A and B) that are targeted by endothelin receptor antagonists (ERAs). ERAs that have been tested in clinical trials include:

Nonselective dual action receptor antagonists – bosentan and macitentan Selective receptor antagonists of endothelin receptor A – ambrisentan and sitaxsentan.

4- Nitric oxide-cyclic guanosine monophosphate enhancers:

PDE5 inhibitors: Sildenafil, tadalafil, and vardenafil are orally administered cyclic GMP phosphodiesterase type 5 (PDE5) inhibitors that prolong the vasodilatory effect of nitric oxide that improves pulmonary hemodynamics and exercise capacity in patients with group 1 PAH. Soluble Guanylate cyclase stimulant (Riociguat) increase the sensitivity of sGC to endogenous nitric oxide, a pulmonary vasodilator and directly stimulate the receptor to mimic the action of NO.

* Refer to individual Lexicomp drug monographs included with UpToDate.

¶Choice of calcium channel blocker is based upon the patient's heart rate. Refer to text. Agent selection There is no single best approach to selecting an agent for PH-specific therapy. to choose an agent based on multiple factors including: WHO functional class, right ventricular function, hemodynamics, vasoreactivity test, and patient characteristics and preferences.

vasoreactivity test: administration of a short-acting vasodilator followed by measurement of the hemodynamic response using an RHC. The test is considered positive or negative.

Treatment of pulmonary arterial hypertension algorithm

WHO: World Health Organization; IV: intravenous; SC: subcutaneous; INH: inhaled. * Endothelin receptor antagonist-phosphodiesterase-5 inhibitor combination is preferred by some experts. Combining phosphodiesterase-5 inhibitors and guanylate cyclase stimulants (riociguat) should be avoided due to the high risk of hypotension. ¶ Options for agents include ambrisentan, bosentan, macitentan, sildenafil, tadalafil, or riociguat. Riociguat is best studied in patients with chronic thromboembolic pulmonary hypertension. Δ These agents are not approved for this use by regulatory agencies. ◊ Some experts use initial combination therapy with a prostanoid and a phosphodiesterase-5 inhibitor

FOLLOW-UP Patients should be seen every three months (or more frequently) if they are receiving parenteral or combination therapy. The same is true of patients who have advanced symptoms, right heart failure, or advanced hemodynamic abnormalities. Less ill patients should be seen every three to six months. The frequency of right heart catheterization (RHC) is made on a case-by-case basis. It is common to repeat a RHC early after the initiation of therapy (3, 6 or 12 months), when the patient deteriorates, and when combination therapy is initiated

SPECIAL POPULATIONS Pregnancy Endothelin receptor antagonists (eg, bosentan) and guanylate cyclase stimulants (riociguat) are absolutely contraindicated in pregnancy (FDA category X) and in women who may become pregnant. A negative pregnancy test is required prior to treatment, monthly during treatment, and at one month after discontinuation of treatment. most women who are pregnant and have pulmonary arterial hypertension (PAH) should be treated with a prostanoid (functional class III, IV), usually epoprostenol. Consultation with an expert is warranted in these women to prevent adverse events (eg, fetal hypoxia, acute cardiovascular collapse). For women of childbearing age with known PAH, pregnancy should be avoided due to the risk of worsening pulmonary vascular hemodynamics. In addition, estrogen- containing contraceptives should be avoided. Surgical (patient or partner) methods of contraception are preferred but dual barrier contraception (eg, progesterone implanted intrauterine device) is an acceptable alternative Altitude and air travel Patients with exposure to high altitude or patients planning air travel should continue their routine PH medications. Supplemental oxygen (2 to 4 L per minute) can also be administered to maintain oxygen saturations above 90 percent. Surgical risk Patients with pulmonary hypertension, in particular those with pulmonary arterial hypertension (PAH) and significant right ventricular dysfunction, are at high risk of complications and death when undergoing anesthesia, mechanical ventilation, and major surgery The perioperative management can be complicated by hemodynamic instability resulting in severe hypoxemia, acute right heart failure/circulatory collapse and death In addition, medication-related complications can increase surgical risk of bleeding (eg, anticoagulants and prostanoids)

Surgical interventions. RIGHT TO LEFT SHUNT Creation of a right to left shunt is not routinely recommended as therapy for the treatment of pulmonary arterial hypertension (PAH). However, in adults with severe symptomatic PAH, such a procedure can be considered

TRANSPLANTATION Transplantation has been performed in patients with idiopathic pulmonary arterial hypertension (IPAH) and is considered by some to be the final effective treatment for selected patients with IPAH. Bilateral lung or heart-lung transplantation is the procedure of choice. Guidelines for when to refer a patient for transplan : 1-Rapidly progressive disease 2-Use of parenteral targeted pulmonary arterial hypertension (PAH) therapy regardless of symptoms or New York Heart Association (NYHA) functional class 3-Known or suspected pulmonary veno-occlusive disease (PVOD) or pulmonary capillary hemangiomatosis

Reference:

Hopkins, W. , Rubin ,L. (2019). Treatment of pulmonary hypertension in adults. In G. Finlay (Ed.) ,UpToDate .Retrieved April 2,2019,from www.uptodate.com/contents/treatment-of-pulmonary-hypertension-in-adults

Done by Pharm D Students: Waad mahajneh

Dania habashneh

Fairouz rayyashi

Supervised by: Dr. Eshraq Al-Abweeny