Overview
Pulmonary hypertension (PH)
Pulmonary hypertension (PH) is defined as an elevated pulmonary arterial pressure.
- Elevated pulmonary arterial pressure consistent with PH: ≥ 20 mm Hg at rest
- Normal pulmonary arterial pressure: 8–20 mmHg
- WHO classifications:
- Group 1: pulmonary arterial hypertension (PAH)
- Group 2: PH due to left heart disease
- Group 3: PH due to lung disease and/or hypoxia
- Group 4: PH due to pulmonary artery obstructions
- Group 5: PH with unclear and/or multifactorial mechanisms
General therapeutic options
- Long-term oxygen:
- Aim to maintain oxygen saturations＞92%
- Helps slow down progression
- Long-term anticoagulation:
- If condition is due to chronic pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism (PE)
- Helps prevent progression in other causes
- Pharmacotherapy (which generally acts via vascular smooth muscle relaxation → vasodilation → drop in pulmonary arterial pressure):
- Nitric oxide–cGMP enhancers (soluble guanylate cyclase (sGC) stimulant, phosphodiesterase type 5 (PDE-5) inhibitors)
- Prostacyclin receptor agonists
- Endothelin receptor antagonists
- Calcium channel blockers (CCBs)
- Surgery:
- Thromboembolectomy for chronic thromboembolic disease
- Very effective
- Severe PH has a very poor survival (＜5 years).
Phosphodiesterase-5 (PDE-5) Inhibitors
Chemistry
- Mimics the purine ring of cGMP
- Medications:
- Sildenafil
- Tadalafil
Chemical structure of sildenafil
Image: “Sildenafil” by Yikrazuul. License: Public DomainMechanism of action
- PDE-5 is an enzyme that regulates smooth muscle tone in blood vessels by degrading cGMP.
- PDE-5 inhibitors are both competitive and selective inhibitors of PDE-5 causing:
- ↓ Hydrolysis of cGMP
- ↑ Intracellular cGMP → ↓ calcium + antiproliferative + anticoagulant effect
- Resultant effects: relaxation of blood vessels → ↑ pulmonary blood flow → ↓ pulmonary arterial pressure
Nitric oxide (NO)–soluble guanylate cyclase (sGC)–cGMP pathway:
Nitric oxide is synthesized in the blood vessels from L-arginine, catalyzed by endothelial NO synthase. Nitric oxide goes to the smooth muscle layer of the vessel and activates sGC by binding its heme group. Soluble guanylate cyclase then converts GTP to cGMP. The downstream effects include vasodilation, inhibition of fibrosis, platelet aggregation, and smooth muscle proliferation. The image indicates areas in the pathway where the medications (PDE-5 inhibitors, sGC stimulators, and nitric oxide) exert their therapeutic mechanisms.
CNGC: cyclic nucleoside gated-ion channel
GMP: guanosine monophosphate
GTP: guanosine triphosphate
NOS: nitric oxide synthase
PDE: phosphodiesterase
PKG: protein kinase G
Pharmacokinetics
- Absorption:
- Rapid oral absorption
- Should be taken on an empty stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach
- Fatty meals can delay absorption.
- Distribution:
- Peaks in 1 hour
- Highly protein bound
- Metabolism:
- Tadalafil with longer half-life than sildenafil
- Hepatic metabolism via cytochrome P450 system (CYP3A)
- Active metabolites
- Excretion: Feces primarily
Indications
- PAH (WHO group 1)
- Other indications:
- Erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction (ED)
- Benign prostatic hyperplasia Benign prostatic hyperplasia Benign prostatic hyperplasia (BPH) is a condition indicating an increase in the number of stromal and epithelial cells within the prostate gland (transition zone). Benign prostatic hyperplasia is common in men > 50 years of age and may greatly affect their quality of life. Benign Prostatic Hyperplasia (BPH)
Adverse drug effects
- CNS:
- Headache
- Paresthesia
- Dizziness
- Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
- Visual disturbances (sildenafil: blue-tinted vision)
- Respiratory:
- Epistaxis
- Rhinitis Rhinitis Rhinitis refers to inflammation of the nasal mucosa. The condition is classified into allergic, nonallergic, and infectious rhinitis. Allergic rhinitis is due to a type I hypersensitivity reaction. Non-allergic rhinitis is due to increased blood flow to the nasal mucosa. Infectious rhinitis is caused by an upper respiratory tract infection. Rhinitis
- Cardiovascular:
- Flushing
- Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
- Syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope
- Tachycardia
- GI:
- Nausea
- Dyspepsia
- Musculoskeletal:
- Myalgia
- Back pain Back pain Back pain is a common complaint among the general population and is mostly self-limiting. Back pain can be classified as acute, subacute, or chronic depending on the duration of symptoms. The wide variety of potential etiologies include degenerative, mechanical, malignant, infectious, rheumatologic, and extraspinal causes. Back Pain
- Genitourinary: priapism
Precautions
- Caution with individuals who may be predisposed to priapism:
- Sickle cell anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
- Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma (MM)
- Leukemia
- Caution in those with:
- History of bleeding
- Cardiovascular diseases
- Hepatic and renal impairment
Contraindications
- Hypersensitivity to PDE-5 inhibitors or any drug component
- Concurrent use of nitrates Nitrates Nitrates are a class of medications that cause systemic vasodilation (veins > arteries) by smooth muscle relaxation. Nitrates are primarily indicated for the treatment of angina, where preferential venodilation causes pooling of blood, decreased preload, and ultimately decreased myocardial O2 demand. Nitrates (e.g., nitroglycerin)
- Use with riociguat, a guanylate stimulator (↑ hypotension)
- Use with protease inhibitors (↑ concentration of PDE-5 inhibitors)
- Prior episode of non-arteritic anterior ischemic optic neuropathy (NAION)
Drug interactions
- An increased risk of hypotension is associated with:
- Ethyl alcohol
- Alpha-1 blockers
- Nitroprusside
- Blood pressure–lowering drugs
- See other medications in contraindications
- CYP3A4 inducers: ↑ concentration of PDE-5 inhibitors
- CYP3A4 inhibitors: ↓ concentration of PDE-5 inhibitors
- Grapefruit juice: ↑ concentration of PDE-5 inhibitors
Soluble Guanylate Cyclase (sGC) Stimulator (Riociguat)
Chemistry
- 1st drug of the class
- Direct stimulator of sGC
Chemical structure of riociguat
Image: “Riociguat” by Vaccinationist. License: Public DomainMechanism of action
- sGC:
- The intracellular mediator for nitric oxide
- Located in smooth muscle component of vessel wall
- Riociguat directly stimulates sGC, leading to:
- ↑ Biosynthesis of cGMP
- ↓ Intracellular calcium → changes actin-myosin contractility → vasodilation
- Riociguat acts independently of NO.
Pharmacokinetics
- Absorption:
- Good oral absorption
- Distribution:
- Bioavailability: 94%
- Half-life: 12 hours
- Protein binding: 95%
- Metabolism:
- Hepatic cytochrome P450 enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
- Excretion:
- Feces and urine
Indications
- Chronic thromboembolic pulmonary hypertension (CTEPH)
- PAH (WHO group 1)
Adverse drug effects
- Embryo fetal toxicity
- Cardiovascular:
- Palpitations
- Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
- CNS:
- Headache
- Dizziness
- GI:
- Dyspepsia
- Nausea
- Vomiting
- Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
- Abdominal distension
- ENT:
- Nasal congestion
- Hemoptysis Hemoptysis Hemoptysis is defined as the expectoration of blood originating in the lower respiratory tract. Hemoptysis is a consequence of another disease process and can be classified as either life threatening or non-life threatening. Hemoptysis can result in significant morbidity and mortality due to both drowning (reduced gas exchange as the lungs fill with blood) and hemorrhagic shock. Hemoptysis
- Epistaxis
- Bleeding
Contraindications
- Hypersensitivity to riociguat or any of its components
- Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
- Concurrent administration with NO donors (e.g., amyl nitrite)
- Use with PDE-5 inhibitors
Drug interactions
- ↑ Risk of hypotension with other antihypertensives
- CYP3A4 inducers: ↑ concentration of PDE-5 inhibitors
- CYP3A4 inhibitors: ↓ concentration of PDE-5 inhibitors
- Antacids ↓ concentration of riociguat
- Smoking ↓ plasma concentration by 50%
Prostacyclin Receptor Analogues
Chemistry
- Synthetic prostacyclin analogues
- Medications:
- Epoprostenol
- Treprostinil
- Iloprost
- Selexipag
Chemical structure of prostacyclin
Image: “Prostacyclin” by Panoramix303. License: CC BY-SA 3.0
Chemical structure of treprostinil
Image: “Treprostinil” by Fvasconcellos. License: Public Domain
Chemical structure of iloprost
Image: “Iloprost” by Vaccinationist. License: Public Domain
Chemical structure of selexipag
Image: “Selexipag” by Vaccinationist. License: Public Domain
Mechanism of action
- Prostacyclin binds to the prostaglandin I2 (PGI2) receptor (called IP) in the plasma membrane of pulmonary artery SMCs.
- Involves the cAMP-dependent pathway:
- Triggers adenylate cyclase (AC) to convert ATP to cAMP
- cAMP activates protein kinase A (PKA), leading to processes that:
- ↓ Calcium by activating potassium channels (membrane hyperpolarization and repolarization)
- Inhibits myosin light-chain kinase → smooth muscle relaxation → vasodilation
- Also exerts antiproliferative effect
- Selexipag differs from the other prostacyclin analogues, as it acts as a selective IP receptor agonist.
Comparison of prostacyclin analogues
| Medications | Pharmacokinetics | Indications | Adverse drug effects |
|---|---|---|---|
| Epoprostenol |
|
|
|
| Treprostinil |
|
|
|
| Iloprost |
|
|
|
| Selexipag |
|
|
|
Contraindications
- Hypersensitivity to the drug or its components
- Drug-specific contraindications:
- Epoprostenol:
- Chronic use in those with heart failure due to severe left ventricular dysfunction
- In those who developed pulmonary edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema during initiation
- Treprostinil: The oral form is contraindicated in severe hepatic impairment.
- Selexipag: Use of strong CYP2C8 inhibitors with selexipag is contraindicated.
- Epoprostenol:
Drug interactions
- Epoprostenol, treprostinil, and iloprost enhance the action of medications with antiplatelet properties.
- Antihypertensives may potentiate and ↓ blood pressure
Endothelin Receptor Antagonists
Chemistry
- Pyrimidine derivatives
- Medications:
- Bosentan
- Macitentan
- Ambrisentan
Chemical structure of bosentan
Image: “Bosentan” by Fvasconcellos. License: Public Domain
Chemical structure of macitentan
Image: “Macitentan” by Anypodetos. License: Public Domain
Chemical structure of ambrisentan
Image: “Ambrisentan” by Fvasconcellos. License: Public Domain
Mechanism of action
- Competitive antagonist of endothelin receptors (endothelin receptor A (ET-A) and endothelin receptor B (ET-B)) on:
- Endothelium
- Vascular smooth muscle
- Causes vasodilation and smooth muscle relaxation
- Ambrisentan is a selective ET-A receptor antagonist, which is in contrast with bosentan and macitentan which are antagonists of both receptors.
Comparison of endothelin receptor antagonists
| Medications | Pharmacokinetics | Indications | Adverse drug effects |
|---|---|---|---|
| Bosentan |
|
|
|
| Macitentan |
|
|
|
| Ambrisentan |
|
|
|
Contraindications
- Hypersensitivity to the drug or its components
- Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care (embryo fetal toxicity)
- Breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding
- Severe liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease
- Drug-specific:
- Ambrisentan: contraindicated in idiopathic pulmonary fibrosis Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. Pulmonary Fibrosis (IPF)
- Bosentan:
- Use with cyclosporine (↑ bosentan levels)
- Use with glyburide (which ↑ hepatotoxic effects)
Drug interactions
- CYP3A4 inhibitors: ↑ drug concentrations
- CYP3A4 inducers: ↓ drug concentrations
- Cyclosporine: may ↑ ambrisentan concentration
Calcium Channel Blockers (CCBs)
Chemistry
- L-type CCB
- Medications:
- Nifedipine
- Amlodipine
- Diltiazem
- Verapamil
Chemical structure of diltiazem
Image: “2D structure of diltiazem” by Vaccinationist. License: Public Domain
Chemical structure of verapamil
Image: “Skeletal formula of verapamil” by Vaccinationist. License: Public Domain
Classes of CCBs
- Dihydropyridines:
- Binds more selectively to vascular smooth muscle calcium channels (vasodilator)
- Can lead to reflex tachycardia
- Example: amlodipine
- Non-dihydropyridine:
- Affects the heart contractility and conduction; less effect on vasodilation
- Does not lead to reflex tachycardia
- Benzothiazepine:
- Mainly acts on the myocardium (myocardial depressant)
- Acts as a cardiac depressant and a vasodilator
- Example: diltiazem
- Phenylalkylamine:
- Acts on cardiac myocytes (strong myocardial depressant)
- Example: verapamil
Mechanism of action
- CCBs bind the L-type calcium channels in cardiac myocytes, cardiac nodal tissues, and VSCMs, leading to:
- Closed L-type channels
- ↓ Calcium entry
- Smooth muscle relaxation → systemic vasodilation
- ↓ Cardiac afterload leads to ↓ blood pressure (effective in hypertension)
- ↓ Myocardial contractility (negative inotropic effect)
- ↓ Atrioventricular node (AVN) conduction velocity (negative dromotropic effect)
- ↓ Automaticity (negative chronotropic effect)
- ↓ Peripheral vascular resistance
Cardiovascular effects of
calcium channel blockers
Calcium Channel Blockers
Calcium channel blockers (CCBs) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBs: dihydropyridines and non-dihydropyridines.
Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers) (CCBs):
Calcium channel blockers slow down the sinoatrial (SA) node, causing a lowered heart rate. Calcium channel blocker intake leads to vascular smooth muscle relaxation, causing vasodilation.
Pharmacokinetics
- Dosage forms: oral, intravenous
- Distribution: protein binding: 80%
- Metabolism: hepatic 1st-pass metabolism, primarily by CYP3A4
- Excretion: renal and feces
Indications
- PH:
- Select cases of PAH (WHO group 1) undergo acute vasoreactivity testing to determine the likelihood of a response to CCBs.
- In those who test positive, proceed with CCB therapy.
- In those who test negative, avoid CCBs (hypotension, death).
- Other indications:
- Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
- Stable angina
- Coronary vasospasm
- Raynaud’s phenomenon
- Supraventricular tachyarrhythmias
- Migraine Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache and cluster headache prophylaxis
- Esophageal hyperperistalsis
Adverse effects
- Dihydropyridines:
- Headache (cerebral vasodilation)
- Reflex tachycardia (especially with short-acting nifedipine)
- Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
- Flushing
- Peripheral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema (dose-dependent; usually with amlodipine)
- Gingival hyperplasia
- Non-dihydropyridines:
- Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation (dose-dependent)
- Fatigue
- Bradycardia
- AVN block
- Worsening of cardiac output
- Gingival hyperplasia
Contraindications
- Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
- Hypersensitivity to CCBs
- Acute coronary syndrome:
- Avoid nifedipine or short-acting dihydropyridines.
- Short-acting dihydropyridines cause reflex tachycardia and worsen myocardial ischemia.
- Use caution in liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease.
Drug interactions
- CYP3A4 inhibitors: ↑ drug concentrations
- CYP3A4 inducers (e.g., rifampin, carbamazepine): ↓ drug concentrations
References
- Brunton, LL, et al. (Eds.). (2018). Goodman & Gilman’s the Pharmacological Basis of Therapeutics, 13th ed., McGraw Hill Medical.
- Condon, DF, Nickel, NP, Anderson, R, Mirza, S, & De Jesus Perez, VA. (2019). The 6th world symposium on pulmonary hypertension: What’s old is new. F1000Research, 8, F1000 Faculty Rev-888. https://doi.org/10.12688/f1000research.18811.1
- Hopkins, W, & Rubin, L. (2021). Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension–specific therapy. In Mandel, J. (Ed.), UpToDate. Retrieved October 20, 2021, from https://www.uptodate.com/contents/treatment-of-pulmonary-arterial-hypertension-group-1-in-adults-pulmonary-hypertension-specific-therapy
- Hopkins, W, & Rubin, L. (2021). Treatment and prognosis of pulmonary arterial hypertension in adults (group 1). In Mandel, J. (Ed.), UpToDate. Retrieved October 20, 2021, from https://www.uptodate.com/contents/treatment-and-prognosis-of-pulmonary-arterial-hypertension-in-adults-group-1
- Kansakar, S, Guragain, A, Verma, D, et al. (2021). Soluble guanylate cyclase stimulators in heart failure. Cureus 13(9): e17781. Retrieved October 25, 2021, from https://doi.org/10.7759/cureus.17781
- Rang, HP, & Dale, MM. (Eds.) (2016). Rang and Dale’s Pharmacology, 8th ed. Elsevier, Churchill Livingstone.
- Rubin, L, & Hopkins, W. (2021) Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults. UpToDate. Retrieved Oct 24, 2021, from https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-pulmonary-hypertension-of-unclear-etiology-in-adults
- Ryu, J, & Frantz, R. (2021). Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis. In King, T. & Mandel, J. (Eds.), UpToDate. Retrieved October 20, 2021, from https://www.uptodate.com/contents/pulmonary-hypertension-due-to-lung-disease-and-or-hypoxemia-group-3-pulmonary-hypertension-treatment-and-prognosis
- UpToDate, Inc. (2021) Sildenafil. UpToDate. Retrieved October 24, 2021, from https://www.uptodate.com/contents/sildenafil-drug-information
- UpToDate, Inc. (2021) Riociguat. UpToDate. Retrieved October 24, 2021, from https://www.uptodate.com/contents/riociguat-drug-information
- UpToDate, Inc. (2021) Macitentan. UpToDate. Retrieved October 24, 2021, https://www.uptodate.com/contents/macitentan-drug-information
- UpToDate, Inc. (2021) Bosentan. UpToDate. Retrieved October 24, 2021, https://www.uptodate.com/contents/bosentan-drug-information
- UpToDate, Inc. (2021) Ambrisentan. UpToDate. Retrieved October 24, 2021, from https://www.uptodate.com/contents/ambrisentan-drug-information.
- UpToDate, Inc. (2021) Epoprostenol. UpToDate. Retrieved October 24, 2021, from https://www.uptodate.com/contents/epoprostenol-drug-information.
- UpToDate, Inc. (2021) Trepostinil. UpToDate. Retrieved October 24, 2021 https://www.uptodate.com/contents/treprostinil-drug-information
- UpToDate, Inc. (2021) Iloprost. UpToDate. Retrieved October 24, 2021, from https://www.uptodate.com/contents/iloprost-drug-information
- UpToDate, Inc. (2021) Selexipag. UpToDate. Retrieved October 24, 2021, from https://www.uptodate.com/contents/selexipag-drug-information
- Pulmonary Arterial Hypertension Guidelines: Guidelines Summary. Retrieved October 20, 2021, from https://emedicine.medscape.com/article/303098-guidelines#g1
