Pulmonary Arterial Hypertension PDF

**Pulmonary Arterial Hypertension** **[Diagnosis]** [Pulmonary arterial pressure] Pressure in the pulmonary arteries Affected by pressure from the heart as well as inherent pressure from the vessels [Pulmonary capillary wedge pressure] Measure of the heart's contribution to pulmonary arterial...

**Pulmonary Arterial Hypertension** **[Diagnosis]** [Pulmonary arterial pressure] Pressure in the pulmonary arteries Affected by pressure from the heart as well as inherent pressure from the vessels [Pulmonary capillary wedge pressure] Measure of the heart's contribution to pulmonary arterial pressure Indirect measure of pressure in left atrium **[Definition]** Pulmonary hypertension (PH) ≠ PAH mPAP ≥ 20 mmHg *[and]* PCWP ≤ 15 mmHg **[Pathophysiology]** Genetics BMPR2 mutations --- inhibits smooth muscle cell apoptosis, leads to proliferation ALK-1 mutations --- small vascular malformation, immune response to mediation [Other risk factors] HIV infections Portal hypertension Schistosomiasis --- **most common worldwide cause** Congenital heart disease Persistent pulmonary HTN of the newborn --- circulation disorder at birth Connective tissue disease (e.g. lupus, systemic sclerosis, rheumatoid arthritis) Idiopathic (IPAH) Drug induced appetite suppressants, amphetamines, cocaine, chemotherapy agents **[Classification]** [WHO Functional Classification of PAH] ----------- -------------------------------------------------------------------------------------------- **Class** **Defintion** Class I No limitation of activity; physical activity does not cause increase in symptoms Class II Mild limitation of physical activity; no discomfort at rest, symptoms with normal activity Class III Less-than-normal activity causes limiting symptoms Class IV Symptoms at rest; unable to perform physical activities ----------- -------------------------------------------------------------------------------------------- **[Symptoms]** [Classic symptoms]: Dyspnea (increased on exertion) Pre-syncope / syncope Chest pain Fatigue Weakness [Symptoms of progressing / advanced disease] Lower extremity edema Hypotension Cyanosis Wheezing Use of accessory muscles during breathing Heart murmur due to valve regurgitation [**Pharmacotherapy** **Goals**] [Reduction of symptoms] "Step down" or maintain functional class status Mitigate progressive nature of disease Decrease number of hospitalizations [Improvement in physical ability] Six-minute walk distance (6MWD) [Cardiopulmonary hemodynamics] Right heart catheterization Echocardiography [**Vasoreactivity Assessment --- CHEST 2019** **Guidelines**] Calcium channel blockers should be used in patients with a positive vasodilator response Diltiazem, nifedipine, amlodipine Risks associated with use in non-responders: e.g. reflex tachycardia, sympathetic stimulation Limited duration of efficacy 50% do not respond after 1 year [**Conventional Therapy --- ESC/ERS 2022** **Guidelines**] [Oral anticoagulation (e.g. warfarin, INR goal of 1.5-2.5)] Consider for IPAH, hereditable PAH, or drug-induced PAH based on limited data [Loop diuretics] Furosemide dosed to maintain euvolemic state Recommended for patients with right ventricle dysfunction based on expert opinion [Oxygen therapy] Goal O2 saturation ≥ 92% Recommendation based on evidence in COPD [Digoxin] Target concentration of 0.5-0.8 ng/mL for symptomatic benefit No longer included as a recommendation, may be used to address arrhythmia [**PAH-Specific Pharmacotherapy --- CHEST 2019** **Guidelines**] CCB therapy if indicated [Class I ] Monitoring + conventional therapy as appropriate Treatment of underlying disease states, contributing causes Birth control, immunizations (recommended for all patients) [Class II] [1st line]: Ambrisentan (ETRA) + Tadalafil (PDE5 inhibitor) [2nd line]: Ambrisentan, sildenafil, bosentan, macitentan, tadalafil, riociguat Prostatcylicn analogs should NOT be used [Class III] [1st line]: Ambrisentan + tadalafil [2nd line]: ambrisentan, sildenafil, bosentan, macitentan, tadalafil, riociguat IV epoprostenol, IV/SC treprostinil suggested as initial therapy in patients with evidence of rapid progression / poor prognosis May add inhaled or oral prostanoid [Class IV] [1st line]: IV epoprostenol or IV/SC treprostinil [2nd line]: inhaled prostanoid in combination with an oral PDE-5 inhibitor and an oral ETRA Keep It Simple, Students! [Class II and III ] [1st line agents]: Ambrisentan + tadalafil [2nd line agents]: monotherapy with ETRA, PDE5 inhibitor, or riociguat (best evidence with ambrisentan and sildenafil) [Class III with rapid progression]: Treat like Class IV [Class IV]: [1st line agents]: parenteral prostanoids [2nd line therapy]: combination of inhaled prostanoid, oral PDE5 inhibitor, and oral ETRA **[Adverse Effects]** [PGI2 and analogs] Systemic administration: hypotension, tachycardia, thrombocytopenia, CNS effects (HA, dizziness), flu-like syndrome, jaw pain, flushing Inhaled products: flushing, cough jaw spasms, HA, insomnia, hypotension flu-like syndrome Lower risk of AEs overall than IV/SC products [PDE5 Inhibitors] HA, hypotension, myalgias, cardiovascular events reported (typically during or after sexual activity) [ETRA] Hepatotoxicity (Bosentan), anemia, edema, HA, sinus congestion High risk of [teratogenicity] if taken during pregnancy (**boxed warning**, REMS program) [Riociguat] HA, N/V/D, dizziness, hypotension, anemia, GERD, palpitations High risk of [teratogenicity] if taken during pregnancy (**boxed warning**, REMS program) +-----------------------------------+-----------------------------------+ | **Class** | **Therapy** | +-----------------------------------+-----------------------------------+ | Class I | - Monitoring + conventional | | | therapy as appropriate | | | | | | - Treatment of underlying | | | disease states, contributing | | | causes | | | | | | - Birth control, immunizations | | | (recommended for all | | | patients) | +-----------------------------------+-----------------------------------+ | Class II | - 1st Line: Ambrisentan | | | (ETRA) + Tadalafil (PDE5I) | | | | | | - 2nd Line: ambrisentan, | | | sildenafil, bosentan, | | | macitentan, tadalafil, | | | riociguat | | | | | | - Prostacyclin analogs | | | should NOT be used | +-----------------------------------+-----------------------------------+ | Class III | - 1st Line: Ambrisentan + | | | Tadalafil | | | | | | - 2nd Line: ambrisentan, | | | sildenafil, bosentan, | | | macitentan, tadalafil, or | | | riociguat | | | | | | - IV epoprostenol, IV/SC | | | treprostinil suggested as | | | initial therapy in | | | patients with evidence of | | | rapid progression/poor | | | prognosis | | | | | | - May add inhaler or | | | oral prostanoid | +-----------------------------------+-----------------------------------+ | Class IV | - 1st Line: IV Epoprostenol or | | | IV/SC Treprostinil | | | | | | - 2nd Line: inhaled prostanoid | | | in combination with an oral | | | PDE-5 inhibitor or oral ETRA | +-----------------------------------+-----------------------------------+ **[Drug Therapy Overview --- CHEST 2019 Guidelines]** [**Drug Adverse** **Effects**] +-----------------------+-----------------------+-----------------------+ | **Class** | **Drugs** | **Adverse Effects** | +-----------------------+-----------------------+-----------------------+ | Endothelin Receptor | Ambrisentan | - Hepatoxicity | | Antagonist (ETRA) | | (Bosentan), | | | | anemia, edema, | | | | HA, sinus | | | | congestion | | | | | | | | - **[Boxed | | | | Warning]{.underli | | | | ne}**: | | | | high risk of | | | | [teratogenicity]{ | | | |.underline} | | | | if taken during | | | | pregnancy (REMS | | | | program) | +-----------------------+-----------------------+-----------------------+ | | Macitentan | | +-----------------------+-----------------------+-----------------------+ | | Bosentan | | +-----------------------+-----------------------+-----------------------+ | Guanylate Cyclase | Riociguat | - HA, N/V/D, | | Stimulator | | dizziness, | | | | hypotension, | | | | anemia, GERD, | | | | palpitations | | | | | | | | - **[Boxed | | | | Warning]{.underli | | | | ne}**: | | | | high risk of | | | | [teratogenicity]{ | | | |.underline} | | | | if taken during | | | | pregnancy (REMS | | | | program) | +-----------------------+-----------------------+-----------------------+ | Phosphodiesterase | Sildenafil | - HA, hypotension, | | Inhibitors (PDE5) | | myalgias, | | | | cardiovascular | | | | events reported | | | | (typically during | | | | or after sexual | | | | activity) | +-----------------------+-----------------------+-----------------------+ | | Tadalafil | | +-----------------------+-----------------------+-----------------------+ | Prostacyclin & | Treprostinil | - [Systemic | | Prostanoids (analogs) | | administration]{. | | | | underline}: | | | | hypotension, | | | | tachycardia, | | | | thrombocytopenia, | | | | CNS effects (HA, | | | | dizziness), | | | | flu-like | | | | syndrome, jaw | | | | pain, flushing | | | | | | | | - [Inhaled | | | | products]{.underl | | | | ine}: | | | | flushing, cough, | | | | jaw spasms, HA, | | | | insomnia, | | | | hypotension, | | | | flu-like | | | | syndromes | | | | | | | | - Lower risk of | | | | AEs overall | | | | than IV/SC | | | | products | +-----------------------+-----------------------+-----------------------+ | | Epoprostenol | | +-----------------------+-----------------------+-----------------------+ | | Iloprost | | +-----------------------+-----------------------+-----------------------+