Pulmonary Hypertension PDF

Pulmonary Hypertension Pharmacotherapy: Respiratory Diseases Presented by: Nouran Omar, PhD Pharmacy Practice & Clinical Pharmacy Future University in Egypt  2 Define pulmonary arteri...

Pulmonary Hypertension Pharmacotherapy: Respiratory Diseases Presented by: Nouran Omar, PhD Pharmacy Practice & Clinical Pharmacy Future University in Egypt  2 Define pulmonary arterial hypertension (PAH). Explain the pathophysiology of PAH. Identify signs and symptoms of PAH and WHO functional classification of PAH patients Learning Recommend appropriate non-pharmacologic therapies used in the treatment of PAH. objectives Determine the role of conventional therapies in the treatment of PAH. Recommend appropriate treatment regimens and monitoring parameters for patients with PAH. Summarize the role of combination therapy in the treatment of PAH.  3 Pulmonary circulation ¬ Pulmonary circulation is the vascular system that conducts blood from the right to left side of the heart through the lungs ¬ Pulmonary arteries are very thin walled and distensible. ¬ Pulmonary vascular resistance (PVR) is a measure of the impedance to flow in the pulmonary vasculature ¬ PVR Depends on pulmonary artery pressure ,left atrial pressure and the cardiac output ¬ Normal pulmonary artery pressure=25/8 mmHg ¬ Normal mean pulmonary artery pressure=15+/- 3mmHg PAH Definition  4 Definition ¬ Pulmonary arterial hypertension (PAH) is a group of conditions relating to elevated blood pressure measured within the pulmonary artery. ¬ Pulmonary hypertension is classified into five groups according to the World Health Organization (WHO) PAH Definition 5  6 Pulmonary hypertension is classified into five groups according to the World Health Organization (WHO) 7  8 PAH Pulmonary arterial hypertension (PAH) or Group 1 pulmonary hypertension is a progressive disease characterized by an elevation in pulmonary arterial pressure and pulmonary vascular resistance. Cardiac catheterization Mean pulmonary artery pressure (mPAP) ≥20 mm Hg Pulmonary capillary wedge pressure (PCWP)≤15 mm Hg Pulmonary vascular resistance (PVR) >2 Wood units (WU) PAH Definition Pathophysiology PAH is characterized by progressive vasoconstriction of the small pulmonary arteries that eventually leads to right ventricular hypertrophy and failure. The right ventricle is thin walled and accustomed to the much lower pressures of the pulmonary system unlike the left ventricle. Key biologic events: endothelial cell dysfunction thrombotic lesions and platelet activation, hypertrophy, fibrosis, and inflammation —all combining to produce vascular remodeling  10 Symptoms ¬ Exertional dyspnea ¬ Fatigue ¬ Weakness ¬ Exertional chest pain ¬ Complaints of general exertion intolerance ¬ Dyspnea at rest as the disease progresses ¬ Syncope ¬ Lower extremity edema PAH  11 Tuesday, November 14, 2023 Sample Footer Text Epidemiology ¬ The prevalence of PAH is estimated to be 15 to 26 patients per million individuals. ¬ More common in females ¬ Due to the presence of cardiac and pulmonary causes of PH, prevalence is higher in individuals aged >65 years. ¬ Globally, LHD is the leading cause of PH. ¬ Lung disease, especially chronic obstructive pulmonary disease (COPD), is the second most common cause.  13 Diagnosis & Evaluation ¬ Hemodynamically by right heart catheterization (RHC) ¬ Echocardiography: assess right heart function & right sided chamber size, estimate pulmonary pressures; used primarily as screening tool & helpful in ruling out other cardiac processes ¬ Evaluation of etiology of PAH: -HIV test, -serologies for connective tissue diseases -hepatitis panel, thyroid function tests -pulmonary function tests (to evaluate for restrictive or obstructive lung disease) -evaluation for chronic thromboembolic disease (Dopplers of lower extremities) ¬ Monitoring disease progression & severity: RHC, WHO functional class, echocardiogram, exercise capacity (6min walk distance or cardiopulmonary exercise testing), BNP ¬ Blood gases ¬ ECG ¬ Signs/Symptoms 14  15 Good exercise capacity Improved right ventricular function Goals for Alleviation of symptoms treatment of Improvement in quality of life PAH Prevention of disease progression Improvement in survival.  16 Non- pharmacological Management ¬ Sodium restriction ¬ Balance fluid intake with output ¬ Smoking cessation ¬ Avoid high altitude ¬ Avoid pregnancy ¬ Immunizations ¬ Pulmonary rehabilitation  17 Pharmacological Management The definition of PAH has changed recently to emphasize earlier diagnosis. Classical definition New definition Mean pulmonary artery Mean pulmonary artery pressure (mPAP) ≥25 mm Hg pressure (mPAP) ≥20 mm Hg Pulmonary capillary wedge Pulmonary capillary wedge pressure (PCWP)≤15 mm Hg pressure (PCWP)≤15 mm Hg Pulmonary vascular resistance Pulmonary vascular resistance (PVR) >3 Wood units (WU) (PVR) >2 Wood units (WU) In patients with mPAP of 20 to 25 mm Hg and PVR All PAH pharmacotherapeutic of 2 to 3 WU, clinical management : intervention studies used the clarifying causes of mild PH classical mPAP and PVR definition risk factor modification of >25 mm Hg and ≥3.0 WU, close follow‐up for symptom progression consideration to clinical trial enrollment.  18 Pharmacological Management Conventional therapy Anticoagulation with warfarin: consider if benefits > risks; target INR: 1.5–2.5 Diuretics: maintain euvolemic state Supplemental oxygen to keep oxygen saturation >90–92% Digoxin: may be used as adjunctive therapy for right heart failure; target range: 0.5–0.8ng/mL Calcium channel blockers: nifedipine, diltiazem, amlodipine (avoid verapamil due to negative inotropic effects) use only if +ve response in vasodilator (vasoreactivity) testing  19 Pharmacological Management Conventional therapy Calcium channel blockers: nifedipine, diltiazem, amlodipine (avoid verapamil due to negative inotropic effects) use only if +ve response in vasodilator (vasoreactivity) testing  20 Pharmacological Management Approved therapies exist for PAH (Group 1) and CTEPH (Group 4). The primary therapy of CTEPH is surgical (pulmonary endarterectomy), and drug therapy is considered as an alternative only if surgery is not possible. For Group 2, 3, and 5 PH patients, there are no approved specific therapies available beyond treatment of the underlying disease. The three main pathways regulating the pulmonary vasomotor tone : ET-1, NO, and prostacyclin pathways.  Prostacyclin a potent vasodilator, inhibits platelet activation, and has antiproliferative properties Prostacyclin synthase is decreased in the pulmonary Molecular arteries in PAH Endothelin-1 abnormalities a potent vasoconstrictor and stimulates PASMC proliferation. in PAH Plasma levels of ET-1 are increased in PAH and clearance is reduced Nitric Oxide a vasodilator and inhibitor of platelet activation and vascular smooth-muscle cell proliferation. the effects of NO are largely mediated by cGMP which is rapidly inactivated by PDE, especially the PDE-5 isoenzymes. 22  23 Phosphodiesterase inhibitor Guanylate cyclase stimulator  24 Pharmacological Management Targeted therapy Endothelin Receptor Antagonists (Bosentan, Ambrisentan, Macitentan ) Endothelin1: peptide produced in vascular endothelial cells; potent vasoconstrictor Mechanism of action: antagonism of endothelin receptors, leading to vasodilation, ↓ systemic vascular resistance, pulmonary vascular resistance, & mPAP; antiproliferative -Bosentan: competitive ETA & ETB receptor antagonist -Ambrisentan: selective ETA receptor antagonist Monotherapy improves exercise capacity, cardiopulmonary hemodynamics, & functional status; also used as combination therapy Can be initiated as early as Class II PAH pts Monitoring: monthly pregnancy test required(teratogenic); monthly LFTs required for bosentan Ambrisentan safe & effective in patients who discontinue bosentan due to ↑ LFTs , monthly monitoring of LFTs is no longer FDA required for ambrisentan  25 Pharmacological Management Targeted therapy Phosphodiesterase-5 Inhibitors (Sildenafil, Tadalafil) Mechanism of action: prevent the phosphodiesterase enzymes from breaking down cGMP, ↑ intracellular concentration of cGMP, leading to vasorelaxation & antiproliferative effects on vascular smooth muscle Monotherapy improves exercise capacity, hemodynamics, & functional status Guanylate cyclase stimulators (riociguat) The only drug approved for use with patients outside Group 1 which is also approved for Group 4. CI: Use of riociguat with phosphodiesterase5 inhibitors (hypotension)  26 Pharmacological Management Targeted therapy Synthetic Prostacyclin & Prostacyclin Analogs (Epoprostenol, Treprostinil, & Iloprost) Mechanism of action: direct vasodilator of systemic & pulmonary vascular beds; inhibits platelet aggregation; has cytoprotective & antiproliferative effects Initiation of prostacyclin analogs typically reserved for WHO Classes III & IV patients Used as mono or combination therapy; ↑ 6min walk distance, improves pulmonary hemodynamics  27 Pharmacological Management Targeted therapy Synthetic Prostacyclin & Prostacyclin Analogs Epoprostenol has a short t-half (3-5 minutes) so it must be given by continuous IV infusion. Drug must be administered by continuous infusion with a central venous catheter and pump, bacteremia, and catheter obstruction are potential complications. Treprostinil has longer t-half than epoprostenol; may ↓ risk of complications that may occur with accidental drug interruption. (available S.C., I.V., inhaled, and oral administration) To prevent complications of use of central venous catheters, aerosolized formulations were developed. The first approved formulation, iloprost (Ventavis), is a PGI2 analog that is given by inhalation  28 Pharmacological Management Targeted therapy Prostacyclin receptor Agonist (selexipag) The limitations of therapies based on prostacyclin analogues, particularly their short half-life, has led to the development of non-prostanoid prostacyclin receptor agonists, such as selexipag. It considerably decreases the risk of death, hospitalization, long-term oxygen therapy, and lung transplantation. 29  30 Pharmacological Management Combination therapy Combination therapy can target multiple pathophysiologic mechanisms in PAH, resulting in improvement in hemodynamics, symptoms, functional class, and exercise capacity. Combination therapy may be started sequentially as PAH progresses or as initial therapy. Adverse effects such as peripheral edema, headache, nasal congestion, and anemia were more common in the combination group than either monotherapy group, although discontinuation rates were similar.  31 Pharmacological Management Combination therapy  32 Pregnancy Pregnancy increases mortality risk in PAH patients. Guidelines recommend encouraging PAH patients to actively avoid pregnancy. The use of two contraceptive methods should be considered. Estrogen containing products should be avoided. Patients who do become pregnant need to be referred as soon as possible to a pulmonary hypertension center All ERAs (bosentan, ambrisentan, and macitantan) are teratogenic, as is riociguat. These medications should be discontinued immediately if a patient becomes pregnant. Monthly pregnancy tests are required for use of ERAs and riociguat Bosentan may decrease the efficacy of oral birth control medications.  33 Monitoring & follow up assessments 34