850-Pulmonary Arterial Hypertension Pharmacy (Anderson) Flashcards
Pulmonary Arterial Hypertension (PAH) defined as:
A sustained elevation of pulmonary arterial pressure greater than or equal to 25 mmHg (nl=15 mmHg), with a mean PCWP or LVEDP less than or equal to 15 mmHg
(Ultimately leads to right ventricular failure and death)
PAH symptoms:
- Fatigue
- dyspnea
- weakness
- dyspnea on exertion (DOE)
-Less common symptoms include: chest pain, near-syncope, syncope, peripheral edema, and palpitations
World Health Organization (WHO) Classification of PAH
Group 1:
- Idiopathic PAH (IPAH)
- Familial PAH (FPAH)
- Associated with APAH:
- Connective tissue disease
- Congenital systemic to pulmonary shunts (large, small, repaired or nonreparied)
- Portal Hypertension
- HIV infection
- Drugs and toxins
- Other (glycogen storage disease, gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy) - Associated with significant venous or capillary involvement:
- Pulmonary veno-occlusive disease
- Pulmonary capillary hemangiomatosis - Persistent PAH of the newborn
(WHO) Classification of PAH
Group 2: PAH with left heart disease
- Left-sided atrial or ventricular heart disease
2. Left-sided valvular disease
(WHO) Classification of PAH
Group 3: PAH associated lung disease and/or hypoxemia
- Chronic obstructive pulmonary disease
- Interstitial lung disease
- Sleep-disordered breathing
- Alveolar hypoventilation disorders
- Chronic exposure to high altitude
- Developmental abnormalities
(WHO) Classification of PAH
Group 4: PAH due to chronic thrombotic disease and/or embolic disease (CTEPH)
- Thromboembolic obstruction of PROXIMAL pulmonary arteries
- Thromboembolic obstruction of DISTAL pulmonary arteries
- Nonthrombotic pulmonary embolism (tumor, parasites, foreign material)
(WHO) Classification of PAH
Group 5: Miscellaneous
- Sarcoidosis, pulmonary Langerhans’ - cell histiocytosis, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediatinitis)
Sarcoidosis: abnormal collection of inflammatory cells that form lumps.
Pathophysiology of PAH: Pulmonary Arterial Pressure (PAP)
- PAP is generated by the right ventricle (RV) ejecting blood into the pulmonary circulation, which acts as a resistance to the output from the RV.
- Pulmonary vasculature is low resistance system
- Mean PAP can be described by:
»> PAP = (CO x PVR) +PVP «<
-CO = cardiac output, PVR = pulmonary vascular resistance, PVP = pulmonary venous pressure - Mean PAP ~15 mmHg, mean PVP ~8 mmHG. The pressure gradient driving flow through the pulmonary circulation is ~7 mmHg (PAP minus PVP)
-Compared to the systemic circulation where the arterial-venous pressure gradient is about 90 mmHg - Blood flow is the same to the systemic and pulmonary system but the resistance is much lower in the pulmonary system.
PAH: Pathogenesis (Pulmonary vascular changes)
- Vasoconstriction
- Imbalance between vasodilators and vasoconstrictors - Smooth muscle cell and endothelia cell proliferation
- Imbalance between growth inhibitors and mitogenic factors - Thrombosis
- Imbalance between antithrombotic and prothrombotic determinants
Mediators of Pulmonary Vascular Responses in PAH
- Vasoconstriction
- Increased thromboxane (TxA2)
- Decreased prostacyclin (PGI2)
- Decreased nitric oxide (NO)
- Increased endothelin (ET-1)
- Increased serotonin (5-HT)
- Decreased vasoactive intestinal peptide (VIP)
Mediators of Pulmonary Vascular Responses in PAH
- Cell Proliferation
- Increased thromboxane (TxA2)
- Decreased prostacyclin (PGI2)
- Decreased nitric oxide (NO)
- Increased endothelin (ET-1)
- Increased serotonin (5-HT)
- Decreased vasoactive intestinal peptide (VIP)
Mediators of Pulmonary Vascular Responses in PAH
- Thrombosis
- Increased thromboxane (TxA2)
- Decreased prostacyclin (PGI2)
- Decreased nitric oxide (NO)
- Increased serotonin (5-HT)
- Decreased vasoactive intestinal peptide (VIP)
Definite Drug-Induced (PAH): drugs and toxins known to induce PAH
- Aminorex
- Fenfluramine
- Dexfenfluramine
- Toxic rapeseed oil
- Benfluorex
- Selective Serotonin Reuptake Inhibitors (increased risk of persistent pulmonary hypertension in the newborns of mothers with intake of SSRIs)
Likely Drug-Induced (PAH): drugs and toxins known to induce PAH
- Amphetamines
- Dasatinib
- L-tryptophan
- Methamphetamines
Possible Drug-Induced (PAH): drugs and toxins known to induce PAH
- Cocaine
- Phenylpropanolamine
- St. John’s Wort
- Amphetamine-like drugs
- Interferon alpha and beta
- Some chemotherapeutic agents such as alkylating agents (mytomycine C, cyclophosphamide) (Alkylating agents are possible causes of pulmonary vent-occulsive disease)
PAH: Diagnostic Evaluation steps
- History, including family history, and physical examination
- Electrocardiography, Chest radiography, Pulmonary-function testing
- Echocardiography
- Ventilation/perfusion scan, Chest CT
- CBC, HIV-1 antibody, LFTs, thyrotropin, antinuclear antibody
- Exclude other secondary causes as indicated (polysomnography)
- Right heart catheterization with vasodilator testing (Needed to confirm PAH Dx)
WHO Functional Classification of Patients with PAH (Class I)
No limitation of usual physical activity; ordinary physical activity dose not cause increased dyspnea, fatigue, chest pain, or presyncope
WHO Functional Classification of Patients with PAH (Class II)
- Mild limitation of physical activity.
- There is no discomfort at rest, but normal physical activity causes increased dyspnea, fatigue, chest pain, or presyncope.
WHO Functional Classification of Patients with PAH (Class III)
- Marked limitation of physical activity.
- There is no discomfort at rest, but less than ordinary activity causes increased dyspnea, fatigue, chest pain, or presyncope
WHO Functional Classification of Patients with PAH (Class IV)
- Unable to perform any physical activity.
- May have signs of RV failure.
- Dyspnea and/or fatigue may be present at rest and symptoms are increased by almost any physical activity
PAH: Markers of disease severity
- The Borg dyspnea index (BDI)
- employs a scale from 0 = no impairment to 10 = severe impairment - The 6 minute walk test (6-MWT)
- A measurement of sub maximal level of exercise which is more reflective of everyday life than a cardiopulmonary exercise test (CPET) - Cardiopulmonary hemodynamic variables
- mPAP, PVR, cardiac output via right heart catheterization
PAH Treatment: General Measures
- Oxygen
- Hypoxemia is a potent vasoconstrictor and contributes to development and progression of PAH
- In patients with PAH, supplement O2 should be used as necessary to maintain O2 saturation >90% at all times - Diet
- Sodium restriction to <2,500 mg/day should be encouraged
- Fluid restriction should be encouraged when necessary - Immunizations
- Annual influenza
- Pneumococcal - Diuretics
- Indicated in patients with evidence of right ventricular failure (peripheral edema, hepatomegaly, ascites, elevated JVD)
- Maintaining normal volume status beneficial to the long-term management of the patient with PAH
- Monitor: vitals, renal function, serum electrolytes - Digoxin
- May be beneficial in patients with refractory ventricular failure and/or atrial dysrrhythmias
PAH Treatment: Oral Anticoagulants
-Microscopic thrombosis has been documented with IPAH and right-sided HF increases risk of PE
-Patients with IPAH should receive anticoagulation with warfarin
»Improved survival has been seen with oral anticoagulation in patients with IPAH
-In patients with PAH occurring in association with other underlying processes, such as scleroderma or congenital heart disease, anticoagulation should be considered
-Oral anticoagulation should be used in any PAH patient with an indwelling catheter
-Target INR range is 1.5-2.5
PAH Treatment: Acute Vasodilator Testing
- Vasodilator testing is used to determine response to vasodilators
- Patients responding to testing have an improved survival with long-term calcium channel blockers (CCB) - Acute vasodilator testing must be done during a right heart catheterization
- Positive response defined as a drop in mean PAP greater than or equal to 10 mmHg to less than or equal to 40 mmHg (10 to 40 mmHg) with an unchanged or increased cardiac output
- Patients with IPAH should undergo acute vasoreactivity testing
- Patients with PAH associated with underlying processes should undergo testing as well - Use a short-acting agent such as IV epoprostenol, IV adenosine, or inhaled nitric oxide
PAH Treatment: Calcium Channel Blockers
- The proportion of patients with a favorable vasodilator response is ~10%
- Nifedipine XL, diltiazem, or amlodipine used most frequently
» Avoid verapamil due to negative (-) inotrope (weakens the force of muscular contractions) - Start low and titrate dose as tolerated
- Monitor:
» Evaluated in 3 months for symptoms, vitals, edema (dihydropyridines)
» Sustained response to CCB therapy is defined as being in FC I or II with normal or near-normal hemodynamics after several months of treatment
What are the names of the drugs for Endothelin-1 Receptor antagonists (ERAs)?
- Bosentan (Tracleer)
- Ambrisentan (Letairis)
- Macitentan (Opsumit)
Endothelin-1 (ET)
- ET-1 is a potent endogenous vasoconstrictor and smooth-muscle mitogen that is over expressed in the plasma and lung tissue of patients with primary PAH.
-ET-1 has two primary receptors (ET_A & ET_B)
»> Activation of ET_A receptor facilitates vasoconstriction and proliferation of vascular smooth-muscle cells
»> ET_B receptors involved in the clearance of ET-1. Activation of ET_B receptors may also cause vasodilation and NO release
ET-1 Activities are mediated by ET_A and ET_B receptors
Endothelial dysfunction creates an imbalance between the vasodilative/antiproliferative (NO and PGI2) and vasoconstrictive/proliferative forces (ET-1), which leads to pathophysiological changes in PAH.
Bosentan (Brand: Tracleer)
-Selectivity: Blocks ET-1 type A & B receptors
-REMS: Contraindicated in pregnancy
1. Pregnancy test monthly
2. Hepatotoxicity (LFTs Q month)
-Drug-drug interactions:
» Substrate of CYP2C9 & 3A4
» Induces CYP2C9, 3A4 & 2C19
Contraindicated with Glyburide & Cyclosporin
Ambrisentan (Brand: Letairis)
-Selectivity: Selective ET-1 type A receptor antagonist
- REMS: Contraindicated in pregnancy (pregnancy test monthly)
- Drug-drug interactions: Substrate of CYP3A4 (major), 2C19 (minor), & P-gp
Macitentan (Brand: Opsumit)
-Selectivity: Non-selective ET-1 type A & B antagonist
- REMS: Contraindicated in pregnancy (Pregnancy test monthly)
- Drug-drug interactions: Substrate of CYP3A4 (major) & 2C19 (minor)
(ERAs) Warnings:
- Decrease Hgb/Hct
- Fluid retention (pulmonary edema, peripheral edema)
- Decreased sperm count
(ERAs) Adverse Effects:
- Headaches
- URI (nasal congestion, cough)
- Flushing
- Hypotension
(ERAs) Monitoring:
- LFTs
- Hgb/Hct
- Pregnancy tests
What are the names of the drugs for Phosphodiesterase Type 5 Inhibitors (PDE5I)?
- Sildenafil
2. Tadalafil
PAH Treatment: PDE5I
- The pulmonary vasodilation effects of NO are mediated though its second messenger, cGMP, which is rapidly degraded by PDE.
- PDE type 5 is the predominant PDE isoform in the lung that metabolizes cGMP, and it has been shown to be up-regulated in PAH
- PDE5Is by inhibiting PDE-5 increase intracellular cGMP and thereby enhances NO-mediated vasodilation
Sildenafil (Revatio) - PDE5I:
> > FDA-indicated for treatment of PAH (WHO Group I) to improve exercise ability
Monitoring: Blood pressure, symptoms, vision, hearing
Drug interactions:
1. Co-administration with nitrates is contraindicated due to risk of severe hypotension
2. Co-administration with potent CYP3A4 inhibitors is not recommended as serum concentrations of sildenafil increase
3. Co-administration with CYP3A4 inducers, including bosentan, may alter plasma levels of either or both medications. Dosage adjustment may be necessary
4. Caution is advised when administered with alpha-blockers and potentially other vasodilators with blood pressure lowering effects
Dose: 20 mg TID (4-6 hours apart)
Tadalafil (Adcirca) - PDE5I:
> > Indicated for the treatment of PAH (WHO Group I) to improve exercise ability
Monitoring: Blood pressure, symptoms, vision, hearing
Drug interactions:
1. Co-administration with nitrates is contraindicated due to risk of severe hypotension
2. Metabolized by CYP3A4 (coadministration with strong inhibitors or inducers of CYP3A4 should be avoided)
-Bosentan may decrease plasma concentrations
Dose: 40 mg once daily
(Renal insufficiency: CrCl 31-80 mL/min use 20 mg once daily; CrCl less than or equal to 30 mL/min, do not use tadalafil
Soluble Guanylate Cyclase (sGC) stimulators (Riociguat MOA)
- Acts in synergy with endogenous NO to stimulate sGC
- Directed stimulates sGC independently of nitric oxide availability
Riociguat (Adempas) is indicated for the treatment of adults with:
- Persistent/recurrent Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (WHO Group 4) after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO fuctioonal class
- PAH (WHO Group 1) to improve exercise capacity, improve WHO functional class and to delay clinical worsening
> > Available only through a special restricted distribution program called Adempas Risk Evaluation and Mitigation Strategy (REMS) Program
Riociguat (Adempas)
- Adverse Effects:
(If hypotensive, start at 0.5 mg)
- Adverse Effects:
1. Headache, dyspepsia, dizziness, nausea, diarrhea, hypotension, vomiting, anemia, GERD, constipation
2. Pregnancy Category: X (teratogenic)
Riociguat (Adempas)
-Monitoring, Pharmacokinetics & Drug interactions:
-Monitoring: Blood pressure, bleeding, symptoms
-Pharmacokinetics: Metabolized by CYP1A1, 3A, 2C8, and 2J2
(Active metabolite, M1, is metabolized by 1A1
-Drug interactions:
» Strong CYP and P-gp/BCRP inhibitors: use lower dose & monitor for hypotension
» Strong 3A inducers (rifampin): may decrease response
» Antacids: decrease absorption, separate by 1 hr
» Tobacco smoking: induces CYP1A1 so may need higher dose
» Contraindicated with nitrates, specific PDE-5I’s, or non-specific PDE-5I’s (dipyridamole, theophylline)
Combination therapy - Ambrisentan + Tadalafil:
• AMBITION trial in 605 treatment naïve PAH patients
- Randomized 2:1:1 to combination, ambrisentan, or tadalafil
- Primary EP: time to first occurrence of (a) death, (b) hospitalization for worsening PAH, (c) >15% decrease from baseline in 6MWD combined with WHO FC III or IV symptoms sustained over 14 days (short-term clinical worsening), or (d) reduction in 6MWD sustained over 14 days combined with WHO FC III or IV symptoms sustained over 6 months (inadequate long-term clinical response).
