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850-Exam 2 material > 850-Pulmonary Arterial Hypertension Pharmacy (Anderson) > Flashcards

850-Pulmonary Arterial Hypertension Pharmacy (Anderson) Flashcards

1
Q

Pulmonary Arterial Hypertension (PAH) defined as:

A

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)

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2
Q

PAH symptoms:

A
  1. Fatigue
  2. dyspnea
  3. weakness
  4. dyspnea on exertion (DOE)

-Less common symptoms include: chest pain, near-syncope, syncope, peripheral edema, and palpitations

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3
Q

World Health Organization (WHO) Classification of PAH

Group 1:

A
  1. Idiopathic PAH (IPAH)
  2. Familial PAH (FPAH)
  3. 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)
  4. Associated with significant venous or capillary involvement:
    - Pulmonary veno-occlusive disease
    - Pulmonary capillary hemangiomatosis
  5. Persistent PAH of the newborn
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4
Q

(WHO) Classification of PAH

Group 2: PAH with left heart disease

A
  1. Left-sided atrial or ventricular heart disease

2. Left-sided valvular disease

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5
Q

(WHO) Classification of PAH

Group 3: PAH associated lung disease and/or hypoxemia

A
  1. Chronic obstructive pulmonary disease
  2. Interstitial lung disease
  3. Sleep-disordered breathing
  4. Alveolar hypoventilation disorders
  5. Chronic exposure to high altitude
  6. Developmental abnormalities
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6
Q

(WHO) Classification of PAH

Group 4: PAH due to chronic thrombotic disease and/or embolic disease (CTEPH)

A
  1. Thromboembolic obstruction of PROXIMAL pulmonary arteries
  2. Thromboembolic obstruction of DISTAL pulmonary arteries
  3. Nonthrombotic pulmonary embolism (tumor, parasites, foreign material)
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7
Q

(WHO) Classification of PAH

Group 5: Miscellaneous

A
  1. Sarcoidosis, pulmonary Langerhans’ - cell histiocytosis, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediatinitis)

Sarcoidosis: abnormal collection of inflammatory cells that form lumps.

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8
Q

Pathophysiology of PAH: Pulmonary Arterial Pressure (PAP)

A
  1. 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.
  2. Pulmonary vasculature is low resistance system
  3. Mean PAP can be described by:
    »> PAP = (CO x PVR) +PVP «<
    -CO = cardiac output, PVR = pulmonary vascular resistance, PVP = pulmonary venous pressure
  4. 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
  5. Blood flow is the same to the systemic and pulmonary system but the resistance is much lower in the pulmonary system.
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9
Q

PAH: Pathogenesis (Pulmonary vascular changes)

A
  1. Vasoconstriction
    - Imbalance between vasodilators and vasoconstrictors
  2. Smooth muscle cell and endothelia cell proliferation
    - Imbalance between growth inhibitors and mitogenic factors
  3. Thrombosis
    - Imbalance between antithrombotic and prothrombotic determinants
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10
Q

Mediators of Pulmonary Vascular Responses in PAH

  1. Vasoconstriction
A
  • Increased thromboxane (TxA2)
  • Decreased prostacyclin (PGI2)
  • Decreased nitric oxide (NO)
  • Increased endothelin (ET-1)
  • Increased serotonin (5-HT)
  • Decreased vasoactive intestinal peptide (VIP)
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11
Q

Mediators of Pulmonary Vascular Responses in PAH

  1. Cell Proliferation
A
  • Increased thromboxane (TxA2)
  • Decreased prostacyclin (PGI2)
  • Decreased nitric oxide (NO)
  • Increased endothelin (ET-1)
  • Increased serotonin (5-HT)
  • Decreased vasoactive intestinal peptide (VIP)
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12
Q

Mediators of Pulmonary Vascular Responses in PAH

  1. Thrombosis
A
  • Increased thromboxane (TxA2)
  • Decreased prostacyclin (PGI2)
  • Decreased nitric oxide (NO)
  • Increased serotonin (5-HT)
  • Decreased vasoactive intestinal peptide (VIP)
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13
Q

Definite Drug-Induced (PAH): drugs and toxins known to induce PAH

A
  1. Aminorex
  2. Fenfluramine
  3. Dexfenfluramine
  4. Toxic rapeseed oil
  5. Benfluorex
  6. Selective Serotonin Reuptake Inhibitors (increased risk of persistent pulmonary hypertension in the newborns of mothers with intake of SSRIs)
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14
Q

Likely Drug-Induced (PAH): drugs and toxins known to induce PAH

A
  1. Amphetamines
  2. Dasatinib
  3. L-tryptophan
  4. Methamphetamines
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15
Q

Possible Drug-Induced (PAH): drugs and toxins known to induce PAH

A
  1. Cocaine
  2. Phenylpropanolamine
  3. St. John’s Wort
  4. Amphetamine-like drugs
  5. Interferon alpha and beta
  6. Some chemotherapeutic agents such as alkylating agents (mytomycine C, cyclophosphamide) (Alkylating agents are possible causes of pulmonary vent-occulsive disease)
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16
Q

PAH: Diagnostic Evaluation steps

A
  1. History, including family history, and physical examination
  2. Electrocardiography, Chest radiography, Pulmonary-function testing
  3. Echocardiography
  4. Ventilation/perfusion scan, Chest CT
  5. CBC, HIV-1 antibody, LFTs, thyrotropin, antinuclear antibody
  6. Exclude other secondary causes as indicated (polysomnography)
  7. Right heart catheterization with vasodilator testing (Needed to confirm PAH Dx)
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17
Q

WHO Functional Classification of Patients with PAH (Class I)

A

No limitation of usual physical activity; ordinary physical activity dose not cause increased dyspnea, fatigue, chest pain, or presyncope

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18
Q

WHO Functional Classification of Patients with PAH (Class II)

A
  1. Mild limitation of physical activity.
  2. There is no discomfort at rest, but normal physical activity causes increased dyspnea, fatigue, chest pain, or presyncope.
19
Q

WHO Functional Classification of Patients with PAH (Class III)

A
  1. Marked limitation of physical activity.
  2. There is no discomfort at rest, but less than ordinary activity causes increased dyspnea, fatigue, chest pain, or presyncope
20
Q

WHO Functional Classification of Patients with PAH (Class IV)

A
  1. Unable to perform any physical activity.
  2. May have signs of RV failure.
  3. Dyspnea and/or fatigue may be present at rest and symptoms are increased by almost any physical activity
21
Q

PAH: Markers of disease severity

A
  1. The Borg dyspnea index (BDI)
    - employs a scale from 0 = no impairment to 10 = severe impairment
  2. 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)
  3. Cardiopulmonary hemodynamic variables
    - mPAP, PVR, cardiac output via right heart catheterization
22
Q

PAH Treatment: General Measures

A
  1. 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
  2. Diet
    - Sodium restriction to <2,500 mg/day should be encouraged
    - Fluid restriction should be encouraged when necessary
  3. Immunizations
    - Annual influenza
    - Pneumococcal
  4. 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
  5. Digoxin
    - May be beneficial in patients with refractory ventricular failure and/or atrial dysrrhythmias
23
Q

PAH Treatment: Oral Anticoagulants

A

-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

24
Q

PAH Treatment: Acute Vasodilator Testing

A
  1. Vasodilator testing is used to determine response to vasodilators
    - Patients responding to testing have an improved survival with long-term calcium channel blockers (CCB)
  2. Acute vasodilator testing must be done during a right heart catheterization
  3. 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
  4. Patients with IPAH should undergo acute vasoreactivity testing
    - Patients with PAH associated with underlying processes should undergo testing as well
  5. Use a short-acting agent such as IV epoprostenol, IV adenosine, or inhaled nitric oxide
25
Q

PAH Treatment: Calcium Channel Blockers

A
  1. The proportion of patients with a favorable vasodilator response is ~10%
  2. Nifedipine XL, diltiazem, or amlodipine used most frequently
    » Avoid verapamil due to negative (-) inotrope (weakens the force of muscular contractions)
  3. Start low and titrate dose as tolerated
  4. 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
26
Q

What are the names of the drugs for Endothelin-1 Receptor antagonists (ERAs)?

A
  1. Bosentan (Tracleer)
  2. Ambrisentan (Letairis)
  3. Macitentan (Opsumit)
27
Q

Endothelin-1 (ET)

A
  1. 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
28
Q

ET-1 Activities are mediated by ET_A and ET_B receptors

A

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.

29
Q

Bosentan (Brand: Tracleer)

A

-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

30
Q

Ambrisentan (Brand: Letairis)

A

-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
31
Q

Macitentan (Brand: Opsumit)

A

-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)
32
Q

(ERAs) Warnings:

A
  1. Decrease Hgb/Hct
  2. Fluid retention (pulmonary edema, peripheral edema)
  3. Decreased sperm count
33
Q

(ERAs) Adverse Effects:

A
  1. Headaches
  2. URI (nasal congestion, cough)
  3. Flushing
  4. Hypotension
34
Q

(ERAs) Monitoring:

A
  1. LFTs
  2. Hgb/Hct
  3. Pregnancy tests
35
Q

What are the names of the drugs for Phosphodiesterase Type 5 Inhibitors (PDE5I)?

A
  1. Sildenafil

2. Tadalafil

36
Q

PAH Treatment: PDE5I

A
  • 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
37
Q

Sildenafil (Revatio) - PDE5I:

A

> > 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)

38
Q

Tadalafil (Adcirca) - PDE5I:

A

> > 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

39
Q

Soluble Guanylate Cyclase (sGC) stimulators (Riociguat MOA)

A
  • Acts in synergy with endogenous NO to stimulate sGC

- Directed stimulates sGC independently of nitric oxide availability

40
Q

Riociguat (Adempas) is indicated for the treatment of adults with:

A
  • 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

41
Q

Riociguat (Adempas)

- Adverse Effects:

A

(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)
42
Q

Riociguat (Adempas)

-Monitoring, Pharmacokinetics & Drug interactions:

A

-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)

43
Q

Combination therapy - Ambrisentan + Tadalafil:

A

• 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).

850-Exam 2 material (19 decks)

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