3. Definition
Normal pulmonary artery pressure is
8-20 mm Hg at rest
Pulmonary hypertension is pressure in
the pulmonary artery that is greater
than 25 mm Hg at rest or 30 mmHg
during physical activity
4. Types
Group 1 PAH (pulmonary
arterial hypertension)
Group 2 PH (left heart disease)
Group 3 PH (lung disease)
Group 4 PH (thromboembolic disease)
Group 5 PH (multifactorial)
5. Etiology
Estimated prevalence of 15-50 cases per
million
Approximately 10% of patients
diagnosed with pulmonary arterial
hypertension (PAH) have a family history
of the disease
◦ Referred to as having familial PAH (FPAH)
Idiopathic PAH (IPAH) has an annual
incidence of 1-2 cases per million people
in the US and Europe
Higher incidence in women
6. Background: Pathophysiology
Life-threatening condition that gets
worse over time
◦ It is high blood pressure (BP) in the
arteries that go from the heart to the lungs
Can be genetic or caused by another
condition
7. Background: Pathophysiology
Platelets, fibroblasts, and circulating cells are involved in the
progression of PAH
The phenotypical change of pulmonary arterial smooth
muscle cells (PASMCs) and pulmonary arterial endothelial
cells (PAECs) results from multiple genetic and acquired
defects and is probably the major cause for the onset of the
disease
◦ Increased PASMC contraction, increased PASMC
proliferation and inhibited PASMC apoptosis, monoclonal
PAEC proliferation, and endothelial injury all are involved in
the development of sustained pulmonary vasoconstriction,
lumen obliteration of small pulmonary arteries with
plexiform lesions, and pulmonary vascular wall thickening
due to medial hypertrophy
8. Risk factors
Congestive heart
failure
Blood clots in the
lungs
Family history
Lupus
Scleroderma
Emphysema
Chronic bronchitis
Pulmonary fibrosis
Sleep apnea
Cirrhosis
HIV/AIDs
Sex (young female)
Drug induced
10. Symptoms
Shortness of breath (SOB)
◦ Usually, starts slowly and gets worse over
time
Chest pain (CP)
Fatigue or dizziness (syncope)
Passing out
Swelling in the ankles and legs
(edema)
Racing pulse or heart palpitations
11. Diagnosis
Hard to spot/diagnose because it
mimics those of other similar
conditions
◦ Will assess medical history and use one
or more tests (ie. blood test, chest X-ray,
CT scan, MRI, electrocardiogram,
echocardiogram, heart catheterization,
pulmonary function test, lung biopsy)
14. Classification
Class I. Diagnosed with pulmonary
hypertension, you have no symptoms
with normal activity
Class II. Have symptoms at rest, but you
experience symptoms such as fatigue,
shortness of breath or chest pain with
normal activity
Class III. Comfortable at rest, but have
symptoms when active
Class IV. Symptoms with physical
activity and while at rest
18. Treatment: Non-pharmacologic
Salt and volume management
Supervised exercise (not too
strenuous)
Avoiding pregnancy
◦ The mortality rate approaches 30 percent
Immunization
◦ Specifically, influenza and pneumococcal
Improving diet
Psycho-social support
19. Treatment: Pharmacologic
All: anticoagulants ± diuretics ±
digoxin ± oxygen
◦ Long-term oxygen therapy is suggested to
maintain arterial blood O2 pressure at 60
mmHg
20. Treatment: Pharmacologic
Acute vasoreactive testing (IPAH or
APAH, ONLY)
◦ Positive: use high dose oral CCB (ie.
nifedipine, diltiazem, or amlodipine)
use long term
◦ Negative: depends on risk
Low/High risk: endothelin receptor antagonist
(ERA) or Phosphodiesterase Type 5 (PDE5)
Inhibitors (oral), [prostanoids: epoprostenol (IV)
or treprostinil (IV/SC), Iloprost (inhaled)],
soluble guanylate cyclase (sGC) stimulators
21. Treatment: Pharmacologic
Low or intermediate risk: monotherapy or
oral combination therapy
High risk: combination therapy including
IV prostacyclin analogs
22. Treatment: Pharmacologic
Prostanoids:
◦ Epoprostenol (Flolan, Veletri): 2 ng/kg/min IV
infusion every 15 min (initial) MOST COMMON
◦ Treprostinil (Remodulin, Tyvasco):
Remodulin (IV) = 1.25 ng/kg/min continuous SQ or
central line IV infusion (initial)
Tyvasco: QID inhalation
◦ Iloprost (Ventavis): 2.5 -5 mcg/inhalation 6-
9x/day
Class AE: D/N/V (dose limiting), flushing,
hypotension, anxiety, chest pain, tachycardia,
edema
◦ Chronic use: anxiety, flu-like symptoms, and jaw
pain (lockjaw with Iloprost)
23. Treatment: Pharmacologic
ERAs:
◦ Bosentan (Tracleer): 62.5 mg PO bid x 4 wks and then 125
mg bid
BBW: hepatotoxicity and Cat X
CI:cyclosporin and glyburide
AE: HA, decrease Hgb, anemia, increase LFTs, upper respiratory
tract infections, edema, male infertility
Monitor: LFTs
◦ Ambrisentan (Letairis): 5 or 10 mg PO qd
BBW: Cat X
AE: peripheral edema, HA, decrease Hgb, flushing, palpitations,
congestion
Monitor: Hgb and hematocrit
Macitatan (Opsiumit): 10 mg PO qd
◦ BBW: hepatotoxicity and Cat X
◦ CI: strong inducers of 3A4
◦ AE: anemia, cold-like symptoms, bronchitis, HA, flu and UTI
◦ Monitor: LFTs
24. Treatment: Pharmacologic
PDE-5 Is:
◦ Sildenafil (Revatio): 10 mg IV tid OR 20 mg
PO tid (4-6 hr apart)
◦ Tadalafil (Adcirca): 40 mg PO qd OR 20 mg
PO qd with mild – moderate renal/hepatic
impairment (avoid with CrCl < 30 mL/min)
Class
◦ CI: nitrates or sildenafil with PI based
regimen, severe hepatic impairment
◦ AE: dizzy, sudden drop in BP, HA, flush,
dyspepsia, back pain (Adcirca), and epistaxis
25. Treatment: Pharmacologic
sGC stimulant:
◦ Riociguat (Adempas): 1 mg PO TID
(initial)
Antacids decrease absorption and should not
be taken within 1 hr of taking medication
BBW: Cat X (do not become pregnant during
and 1 month after treatment)
CI: nitrates or NO donors, PDE inhibitors
AE: HA, dyspepsia and gastritis, dizziness,
N/D/V, hypotension
Monitor: BP (baseline and every 2 weeks)
26. Treatment: Pharmacologic
If fail therapy, add another agent
If fail that, lung transplant or atrial
septostomy (Last option)
27. News
FDA approved Uptravi (selexipag)
tablets to treat adults with pulmonary
arterial hypertension (PAH): approved
through the Orphan drug designation
◦ Developed by Actelion
Selexipag is a selective prostacyclin-
receptor agonist that targets a well-
known disease pathway that opens
blood vessels to the lungs and
improves heart function
Due to the non-specific nature of the symptoms, PAH is unfortunately most frequently diagnosed when patients have reached an advanced stage of disease
IPAH: rare progressive disease characterized by abnormally high blood pressure (hypertension) in the pulmonary artery.
Persistent pulmonary hypertension of the newborn (PPHN) arises when the normal decrease in pulmonary vascular tone does not occur after birth. Severe PPHN has been estimated to occur in 0.2% of live-born term infants, and some degree of pulmonary hypertension complicates the course of more than 10% of all neonates with respiratory failure
With PAH, the tiny arteries in your lungs become narrow or blocked. Therefore, it is harder for blood to flow through them, and that raises the blood pressure in the lungs. The heart has to work harder to pump blood through those arteries, and after a while the heart muscle gets weak. Eventually, it can lead to heart failure.
Can cause PAH:
Congestive heart failure
Blood clots in the lungs
HIV
Illegal drug use (like cocaine or methamphetamine)
Liver disease (such as cirrhosis of the liver)
Lupus, scleroderma, rheumatoid arthritis, and other autoimmune diseases
A heart defect you're born with
Lung diseases like emphysema, chronic bronchitis, or pulmonary fibrosis
Sleep apnea
Accordingly, future efforts directed at developing effective therapeutic strategies for PAH should target multiple genes, gene products, and signal transduction pathways.
Plexiform lesions are a characteristic vascular change of pulmonary arteries
“medial hypertrophy” or enlargement of the muscular layer of the pulmonary artery
Anorexigen-associated PAH: Appetite suppressant drugs were the first well-established risk factors for the development of PAH
fenfluramine-induced PAH patients: share clinical, functional, haemodynamic and genetic features with idiopathic PAH patients, as well as similar overall survival rates. These observations suggest that fenfluramine derivatives may act as a trigger for PAH without influencing its clinical course. Benfluorex is a benzoate ester that shares similar structural and pharmacological characteristics with fenfluramine derivatives. The active and common metabolite of each of these molecules is norfenfluramine, which itself has a chemical structure similar to that of amphetamines. Given, that benfluorex shares the same active metabolite as fenluramine derivatives, it is highly probable that benfluorex triggers PAH. Amphetamines, methamphetamines and cocaine are considered to be risk factors for PAH, based on case reports and pharmacological similarities to fenfluramine.
Dasatinib-induced PAH: a large inhibition spectrum and lack of specificity of TKIs may be responsible for unexpected toxicities, even at the pulmonary vascular level.
RF: heard disease, congenital heart defects, scleroderma (chronic connective tissue disease generally classified as one of the autoimmune rheumatic diseases), HIV, a family history of PAH
Example
Right heart catheterisation (RHC) plays a central role in identifying pulmonary hypertension (PH) disorders, and is required to definitively diagnose pulmonary arterial hypertension (PAH) gold standard for diagnosis.
Characterised by the presence of pre-capillary PH, PAH is determined by a PAWP ≤15 mmHg in addition to a mean PAP ≥25 mmHg at rest and a pulmonary vascular resistance (PVR) >3 Wood units
This is the next test that is done to determine what medication to add to the patients drug regimen. This is only for patients with idiopathic, heritable or drug-induced PAH can undergo an acute vasoreactor test if necessary. Also, this test is used for initial treatment, if not already on therapy. Acute vasoreactive testing: identify the small minority of patients who may benefit from an oral calcium channel blocker. Inhaled nitric oxide (iNO) is the compound of choice for the acute test and intravenous epoprostenol or adenosine may also be used as an alternative (but with a risk of systemic vasodilator effects). More recently, inhaled iloprost has been able to identify patients who may benefit from long-term therapy with CCBs.
Therapy will be chronic!!
Monotherapies with the strongest evidence include endothelin receptor antagonists and phosphodiesterase type 5 inhibitors, while the combination therapy with the strongest evidence is ambrisentan plus tadalafil
Prostanoids: potent vasodilators (pulmonary and systemic vascular beds) + inhibit platelet aggregation. Avoid interruption in therapy and IV is most potent. May incr effects of antihypertensive and antiplatelets.
Epoprostenol: Alter the infusion by 1- to 2-ng/kg/min increments at intervals sufficient to allow assessment of clinical response. Given through a central catheter.
ERAs: vasoconstrictor with cellular proliferative effects.
Bosentan and Ambrisentan REMS program
Don’t use with St. John’s wort or grapefruit juice
Bosentan level may incr with 2c8/9 and 3a4 inh
PDE-5 Is: incr cGMP concentrations lead to pulmonary vasculature relaxation and vasodilation.
Sudden vision loss or vision problems, hearing problem or hearing loss (rare)
Caution with the use of alpha blockers at the same time
Riociguat does so via a dual mechanism of action: It sensitizes sGC to endogenous NO, and it directly stimulates sGC receptors independent of NO availability, resulting in vasorelaxation and antiproliferative effects. Approved 2013.
REMS program
Atrial septostomy is a procedure where a small hole is made in the wall between the left and right atria of the heart. The hole can be made using a cardiac catheter (a thin flexible tube, which is inserted into the chambers or blood vessels of the heart).
Common side effects observed in those treated with Uptravi in the trial include headache, diarrhea, jaw pain, nausea, muscle pain (myalgia), vomiting, pain in an extremity, and flushing.