Pulmonary Arterial Hypertension Flashcards
class:
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Warnings:
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Monitoring:
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Drug-Drug/Food interactions:
class:
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(PH) Pulmonary Hypertension:
is characterized by continuous high blood pressure in the pulmonary arteries.
A normal pulmonary artery pressure (PAP) ranges from:
8 - 20 mmHg when resting
PH is defined as a mean PAP (mPAP) of ____________
> or equal to 25 mmHg in the setting of normal fluid status
The WHO classifies pulmonary hypertension into 5 groups:
Group 1-
Group 2-
Group 3-
Group 4-
Group 5-
*Group 1- pulmonary arterial hypertension (PAH) with No identifiable cause
Group 2- pulmonary hypertension due to Left Heart Disease
Group 3- pulmonary hypertension due to lung diseases (COPD, pulmonary fibrosis, emphysema) and/or hypoxia
Group 4- (CTEPH) Chronic Thromboembolic Pulmonary Hypertension, which occurs in a minority of pulmonary embolism survivors. (Warfarin, with an INR goal of 2-3 is recommended for CTEPH)
Group 5- pulmonary hypertension with unclear or multifactorial mechanisms that DO NOT fit in the other group categories (ex sarcoidosis)
When there is no identifiable cause, it is called _________
primary or idiopathic
Hypoxia -
an absence of enough oxygen in the tissues to sustain bodily functions.
How is PAH diagnosed? How do we know the mPAP is elevated?
we have to do a right heart catheterization
During the right heart catheterization, short acting vasodilators (________) are administered for __________
If the mPAP falls by at least ___________ to an absolute value ______________, then the patient is considered a responder, and should be initially treated with __________.
(inhaled nitric oxide, IV epoprostenol, or IV adenosine)
vasoreactivity testing
10 mmHg
less than 40 mmHg
oral calcium channel blocker
-
-
- cocaine & methamphetamines
- SSRI use during pregnancy, can lead to PH in the newborn
- Weight loss drugs (phentermine, phendimetrazine, dithylpropion and others)
Pulmonary Arterial Hypertension stems from the imbalance in __________ and __________.
__________ are increased
_________ are decreased
There is also an imbalance of _________ and _________.
This leads to __________
This results in _________
vasoconstrictors
vasodilator substances
vasoconstrictors
vasodilator substances
-proliferation & apoptosis
-Arteries thicken and scar tissue forms. As the walls thicken and scar, the arteries become increasingly narrower. With these changes it makes it more difficult for the right ventricle to pump blood.
- increased pressure in pulmonary vasculature. Which makes it difficult for the right ventricle to pump blood through the pulmonary arteries and into the lungs due to this increased pressure. As a result of the right ventricle working harder, it becomes enlarged and right heart failure develops.
“if right ventricle is failing, blood backs up behind it, stretching things out”
Vasoconstrictor substances include:
endothelin-1
thromboxane A2 (TXA2)
which are increased in PAH
Vasodilator substances include
prostacyclins
which are decreased in PAH
__________ is the most common cause of death in people who have PAH
Heart Failure
Symptoms of PAH include:
*fatigue
*dyspnea
chest pain
syncope
edema
tachycardia and/or Raynaud’s phenomenon
-
-
-
-
- sodium restricted diet of < 2.4 grams per day to help manage volume status
-Avoid certain medications like NSAIDs (which increase sodium and water retention) - routine immunizations against annual influenza and pneumococcal pneumonia
Drug treatment algorithm:
Drug Treatment for PAH: what are the classes of medications approved for PAH?
warfarin +/- loop diuretics +/- oxygen +/- digoxin
(loop diuretics for volume overload)
(digoxin to improve cardiac output or control heart rate in afib)
right heart catheterization AND acute vasoactive testing (when MD gives patient vasodilator)
*cause remember the vasoconstriction is predominating in pulmonary vasculature of PAH”
if patient is a responder (+) ——> Oral CCB (nifedipine ER, diltiazem, amlodipine), verapamil NOT recommended
if patient not a responder (-) ——> Initiate a PAH-approved drug
- prostacyclins
- endothelin receptor antagonists
- PDE-5 inhibitors
- soluble guanylate cyclase stimulator
Pulmonary Arterial Hypertension creates a _________.
pro-thrombotic state and increased risk for blood clots.
If warfarin is used for PAH, it should be titrated to an INR goal of
1.5 - 2.5
Digoxin is a positive inotrope. Meaning ________
Increases Force of Ventricular Contraction
Verapamil is a negative inotrope. Meaning ________
Decreases Force of Ventricular Contraction
Negative chronotropes =
Decrease Heart Rate
exs. beta blockers
Positive chronotropes =
Increase Heart Rate
patients who are unable to be physically active and with signs of right heart failure, which may be present at rest.
First line treatment for PAH is an ____________
IV prostacyclin analogue
Prostacyclin analogues:
- are started at a small dose and then slowly increased as patient tolerates
- dose only changed under physician supervision
- Life threatening if stopped suddenly. AVOID interruptions
- parenteral administration
- sterile compounding technique critical
- central line needed for home IV use
- IV cassette or SC syringe changed every 1-3 days dependent upon product and route
- if suddenly stopped, will led to pulmonary edema, serious rapid downward spiral, acute heart failure
Flolan
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epoprostenol
aka prostacyclin
class: prostacyclin receptor agonists/prostacyclin analogues
Indications: Pulmonary arterial hypertension
MOA: is a potent vasodilator (of both pulmonary and systemic vasculature) and inhibitor of platelet aggregation.
Dosage forms: Continuous IV infusion via central venous catheter
Dosing:
Start at 2ng/kg/min and increase by 1-2 ng/kg/min in 15 minute intervals based on clinical response; usual dose is 25-40 ng/kg/min (can be higher)
Max dose:
Contraindications:
- (epoprostenol): heart failure with decreased left ventricular ejection fraction
Warnings:
- vasodilation reactions (hypotension, flushing. HA)
- Rebound Pulmonary Hypertension (with interruption of large decrease in dose), which can be fatal
- increased risk of bleeding
- Chronic IV infusions: sepsis and bloodstream infections
Side Effects:
- hypotension, flushing, jaw pain, headache, N/V/D, dizziness, edema
- infusion-site pain
- anxiety, chest pain, palpitations
Monitoring:
Pearls/Notes:
- Must be Protected from light before reconstitution and during infusion
- parenteral agents (Flolan, Veletri, Remodulin) are very potent vasodilators; AVOID interruptions and sudden, large dose reductions
- Flolan requires use of ICE packs for stability
- t1/2 half-life = ~5min
- Due to short half-lives, it is essential to have immediate access to a backup pump, infusion sets and medication
- can be administered by continuous IV infusion at home using an ambulatory infusion pump
- IV cassette or SC syringe changed every 1-3 days depending upon the product and route patient uses
Drug-Drug/Food interactions:
Veletril
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epoprostenol
class: prostacyclin receptor agonists/prostacyclin analogues
Indications: Pulmonary arterial hypertension
MOA: is a potent vasodilator (of both pulmonary and systemic vasculature) and inhibitor of platelet aggregation.
Dosage forms: Continuous IV infusion via central venous catheter
Dosing:
Start at 2ng/kg/min and increase by 1-2 ng/kg/min in 15 minute intervals based on clinical response; usual dose is 25-40 ng/kg/min (can be higher)
Max dose:
Contraindications:
- (epoprostenol): heart failure with decreased left ventricular ejection fraction
Warnings:
- vasodilation reactions (hypotension, flushing. HA)
- Rebound Pulmonary Hypertension (with interruption of large decrease in dose), which can be fatal
- increased risk of bleeding
- Chronic IV infusions: sepsis and bloodstream infections
Side Effects:
- hypotension, flushing, jaw pain, headache, N/V/D, dizziness, edema
- infusion-site pain
- anxiety, chest pain, palpitations
Monitoring:
Pearls/Notes:
- **Must be Protected from light before reconstitution and during infusion
- parenteral agents (Flolan, Veletri, Remodulin) are very potent vasodilators; AVOID interruptions and sudden, large dose reductions
- t1/2 half-life = ~5min
- Due to short half-lives, it is essential to have immediate access to a backup pump, infusion sets and medication
- patient can mix product and using clean technique administer at home
- IV cassette or SC syringe changed every 1-3 days depending upon the product and route patient uses. “cassette’s get changed every day”
Drug-Drug/Food interactions:
Remodulin
treprostinil
class: prostacyclin receptor agonists/prostacyclin analogues
Indications: Pulmonary arterial hypertension
MOA: is a potent vasodilator (of both pulmonary and systemic vasculature) and inhibitor of platelet aggregation.
Dosage forms: given via continuous SC pump or IV via central venous catheter infusion.
Dosing: start at 1.25ng/kg/min and increase at weekly intervals, up to 40ng/kg/min (and possibly more)
Max dose:
Contraindications:
- (epoprostenol): heart failure with decreased left ventricular ejection fraction
Warnings:
- vasodilation reactions (hypotension, flushing. HA)
- Rebound Pulmonary Hypertension (with interruption of large decrease in dose), which can be fatal
- increased risk of bleeding
- Chronic IV infusions: sepsis and bloodstream infections
Side Effects:
- hypotension, flushing, jaw pain, headache, N/V/D, dizziness, edema
- infusion-site pain
- anxiety, chest pain, palpitations
Monitoring:
Pearls/Notes:
- parenteral agents (Flolan, Veletri, Remodulin) are very potent vasodilators; AVOID interruptions and sudden, large dose reductions
- t1/2 half-life = ~4 hours
- Due to short half-lives, it is essential to have immediate access to a backup pump, infusion sets and medication
Drug-Drug/Food interactions:
treprostinil levels are increased by CYP2C8 inhibitors (ex. gemfibrozil) AND decreased by CYP2C8 inducers (rifampin).
Tyvaso
treprostinil
class: prostacyclin receptor agonists/prostacyclin analogues
Indications: Pulmonary arterial hypertension
MOA: is a potent vasodilator (of both pulmonary and systemic vasculature) and inhibitor of platelet aggregation.
Dosage forms: inhalation
Dosing:
Max dose:
Contraindications:
- (epoprostenol): heart failure with decreased left ventricular ejection fraction
Warnings:
- vasodilation reactions (hypotension, flushing. HA)
- Rebound Pulmonary Hypertension (with interruption of large decrease in dose), which can be fatal
- increased risk of bleeding
- Chronic IV infusions: sepsis and bloodstream infections
Side Effects:
- hypotension, flushing, jaw pain, headache, N/V/D, dizziness, edema
- infusion-site pain
- anxiety, chest pain, palpitations
- cough with inhaled products
Monitoring:
Pearls/Notes:
- parenteral agents (Flolan, Veletri, Remodulin) are very potent vasodilators; AVOID interruptions and sudden, large dose reductions
- t1/2 half-life = ~4 hours
-
Drug-Drug/Food interactions:
treprostinil levels are increased by CYP2C8 inhibitors (ex. gemfibrozil) AND decreased by CYP2C8 inducers (rifampin).
Orenitram
treprostinil
class: prostacyclin receptor agonists/prostacyclin analogues
Indications: Pulmonary arterial hypertension
MOA: is a potent vasodilator (of both pulmonary and systemic vasculature) and inhibitor of platelet aggregation.
Dosage forms: oral ER tablet
Dosing:
Max dose:
Contraindications:
- (epoprostenol): heart failure with decreased left ventricular ejection fraction
Warnings:
- vasodilation reactions (hypotension, flushing. HA)
- Rebound Pulmonary Hypertension (with interruption of large decrease in dose), which can be fatal
- increased risk of bleeding
- Chronic IV infusions: sepsis and bloodstream infections
Side Effects:
- hypotension, flushing, jaw pain, headache, N/V/D, dizziness, edema
- infusion-site pain
- anxiety, chest pain, palpitations
Monitoring:
Pearls/Notes:
- parenteral agents (Flolan, Veletri, Remodulin) are very potent vasodilators; AVOID interruptions and sudden, large dose reductions
- oral tablet shell does not dissolve (ghost tablet)
-
Drug-Drug/Food interactions:
Ventavis
iloprost
class: prostacyclin receptor agonists/prostacyclin analogues
Indications: Pulmonary arterial hypertension
MOA: is a potent vasodilator (of both pulmonary and systemic vasculature) and inhibitor of platelet aggregation.
Dosage forms: inhalation
Dosing:
Max dose:
Contraindications:
- (epoprostenol): heart failure with decreased left ventricular ejection fraction
Warnings:
- vasodilation reactions (hypotension, flushing. HA)
- Rebound Pulmonary Hypertension (with interruption of large decrease in dose), which can be fatal
- increased risk of bleeding
- Chronic IV infusions: sepsis and bloodstream infections
Side Effects:
- hypotension, flushing, jaw pain, headache, N/V/D, dizziness, edema
- infusion-site pain
- anxiety, chest pain, palpitations
- cough with inhaled products
Monitoring:
Pearls/Notes:
- parenteral agents (Flolan, Veletri, Remodulin) are very potent vasodilators; AVOID interruptions and sudden, large dose reductions
Drug-Drug/Food interactions:
Uptravi
selexipag
class: prostacyclin receptor agonists/prostacyclin analogues
Indications: Pulmonary arterial hypertension
MOA: is a potent vasodilator (of both pulmonary and systemic vasculature) and inhibitor of platelet aggregation.
Dosage forms: oral tablet
Dosing:
Max dose:
Contraindications:
- (epoprostenol): heart failure with decreased left ventricular ejection fraction
Warnings:
- vasodilation reactions (hypotension, flushing. HA)
- Rebound Pulmonary Hypertension (with interruption of large decrease in dose), which can be fatal
- increased risk of bleeding
- Chronic IV infusions: sepsis and bloodstream infections
Side Effects:
- hypotension, flushing, jaw pain, headache, N/V/D, dizziness, edema
- infusion-site pain
- anxiety, chest pain, palpitations
Monitoring:
Pearls/Notes:
- parenteral agents (Flolan, Veletri, Remodulin) are very potent vasodilators; AVOID interruptions and sudden, large dose reductions
Drug-Drug/Food interactions:
- Avoid with strong CYP2C8 inhibitors
Which prostacyclin receptor agonists come as an inhalation?
treprostinil (Tyvaso)
iloprost
which prostacyclin receptor agonists come as an oral tablet?
teprostinil (Orenitram)
selexipag (Uptravi)
ERAs
Endothelin Receptor Antagonists
- block endothelin receptors on pulmonary artery smooth muscle cells
SE: vasodilatory side effects
endothelin is a _____________ with cell proliferative effects
vasoconstrictor
Tracleer
class:
Indications:
MOA:
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Drug-Drug/Food interactions:
bosentan
class: endothelin receptor antagonist
Indications: pulmonary arterial hypertension
MOA: block endothelin receptor on pulmonary artery smooth muscle cells. Preventing the vasoconstrictor endothelin from binding.
Dosage forms: oral tablet
Dosing:
< 40kg: 62.5mg BID
> or equal to 40kg: 62.5mg BID (for 4 weeks), then 125mg BID
Boxed Warnings:
Teratogenic (women of childbearing potential must have a negative pregnancy test prior to initiation of therapy and monthly thereafter
Available only through individual REMS programs (Bosentan REMS Program, Ambrisentan REMS Program and Opsumit REMS Program); prescribers, pharmacies and patients must enroll (only female patients required to be enrolled in the Ambrisentan REMS Program and Opsumit REMS Program
**Bosentan: hepatotoxicity (increase AST/ALT and liver failure)
Contraindications:
* Pregnancy
* Bosentan DO NOT USE with cyclosporine or glyburide
Warnings:
- hepatotoxicity, decreased Hgb/Hct, fluid retention
- Bosentan: hypersensitivity reactions (rash, angioedema, DRESS)
Side Effects:
- *headache, upper respiratory tract infections (nasal congestion, cough, bronchitis), flushing, hypotension, edema
Monitoring:
- LFTs, bilirubin, Hgb/Hct, pregnancy tests
Pearls/Notes:
** bosentan is approved for children 3 and older
Drug-Drug/Food interactions:
- can decrease the effectiveness of hormonal contraceptives (at least one barrier method of contraception, if not two, is recommended)
Letairis
class:
Indications:
MOA:
Dosage forms:
Dosing:
Max dose:
Contraindications:
Warnings:
Side Effects:
Monitoring:
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Drug-Drug/Food interactions:
ambrisentan
class: endothelin receptor antagonist
Indications: pulmonary arterial hypertension
MOA: block endothelin receptor on pulmonary artery smooth muscle cells. Preventing the vasoconstrictor endothelin from binding.
Dosage forms: oral tablet
Dosing:
Boxed Warnings:
Teratogenic (women of childbearing potential must have a negative pregnancy test prior to initiation of therapy and monthly thereafter
Available only through individual REMS programs (Bosentan REMS Program, Ambrisentan REMS Program and Opsumit REMS Program); prescribers, pharmacies and patients must enroll (only female patients required to be enrolled in the Ambrisentan REMS Program and Opsumit REMS Program
Contraindications:
* Pregnancy
Warnings:
- hepatotoxicity, decreased Hgb/Hct, fluid retention
Side Effects:
- *headache
Monitoring:
- LFTs, bilirubin, Hgb/Hct, pregnancy tests
Pearls/Notes:
Drug-Drug/Food interactions:
Opsumit
class:
Indications:
MOA:
Dosage forms:
Dosing:
Max dose:
Contraindications:
Warnings:
Side Effects:
Monitoring:
Pearls/Notes:
Drug-Drug/Food interactions:
macitentan
class: endothelin receptor antagonist
Indications: pulmonary arterial hypertension
MOA: block endothelin receptor on pulmonary artery smooth muscle cells. Preventing the vasoconstrictor endothelin from binding.
Dosage forms: oral tablet
Dosing:
Boxed Warnings:
Teratogenic (women of childbearing potential must have a negative pregnancy test prior to initiation of therapy and monthly thereafter
Available only through individual REMS programs (Bosentan REMS Program, Ambrisentan REMS Program and Opsumit REMS Program); prescribers, pharmacies and patients must enroll (only female patients required to be enrolled in the Ambrisentan REMS Program and Opsumit REMS Program
Contraindications:
* Pregnancy
Warnings:
- hepatotoxicity, decreased Hgb/Hct, fluid retention
Side Effects:
- *headache
Monitoring:
- LFTs, bilirubin, Hgb/Hct, pregnancy tests
Pearls/Notes:
Drug-Drug/Food interactions:
(PDE-5) phosphodiesterase enzyme-5 is responsible for the ________
degradation of cyclic guanosine monophosphate (cGMP)
PDE-5 inhibitors
inhibit PDE-5 enzyme and prevent cGMP breakdown. This increases concentrations of cGMP, which lead to pulmonary vasculature relaxation and vasodilation.
What PDE-5 inhibitors are approved for use in pulmonary arterial hypertension?
(Revatio) - sildenafil
(Adcirca) - tadalafil
Revatio
class:
Indications:
MOA:
Dosage forms:
Dosing:
Max dose:
Contraindications:
Warnings:
Side Effects:
Monitoring:
Pearls/Notes:
Drug-Drug/Food interactions:
sildenafil
class: PDE-5 inhibitor
Indications: Pulmonary arterial hypertension
MOA: inhibit PDE-5 enzyme and prevent cGMP breakdown. This increases concentrations of cGMP, which lead to pulmonary vasculature relaxation and vasodilation.
Dosage forms: tablet, oral suspension, injection
Dosing:
IV: 2.5-10mg TID
Oral: 5-20mg TID, taken 4-6 hours apart
Max dose:
Contraindications:
DO NOT USE with Nitrates OR riociguat(Adempas)
Retavio: Avoid taking with protease inhibitors (atazanavir, ritonavir, others)
Warnings:
Hearing loss (with or without tinnitus and dizziness), vision loss [rare but may be due to nonarteritic anterior ischemic optic neuropathy (NAION)], hypotension, priapism (seek emergency medical care if erection lasts > 4 hours), pulmonary edema.
Side Effects:
headache, dizziness, hypotension, flushing, epistaxis(nosebleed), N/D, extremity or back pain
Monitoring:
Pearls/Notes:
Drug-Drug/Food interactions:
Adcirca
class:
Indications:
MOA:
Dosage forms:
Dosing:
Max dose:
Contraindications:
Warnings:
Side Effects:
Monitoring:
Pearls/Notes:
Drug-Drug/Food interactions:
tadalafil
class: PDE-5 inhibitor
Indications: Pulmonary arterial hypertension
MOA: inhibit PDE-5 enzyme and prevent cGMP breakdown. This increases concentrations of cGMP, which lead to pulmonary vasculature relaxation and vasodilation.
Dosage forms: tablet
Dosing:
40mg daily
20mg daily if mild to moderate renal or hepatic impairment
CrCl < 30 mL/min: Avoid Use
Severe Hepatic impairment Avoid Use
Contraindications:
DO NOT USE with Nitrates OR riociguat(Adempas)
Warnings:
Hearing loss (with or without tinnitus and dizziness), vision loss [rare but may be due to nonarteritic anterior ischemic optic neuropathy (NAION)], hypotension, priapism (seek emergency medical care if erection lasts > 4 hours), pulmonary edema.
Side Effects:
headache, dizziness, hypotension, flushing, epistaxis(nosebleed), N/D, extremity or back pain
Monitoring:
Pearls/Notes:
Drug-Drug/Food interactions:
Alyq
tadalafil
sGC stimulator
soluble guanylate cyclase stimulator
Soluble guanylate cyclase (sGC) is a receptor for endogenous __________
nitric oxide
which medication is a soluble guanylate cyclase stimulator?
(Adempas) riociguat
rye-o-cig-you-at
ah-dem-pas
Adempas
class:
Indications:
MOA:
Dosage forms:
Dosing:
Max dose:
Contraindications:
Warnings:
Side Effects:
Monitoring:
Pearls/Notes:
Drug-Drug/Food interactions:
riociguat
class: soluble guanylate cyclase stimulator
Indications: pulmonary arterial hypertension group 1 & group 4 (CTEPH)
MOA: drug sensitizes sGC to endogenous nitric oxide and directly stimulates receptor at a different binding site. This increases cGMP, leading to relaxation and antiproliferative effects in the pulmonary artery smooth muscle cells.
Dosage forms: tablet
Dosing: start with 0.5-1 mg TID, and increase by 0.5 mg TID every 2 weeks if SBP > 95 mmHg
Max Dose: 2.5mg TID
Boxed Warnings:
* Teratogenic (women of childbearing potential must have a negative pregnancy test prior to initiation of therapy and monthly thereafter)
** Available only through the Adempas REMS program; prescribers, pharmacies and female patients must enroll**
Contraindications:
*Pregnancy
* Do NOT Use with nitrates
*Do NOT use with PDE-5 inhibitors
Warnings:
hypotension, bleeding, pulmonary edema
Side Effects:
headache, dizziness, N/V/D, dyspepsia
Monitoring:
Pearls/Notes:
Drug-Drug/Food interactions:
Smoking increases riociguat clearance; the dose may need to be decreased with smoking cessation.
- separate from antacids by > 1 hour
Pulmonary fibrosis
- is scarring and damage of lung tissue
- presents as exertional dyspnea with nonproductive cough
Select Drug that can cause Pulmonary fibrosis:
- amiodarone
- dronedarone
- bleomycin
- busulfan
- carmustine
- lomustine
- nitrofurantoin
- sulfasalazine
What two medications are approved for pulmonary fibrosis that slow the rate of decline in lung function?
(Esbriet) pirfenidone
(Ofev) nintedanib
What is Pulmonary Arterial Hypertension?
- It is when someone has High Blood Pressure in the Pulmonary artery
- (mPAP greater than or equal to > 25 mmHg)
mPAP = mean Pulmonary Arterial Pressure
What is the normal mean Pulmonary Arterial Pressure range?
8 - 20 mmHg
How is Pulmonary Arterial Hypertension (PAH) diagnosed?
- a right heart catheterization
What are Key drugs that can cause PAH?
- cocaine
- SSRI use during pregnancy Increases risk of persistent pulmonary hypertension of a newborn (PPHN)
- Weight loss drugs (diethylpropion, phendimetrazine, phentermine)
- Methamphetamine/Amphetamines
Others:
(Sprycel) dasatinib
(Proglycem) diazoxide
(Fintepla) fenfluramine - indicated for seizures associated with Lennox-Gastaut and Dravet syndrome.
Pulmonary Arterial Hypertension Pathophysiology:
- stems from some kind of imbalance between vasoconstrictor and vasodilator substances.
Vasoconstrictor substances include: [__________1______________]
Vasodilator substances include: (___________2____________)
- - the vasoconstrictor substances are increased AND the vasodilator substances are decreased.
- ## This results in increased vasoconstriction of the pulmonary vasculature leading to increased pressure in the pulmonary vasculature AND reduced blood flow.
- there is also an imbalance between cell proliferation and apoptosis (cell death) in the walls of the pulmonary arteries. [Here cell proliferation is winning out, the inside of the pulmonary artery wall is getting thicker which also contributes to increased pressure.
- as that intimal wall of the pulmonary artery gets disrupted, it creates a sore and can activate the coagulation cascade. This can contribute to the formation of thrombosis (clots).
So ________3__ is going to be a part of the management strategy for most patients with Pulmonary Arterial Hypertension. - All these issues contribute to an enlarged stretched out right ventricle AND _______4____.
Symptoms include:
1) Vasoconstrictor substances: [endothelin-1 and thromboxane A2 (TXA2)]
2) Vasodilator substances: (prostacyclins)
3) Warfarin
4) Right Heart Failure
Symptoms Clinical Presentation:
- fatigue
- dyspnea (shortness of breath)
- chest pain
- syncope (loss of consciousness)
- edema
- Raynaud’s phenomenon = decreased oxygenation of the extremities, very cool/borderline cyanotic
Remember when blood comes into the heart, in enters the right atrium, passing Tricuspid valve and into the right ventricle. The blood exits the right ventricle passing the pulmonary valve, now traveling through PULMONARY ARTERIES to the LUNGS where it picks up oxygen. Now that the blood has oxygen it returns to the heart through the pulmonary veins and into the left atrium. From left atrium the oxygen rich blood passes Mitral valve into the left ventricle, where it then exits through the aortic valve into the aorta
- if the right ventricle starts to fail, blood backs up, right ventricle starts to strech out.
PAH Treatment Algorithm:
Some of the baseline therapies that we need to consider in someone with PAH include:
- Warfarin (+/-)
- Diuretics (+/-) “Loop” for volume overload
- Oxygen (+/-)
- Digoxin (+/-) “to improve cardiac output or control heart rate in afib”
If we use warfarin in a patient with PAH. What is the target INR goal?
*remember - PAH creates a pro-thrombotic state. So warfarin will be part of management strategy.
INR goal is [1.5-2.5]
Non-drug Treatment:
- sodium restriction
- immunizations
Digoxin is considered ___________
a (+) positive inotrope
PAH Treatment Algorithm:
Diagnosis is made with ___________
What mPAP would someone need for a confirmed diagnosis?
Right Heart Catheterization and getting the pulmonary arterial pressure.
Greater than or equal to 25 mmHg
PAH Treatment Algorithm:
Once we have that diagnosis, usually during right heart catheterization. We do a Acute Vaso reactive Testing/Challenge.
This is when the physician ____________
- gives the patient a short acting vasodilator. (e.g. inhaled Nitric Oxide) and then assesses the patients response to that vasodilator.
remember - cause the problem here is that vasoconstriction is predominating. So, if we give a vasodilator and the patient responds [mPAP falls by at least 10 mmHg to an absolute value less than 40 mmHg] that patient is considered a responder AND is considered a candidate for an oral (CCB) Calcium Channel Blocker therapy.
**[Can use really and oral CCB except NO verapamil] **
- amlodipine
- long acting nifedipine
- diltiazem
verapamil has pretty ___________ effects
negative inotropic
PAH Treatment Algorithm:
If the patient does not maintain a sustained response with an oral CCB or does not respond to the short acting vasdilator.
Then we need to start the patients on a PAH-approved drug. The classes of medications include:
-1
-2
-3
-4
1) Prostacyclin’s
2) (ERA) Endothelin Receptor Antagonists
3) (PDE-5i) Phosphodiesterase-5 inhibitors
4) Soluble guanylate cyclase stimulators
Patients that have the most Severe PAH will need to be on __________________.
Prostacyclin’s
class:
Indications:
MOA:
Dosage forms:
Dosing:
Max dose:
Contraindications:
Warnings:
Side Effects:
Monitoring:
Pearls/Notes:
Drug-Drug/Food interactions:
- all are very Potent Vasodilators for both (pulmonary and systemic vasculature) and platelet inhibitors.
- we are going for that pulmonary vasodilation But these are going to vasodilate everything.
- ## some of these products are given via a continuous IV pump at home [epoprostenol, treprostinil] - [Veletri, Remodulin & Flolan]
- So these are going to be associated with a lot of side effects, including:
- vasodilatory (dizziness, hypotension, flushing, headache)
- GI
- Anxiety, chest pain/palpitations
- edema
- ## jaw pain* unique, we don’t know entirely why that happens. Reported always at a fairly high incidence.
- neuropathy
- site pain with SubQ treprostinil
- cough with inhaled products
- Started at a small dose and then slowly increased as patient tolerates.
- Dose only changed under physician supervision.
- Life threatening if stopped suddenly.
- ## t1/2 of epoprostenol ~5min vs. treprostinil ~4 hours.Parenteral administration
- Sterile Compounding technique critical
- Central line needed for home IV use
- IV cassette or SC syringe changed every 1-3 days dependent upon product and route
Uptravi
selexipab
- oral tablet formulation
- the receptor agonist
Prostacyclin’s:
Warnings:
- patients can experience vasodilation reactions once starting medication and when dose adjustments are needed. (hypotension, flushing, headache, dizziness).
- Once patient starts medication, the medication cannot be abruptly stopped. Patient becomes heavily dependent of the vasodilatory effects. Abruptly stopping medication will lead to rebound pulmonary hypertension, flash pulmonary edema, and a serious rapid downward spiral, to acute heart failure and possible death if not addressed quickly.
- Avoid interruptions and sudden, large dose reductions.
- patients on Chronic IV infusions: are at increased risk for sepsis and blood stream infections.
treprostinil and selexipag levels are increased with ______1_______ and deceased with ____2____.
_________ should be avoided with taking these medications.
_____4____ should be avoided with selexipag (Uptravi)
1) CYP2C8 inhibitors
2) CYP2C8 inducers
gemfibrozil- CYP2C8 inhibitor
4) rifampin- CYP2C8 inducer
Flolan
Veletri
epoprostenol
Must be protected from light before reconstitution and during infusion
- Not just the drug itself but even the tubing.
- *Also needs ice packs for stability. Needs to stay cold.
- Very short half-life (t1/2) = ~6min
-
Contraindication:
- heart failure with decreased left ventricular ejection fraction.
- drug blocks endothelin receptors, allowing for vasodilation and preventing endothelin from binding and carrying out vasoconstriction.
bosentan (Tracleer)
- - - approved for children 3 years old and older
Boxed Warnings:
-** Restricted Access Programs: Teratogenic (embryo-fetal toxicity) **
Bosentan REMS program
Ambrisentan REMS program
(Opsumit) REMS program
- women of childbearing potential must have a negative pregnancy test prior to initiation of therapy and monthly thereafter.
- - - prescribers, pharmacies, and patients must enroll
-* (only female patients required to be enrolled in the Ambrisentan and Opsumit REMS programs)
——————————————————————————————————————
Boxed Warnings:
bosentan (Tracleer): hepatotoxicity (increased ALT/AST and liver failure)
——————————————————————————————————————–
Contraindications:
*Pregnancy
bosentan (Tracleer): Use with cyclosporine or glyburide
ambrisentan (Letairis): idiopathic pulmonary fibrosis
——————————————————————————————————————–
Side effects:
- *headache
- edema
- hypotension
- flushing
- nasal congestion/cough
- upper respiratory tract infections
——————————————————————————————————————–
Consider CYP drug interactions:
bosentan (Tracleer):
- substrate and inducer of CYP3A4 and CYP2C9
- levels increase with CYP2C9 inhibitors (amiodarone, fluconazole)
- levels increase with CYP3A4 inhibitors (ritonavir)
- Contraindicated with cyclosporine (Neoral, Gengraf, SandIMMUNE) & glyburide (Glynase)
- bosentan can decrease the effectiveness of hormonal contraceptives. **(At least one barrier method of contraception, if not two, is recommended) **
ambrisentan (Letairis)
- major substrate of CYP3A4, minor substrate of CYP2C19 & P-gp
- cyclosporine (Neoral, Gengraf, SandIMMUNE) can increase the serum concentration of ambrisentan. Limit the dose of ambrisentan to 5mg daily when given with cyclosporine.
——————————————————————————————————————–
macitentan (Opsumit)
- major substrate of CYP3A4, minor substrate of CYP2C19
- Strong CYP3A4 inhibitors and inducers should be AVOIDED
——————————————————————————————————————–
Monitoring:
- LFTS
- bilirubin
- Hgb/Hct
- pregnancy tests
——————————————————————————————————————–
Warnings:
- hepatotoxicity
- decreased (Hgb) hemoglobin
- decreased (Hct) hematocrit
(e.g. pulmonary edema, peripheral edema),
- decreased sperm counts
bosentan (Tracleer)- hypersensitivity reactions (e.g. rash, angioedema, anaphylaxis, DRESS)
(PDE-5i) Phosphodiesterase-5 inhibitors:
MOA: drug inhibits [PDE-5] the enzyme responsible for the breakdown of cyclic guanosine monophosphate (cGMP). With increased cGMP concentrations this leads to pulmonary vasculature relaxation and vasodilation.
sildenafil (Revatio)
- Dosing: 5-20mg TID, taken 4-6 hours apart
- Avoid using sildenafil for PAH in patients taking PI-based regimens (protease inhibitors)
tadalafil (Adcirca, Alyq)
- Dosing: 40mg daily
- 20mg daily if mild-moderate renal or hepatic impairment
*Avoid if CrCl is less than < 30 mL/min
Severe Hepatic impairment: Avoid Use
Contraindications:
** Revatio: Avoid taking with protease inhibitors (e.g. atazanavir, ritonavir, etc.)
** Use with Nitrates or riociguat (Adempas)
Warnings:
Side effects:
- dizziness, hypotension, headache
Drug Interactions:
Soluble Guanylate Cyclase stimulator (sGC):
MOA:
Soluble guanylate cyclase (sGC) is a receptor for Nitric Oxide made in the body. Adempas sensitizes sGC receptor to endogenous nitric oxide and directly stimulates the receptor by binding at a different binding site. This increases cGMP, leading to relaxation and antiproliferative effects in the pulmonary artery smooth muscle cells.
riociguat (Adempas)————-rye-o-sig-you-at
* approved for both PAH and CTEPH**
Is a major substrate for CYP3A4, CYP2C8 and P-gp.
Boxed Warnings:
**Teratogenic: women of childbearing potential must have a negative pregnancy test prior to initiation of therapy and monthly thereafter)
** Available only through the Adempas REMS Program; prescribers, pharmacies and female patients must enroll.
Contraindications:
** Pregnancy, use of PDE-5 inhibitors or nitrates
Warnings:
hypotension*, bleeding, pulmonary edema
Side effects:
-* headache
- dyspepsia (indigestion)
- dizziness
- N/V/D
Drug Interactions:
- separate from antacids by greater than > 1 hour
- smoking increases clearance of riociguat; the dose may need to be
-
- Do NOT Use with Nitrate medications
- Do NOT Use with PDE-5 inhibitors
-
Pulmonary fibrosis:
- is scarred or damaged lung tissue.
clinical presentation: presents as exertional dyspnea (shortness of breath) with nonproductive cough. As the condition worsens, breathing becomes more labored.
(IPF) idiopathic pulmonary fibrosis:
- poor prognosis
- 5-year survival (20-30% once diagnosed)
Various Causes:
Toxin exposure:
- asbestos, silica
Drugs: [If the condition id drug induced, the offending drug should be discontinued]
Tx: chronic oxygen supplementation
-
-
-
- amiodarone/dronedarone——————antiarrhymics,
- bleomycin
- busulfan
- methotrexate
- nitrofurantoin
- sulfasalazine
- Carmustine/Lomustine
