Pulmonary Arterial Hypertension

Question 1

Guidelines and endorsing organization for the guidelines

Answer 1

Journal of the American College of Cardiology (JACC)

Question 2

Pharmacotherapy classes used to treat PAH

Answer 2

CCBs
Soluble guanylate cyclase (sGC) stimulators
Phosphodiesterase (PDE5) inhibitors
Endothelin receptor antagonists (ERAs)
Prostacyclin analogs
Prostacyclin IP-receptor agonists

Question 3

Goals of therapy

Answer 3

improve NYHA functional class
Improve exercise tolerance
Improve hemodynamic profile and symptoms
Slow time to clinical worsening
Slow disease progression

Question 4

Pharmacotherapy for PAH restricted through REMs

Answer 4

sCG stimulator: Riociguat (Adempas)- birth defects
ERAs: Ambrisentan (Letairis)- birth defects, Bosentan (Tracleer)- hepatotoxicity, birth defects, Macitentan (Opsumit)- birth defects

Question 5

Drugs/toxins that cause PAH

Answer 5

cocaine, phenylpropanolamine, St. John’s Wort, SSRIs in newborns, amphetamine-like drugs, interferon alpha and beta

Question 6

Soluble guanylate cyclase (sGC) inhibitors

Answer 6

MOA: sensitize sGC to endogenous NO => vasodilation. Also directly stimulates sGC, increasing cGMP w/ subsequent vasodilation

Riociguat (Adempas)

Must give med guide w/ prescription

Question 7

Riociguat

Answer 7

Adempas - sGC inhibitor
Dose: 1mg PO TID; 0.5mg PO TID w/ intolerable hypotension
Pearls: SBP >95mmHg w/ no s/s of hypotension increase dose by 0.5mg TID every 2wks to 2.5mg TID or highest tolerated dose
metabolized via BCRP, CYP2C8/3A4 and eliminated by p-gp
adjust dose in smokers and pts w/ multi-pathway CYP and P-gp/BCRP inhibitors
CI: pregnancy, co-administration of nitrates, PDE5 inhibitors
No dose adjustment for CrCl >15ml/min or mild/mod hepatic impairment

Question 8

Riociguat AEs

Answer 8

fetal harm, hypotension, HA, dizziness, dyspepsia, bleeding

Question 9

PDE5 Inhibitors

Answer 9

MOA: prevent the breakdown of cGMP
(NO –> guanylate cyclase –> increase cGMP => vasodilation)

FDA approved: sildenafil (Revatio), tadalafil (Adcirca)
Non-FDA approved: vardenafil (Levitra)

Question 10

Sildenafil citrate

Answer 10

Revatio - PDE5 inhibitor
Dose: 5-40mg po TID (max: 240mg/day)
Pearls: metabolized by CYP3A4, avoid grapefruit juice
CI: nitrates, riociguat, protease inhibitors
Counsel on priapism

Question 11

Sildenafil citrate AEs

Answer 11

flushing, HA, hypotension (associated w/ alcohol use and antihypertensives), diarrhea, visual disturbances, reports of hearing loss

Question 12

Tadalafil

Answer 12

Adcirca - PDE5 inhibitor
Dose: 40mg QD (max: 40mg/day)
Pearls: metabolized by CYP3A4, avoid grapefruit juice,
CI: nitrates, riociguat, protease inhibitors –> dose adjust w/ ritonavir
Dose adjust CrCl 31-80 ml/min and mild-mod hepatic impairment: 20mg QD (renally active metabolite)

Question 13

Tadalafil AEs

Answer 13

flushing, HA, hypotension (associated w/ alcohol use and antihypertensives), nausea, myalgia, visual disturbances

Question 14

Endothelin Receptor Antagonists

Answer 14

Competitively inhibits endothelin-1 receptors
ETa receptor: pulmonary vascular smooth muscle, stimulation –> vasoconstriction and cellular proliferation
ETb receptor: pulmonary vascular endothelial cells and smooth muscle cells, stimulation –> vasodilation, anti-proliferative effects and endothelin clearance

CI: pregnancy

Ambrisentan (Letairis)
Bosentan (Tracleer)
Macitentan (Opsumit)

Must give med guide w/ prescription

Question 15

Ambrisentan

Answer 15

Letairis - Endothelin Receptor Antagonists
» affinity for ETa receptor
Dose: 5mg QD (max: 10mg/day)
Pearls: minor metabolism by CYP 2C19/3A4, eliminated by P-gp, don’t exceed 5mg/day w/ cyclosporine (decreases metabolism)
Adjust dose in hepatic impairment that develops (LFTs 5x ULN - decrease dose)
Don’t crush/split/chew

Question 16

Bosentan

Answer 16

Tracleer - Endothelin Receptor Antagonists
ETa and ETb receptor affinity (A»B)
Dose: <40kg: 62.5mg BID, >40kg: 62.5mg BID x4 wks, increase to 125mg BID
Pearls: Minor metabolism by CYP2C9/3A4, induces CYP2C9 (weak/mod)/3A4 (mod), avoid grapefruit juice, dose adjust w/ ritonavir
Adjust dose in hepatic impairment that develops
CI: concurrent cyclosporine or glyburide (increases LFTs)

Question 17

Macitentan

Answer 17

Opsumit - Endothelin Receptor Antagonists
Tissue selective ET receptor antagonist, ETa and ETb receptor affinity (A»B)
Dose: 10mg QD (max: 10mg/day)
Pearls: metabolized by CYP3A4, Don’t crush/split/chew
Fewer drug-drug interactions than ambrisentan and bosentan

Question 18

Endothelin Receptor Antagonists AEs

Answer 18

HA, anemia, fluid retention/peripheral edema, respiratory complications, decrease spermatogenesis, hepatic impairment, flushing and dyspepsia w/ Ambrisentan

Question 19

Prostacyclin Analogs

Answer 19

MOA: vasodilate pulmonary arteries, impair platelet aggregation, anti-proliferative effects on pulmonary endothelial cells
IV and SQ forms (high potential for calculation-related med errors)

IV: epoprostenol (Flolan, Veletri), trepostonil (Remodulin)
SQ: trepostonil (Remodulin)
Inhaled: trepostonil (Tyvaso), Iloprost (Ventavis)
Oral: trepostonil (Orenitram)

Question 20

Epoprostenol

Answer 20

Flolan, Veletri - Prostacyclin Analogs
Continuous Infusion: 2ng/kg/min via central venous catheter
MD: 25-40 ng/kg/min
Dose adjust based on PAH symptoms and tolerability to side effects
ISMP list b/c of heighened risk of significant pt harm if used in error
Pearls: special ambulatory infusion pumps: Veletri: stable at room temp, Flolan: must be kept on ice, use caution in pts w/ risks for bleeding, chronic CI associated w/ local infections and serious blood stream infections of indwelling central venous catheter, DC if pt develops pulmonary edema
CI: HF (w/ low EF) due to severe left ventricular dysfunction
Only available from CVS Caremark or Accredo Health Inc

Question 21

Epoprostenol AEs

Answer 21

AEs are used as a guide for dose-titration for pt tolerance

flushing, HA, n/v, hypotension, anxiety/agitation, chest pain, jaw pain

Question 22

Treprostonil (SQ and IV)

Answer 22

Remodulin - Prostacyclin Analogs
SQ: administer via ambulatory pump 1.25 ng/kg/min, can administer up to 72hrs at >98F
IV: infused via central venous catheter infusion pump 1.25 ng/kg/min, can administer up to 48hrs >98F
SQ and IV: can decrease to 0.625 ng/kg/min due to AEs (site reaction won’t get better)

Question 23

Treprostonil (Remodulin) AEs

Answer 23

Infusion site pain/reaction (~85% of pts), rash, dose related: HA, n/v, jaw pain
hypotension

Question 24

Treprostonil inhaled

Answer 24

Tyvaso - Prostacyclin Analogs
Dose: 18mcg (or 3 inhalations) QID
If tolerated increase by additional 3 inhalations at 1-2 wk intervals, target/max dose: 54mcg (9 puffs) QID

Safety/efficacy hasn’t been established in underlying pulmonary disease (asthma, COPD)

Question 25

Treprostonil (Tyvaso) AEs

Answer 25

cough/throat irritation, dose related: HA, dizziness, nausea, diarrhea, flushing

Question 26

Treprostonil (Tyvaso, Remodulin) clinical pearls

Answer 26

avoid abrupt DC, metabolized through CYP2C8, concomittant diuretics, antihypertensives, vasodilators may increase risk of hypotension, may inhibit platelet aggregation --> increased risk of bleeding IV/SQ: prescribing/access restriction - only available from CVS Caremark or Accredo Health Inc., mild-mod hepatic impairment adjust dose: 0.625ng/kg/min using IBW --> use w/ caution and titrate slowly

Question 27

Iloprost

Answer 27

Ventavis - Prostacyclin Analogs Dose: Inhaled: 2.5mcg w/ specific inhalation system, if tolerated increase to 5mcg inhaled 6-9x/day, no more than q2h (45mcg) during waking hrs Max dose: 45mcg/day (5mcg/dose 9 times per day) Pearls: Don't start is SBP <85mmHg (b/c of hypotension), safety and efficacy haven't been established in concurrent pulmonary diseases (COPD, severe asthma, acute pulmonary infection), may induce bronchospasm in hyper-reactive airways, may inhibit platelet aggregation --> increase bleeding risk, hepatic impairment- consider increasing dosing interval (q3-4h)

Question 28

Iloprost AEs

Answer 28

cough, flu-like symptoms, dose related: nausea, HA, hypotension/syncope, flushing, jaw pain

Question 29

Prostacyclin IP-receptor agonists

Answer 29

IP receptor: 1 of 4 prostanoid receptors, regulates vascular tone, platelet activation, immunologic cell responses, expressed in vascular smooth muscle cells (SMC) and platelets, activation of IP receptor triggers SMC vasodilation and inhibition of SMC proliferation and platelet aggregation Selexipag (Uptravi) - agonist of the prostacyclin IP receptor

Question 30

Selexipag

Answer 30

Uptravi - Prostacyclin IP-receptor agonists Dose: 200mcg PO BID, increase by 200mcg BID weekly to highest tolerated dose (max: 1600mcg BID) Pearls: major substrate of BCRP, CYP2C8, take w/ food, avoid use in severe hepatic impairment, DC if pt develops pulmonary edema

Question 31

Selexipag AEs

Answer 31

flushing, HA, GI (n/v/d), myalgia, jaw pain, pulmonary edema

Question 32

General Considerations w/ PAH

Answer 32

avoid heavy lifting (syncope), participate in low level graded aerobic activity (improves peak oxygen consumption), avoid high altitudes (may need supplemental oxygen on planes), salt restriction to <2400mg/day, avoid in pregenancy, get immunizations (flu, pneumoccal)