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PH Meds Flashcards

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1
Q

Differentiate dosing of the PDE5i

A

Tadalafil (adcirca) 20-40mg daily
t1/2 15-17 hours

Sildenafil 20-80mg TID
t1/2 4 hrs

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2
Q

Which classes of PH drugs work on NO pathway

(a) Mechanism of vasodilation

A

iNO pathway drugs

-PDE5 present in pulmonary vasculature to breakdown cGMP. So PDE5i reduce breakdown of cGMP => more cGMP => smooth muscle relaxation = vasodilation
-sGC agonist (riociguat) works slightly up-stream of PDE5i. Sensitizes soluble guanylate cyclate to NO and activates sGC (independently of NO) to increase cGMP production => smooth muscle relaxation = vasodilation

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3
Q

Drug-drug interactions to consider with PDE5i

A

PDE5i
-contraindicated with riociguat due to hypotension = category X
-consider not using with protease inhibitors (HIV patients) = category D

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4
Q

Adverse effects of PDE5i

A

Both sildenafil and tadalafil:

Common: headache, flushing, hypotension
Uncommon: hearing/vision loss (can be unilateral and irreversible)m epistaxis

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5
Q

Which PDE5i requires renal dose adjustment

A

Tadalafil requires renal dose adjustment, sildenafil does not

CrCl < 50 consider maxing out dose of tadalafil at 20mg daily or 40mg q48h

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6
Q

Compare PDEi onset of action and half-life

A

Both sildenafil and tadalafil onset of action ~60 minutes

Sildenafil t1/2- 4 hours
Tadalafil t1/2- 15-17 hours

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7
Q

Riociguat starting dose

A

Riociguat: starting dose generally 1 mg TID (or 0.5mg TID if c/f hypotension)

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8
Q

Riociguat max dose

(a) Uptitration schedule

A

Riociguat: starting dose generally 1 mg TID (or 0.5mg TID if c/f hypotension)

(a) Uptitrate by 0.5mg q2-4 weeks as BP tolerates to max 2.5mg TID

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9
Q

Contraindications to riociguat

A

Riociguat contraindications
-pregnancy
-concomitant use of PDE5i due to hypotension
-ILD-PH

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10
Q

2 FDA-approved indications for riociguat

A

Riociguat FDA-approved indications

  1. CTEPH
  2. Group I (idiopathic) PAH
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11
Q

How to cross-titrate PDE5i to riocguat for CTEPH

A

Riociguat is a better drug for CTEPH- so if on PDE5i then consider transition

Sildenafil stop 24 hrs, tadalafil stop 48 hrs before initiating riociguat (1 mg TID generally starting dose unless c/f hypotension 0.5mg TID)

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12
Q

Exact mechanism of adempas

A

Adempas = riociguat
soluble guanylate cyclase agonist

  1. stabilizes No-sGC binding to sensitize soluble guanylate cyclase to soluble NO
  2. independent of NO, directly stimulates soluble guanylate cyclase to make more cGMP

More cGMP => vasodilation

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13
Q

Compare mechanism of adempas and adcirca

A

iNO pathway drugs

-PDE5 present in pulmonary vasculature to breakdown cGMP. So PDE5i reduce breakdown of cGMP => more cGMP => smooth muscle relaxation = vasodilation
-sGC agonist (riociguat) works slightly up-stream of PDE5i. Sensitizes soluble guanylate cyclate to NO and activates sGC (independently of NO) to increase cGMP production => smooth muscle relaxation = vasodilation

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14
Q

Dosing algorithm for sildenafil

A

Initiate at 20mg TID, then increase (as BP tolerates) by 20mg q month to maximum 80mg TID

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15
Q

Side effects of ERAs

A

ERAs side effects (ambristentan, macitentan, bosentan)
-fluid retention = edema, swelling
-transaminitis: worst with bosentan so bosentan requires monthly LFTs
-anemia (~1 point drop in Hgb)
-upper respiratory infections: bronchitis, naso/pharyngitis

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16
Q

Compare dosing regimens for the 3 ERAs

A

ERA dosing

Ambrisentan- start 5mg daily, after a month increase to 10mg daily
Macitentan- 10mg daily
Bosentan- start 62.5mg BID, after a month increase to 125mg BID

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17
Q

Which ERAs has the most drug-drug interactions

A

Bosentan has the most DDIs

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18
Q

ERAs require what baseline bloodwork?

Study These Flashcards
A

All ERAs require baseline hCG
Bosentan has highest hepatotoxicity risk => requires monthly LFTs

19
Q

Off-label use for bosentan

Study These Flashcards
A

Bosentan off-label used for Raynaud’s and digital ulceration in systemic sclerosis

20
Q

Differentiate mechanism of the ERAs

Study These Flashcards
A

Endothelin receptor antagonists

Bosentan and macitenan inhibit endothelin receptor A and B (nonselective)
Ambrisentan more selective, inhibits only endothelin receptor A (ETa)

21
Q

Match class of PH drug with side effect

(a) Anemia
(b) Hearing loss
(c) Bleeding
(d) Jaw pain

Study These Flashcards
A

PH drug side effects

(a) 1 point drop in Hb expected from ERAs
(b) Hearing loss can be seen in PDE5i
(c) Bleeding in prostacyclin analogues because inhibits platelet aggregation
(d) Jaw pain in prostacyclin analogues

22
Q

Explain mechanism of ERAs

Study These Flashcards
A

Endothelin receptor antagonist- blocks endothelin receptors A and B on vascular smooth muscle to block smooth muscle proliferation and vasoconstriction

23
Q

Mechanism of uptravi

Study These Flashcards
A

Uptravi- selective IP receptor agonist to activate intracellular adenylyl cylase to make more cAMP => vasodilation

24
Q

Mechanism by which selexipag can increase bleeding

Study These Flashcards
A

Activates prostacyclin receptor which => vasodilation and inhibits platelet aggregation

25
Main side effects of selexipag
Selexipag side effects, same as other prostacyclins -flushing, headache, jaw pain -GI: nausea, vomiting, diarrhea
26
Dosing regimen for selexipag
Selexipag (uptravi) start at 200mcg BID, increase by 200mcg BID weekly to goal dose 1,600mcg BID -monitor for GI intolerance
27
DDI to be aware of for uptravi
Uptravi and plavix (clopidogrel): for pts on plavix dose reduce uptravi to daily (insteaad of BID) due to reduced hepatic clearance of uptravi's activate metabolites
28
Describe mechanism of 3 drugs that work on NO pathway
NO activates soluble guanylate cyclase (sGC) to generate more cGMP. cGMP --> arteriole smooth muscle relaxation 1. iNO 2. sGC stimulator = riociguat 3. PDE5i reduces degradation of cGMP
29
Differentiate mechanism of the three ERAs
Endothelin receptor antagonists b/c endothelin is a potent vasoconstrictor and smooth muscle mitogen (PH pts overexpress endothelin in lung and plasma) -both bosentan (tracleer) and macitentan (opsumit) block both endothelin A and B receptors While Ambristentan (letairis) blocks endothelin A selectively
30
Mechanism of prostacyclin pathway medications
Prostacyclins bind IP receptors to increase cAMP => pulmonary vasodilation
31
Half life of flolan vs. remodulin
Flolan (IV epoprostinil) half life < 5 mins While remodulin (IV treprostinil) has a half life of ~3 hrs
32
Mechanism of vision changes 2/2 tadalafil
PDE6 inhibition in the retina => vision changes
33
RESPITE ERJ 2017 (a) Main outcomes
RESPITE- ERJ 2017 Switching from PDE5i to riociguat in pts who don't reach treatment goals with PDE5i 51 patients completed, most on concomittant ERAs (a) improved 6MWT by 31m, proBNP decreased by 347, WHO FC improved in half
34
Timeline to switch PDE5i to ERA (how long should the transition take)
in RESPITE (ERJ 2017, trial that showed benefit in 6MWT, reduction in BNP, improved FC in half): 1-3 day PDEi free period then riociguat adjusted to 2.5mg TID max
35
Name of selexipag trial
Phase 3 GRIPHON trial (PGI receptor agonist in pulmonary hypertension) NEJM 2015
36
GRIPHON trial for selexipag primary outcome
GRIPHON trial (PGI receptor agonist in pulmonary hypertension)- NEJM 2015 Primary outcome = composite of death from any cause or complication related to PAH (admission to hospital, progression of disease, need for lung txp listing, requirement of parenteral prostacyclin) -lower in selexipag group
37
Options for escalation in pts taking ERA/PDE5i
1. Switch NO pathway drug from PDE5i to riociguat based on REPLACE trial (Lancet 2021) that showed clinical improvement in PAH pts (not group II or III) with intermediate risk of 1-yr mortality already on ERA/PDE5i -IIb recommendation in ESC/ERS guidelines 2. Add prostacyclin pathway drug -IIa recommendation
38
REPLACE trial (PDE5i to Riociguat) (a) Pt selection (b) Primary outcome (c) Clinical takeaway
REPLACE trial- Lancet 2021 (a) 225 adults with PAH (excluded if significant lung or L heart disease) already on ERA/PDE5i with intermediate risk of 1-year mortality (b) Primary outcome- clinical improvement based on 6MWD, WHO FC, NT pro-BNP -better in riociguat -fewer adverse events in riociguat (c) Strategy for escalation of therapy in PAH pts on ERA/PDE5i is to switch NO pathway agent from PDE5i to riociguat
39
Which ERA has the best tolerability profile? In what 3 adverse events?
Macitentan better tolerated than both ambrisentan and bosentan (bosentan the worst) in - LE edema - LFT abnormality - equal Hb drop
40
Differentiate ETA and ETB receptors- which is impacted by which ERAs?
ETA (endothelin receptor A) is on vascular smooth muscle and mediates vasoconstriction - hence why ambrisentan (made 2nd) was made ETA selective but that didn't pan out to be better ETB on endothelial cells regulates endothelin clearance and NO/PGE release Macitentan and bosentan both ETA/ETB, while ambrisentan is ETA selective
41
Differentiate half life of flolan and IV remodulin
Half life IV flolan (epoprostenol) < 6 mins IV treprostinil (remodulin): 34 minutes (vs. 85 minutes of subQ remodulin)
42
Differentiate half life of IV and subQ remodulin
Half life IV flolan (epoprostenol) < 6 mins IV treprostinil (remodulin): 34 minutes (vs. 85 minutes of subQ remodulin)
43
Risk of interruption or withdrawal of IV prostanoids
44
How to minimize infusion site pain/reaction of subq mode of administration
Not dose dependent! So answer isn't to lower the dose of remodulin Instead manage with local, topical, or systemic analgesics

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