PH Meds Flashcards
Differentiate dosing of the PDE5i
Tadalafil (adcirca) 20-40mg daily
t1/2 15-17 hours
Sildenafil 20-80mg TID
t1/2 4 hrs
Which classes of PH drugs work on NO pathway
(a) Mechanism of vasodilation
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
Drug-drug interactions to consider with PDE5i
PDE5i
-contraindicated with riociguat due to hypotension = category X
-consider not using with protease inhibitors (HIV patients) = category D
Adverse effects of PDE5i
Both sildenafil and tadalafil:
Common: headache, flushing, hypotension
Uncommon: hearing/vision loss (can be unilateral and irreversible)m epistaxis
Which PDE5i requires renal dose adjustment
Tadalafil requires renal dose adjustment, sildenafil does not
CrCl < 50 consider maxing out dose of tadalafil at 20mg daily or 40mg q48h
Compare PDEi onset of action and half-life
Both sildenafil and tadalafil onset of action ~60 minutes
Sildenafil t1/2- 4 hours
Tadalafil t1/2- 15-17 hours
Riociguat starting dose
Riociguat: starting dose generally 1 mg TID (or 0.5mg TID if c/f hypotension)
Riociguat max dose
(a) Uptitration schedule
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
Contraindications to riociguat
Riociguat contraindications
-pregnancy
-concomitant use of PDE5i due to hypotension
-ILD-PH
2 FDA-approved indications for riociguat
Riociguat FDA-approved indications
- CTEPH
- Group I (idiopathic) PAH
How to cross-titrate PDE5i to riocguat for CTEPH
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)
Exact mechanism of adempas
Adempas = riociguat
soluble guanylate cyclase agonist
- stabilizes No-sGC binding to sensitize soluble guanylate cyclase to soluble NO
- independent of NO, directly stimulates soluble guanylate cyclase to make more cGMP
More cGMP => vasodilation
Compare mechanism of adempas and adcirca
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
Dosing algorithm for sildenafil
Initiate at 20mg TID, then increase (as BP tolerates) by 20mg q month to maximum 80mg TID
Side effects of ERAs
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
Compare dosing regimens for the 3 ERAs
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
Which ERAs has the most drug-drug interactions
Bosentan has the most DDIs
ERAs require what baseline bloodwork?
All ERAs require baseline hCG
Bosentan has highest hepatotoxicity risk => requires monthly LFTs
Off-label use for bosentan
Bosentan off-label used for Raynaud’s and digital ulceration in systemic sclerosis
Differentiate mechanism of the ERAs
Endothelin receptor antagonists
Bosentan and macitenan inhibit endothelin receptor A and B (nonselective)
Ambrisentan more selective, inhibits only endothelin receptor A (ETa)
Match class of PH drug with side effect
(a) Anemia
(b) Hearing loss
(c) Bleeding
(d) Jaw pain
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
Explain mechanism of ERAs
Endothelin receptor antagonist- blocks endothelin receptors A and B on vascular smooth muscle to block smooth muscle proliferation and vasoconstriction
Mechanism of uptravi
Uptravi- selective IP receptor agonist to activate intracellular adenylyl cylase to make more cAMP => vasodilation
Mechanism by which selexipag can increase bleeding
Activates prostacyclin receptor which => vasodilation and inhibits platelet aggregation
Main side effects of selexipag
Selexipag side effects, same as other prostacyclins
-flushing, headache, jaw pain
-GI: nausea, vomiting, diarrhea
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
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
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
- iNO
- sGC stimulator = riociguat
- PDE5i reduces degradation of cGMP
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
Mechanism of prostacyclin pathway medications
Prostacyclins bind IP receptors to increase cAMP => pulmonary vasodilation
Half life of flolan vs. remodulin
Flolan (IV epoprostinil) half life < 5 mins
While remodulin (IV treprostinil) has a half life of ~3 hrs
Mechanism of vision changes 2/2 tadalafil
PDE6 inhibition in the retina => vision changes
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
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
Name of selexipag trial
Phase 3 GRIPHON trial (PGI receptor agonist in pulmonary hypertension) NEJM 2015
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
Options for escalation in pts taking ERA/PDE5i
- 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 - Add prostacyclin pathway drug
-IIa recommendation
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
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
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
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)
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)
Risk of interruption or withdrawal of IV prostanoids
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
