pulmonary hypertension - sGC stimulators/ PDE inhibitors

NO is synthesized where, diffuses to what, what effect

endothelial cells; smooth muscle cells; vasodilation

when is inhaled NO used

in neonates with persistent hypertension / acute hypoxemic respiratory failure

endogenous NO production is reduced in what diseases (type)

type 1 PH; pulmonary HTN with connective tissue disease and interstitial lung disease

GC stimulators are approved for which types of HTN

I and IV

PDE5 inhibitors have been approved for which types of pulmonary HTN

type 1

GC does what and what effect does that have

GTP —> cGMP —> relaxation

what inactivates cGMP

PDE

vascular relaxation can be enhanced by what 3 things (all targeting NO pathway)

increasing NO bioavailability

activating / enhancing activity of GC

inhibiting breakdown of cGMP by PDE

organic nitrate vasodilators r used for what

increasing NO bioavailability to treat ANGINA

GC stimulators use for what

pulmonary hypertension

PED5 inhibitors r used for what

PH and erectile dysfunction

how many of these 3 drugs categories can u be on at once

just 1 otherwise risk for severe hypotension with any combo

riociguat therapeutics use / dosage form (what grps of PH)

oral; tx of group I (class II/III) PH and group IV chronic thromboembolic PH

riociguat moa

dual moa; sensitizes GC to endogenous NO and stimulates GC activity in absence of NO

riociguat dose frequency and half life

2-3 times daily; 12 hours

riociguat elimination (where and what form)

liver and kidney as metabolites (not patent drug)

riociguat BBB

potential to cause birth defects if taken when preggo

riociguat other AE’s from MOA

follow from vasodilation mech: hypotension, syncope

riociguat AE’s other

headache, dyspepsia, edema, nausea

SAR: riociguat to vericguat what parts of molecule changed (2)

changes to bicyclic core

terminal carbamate: terminal O-methyl NH-carbamate is not only grp with good sGC stimulation but it does have longest half life

verociguat therapeutic use and dosage form

oral; to reduce risk of mortality and morbidity from HFrEF or HFpEF (post-HF hospitalization)

verociguat moa

dual moa: sensitizes GC to endogenous NO and stimulates GC activity in the absence of NO (same as riociguat)

verociguat dose frequency and half life

once a day; 30 hours

verociguat elimination where and what form

liver: parent

kidney: metabolite

sildenafil therapeutic use and dosage form (2)

oral/ IV; tx of group 1 (class II and III) PH

sildenafil and epoprostenol tog do what

slow disease progression

dosage form and use of viagra

oral; ED

sildenafil dose frequency and dose

3 times daily

5-20 mg

circulating major metabolite name and activity

des-methyl sildenafil ; provides 20% of PH efficacy

sildenafil ADME was optimized for what indication

ED; 50-100 mg 1 hour before sexual activity

can pediatrics use sildenafil

no mortality observed

sildenafil adverse effects

epistaxis (nose bleeds), headache, dyspepsia, flushing, insomnia, erythema, dyspnea, rhinitis

sildenafil causes what weird color thing and why

transient impairment of telling blue and green apart bc of inhibition of retinal PDE6

taldalafil therapeutic use and dosage form

oral/IV for tx of group I (class II and III) PH

what’s cialis dosage form, indication, and relation to taldalafil

brand name ; oral for ED and BPH

taldalafil adme was optimized for what indication and dose frequency

PH ; once daily (40mg)

taldalafil ED dose

2.5-20 mg daily

taldalafil AE’s and difference from sildenafil AE’s

same as sildenafil BUT no visual impairment bc more selective for PDE5 instead of PDE6

SAR sildenafil to tadalafil what changed

sildenafil: 2 hydrogen bonds

tadalafil: 1 hydrogen bond

sildenafil bs tadalafil PDE5 vs PDE6 selectivity

sildenafil: 16 fold more selective for 5 vs 6

tadalafil: 200 fold more selective for 5 vs 6