Pulmonary Hypertension Drugs Flashcards
Prostanoids
Epoprostenol: MOA
• Mimics the actions of endogenous prostacyclin, compound that
- promotes vascular relaxation
- suppresses growth of vascular smooth muscle cells
- inhibits platelet aggregation
• Exerts these effects by binding to G-protein coupled receptor on cell membrane to generate cAMP
Prostanoids
Epoprostenol: Effects
- lowers pulmonary arterial resistance
- decreases pulmonary arterial pressure
• increases exercise
tolerance
• improves short- term survival
Prostanoids
Epoprostenol: Clinical Applications
PAH
Prostanoids
Epoprostenol: Pharmacokinetics
has very short half-life (~ 6 min) and must be given by continuous IV infusion with a pump that can keep the drug cold
Prostanoids
Epoprostenol: Toxicities
• Serious adverse effects:
- sepsis due to chronic catheter
- life-threatening problems if pump lines become clogged
• common side effects:
- nausea and vomiting (32%)
- headache (49%)
- flushing (58%)
- jaw pain
Prostanoids
Treprostinil: MOA
• Mimics the actions of endogenous prostacyclin, compound that
- promotes vascular relaxation
- suppresses growth of vascular smooth muscle cells
- inhibits platelet aggregation
• Exerts these effects by binding to G-protein coupled receptor on cell membrane to generate cAMP
Prostanoids
Treprostinil: Effects
- lowers pulmonary arterial resistance
- decreases pulmonary arterial pressure
• increases exercise
tolerance
• improves short-term survival
Prostanoids
Treprostinil: Clinical Applications
PAH
Prostanoids
Treprostinil: Pharmacokinetics
• Initially approved for continuous SUBCUTANEOUS INFUSION, BUT –> PAIN
- now, often diluted 1:2 and administered with pump IV similar to epoprostenol
- Has LONGER HALF- LIFE (~4 hrs) vs 6 min of epoprostenol, and DOESN’T REQUIRE REFRIGERATION
- qid inhalation form is now also available
Prostanoids
Treprostinil: Toxicities
• Serious adverse effects:
- sepsis due to chronic catheter
• Common side effects: - site pain with subcutaneous infusion (~85%) - jaw pain - diarrhea - edema - nausea
• if inhaled: cough (54%), headache (41%), throat irritation (25%), plus lower incidences of nausea, flushing and dizziness
Prostanoids
Iloprost: MOA
• Mimics the actions of endogenous prostacyclin, compound that
- promotes vascular relaxation
- suppresses growth of vascular smooth muscle cells
- inhibits platelet aggregation
• Exerts these effects by binding to G-protein coupled receptor on cell membrane to generate cAMP
Prostanoids
Iloprost: Effects
- lowers pulmonary arterial resistance
- decreases pulmonary arterial pressure
• increases exercise
tolerance
• improves short- term survival
Prostanoids
Iloprost: Clinical Applications
PAH
Prostanoids
Iloprost: Pharmacokinetics
Administered by INHALATION 6-9 times per
day
Prostanoids
Iloprost: Toxicities
• Serious adverse effects:
- fainting due to hypotension (especially if SBP < 85 mm Hg)
• Common side effects:
- cough (39%)
- headache (30%)
- flushing (27%)
- jaw pain (12%)
Prostanoids
Selexipag: MOA
• Mimics the actions of endogenous prostacyclin, compound that
- promotes vascular relaxation
- suppresses growth of vascular smooth muscle cells
- inhibits platelet aggregation
• Exerts these effects by binding to G-protein coupled receptor on cell membrane to generate cAMP
Prostanoids
Selexipag: Effects
- lowers pulmonary arterial resistance
- decreases pulmonary arterial pressure
• increases exercise
tolerance
• improves short- term survival
Prostanoids
Selexipag: Clinical Applications
PAH
Prostanoids
Selexipag: Pharmacokinetics **
- ADMINISTERED ORALLY, BID. **
* tablets are $225 ea, $350 ea for higher doses **
Prostanoids
Selexipag: Toxicities
• Common side effects:
- headache
- flushing
- diarrhea, nausea, vomiting
- jaw, limb, muscle pain
- skin rash
Endothelin Antagonist
Bosentan: MOA
NONSPECIFICALLY blocks ET(A) and ET(B) endothelin
receptors
Endothelin Antagonist
Bosentan: Effects
improves exercise
tolerance and slows symptom progression
Endothelin Antagonist
Bosentan: Clinical Application
PAH
Endothelin Antagonist
Bosentan: Pharmacokinetics
• oral drug
•~50% bioavailability in
presence or absence of food
• metabolized by liver, highly
protein-bound
Endothelin Antagonist
Bosentan: Toxicities
• Serious Adverse Effects:
- hepatotoxicity (11%,
potentially fatal)
- teratogenesis (FDA category X)
• Other Adverse Effects:
- headache, flushing, peripheral edema, nasal congestion, anemia and reduced sperm production
• Drug Interactions:
- Accelerates metabolism
- warfarin
- ORAL CONTRACEPTIVES… must use 2 forms of birth control
- Increases levels of many other drugs including cyclosporine or glyburide
Endothelin Antagonist
Ambrisentan: MOA
SELECTIVELY blocks ET(A) receptors, the
receptors that cause vasoconstriction and promote cell proliferation
Endothelin Antagonist
Ambrisentan: Effects
improves exercise
tolerance and slows symptom progression
Endothelin Antagonist
Ambrisentan: Clinical Applications
PAH
Endothelin Antagonist
Ambrisentan: Pharmacokinetics
Oral drug
Endothelin Antagonist
Ambrisentan: Toxicities
• Serious adverse effects:
- teratogenesis (FDA category X)
- (does not damage liver)
• Others include peripheral edema, nasal congestion, anemia and reduced sperm production
• Drug Interactions:
- Does NOT accelerate metabolism of warfarin and oral contraceptives, but still must use 2 forms of birth control
non-selective agent distinguished by ~18 hr half life that permits once/day dosing; cytochrome P450 effects similar to bosentan
macitentan
Phosphodiesterase Type V Inhibitors:
Sildenafil (Viagra): MOA
SELECTIVELY BLOCKS PHOSPHODIESTERASE TYPE V, enzyme that breaks down cGMP, an important intracellular mediator of smooth muscle relaxation
Phosphodiesterase Type V Inhibitors:
Sildenafil (Viagra): Effects
improves exercise
tolerance and slows symptom progression
Phosphodiesterase Type V Inhibitors:
Sildenafil (Viagra): Clinical Applications
PAH
Phosphodiesterase Type V Inhibitors:
Sildenafil (Viagra): Pharmacokinetics
oral drug, half-life ~ 4 hrs
Phosphodiesterase Type V Inhibitors:
Sildenafil (Viagra for ED and Revatio for PAH): Toxicities
- well tolerated, with headache, flushing and dyspepsia being most common
- rarely see priapism
- can also rarely cause visual disturbances (e.g., lack of color discrimination) and sudden hearing loss
- causes mild hypotension when used alone, but much greater drops are seen if used along with α-blockers for hypertension or nitrates for anginal pain
longer t1/2 than Sildenafil
Tadalafil
Phosphodiesterase Type V Inhibitors:
Riociguat: MOA
• Dual mode of action
- sensitizes soluble
guanylate cyclase (sGC) to endogenous nitric oxide (NO) by stabilizing the NO-sGC binding
- directly stimulates sGC independent of NO
- increased generation of cGMP –> increased vasodilation
Phosphodiesterase Type V Inhibitors:
Riociguat: Effects
improves exercise
tolerance and slows symptom progression
Phosphodiesterase Type V Inhibitors:
Riociguat: Clinical Applications
PAH, also type 4 PH
Phosphodiesterase Type V Inhibitors:
Riociguat: Pharmacokinetics
oral drug, half-life in
patients of ~ 12 hrs
Phosphodiesterase Type V Inhibitors:
Riociguat: Toxicities
- hypotension, headache, dizziness and dyspepsia are among the more common significant adverse effects; rarely see severe bleeding
- may cause fetal harm, so only available to women with negative pregnancy test and should avoid pregnancy for 1 month after stopping
- should not be administered with nitric oxide donors or type V phosphodiesterase inhibitors
- multiple potential drug interactions at both transporters and cytochrome P450
