850- Prostanoids drugs Flashcards
Prostanoids (Prostaglandin I_2 - Prostacyclin):
- Arachidonic acid is converted to PGI_2 in the vascular endothelium through a multi-step process involving prostacyclin synthase and COX.
- PGI_2 induces relaxation of vascular smooth muscle by stimulating the production of cyclic AMP (cAMP)
- In addition, it is a powerful inhibitor of platelet aggregation
- PGI_2 concentrations are decreased in PAH
Prostanoids: Epoprostenol (Flolan)
- Epoprostenol (PGI_2, prostacyclin), is a naturally occurring prostaglandin with potent vasodilatory activity and inhibitory activity of platelet aggregation
- Indicated for the long-term IV treatment of IPAH and PH associated with the scleroderma spectrum of disease in FC class III-IV patients who do not respond adequately to conventional therapy
Prostanoids: Epoprostenol Sodium
- (Flolan)
- Flolan: Administered via continuous IV infusion
- T1/2 ~6 minutes
- Requires indwelling central venous catheter
- Unstable at room temp (stable only for 8 hours), best kept cold during infusion (stable for 24 hours)
- Protect from light
> > Avoid abrupt discontinuation: Associated with symptomatic deterioration and perhaps death (within 20-30 minutes)
Prostanoids: Epoprostenol Sodium
- (Veletri)
- Veletri: more stable formulation of epoprostenol
- Stable for 48 to 72 hours depending on concentration
- Protect from light
> > Avoid abrupt discontinuation: Associated with symptomatic deterioration and perhaps death (within 20-30 minutes)
Prostanoids: Epoprostenol Sodium
Drug Interactions, and Contraindications
- Drug interactions:
- Risk of hypotension with antihypertensives
- Antiplatelets and anticoagulants increase risk of bleeding
- Increases digoxin concentrations - Contraindications:
- Heart Failure with preserved ejection fraction (HFrEF)
Prostanoids: Epoprostenol Sodium
Adverse Events
- Adverse events
- Headche (46%), jaw pain with mastication (75%), flushing (23%), diarrhea (50%), nausea, erythematous rash (25%), muscle aches and pains
- Delivery-related: sepsis, cellulitis, hemorrhage, and pneumothorax (4% for each)
Prostanoids: Treprostinil (Remodulin)
FDA-approved 2002
-A synthetic prostacyclin analogue
-Indicated for the treatment of PAH in patients with NYHA Class II- IV symptoms to diminish symptoms associated with exercise.
-Can be administered via continuous IV infusion or continuous SC infusion
»T1⁄2: 4 hours
Prostanoids: Treprostinil (Remodulin), FDA-approved 2002
Adverse events & Monitoring
- Adverse events:
1. For SC infusion: infusion site pain and infusion site reaction (redness and swelling). Often severe and could lead to treatment with narcotics or discontinuation
2. For IV infusion: line infections, sepsis, arm swelling, paresthesias, hematoma and pain were most common.
3. General side effects (>5% more than placebo): diarrhea, jaw pain, vasodilation, and edema. - Monitoring
1. AE’s, vitals signs, and PAH symptoms
Prostanoids: Treprostinil (Tyvaso®)
• Inhaled formulation, FDA-approved 7/2009
• Indicated for treatment of PAH, WHO Group 1, to improve exercise ability.
◦ Studied in mainly NYHA-FC III symptoms on background bosentan or sildenafil therapy.
Prostanoids: Treprostinil (Tyvaso®)
Adverse Effects
- Cough
- headache
- throat irritation
- nausea
- flushing
- syncope
- Bleeding
- hypotension
Prostanoids: Treprostinil (Orenitram®)
Indication and adverse effects
- Oral extended-release tablet, FDA approval 12/2013
- Indicated for PAH (WHO Group 1) to improve exercise capacity.
- Available in 0.125 mg, 0.25 mg, 1 mg, & 2.5 mg
- . Adverse effects: headache (63%), flushing (15%), nausea (30%), diarrhea (30%), hypokalemia (9%), jaw pain (11%).
Prostanoids: Treprostinil (Orenitram®)
Drug interactions & Patient counseling
- Drug Interactions
• Increased bleeding risk with anticoagulants
• Increased risk of hypotension with BP lowering drugs
• Strong CPY2C8 inhibitors (gemfibrozil), use 0.125mg starting dose - Patient counseling
• Abrupt discontinuation could result in worsening of PAH symptoms.
• Take with food.
• Swallow tablets whole. Do not split, chew, crush, or break. Do not take a tablet that is damaged or broken.
• The tablet shell remains intact during GI transit and is eliminated in the feces.
• Do not take with alcohol.
Prostanoids: iloprost
-Inhaled Iloprost (Ventavis®)
(Indication)
- A synthetic analogue of prostacyclin
- Indicated for the treatment of PAH (WHO Group I) in patients with NYHA Class III or IV symptoms.
- Administered via inhalation
- T1⁄2: 20–25 minutes
Prostanoids: iloprost
-Inhaled Iloprost (Ventavis®)
(Adverse Effects & Monitoring)
- Adverse effects
• vasodilation (flushing), cough, headache, trismus (lockjaw) and insomnia. - Monitoring
• AEs, vitals signs, and PAH symptoms
Non-prostanoid – IP prostacyclin receptor agonist: Selexipag (Uptravi®)
(Indication)
(Tablet, FDA approved 12/2015)
- Selective, non-prostanoid, IP prostacyclin receptor agonist.
• Structurally distinct from prostacyclin
• Hydrolyzed by carboxylesterase I to active metabolite
• Active metabolite is 37-fold as potent as selexipag
• Parent and metabolite metabolized by CYP2C8 and to lesser extent CYP3A4. - Indicated for PAH (WHO Group 1) to delay disease progression and reduce risk of hospitalization for PAH.
- Available in 200, 400, 600, 800, 1000, 1200, 1400, and 1600mcg tablets.
