PAH- Med Chem

Question 1

bosenten (Tracleer)

Answer 1

• pyrimidine/sulfonamide
• competitive antagonist
• t ½ life: 5 hrs
• Induces CYP 2C9
• liver injury & teratogenicity
• higher affinity for ETa than ETb
• can block bile acid transport in the liver (liver damage)
• produces an active metabolite

Question 2

ambrisenten (Letairis)

Answer 2

• pyrimidine/ CAA
• insoluble in water @low pH, solubility ↑ @ higher pH
• rapidly absorbed
• t ½ life: 9 hrs
• m: CYP 3A4, 2C19, & UGT’s
• teratogenic/ potential liver damage
• converting it to the salt form makes it more soluble
• > 77 fold for ETa selectivity
• ether cleavage: you’ll see the molecule in 2

Question 3

macitentan (Opsumit)

Answer 3

• pyrimidine/ sulfamide
• de-propylated to active metabolite
• teratogenic - nonselective antagonist for ETa and ETb
• lipophilc molecule
• active metabolite 40% of total activity

Question 4

sildenafil

Revatio

Answer 4

• purine derivative
• rapidly absorbed after PO
• t ½ life: 4 hrs
• CYP 3A (maj) & CYP 2C9 (min)
• pre-systemic metabolism => intestinal and 1st pass
• metabolite is less active that PD

Question 5

tadalafil

Adcirca

Answer 5

• PO admin
• t ½ life: 17.5 hrs
• metabolized by 3A4
• endol FG

Question 6

Nitric Oxide

INOmax

Answer 6

• unchanged gas for inhalation
• Short DOA: rapid metabolism to nitrate ion
• direct replacement for endo NO
• become ionized through metabolism

Question 7

riociguat

Adempas

Answer 7

• pyrimidine “NO-sGC-cGMP” activator
• CYP1A1 forms a less activate metabolite
• teratogenic
• plasma concentrations in smokers ↓ by 50-60%
• co-administration w/ CYP inhibitors may lead to hypotension
• can ↑ production of cGMP w/ and w/o NO being present

Question 8

epoprostenol

Flolan

Answer 8

• salt of prostacyclin
• reconstituted w/ glycine buffer @ pH 10-11
• stability:

Question 9

treprostinil

Remodulin

Answer 9

• synthetic and stable (5 yrs at RT)
• ROA: PO, inhalation, IV,SC
• rapidly absorbed (100 %BA)
• t 1/2 85 mins
• lipophilic molecule
• still a short acting molecule
• improvement from epoprostenol
• 5 metabolites are known but the metabolic enzymes are UNKNOWN

Question 10

iloprost

Ventavis

Answer 10

• synthetic analog of prostacyclin (PGI2)
• 16s isomer is 5x > 16 R
• dilates areterial vascular beds (sys & pulm)
• stable at RT (t ½ life: 30mins)
• M: β-oxidation to inavtive cmpds
• local activity: coats on lungs alveoli due to the liquid drug being inhaled
• sequential loss of acidic acid

Question 11

selexipag

Uptravi

Answer 11

• rapidly absorbed after PO and hydrolyzed to active metabolite
• PD and AM are highly protein bound
• metabolite is more potent than parent drug

Question 12

Pathways in PAH

Answer 12

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