Block 1 - Cystic Fibrosis + PAH Pharmacology Flashcards
List the ideal therapies of CF?
- Airway clearance
- GI enzyme and nutritional supplements
- Control inflammation
- CFTR correctors and patentors
- Lung/organ transplants
Can you replace only one lung?
No you need to replace both cause they both contain infection
How can drugs help with airway clearance?
- ALbuterol
- Hypertonic Saline (Hypersal) Neb
- Dornase alfa (Pulmozyme)
- NAC (Mucosal)
- Chest physiotherapy
- ICS, LABA, Inhaled antibiotics
What help with GI enzymes and nutrition?
- PERT
- PPI or H2 antagonist
- ADEK
- Electrolyte replacement
- High calorie/fat diet
How would you control inflammation in CF?
- OCS (benefit needs to outweigh the risk)
How does albuterol help with airway clearance?
Proventil allows bronchodilation and increase ciliary efficacy
How does hypertonic saline help with airway clearance?
Hyper-sal hydrates the lung surface
How does dornase help with airway clearance?
Pulmozyme is a recombinant human deoxyribonuclease that breaks down DNA in the sputum decreasing its viscosity
How does N-acetycysteine help with airway clearance?
Mucosal is a mucolytic that thins out and dissolves lung mucus
How does chest physiotherapy help with airway clearance?
- Postural drainage and percussion
- High frequency chest wall oscillation (vest)
What drugs can be used to clear airways for CF?
ICS, inhaled LABA, inhaled antibiotics
How does CF affect mucous?
- Salt transport dehydrates mucous causing it to become sticky and thick
How do you resore airway surface liquids? MOA?
Bronchitol (Mannitol) is a dry powder rehydrates airways and lungs promoting productive coughing (modest effect)
What is the difference between CFTR correctors and potentiators?
C: Facilitates the folding and presentation of the mature CFTR protein increasing the trafficking of CFTR proteins to the outer membrane
P: Facilitates Cl- transport by increasing CFTR channel effect increasing the probability of Cl- channels opening
What are examples of CFTR Correctors?
- Lumacaftor
- Tezacaftor
- Elexacaftor
What are examples of CFTR potentiators?
- Invacaftor
What is the MOA of ivacaftor?
Kalydeco facilitates Cl- trasport by increasing its CFTR effectiveness to increase Cl- channel opening
Who qualifies for Kalydeco? Dose?
2 or older, with 1 mutation (G551D)
150 mg PO BID w/ fatty foods
What are the ADRs of Kalydeco?
Ivacaftor: Abdominal pain, increased hepatic enzymes, HA, URTI, congestion, nausea, rash rhinitis, dizziness, arthralgia
What is the MOA of Orkambi? Age of patients?
Lumacaftor+Ivacaftor stabilizes F508del-CFTR in proving folding of the protein (Luma) -> processing and trafficking of mature protein cell surface
6 YO w/ 2 copies of F508 del mutation
What is the Symdeko MOA? Age of patients?
Tezacaftor+Ivacaftor is a corrector
12 YO w/ 2 copies of F508del mutation or at least 1 mutation in CFTR gene responsive to therapy
How does Orkambi’s combo promote its efficacy
Lumacaftor allows more CFTR to reach the surface while Ivacaftor keeps the CFTR Cl- channel open
What is the MOA of Ivacaftor?
Allow more chloride ions to pass in and out the cells helping keep a balance of salt and water in organs (lungs)
What is the ADR of Luacaftor/Ivacaftor
Orkambi brings chest discomfort, dyspnea, respiratory discomfort requiring liver toxicity monitoring
What are the ADRs of Tezacaftor/Ivacafotor?
Symdeko brings nausea, HA, sinus congestion, DIOS, cataracts requiring liver toxicity monitoring
Trikafta qualifications for treatment?
Elexacaftor/tezacaftor/ivacaftor require patients to have at least 1 f508del mutation or at least one other mutation responsive to drug (e and t, correctors; i, potentiator)
Describe the outcomes and disadvantages of using CFTR modulators?
- Don’t cure or restore full function of protein
- Effective in relieving symptoms increasing lifespan
What are disadvantages of the elexacafotr/texacaftor/ivacaftor combo?
Expensive
What is another treatment alternative to no CFTR protein CF?
Gene therapy
What is the goal of gene therapy for CF?
Replace the defective CF gene in the lungs to cure CF or slow the progression of the disease
How is gene therapy administered? Barriers?
Inhaling a spray that delivers normal DNA to the lungs
Involve delivery of vectors
What are the goals of treating PAH?
- Alleviate symptoms, improve exercise and quality of life
- Improve cardiopulmonary hemodynamics and prevent RVHF
- Delay time to clinical worsening
- Reduce morbidity and mortality
What are the targets of PAH therapies?
- Prostaglandin pathways
- Endothelin pathways
- NO pathway
- Vasodilators and anticoagulants
What are therapeutic classes for PAH?
- Prostaglandin analogs
- Endothelian receptor antagonist
- PDEi
- Soluble guanylate cyclase stimulator (sGC)
- Calcium channel antagonists
What are prostacyclin receptor agonist MOA?
Bind to prostaglandin I2 receptor targeting 3 of the pathologic changes that occur in PAH
1. Vasodilation
2. Inhibits Platelet aggregation
3. Inhibits smooth muscle proliferation
4. Inotropic effects
What are the prostacyclin analogs? Dosage forms?
- Epoprostenol (Flolan, Veletri) - IV
- Treprostinil (Remodulin - IV, SC; Tyvaso - INH; Orenitram - Oral)
- Iloprost (Ventavis - INH)
- Selexipag (Uptravi - Oral)
What are some endothelin receptor antagonists? Dosage forms?
- Bosentan (Tracleer - PO)
- Macitentan (Opsumit - PO)
- Ambrisentan (Letairis - PO)
What are the PDE5is? Dosage forms?
- Sildenafil (Revatio - PO)
- Tadalafil (Adcirca - PO)
What are examples of soluble guanylate cyclase stimulators? Dosage forms?
Riociguat (Adempas - PO)
What are examples of CCBs?
- Amlodipine (Norvasc)
- Diltiazem (Cardizem, Tiazac)
- Nifedipine (Adatta, Procardia)
What is the difference between the brands of Treprostinil?
Dosage forms
What is the MOA of Iloprost? How is it eliminated? ADRs?
Ventavis
Synthetic drug of prostacyclin
70% in urnine and 10% feces
Cough, flushing, jaw pain, syncope
How does Uptravi differ from other prostacyclin receptor agonists? CIs?
Selexipag is a prodrug metabolizes by the liver to activate, 13 fold affinity higher at the IP receptor and half life of 8hr
CYP2C8 inhibitors
What is the MOA of epoprostenol?
Derivative of PGI2 that causes vasodilation and platelet aggregation inhibiton
How is epoprostenol absorbed?
- Requires central venous circulation to achieve selective pulmonary vasodilation and a portable infusion pump
- Due to 6 minute half life
How do endothelial cells play a part in the pulmonary vascular structure? Mechanism?
Produce vasoconstrictors and catalyzes conversion of angiotensin 1 -> 2
ET-1 and TXA2
Differentiate the 2 endothelial vasoconstrictors? What do they do?
ET1: potent, prolonging vasoconstriction, increasing vascular tone and PVR
TXA2: Stimulates platelet aggregatio -> thrombosis and increased PVR
Differentiate the 2 endothelial vasoconstrictors? What do they do?
ET1: potent, prolonging vasoconstriction, increasing vascular tone and PVR
TXA2: Stimulates platelet aggregatio -> thrombosis and increased PVR
What is the function of Endothelian 1 antagonists?
Target ET1 by blocking receptors on endothelium and vascular smooth muscle
What is the MOA Bosentan? How is it administered? ADRs?
Tracleer is a ompetitive antagonist of ETA and B, CYP2C9 and 3A4
PO BID
Hepatic toxicity, teratogenicity
What is the MOA of Macitentan? How is it different than Tracleer? ADRs?
Opsumit is competitive at ETA and B and has less hepatoxicity
QD
Teratogenicity
What is the MOA of Ambrisentan? Administration? ADRs?
Letairis is competitive specific ETA blocker
PO QD
Hepatic toxicity and teratogenicity
What is the Black bow warnings associated with ET1 antagonists
Teratogenicity
What is the function of PDE5? Where are they found?
Regulates intracellular cGMP in the arterial walls
What is the MOA of PDE5i in general?
Inhibiting PDE5 facilitating the effect of NO increasing cGMP levels and relaxing pulmonary vascular smooth muscle
Increases blood flow to heart
What are reported ADRs of PDE5is? CIs?
HA, congestion, cardiac events, HTN
Nitrates
Describe the mechanism of soluble guanylate cyclase?
- NO binds to sGC mediating synthesis of cGMP
- cGMP-dependent protein kinase (PKG) increases cytosolic calcium ion concentrations -> decreased actin-myosin contractility -> vasodilation
How is sGC affected in PAH patients?
No synthase -> lower endothelial cell-derived NO -> reduced vasodilation
What is the MOA of Adempas? ADRs?
Stimulate sGC activity independent of NO increasing cGMP -> vasodialtion
Can cause brith defects and can only be prescribed through the Edemas REMS program
What drug classes are sometimes combined for PAH treatments? Why are they considered beneficial? Cons?
PDE5 and ERA
Enhance efficacy and compliance
Increase ADRs