Pulmonary Pharmacology 2 Flashcards
targets for drug therapy of pulmonary arterial hypertension
- endothelin-1 pathway
- prostacyclin (PGI2) pathway
- nitric oxide pathway
PH tx: nitric oxide (NO) - MOA
*activates guanylyl cyclase to increase cGMP in vascular smooth muscle (receptor for NO is sGC [soluble guanylate cyclase])
*pulmonary VASODILATOR:
-increased blood flow to lung and decreased pulmonary vascular resistance
-reduced pulmonary artery pressure and improved perfusion of ventilated areas of the lung
nitric oxide (NO) - uses
*cardiac surgery
*variety of pediatric respiratory conditions
*ARDS?
*pulmonary arterial hypertension?
nitric oxide (NO) - ADEs
*hypotension
*methemoglobinemia
*note - not used much in pulmonary hypertension due to difficultly in administration
Riociguat - drug class, MOA
*drug class: oral “guanylate cyclase stimulant” (sGC stimulator)
*MOA: increases cGMP → vasodilation
-directly stimulates the nitric oxide receptor (sGC)
-increases the sensitivity of sGC to endogenous NO
Riociguat - ADEs
*hypotension
*dizziness
*headache
*contraindicated in pregnancy
Riociguat - uses
*pulmonary arterial hypertension
PDE-5 inhibitors (phosphodiesterase 5 inhibitors) - MOA, examples
*MOA: inhibits PDE-5 → increased cGMP → smooth muscle relaxation → increased blood flow
*examples: sildenafil, tadalafil
*ADEs: flushing, headache, indigestion, nasal congestion, insomnia
*contraindicated in patients on nitrates or riociguat
sildenafil - drug class, MOA, ADEs
*drug class: PDE-5 inhibitor
*MOA: inhibits PDE-5 → increased cGMP → smooth muscle relaxation → increased blood flow
*used for pulmonary hypertension
*ADEs: flushing, headache, indigestion, nasal congestion, insomnia
*contraindicated in patients on nitrates or riociguat
tadalafil - drug class, MOA, ADEs
*drug class: PDE-5 inhibitor
*MOA: inhibits PDE-5 → increased cGMP → smooth muscle relaxation → increased blood flow
-used to treat pulmonary hypertension
*ADEs: flushing, headache, indigestion, nasal congestion, insomnia
*contraindicated in patients on nitrates or riociguat
prostaglandins & prostacyclin analogues to treat pulmonary arterial hypertension
*prostacyclin (PGI2) lowers peripheral, pulmonary, and coronary vascular resistance
*examples: esoprostenol (PGI2), trepostinil, iloprost, selexipag)
*ADEs: flushing, headache, hypotension, dizziness, bleeding (inhibits platelet aggregation)
endothelin receptor antagonists
*endothelin-1 (ET-1) is a potent vasoconstrictor
*there is increased ET-1 in PAH, so we want to block the receptor
*MOA - competitively antagonize endothelin-1 receptors → decreased pulmonary vascular resistance
*examples: bosentan, macitentan, ambrisentan
*ADEs: HEPATOTOXICITY, peripheral edema, flushing, contraindicated in pregnancy
categories of therapies for pulmonary hypertension
*endothelin receptor antagonists
*PDE-5 inhibitors
*prostacyclin analogs
drugs used for treatment of fibrotic interstitial lung diseases
*pirfenidone
*nintedanib
*azathioprine
*mycophenolate
*tocilizumab
*methotrexate, rituximab, cyclophosphamide
*adalimumab, abatacept
*infliximab
algorithm for management of pulmonary fibrosis
- glucocorticoids
- prophylaxis for PCP (TMP-sulfa)
- other anti-inflammatories
- antifibrotic agents
- non-pharmacologic treatments (supplemental oxygen, psychosocial support, smoking cessation, end-of-life care)
nintedanib - drug class, MOA, ADEs
*drug class: antifibrotic agent used in pulmonary fibrosis
*MOA: KINASE INHIBITOR that prevents proliferation, migration, and transformation of fibroblasts in the lungs
*reduces annual FVC decline and # of acute exacerbation
*ADEs: diarrhea, increased LFTs, cannot use if fully anticoagulated
pirfenidone - drug class, MOA, ADEs
*drug class: antifibrotic agent used in pulmonary fibrosis
*MOA: not clearly known; inhibits various growth factors and cytokines; anti-fibrotic effect
*ADEs: rash, PHOTOSENSITIVITY, increased LFTs, lots of CYP450 drug interactions
azathioprine - drug class, MOA, ADEs
*drug class: purine antimetabolite (derivative of 6-mercaptopurine) used in pulmonary fibrosis and others
*MOA: reduces intracellular purine nucleotide synthesis; decreased numbers of T and B lymphocytes
*ADEs: bone marrow suppression, pancreatitis, teratogenic
*do NOT give with allopurinol or febuxostat
mycophenolate mofetil - drug class, MOA, ADEs
*drug class: IMP inhibitor; drug for interstitial lung disease and transplants
*MOA: inhibits Inosine Monophosphate Dehydrogenase (IMP), which inhibits de novo purine synthesis; blocks proliferation of T and B lymphocytes
*ADEs: nausea, diarrhea, constipation, leukopenia, teratogenic
tocilizumab - drug class/MOA
IL-6 inhibitor
pulmonary embolism treatment
anticoagulants!
big picture treatment differences in lung cancers
*small cell lung cancer: chemo (surgery is difficult because it is usually disseminated at presentation)
*non-small cell lung cancer: surgical resection is best chance if caught early; some have sensitive mutations that can be treated with targeted chemo
Small Cell Lung Cancer - treatment regimen
*cisplatin + etoposide or carboplatin + etoposide
Non-Small Cell Lung Cancer - treatment regimen
*resect if you can
*most chemo regimens have a backbone of cisplatin or carboplatin
*PD-1/PD-L1 inhibitors are playing an expanding role
*use other agents to target various mutations and other tumor characteristics if present
platinums (cisplatin & carboplatin)
*traditional chemotherapy
*MOA: cross-link DNA (cell-cycle nonspecific)
*ADEs:
-cisplatin: NEPHROTOXICITY, N/V
-carboplatin: neurotoxicity, vomiting, hypersensitivity
-oxaliplatin: peripheral neuropathy
ironotecan
*topoisomerase I inhibitor
*class: camptothecin
*ADEs: SEVERE DIARRHEA, myelosuppression
etoposide
*topoisomerase II inhibitor
*class: epipodophyllotoxins
*ADEs: myelosuppression
programmed cell death protein 1 (PD-1) & PD-Ligand-1 (PD-L1) inhibitors - why do these work?
*we have a “checkpoint” to keep T cells from attacking normal cells: PD-1 ligands interact with PD-1 (receptor) to downregulate T cell activation
*many tumors express PD-1 ligands and inactivate T cells from killing the tumor cells
*interrupting this PD-L1/PF-1 interaction removes the inhibition of T cells, restoring their anti-tumor immune response
*our medications are antibodies to either PD-1 or PD-L1
PD-1 receptor blockers used in lung cancer
*pembrolizumab
*nivolumab
PD-L1 ligand blockers used in lung cancer
*atezolizumab
*durvalumab
PD-1/PD-L1 inhibitor toxicities
*derm: rash, vitiligo
*diarrhea, colitis
*pneumonitis
*fatigue
*anemia
*cardiotoxicities (including myocarditis)
4 drugs used for tuberculosis
- isoniazid
- rifampin
- ethambutol
- pyrazinamide (PZA)
isoniazid - MOA, ADEs, info
*part of the regimen for treating TUBERCULOSIS
*MOA: inhibits mycolic acid synthesis, which interferes with cell wall synthesis
*it is a prodrug (resistance can occur)
*metabolized by ACETYLATION (there is a lot of genetic diversity to see how fast they can do this)
*inhibits CYP450
*ADEs: HEPATOTOXICITY, peripheral neuropathy, ataxia, paresthesia, rash, fever, drug-induced SLE, myelosuppression
rifampin - MOA, ADEs, info
*part of the regimen for treating TUBERCULOSIS
*MOA: block RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase
*metabolized by the liver
*ADEs: orange/red discoloration of body fluids, GI, flu-like syndrome, derm reactions, hepatitis
*POTENT INDUCER OF CYP450 (need to look over every med before giving)
ethambutol
*part of the regimen for treating TUBERCULOSIS
*ADEs: OPTIC NEUROPATHY, hepatotoxicity, GI
pyrazinamide
*part of the regimen for treating TUBERCULOSIS
*ADEs: hepatotoxicity, inhibits uric acid excretion, GI, etc
TB treatment regimen: latent infection
*rifampin for 4 months
TB treatment regimen: active infection
*INH + rifampin + ethambutol + PZA for 2 months
*INH + rifampin for 4 more months
