Drugs Flashcards
DMARDs
RA
Disease modifying anti-rheumatic drugs
immunosuppressive agents with goal of inducing/maintaining remission - all oral
methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, azathiopurine
“My Lucky Sister Has Arthritis”
Biologics
RA
newer, made by molecular biologic techniques
targets cytokines, T cell activation and depletion of B cells
Anakinra, TNF inhibitors (etanercept, adalimumab, certolizumab, golimumab, infliximab), Abatacept, Tocilizumab, Tofacitinib, Rituximab
ATATTR (ATT totally rules)
TNF inhibitors
RA
pro-inflammatory cytokine
produced by macrophages
reduces joint inflammation and damage to joints
Etanercept (Enbrel): subcutaneous; binds TNF and blocks its interaction with receptors
Adalimumab (Humira): subcutaneous; human monoclonal antibody directed against TNF
Certolizumab (Cimzia): subcutaneous; Fab fragment of a humanized monoclonal antibody directed against TNF
Golimumab (Simponi): subcutaneous; human monoclonal antibody directed against TNF
Infliximab (Remicade): infusion; chimeric monoclonal antibody directed against TNF
methotrexate
first line treatment; give folic acid to prevent side effects
RA
increases adenosine release from cells which can dampen cellular inflammation
inhibits dihydrofolate reductase (why need to give folate)
side effects: oral ulcers, nausea, cytopenias, liver toxicity
NOT FOR PREG. WOMEN -> induces abortions
dose: 15-25mg/week
leflunomide
RA
inhibits pyrimidine synthesis which leads to reduction of lymphocytes
is a pro-drug; enterohepatocyte circulation leads to long half life
side effects: diarrhea, cytopenias, liver toxicity
DO NOT GIVE TO PREG WOMEN
sulfasalazine
RA
sulfapyridine is active moiety; mechanism of action not known
side effects: rash, GI upset, hepatotoxicity, cytopenias
hydroxychloroquine
RA
mildest; also used for SLE
inhibits activity of TLRs and acidification of lysosomes ultimately interfering with antigen processing
side effects: rare retinal toxicity
azathiopurine
RA
pruine synthesis inhibitor
not often used due to side effects: cytopenias, rash, GI upset, pancreatitis
Etanercept (Enbrel)
RA
subcutaneous; binds TNF and blocks its interaction with receptors - is a fusion protein of TNF receptor linked to Fc portion of IgG
The only TNF that is not a monoclonal antibody
Adalimumab (Humira)
RA
subcutaneous; human monoclonal antibody directed against TNF
Certolizumab (Cimzia)
RA
subcutaneous; Fab fragment of a humanized monoclonal antibody directed against TNF
Golimumab (Simponi)
RA
subcutaneous; human monoclonal antibody directed against TNF
Infliximab (Remicade)
RA
infusion; chimeric monoclonal antibody directed against TNF
Anakinra
RA
antagonist of IL-1 receptor
does not work very well but is FDA approved
Abatacept
RA
Binds CD90/86 on APCs blocking the interaction of CD28 between APCs and T cells
blocks the costimulation of T cells -> blocks T cell activation which are the center cells of pathogenesis
prevents joint damage and inflammation; short and long term benefits
Tocilizumab
RA
humanized monoclonal antibody targeting IL-6 receptor
reduces inflammation and joint damage -> helps to prevent natural history of RA
Rituximab
RA
monoclonal antibody directed against CD20 antigen on B lymphocytes -> depletes B cells but NOT existing plasma cells
also works for B cell cancers
Tofacitinib
RA
inhibits JAK enzymes, which prevents cytokine/growth factor mediated gene expression and intracellular activity of immune cells
target synthetic DMARD
oral
totally different pathway that is early in the disease pathogenesis
triple therapy
for RA: methotrexate, sulfasalazine, hydroxychloroquine
NSAIDs vs Glucocorticoids
NSAIDs: block cyclooxygenase (COX)…very specific
GC: block phospholipase A2 (PLA2) and some can affect COX
what is the molecular path to inflammation?
phospholipids (cell membrane) —- phospholipase A2 (PLA2) —> Arachidonic Acid —– cyclooxygenase (COX) —-> prostaglandin H2 (PGH2), which are pro-inflammation mediators
anti-inflammatory goals
reduced prostanoid synthesis
anti-nociceptive
desensitization of nociceptors…NSAIDs help to block pain
antipyretic
block hypothalamic triggers for fever
antithrombotic
inhibition of platelet aggregation (decrease TXA2)
mostly use aspirin…81mg-325mg/day
fetal circulation
closure of patent ductus
prostaglandins are important for maintaining the ductus arteriosus
clinical use of NSAIDs vs GCs
NSAIDs: inflammation, pain, fevers, migraines, dysmenorrhea (menstrual cramping), to close the patent ductus arteriosus, cardioprotection (aspirin), flushing (mast cell degranulation)
GCs: immune reaction-related inflammation, acute and chronic autoimmune disease (low doses), organ transplantation (high doses), modulates inflammation and immune function, but has serious side effects with chronic use
COX isozyme distribution
COX1: GI tract mostly…esophagus, stomach, intestines, liver, pancreas, kidney and platelets; constitutively expressed
COX2: brain, kidney, bone, pancreas, female reproductive tract, vascular endothelium; induced esp in inflammatory conditions
COX selectivity
COX1: homeostatic functions - selective, irreversible inhibition of COX1 is basis for cardioprotective effects of low-dose Aspirin; promotes vasoconstriction and platelet aggregation
COX2: inflammation - selective inhibition of COX-2 results in an increase in risk of CV death; promotes vasodilation and inhibits platelet aggregation
most of COX1 have some affinity for COX2, but since COX2 has a hydrophobic binding pocket not all of COX2 will work for COX1
aspirin and its interaction with COX
aspirin reacts with serine residues on COX1 and COX2 so it actually irreversibly inhibits the enzyme by adding an acetyl group via a covalent bond
NSAIDs and aspirin will compete for the COX bonding site and aspirin will win. so give aspirin before NSAID so as to gain the cardiac prevention effects and still get the pain reliever
thought that naproxen may be least likely NSAID to compete with aspirin
side effects of cox selective drugs
COX1 selective: ulceration; other GI complications
COX2 selective: thrombotic event, CHF/HTN, other CV complications
best nsaid for viral infection
acetiminophen; avoid aspirin and salicylates in pediatric patients
approved NSAIDs
cox2: celecoxib
cox1: aspirin, ibuprofen, indomethacin, ketorolac, naproxen, meloxicam
celecoxib
only cox2 inhibitor on market
aspirin
cox1 inhibitor; irreversible and covalent inhibitor; low-dose cardioprotective dosing
not typically used at higher anti-inflammatory dosing
ibuprofen
most common; cox1 inhibitor
ketorolac
cox1 inhibitor; used for post-operative pain; high risk of GI ulceration
limit use to 5 days per prescriber labeling
IV
meloxicam
cox1 inhibitor (relative COX-2 selectivity); convenient once daily dosing; use for chronic NSAID therapy
dosing for anti-inflammatory vs analgestic effect for ibuprofen and naproxen
ibuprofen
- anti-inflammatory: 2400-3600 mg/day
- analgestic: 1200-1600 mg/day
naproxen
- anti-inflammatory: 1000 mg/day
- analgestic: 440 mg/day
complications of NSAID use with methotrexate
with high doses of methotrexate in combination of NSAIDs, the kidneys cannot secrete the methotrexate
so can use NSAIDs with RA treatment but not for cancer treatment IF methotrexate is being used
complications of NSAID use with methotrexate
with high doses of methotrexate in combination of NSAIDs, the kidneys cannot secrete the methotrexate
so can use NSAIDs with RA treatment but not for cancer treatment IF methotrexate is being used
acetaminophen
NOT and NSAID
reduce fever and help with mild pain
be cause of use with ethanol -> can get hepatotoxicity with overdose or high daily doses (> 4 g/day)
once damage is done it is irreversible
general effects of cortisol
genomic: upregulate genes involved in inflammation (can cross into nucleus very easily
non-genomic: interact with other signaling pathways: inhibits NF-kB, IL-1, MAPK and Annexin I (activates Annexin I which inhibits activation of AA metabolism)
general effects of cortisol
genomic: upregulate genes involved in inflammation (can cross into nucleus very easily
non-genomic: interact with other signaling pathways: inhibits NF-kB, IL-1, MAPK and Annexin I (activates Annexin I which inhibits activation of AA metabolism)
GC high dose short term use side effects
hyperglycemia NA+/H2O retention hypertension insomnia, behavioral changes WBC increase with L shift (increased bands, decreased other WBCs) increased appetite and weight gain gastritis, GI bleed, pancreatitis
gc long term use side effects
cushing's syndrome (moon face/buffalo hump...fat redistribution) potential addisonian crisis with stress increased risk of infection impaired wound healing, acne, thinning of skin cataracts, glaucoma osteoporosis growth impairment mscle weakness withdrawal: myalgia, athralgia, malaise
mineralcorticoid effects
hydrocortisone > prednisone > dexamethasone
more potent glucocorticoid = less minearlocorticoid effect
fludrocortisone is potent minearlocorticoid
dosing of GC
try to replicate normal circadian levels
2/3 in am and 1/3 at 4 pm
drug interactions with GC
susceptible to drug-drug interactions through CYP3A4 (ie they inhibit CYP3A4)
proton pump inhibitors (omeprazole) or histamine-2 receptor antagonists in high doses (famotidine) may reduce GI side effects
ipilimumab
anti-CTLA-4
so binds to CTLA-4, thus inactivating it so that B7 can bind to CD28 and turn on the T cells
use for cancer, metastatic carcinoma
abatacept
Ig-CTLA-4
intercepts the B7…so it binds to the B7 on APCs which means that the T cell cannot be activated
Nivolumab
anti-PD-1
blocks tolerance -> PD-1 is an inhibitory co-receptor on T cells…blocking PD-1 means keeping the t cell turned on
melanoma
Sipleucel-T
dendritic cell vaccine
cells incubated with PAP
prostate cancer
