anti-inflammatory biological agents and corticoids Flashcards
- what are goals of RA therapy?
- what are non-pharmacologic therapies?
goals of RA therapy
stop inflammation
relieve symtpoms
prevent joint and organ damage
nonpharmacologic therapies
patient education
rest
physcial therapy
occupational therapy
nutrition and dietary therapy
bone protection
cardiovascular risk reduction
vaccination
- what is the drug of choice for additional pain relief if required?
- what are benefits of NSAIDs?
acetaminophen
NSAIDs are the drug of first choice for RA due to effcacy and rapid onset of action
benefit derive from primarily anti-inflammatory action, but also pain relief
either 1st generation (aspirin and other NSAIDs that inhibit COX-1 and COX-2 (naproxen) or second generation COX-2 inhibitor celecoxib can be used
but does not alter disease progression
hydrocotisone--> prednisolone–> nonfluorinated prednisolones or fluorinated prednisolones
which drugs are in the nonfluorinated vs the fluroinated?
what is the benefit of glucocorticoids and the adverse effects?
non-fluorinated prednisolones
-methylprednisolone
fluorinated prednisolones
- Betamethasone
- Dexamethasone
- Triamcinolone
NOTE: adding F increases potency and half-life
benefits
suppress inflammation, inhibit antigen presentation, cytokine production and lymphocyte production
causes
lymphocytopenia (redistribution to lymph node)
monocytopenia due to resdistribution
neutrophilia
eosinopenia
PLA2 blokade, decreases eicosanoid synthesis
decreased IL-1 production, loss of T-cell responsiveness to IL-2
many adverse effects includes
psychosis, impaired glucose tolerance, salt/water retention, osteoporosis, increased susceptibility to opportunistic infections, truncal obesity, buffalo hump, striae, acne, hirsutism
NOTE: remember that abruptly stopping exogenous glucocorticoids rather than discontinuing them slowly can be deadly, but stopping is not an option to those with endogenous glucocorticoid excess
in sicker patient, predisone is frequently added for a short period to regimen for rapid minimize disease activity while awaiting clinical response to slower-acting DMARD (disease modifying anti-rheumatic drug)
when used for < 1 month, glucocorticoids are more effective than either placebo or an NSAID
glucocorticoid are effective for < 6 months
generally should not be used chronically without concurrent DMARD…dose 5mg/day can be taken without adverse effect but no reduction in disease progression due it causing Cushings
MOA: glucocorticoid receptor complexing with NF-kB and AP1 transcription factors is a major indirect mechanism for immunosuppression
lipocortin, an inhibitor of PLA2 is among the genes activated
Treat autoimmune disease like RA
to relieve pain and inflammation while awaiting DMARD effects. treat flare
can be given PO, IM, intra-articularly
nonbiologic DMARDs:
inhibitor of dihydrofolate reductase with loss of TH4 causing a thymineless death
MOA: undergoes polyglutamation–> that accumulates in cells over multiple weeks, also blocks thymidylate synthase and 5-aminoimidazole-4-carboxamide ribonucleotide (AICR) transformylase
resulting AICAR accumulation leads to a_densoine efflux_, which binds to purinergic GPCRs to exert anti-flammatory effects
effects are faster than other DMARDs (3-6 weeks)
works for 80% of patients
clinical application: drug of choice for RA, can be used in combo with other DMARDs and often continued when patients are switched to biologic DMARDs
can be given oral or injection
toxicities:
low dose used in immunosuppression is well-tolerated, but take weekly folate
high dose causes bone marrow suppression, GI ulceration, pneumonitis, hepatic fibrosis
can cause fetal death and congenital abnormalities
Methotrexate- can block purine synthesis and thymidine synthesis
nonbiologic DMARDs:
MOA: lipophilic weak base, the free base form can accumulate in lysosomes increasing the pH of lysosomes
effects: higher pH in lysomal vesicles in APC l_imits association of peptide to class 2 MHC_ in compartment for peptide loading prior to transport to cell membrane
can slow disease progression, but has a delayed onset (3-6 months)
clinical application
antimalarial
can be first choice for mild RA with lack of poor prognostic features
often combo with methotrexate +/- sulfasalazine to attempt control of severe RA
also used in lupus
safe in pregnancy
half-life is 23 days
use loading dose
toxicities: retinal damage (low dosage carries little risk)
hydroxychloroquine
nonbiologic DMARDs:
MOA: 30% rapidly absorbed by small bowel to undergo enterohepatic circulation, metabolized to 5-ASA and sulfapyridine (active in RA) unlike in IBD where is its 5-ASA
clincal application
for RA, used alone or in combo with hydroxychloroquine and or methotrexate (triple therapy)
ok to used to pregnancy, less studies, no obvious risk
toxicities: GI side effects is most common (D/C with N/V diarrhea, abdominal pain)
inhibit folic absorption (supplement required)
a sulfa drug- pruritis, rash, urticaria
serious effects: hepatitis or bone marrow suppression are rare
sulfaslazine
nonbiologic DMARDs:
MOA: inhibition of dihydroorotate dehydrogenase to block the synthesis of pyrimidine
effects: inhibits T cell proliferation (memory T cells) and antibody production
block leukocyte adhesion, dendritic cell function
clinical application: alternative nonbiologic DMARD to methotrexate
2nd choice drug
can also be used in combo with MTX, sulfasalazine or hydroxychloroquine
half-life 16 days so loading dose
toxicities: most common are diarrhea, respiratory infection, reversible alopecia (hairless), rash, nausea
hepatotoxic
associated with pancytopenia, Steven-johnson syndrome, severe hypertension
Leflunomide
other nonbiologic DMARDs in the past
penicillamine-suppress bone marrow
gold salt-pruritis, purplish, gray skin discoloration
protein A column-pull IgG complexes from plasma
general rule, these drugs can be combined with non-biologic DMARDS, but not other biologic DMARDs
faster, higher rate of response, but more expensive, increased risk for severe adverse effects
what are the definition of the nomenclature of
- -cept
- -mab
- -ximab
- -zumab
- -umab
- refers to fusion of receptor to Fc part of human IgG1
- indicates a monoclonal antibody
- indicates a chimeric mAb
- indicates a humanized mAb
- indicates human mAb origin
Biologic DMARDs
MOA: work by neutralizing TNF
effects
highly effective at reducing rheumatoid arthritis and disease progression
clinical application
moderate-severe rheumatoid arthritis, generally after traditional DMARDs have proven to be ineffective
often used in combo with methotrexate
toxicities
all agents pose risk of developing serious infections like tuberculosis
patient can have severe allergic reactions, HF, liver failure, hematological disorders, neurologic disorders or cancer
Tumor necrosis factor antagonist
biologic DMARDs
Etanercept:
a soluble p75 TNF receptor fusion protein that consist of two p75 TNF receptors bound to the Fc portion of IgG. It is administered once or twice weekly via subcutaneous
injection.
Infliximab: a chimeric mAb directed against TNF.
Infliximab is administered via IV approximately every six weeks once a steady state has been achieved.
Adalimumab: a recombinant fully human anti‐TNF mAb that is administered subcutaneously rather than by intravenous infusion every two weeks.(best‐selling drug in the world)
what does Rituximab bind to?
CD20 on B cells
biologic DMARDs
MOA: target CD20
effect: as a consequence of plasma cell resistance, overall immunoglobulin levels (in normal range) despite profound B cell lymphopenia that persist for months following a single course
clinical application
IV every 6 months
indicated in combo with MTX for patients with RA who have not responded to TNF antagonist
postive testing for rheumatoid factor or anti-cyclic citrullinated peptide (CCP) antibodies predicts a greater likelihood of responsiveness
IV
toxicities: infusion related hypersensitivity reactions
mucocutaneous reaction including steven johnson syndrome, hepatitis B reactivation, associated with progressive multifocal leukoencephalopathy
Rituximab-B-cell depleting agent
biological DMARD
MOA: prevents CD28 from binding to its counter-receptor, CD80/CD86 (high affinity)
clinical application
IV once/4 weeks, but available as SC once/week
moderate-severe rhematoid arthritis
can be used with MTX
toxicities: generally well-tolerated
can have serious infection-pneumonia, cellulitis, bronchitis, diverticulitis, pyelonephritis and urinary tract infections
Abatacept-T cell activation inhibitor
