Immunosuppressive meds Flashcards
current use of immunosuppression?
organ transplant
tx of AI disorders and various rheumatologic conditiosn esp RA
major risk involved in use of DMARDs?
pt becomes more vulnerable to infxns and malignancy
3 goals of immunosuppressive therapy?
induce or maintain a remission
reduce the frequency of flare or relapse
allow tapering of glucocorticoids while maintaining disease control
why does organ transplantation usu result in reject (if not for immunosuppressive drugs)?
dt difference in human leukocyte ag b/w donor and recipient
difference in HLA presentation = body attempts to remove it
SEs of long term steroid use to prevent organ rejection?
increased susceptibility to infxns, poor wound healing, hyperglyceremia, increased risk for osteoporosis, Cushing’s syndrome, potential adrenal suppression
4 cytotoxic immunosuppressive drugs?
cyclophosphamide, chlorambucil, ethotrexate, azathioprine
class of drugs that suppresses the immune system by inhibiting the proliferation of fxn or lymphocytes?
cyclosporine and tacrolimus - target calcineurin and thereby inhibit the production of IL-2 by activated lymphocytes
overlap of what other condition immunosuppressive drugs can be used to tx? common MOA?
chemotherapy
both utilize clonal expansion of B and T lymphocytes
class of methotrexate? indications?
class: anti-metabolite and anti-folate immunosuppressant andchemotherapeutic
indications: CA, AI dzs (RA, psoriasis, psoriatic arthritis, lupus, Crohn’s dz), abortifacient
MOA of methotrexate? how to deliver? SEs?
MOA: anti-metabolite and anti-folate drug
can give PO, IV, IM, SQ, IT; oral given on a weekly basis
assess creatinine every 2 mos (minimum)
SE: CNS reactions, N/V, oral ulcerations, hepatitis, blood dyscrasias, immunosuppression, fatigue, fever, dizziness, ulcerative stomatitis, low WBC count, acute pneumonitis, pulmonary fibrosis
PG category of methotrexate?
class x - HIGHLY teratogenic
class of azathioprine/imuran? indications? MOA?
class: purine anti-metabolite immunosuppressant
indications: prevention of transplant rejection, IBD, SLE, RA
MOA: metabolic breakdown products of azzthioprine act to inhibit purine synthesis which will block protein synthesis, particularly in cells that experience rapid turnover
how to deliver azathiprine/imuran? SEs?
can give PO, IV; metabolites primarily excreted in urine
SEs: rapidly growing cells most readily affected - hair loss, BM suppression, GI toxicity, leukopenia, thrombocytopenia, decreased ability to fight infxn, can cause pancreatitis, birth defects
class of cyclosporine/sandimmune? indications? MOA? how to deliver?
class: immunosuppressant drug derived from soil fungus
indications: prevent rejection of KD, liver and heart transplants as well as tx of RA & other AI dzs such as severe psoriasis
MOA: T-cell inhibition, blocks signal to lymphocytes to produce IL-1, IL-2, IL-3, IL-4, interferon gamma
can deliver PO, IV, blood levels must be carefully monitored
SEs of cyclosporine/sandimmune?
SEs: N/V, diarrhea, loss of appetite, high BP, KD damage, tremors, H/A, seizures, excessive hair growth, excessive gum growth, confusion, coma, gout, increased risk for infxn, can lead to sepsis
what phase of the cell cycle does methotrexate affect?
synthesis, S phase of the cell cycle
how long can it take for azathioprine to work?
can take up to 1 year!
food which can affect levels of cyclosporine/sandimmune? what does it cause?
grapefruit juice
causes more cyclosporine to remain in the blood b/c inhibits the CYP P450 3A4 enzyme
class of tacrolimus/prograf? indications? MOA? strength compared to cyclosporine?
class: immunosuppressant drug related to macrolide class of antibiotics extracted from soil microorganisms
indications: protect against rejection of organ transplantation, topical tx of severe eczema
MOA: T-cell inhibition similar to that of cyclosporine
tacrolimus is about 100x more potent in immunosuppressive effects than equal volume of cyclosporine
how to give tacrolimus/prograf? enzyme system it utilizes and therefore what elevate levels? SEs?
give PO, IV, topically
metabolized by the P450 enzyme system so grapefruit juice needs to be avoided so as to prevent the accidental increased blood levels
SEs: N/V, diarrhea, loss of appetite, HTN, KD damage, increased risk of infxn
DMARDs are generally used for what? what conditions can it be used for?
used to slow down disease progression
first used in RA, but has come to be used for Crohn’s dz, SLE, idiopathic thrombocytopenic purpura, myasthenia gravis and other conditions
5 main DMARDs we’ll talk about?
etanercept (enbrel) adalimumab (humira) infliximab (remicadee) azathioprine (imuran) cyclosporine/sandimmune
TNF-a is produced by what cells?
cytokine produced by monocytes and MOs
3 types of TNF receptors?
- embedded in WBCs that respond to TNF by releasing other cytokines
- soluble TNF receptors which are used to deactivate TNF and blunt the immune response
- surface of almost all nucleated cells
etanercept mimics what?
mimics inhibitor effects of naturally occurring soluble TNF-receptors
fusion protein so greatly extended half-life in the bloodstream therefore lasting biological effect
actions of IL-1 and TNF-a in relation to the immune system?
mediate inflammation and bone resorption in RA
class of etanercept/enbrel? indications? MOA? how to give?
class: DMARD recombinant DNA drug
indications: moderate to severe RA, moderate to severe polyarticular juvenile arthritis, psoriatic arthritis, ankylosing spondylitis, moderate to severe plaque psoriasis
MOA: reduction of inflammatory response via anti-TNF alpha therapy
give SQ, dosed once or twice weekly
how is etanercept made?
recombinant DNA drug made by combining 2 proteins - links human soluble tumor necrosis factor alpha receptor to Fc component of human immunoglobulin
etanercepts effect on WBCs?
mediates immune response by increasing the transport of WBCs to sites of inflammation, through additional molecular mechs which initiate and amplify inflammation
SEs of etanercept? cost?
SEs: notable decreased resistance to infxn, potential for increased risk for leukemia, lymphoma and solid tumors, liver injury, CHF, demyelinating CNS disorders
cost: $12,000-$16,000+ per year
class of infliximab/remicade? indications? MOA?
class: DMARD, recombinant-DNA drug
indications: RA, Crohn’s dz, UC, ankylosing spondylitis, psoriatic arthritis, psoriasis
MOA: neutralizes biological activity of TNFa by binding with high affinity to soluble TNFa and trans-membrane forms of TNFa thus preventing effective binding of TNFa w/its receptors
how is infliximab/remicade given? why?
administered IV typically at 6-8 wk intervals
cannot be administered orally b/c digestive system would destroy the drug
difference in activity between infliximab and etanercept?
infliximab causes programmed cell death of TNFa expressing activated T cells but etanercept does not have this activity
most widely used anti-TNFa biologic drug for the tx of RA?
etanercept/enbrel
most widely used anti-TNFa biologic drug when “all FDA approved indications of the drugs are considered?”
infliximab/remicade
FDA approved to tx Crohn’s, UC (etanercept does not have FDA approval for treating these)
SEs of anti-TNFa therapy?
fatal blood disorders, infxns, rare reports of lymphoma, solid tissue CAs, rare reports of serious liver injury, rare reports of demyelinating CNS d/os, rare reports of CHF
how does infliximab work?
blocks the action of TNFa by preventing it from binding to its receptor in the cell
causes programmed cell death of TNFa expressing activated T lymphocytes
hydroxychloroquine/plaquenil indications?
anti-malarial drug that is also useful in treating RA, systemic lupus erythematosus, Sjogren’s syndrome, post-lyme arthritis
for prevention of malaria, usual adult dose of hydroxychloroquine? dosing for suppressive therapy? acute dosing?
prevention: 400 mg/d 2 wks prior to possible exposure
suppressive therapy continues for 8 wks after leaving contagious area
acute: either single 800 mg dose or 800 mg followed by 400 mg 6–8 hrs later then 400 mg/d for 2 consecutive days
dosing of hydroxychloroquine for SLE?
400 mg 1-2x/d for several wks or months, may be reduced to 200-400 mg/d for maintenance
dosing of hydroxychloroquine for RA?
400-600 mg/d for flare-ups or as starting dose; may take between 4-12 wks to see notable improvement; maintenance dose is 200-400 mg/d
effect of hydroxychloroquine/plaquenil on lysosomal pH? effect on TLRs?
increases lysosomal pH in antigen presenting cells
also blocks activation of TLRs on plasmacytoid dendritic cells
which TLR recognizes DNA-containing immune complexes and what is its downstream effect? how does hydroxychloroquine effect this and what does it lead to?
TLR-9 –> leads to production of interferon and causes dendritic cells to mature and present antigen to T cells
hydroxychloroquine decreases TLR 9 signaling which reduces the activation of dendritic cells and ultimately reduces the inflammatory process
class of hydroxychloroquine/plaquenil? indications? MOA?
class: immunosuppressant and anti-malarial
indications: RA, SLE, Sjogren’s, malaria in areas where there is low risk for hydroxychloroquine resistant malaria
MOA: action of the drug may involve an anti-spirochete activity as well as an anti-inflammatory activity
how to give hydroxychloroquine/plaquenil? SEs? sxs of overdose?
PO
sxs of overdose can occur w/in 1/2 hour of taking med
overdose sxs: drowsiness, H/A, vision problems, SOB, convulsions, corneal macular damage - indicates need yearly dilated eye exams
SEs: abd cramps, diarrhea, reduced appetite, H/A, N/V, vision difficulties, tinnitus, hearing loss, diminished reflexes, hives, itching, rash, loss of hair, weakness, anemia
pts w/G6PD deficiency can experience what SE when taking hydroxychloroquine/plaquenil?
can cause severe anemia
gold salt compounds act to do what and can be used in what dzs?
act to reduce inflammation
can be used in RA, IBD, psoriatic arthritis, membranous nephritis, SLE, infrequently juvenile rheumatoid arthritis
sometimes used for kids w/progressive poly-arthritis who are unresponsive to NSAIDs, methotrexate and other meds like DMARDs
MOA of gold salts? SEs?
MOA: proposed anti-mitochondrial activity + induce cell apoptosis
SEs: dermatitis, thrombocytopenia, leukopenia, pancytopenia, aplastic anemia, proteinuria, stomatitis, metallic taste, skin pigmentation, enterocolitis, cholestatic jaundice, peripheral neuropathy, pulmonary infiltrates, corneal deposits of gold, nitroid rxn
how to give gold salts? capsule form called? what labs need to be performed regularly?
can give PO or IM (PO has fewer SEs)
auranofin is the capsule form
need to perform routine urine test to check for protein and blood
$500-$700/month!
how long does it take for gold salts to be effective? problem it can cause in relation to kidneys? SEs?
generally requires up to 2 mos of use to reach a steady state
in 10 d, only 70% of administered gold slats are excreted therefore can potentially exacerbate any renal toxicity
SEs: decreased appetite, nausea, alopecia, diarrhea, rash, thrombocytopenia, renal toxicity
