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82 Cards in this Set

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Five Main Groups of Immunosuppressives
corticosteroids, cytotoxic agents, immunosuppresants, NSAIDs, Antihistamines
Drugs interfering with mediator production
corticosteroids, NSAIDs, anti-histamines, anti-TNF drugs (infliximab, entanercept)
Anti-TNF Drugs
Infliximab, entanercept
Two main categories of immune system diseases
Hypersensitivity - exaggerated immune reponse; Autoimmune - immune reaction against self antigens
What are eicosanoids
prostaglandins, thomboxanes, leukotrienes
PGE and PGI effects
induce arteriolar dilatation, sensitize aff nerve endings to stimulie (lowers pain threshold)
PGF and TXA effects
induce venule constriction
Leukotriene C and D effects
increase vascular permeability
LTB4 effects
potent chemotactic mediator for leukocytes
Histamine actions
increases vascular permeability, smooth muscle contraction, activation of afferent sensory nerve endings
Platelet Activating Factor (PAF) effects
increased mediator release from platelets, increased vascular permeability, smooth muscle contraction, neutrophil activation
TNF-alpha effects
activates neutrophils, endothelial cells and fibroblasts. Affects function of synoviocytes and chondrocytes
IL-8 Effects
localization of leukocytes
C3a effects
mast cell degranulation, smooth muscle contraction
C5a effects
mast cell degranulation, leukocyte chemotaxis, neutrophil activation, smooth muscle contraction, increased capillary permeability
Bradykinin effects
vasodilation, smooth muscle contraction, increased capillary permeability, pain, prostaglandin production
Fibrinopeptide effects
increased vascular permeability, chemotaxis
prostaglandin E2 effects
vasodilation, potentiates increased vasc permeability mediated by others
LTD4 Effects
smooth muscle contraction, vascular permeability
where does arachidonic acid come from?
released from membrane phospholipids by phospholipase A2
Phospholipase A2 activity increased by:
intracellular free calcium, which happens in response to hormones, trauma, etc
Corticosteroid MOA
inhibit production of arachidonic acid by inducing lipocortin production (lipocortin inhibits phospholipase A2); opposing induction of COX-2; inhibits release of mediators, decrease sythesis of PAF and IL-2; initiate apoptosis in rapidly dividing lymphocytes
lipocortin effects
inhibits phospholipase A2
Two major arachidonic acid pathways
cyclooxygenase and lipooxygenase
Cyclooxygenase Pathway products
prostaglandins, prostacyclin, thromboxane
Lipooxygenase Pathway products
leukotrienes
Aspirin and NSAID MOA
inhibit COX
COX-1 expression pattern
constitutive
COX-2 expression pattern
inducible
COX-2 inhibition
glucocorticoids inhibit its synthesis
Where does lipooxygenase pathway take place?
leukocytes and platelets
Zileuton MOA
inhibits 5-lipooxygenase
Zafirlukast MOA
LTD4 receptor antagonist
Corticosteroid duration of action, short to long
cortisol, prednisone, triamcinolone, dexamethasone
Corticosteroid commonly used in systemic treatment
prednisone
Acute therapy toxicity of corticosteroids
none
Chronic corticosteroid toxicity
adrenal suppression, cushinoid sx, salt/water retention, HTN, hypokalemia, gastric ulceration, osteoporosis, growth retartdation
why do you taper off corticosteroid therapy?
1) potential flare up of underlying dz, 2) acute adrenal insufficiency from feedback inhibition
three strategies to reduce systemic toxicity of corticosteroids
topical administration, every-other-day tx, combine with other immunosuppressants
examples of immunosuppressant antibiotics (4)
clyclosporine, tacrolimus, sirolimus, mycophenolate mofetil
Cyclosporine and tacrolimus MOA
Bind small proteins (cyclosporine: cyclophilin; tacrolimus: FKBP), prevent its binding to calcineurin which then doesn’t activate NFAT (promotes lots of cytokine production)
Sirolimus MOA
binds FKBP, also effects w/ mTor and inhibits second phase of t-cell activation (response to cytokines), also inhibits B-cells
Mycophenolate Mofetil MOA
converted in body to MPA, which inhibits inosine monosphate dehydrogenase (IMPDH), inhibits de novo purine synthesis, and lymphocytes cannot make enough GMP via salvage pathway
Cyclosporine clinical uses
organ transplantation, rheumatoid arthritis, Crohn's disease, same with tacrolimus
Sirolumus and Mycophenolate Mofetil Clinical Uses
mostly adjunctive, MM also in rheumatoid arthritis and lupus nephritis
Cyclosporine/Tacrolimus toxicities
nephrotoxicity as interstitial fibrosis and tubular injury
Sirolimus toxicities
myelosuppression, thrombocytopenia, liver dysfxn, hypertriglyceridemia
Mycophenolate Mofetil toxicities
myelosuppression, GI
Cytotoxic Drugs MOA
prevent clonal expansion of lymphocytes
example of cytotoxic drug
Azithioprine
cytotoxic drug toxicities
BM suppression, mucositis
methotrexate toxicity
nephrotoxic (crystalluria)
Cyclophosphamide toxicity
hemorrhagic cystitis
Muromonab MOA
binds CD3, transiently activates, then inhibs proliferation
Daclizumab, basiliximab MOA
binds IL-2a subunit
examples of cytotoxic drugs
azathiprine, cyclophosphamide, methotrexate, mercaptopurine
NSAID MOA
COX inhibition
Aspirin MOA
irreversibly inhibit COX by acetylation
Clinical uses of NSAIDS
analgesia, antiypresis, antiinflammatory
How do NSAIDs provide analgesia?
inhibit prostaglandin formation that sensitize peripheral receptors to nociceptive mediators; not as effective against visceral pain
How do NSAIDs provide antipyresis?
Lower set point in hypothalamus, by reducing IL-1
Main NSAID toxcicities (5)
GI ulcer, Nephrotoxicity, increase bleeding time, prolong gestation, hypersensitivity
how do NSAIDs cause GI Ulcer?
lose protective effects of PG, can use PGE1 analog misprostol to reduce incidence
How do NSAIDs increase bleeding time?
decreased TXA2 from COX1 inhibition, permanently affects platelets because they cant synth new proteins
indomethacin usage
potent cox inhibitor, acute arthritic inflammation (acute gout)
What is Reye Syndrome?
severe hepatic injury and encephalopathy in kids w/ viral infxns (esp influenza) when given ASA
ASA effect on uric acid elimination
inhibit tubular secretion of uric acid, can cause acute gout
Salicylism (overdose)
tinnitus, dizziness, gi distress, hyperventilation, death due to CNS failure/CV collapse
how to treat salicylate overdose
increase urine volume, alkalinize it
Acetaminophen overdose
irreversible hepatic necrosis (~30 tablets), due to toxic metabolites overwhelming detox mechanism
4 older DMARDs
hydoxychloroquine, sulfasalazine, gold salts, penicillamine
5 newer DMARDs
etanercept, infliximab, adalimumab, anakinra, leflunomide
Etanercept MOA
recombinant fusion prot of two TNF receptors fused with human IgG Fc, binds and inactivates TNF
Infliximab MOA
human/mouse Ab directed against TNF-a
adalimumab MOA
human mAB blocking TNF-a
anakinra MOA
recombinant human IL1-Ra, inhibits IL-1 binding to normal receptors
Leflunomide MOA
inhibits dihydro-orotic acid dehydrogenase, decreases UMP formation, less RNA
three strategies against Gout
reduce inflammator response (corticosteroid, NSAID, colchicine); enhance renal excretion (uricosuric agent); inhibit uric acid formation (allupurinol)
colchicine MOA
inhibits microtubule depolymerization, increases LTB4, impairs granulocyte migration/function
2 uricosuric agents
probenecid and sulfinpyrazone
allopurinol MOA
inhibits xanthine oxidase, which converts hypoxanthine into xanthine and xanthine into uric acid
Activation of H1 receptors leads to:
increased capillary dilation and permeability, contraction of bronchiolar smooth muscle, activation of peripheral nociceptive receptors, cardiac depression