Immunosuppressive and Anti-Histamine Drugs
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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