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Immunosuppressants
Jason Ryan, MD, MPH
Immune Suppression
• Commonly used drugs:
• NSAIDs, Steroids
• Less commonly used drugs:
• Cyclosporine/Tacrolimus
• Sirolimus AfraTafreeh.com
• Methotrexate
• Mycophenolate
• Cyclophosphamide
• Azathioprine
• TNF-α inhibitors
• Hydroxychloroquine
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Cyclosporine & Tacrolimus
• Both drugs inhibit calcineurin
• Calcineurin activates (via dephosphorylation) NFAT
• Nuclear factor of activated T-cells
• Important transcription factor for many cytokines
P IL-2
NFAT NFAT Nucleus
Calcineurin
Other
Cytokines
Cyclosporine & Tacrolimus
• Cyclosporine: binds to cyclophilins
• Complex inactivates calcineurin
• Tacrolimus: binds to FK-506 binding protein
• Complex inactivates calcineurin
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Cyclosporine & Tacrolimus
• Autoimmune diseases, organ transplants
• Similar side effects
• Both drugs metabolized P450 system
• Many drug-drug interactions
• Can raise/lower levels/effects
Cyclosporine & Tacrolimus
• Nephrotoxicity
• Most important and limiting side effect
• Vasoconstriction of the afferent/efferent arterioles
• Hypertension
• Via renal vasoconstriction (salt/water retention)
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• Diltiazem drug of choice
• Impairs cyclosporine metabolism (↑ drug levels)
• Treats HTN and allows lower dose cyclosporine to be used
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Cyclosporine & Tacrolimus
• Hyperuricemia and gout
• Hyperglycemia (may impair insulin secretion)
• Neurotoxicity (usually tremor)
Cyclosporine
• Two unique side effects
• Not reported with tacrolimus
Lesion/Wikipedia
• Gingival hyperplasia
• Hirsutism
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Wikipedia/Public Domain
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Sirolimus
Rapamycin
• Kidney transplant, drug-eluting stents
• Inhibits mTOR (mechanistic target of rapamycin)
• Binds FK binding protein
• Same target as Tacrolimus
• Does NOT inhibit calcineurin
• Inhibits mTOR
• Blocks response to IL-2 in B/T cells
• Blocks signaling pathways
• Cell cycle arrest in the G1-S phase
• No growth/proliferation
Sirolimus
Rapamycin
• Anemia, thrombocytopenia, leukopenia
• Hyperlipidemia
• inhibition of lipoprotein lipase
• Hyperglycemia
• Insulin resistance AfraTafreeh.com
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Coronary Stents
• “Drug-eluting stents” (DES)
• Coated with anti-proliferative drug
• Blunts scar tissue growth (restenosis)
• Sirolimus
• Everolimus
• Paclitaxel
Wikipedia/Public Domain
Methotrexate
• Chemotherapy, autoimmune diseases
• Mimics folic acid - inhibits dihydrofolate reductase
dUMP dTMP
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Thymidylate
Synthase
N, N Methylene-THF DHF
Dihydrofolate
THF Reductase
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Methotrexate
Side Effects
• Myelosuppression
• Reversible with leucovorin (folinic acid )
• Converted to THF
• Does not require dihydrofolate reductase
• “Leucovorin rescue”
• Stomatitis/Mucositis (mouth soreness)
• Occurs with many chemo agents
• DNA damage → cytokine release
• Cytokines damage epithelium
• Loss of mucosal integrity → pain, bacterial growth
• Abnormal LFTs, GI upset
The pathobiology of mucositis. Sonis ST. Nat Rev Cancer. 2004;4(4):277
Mycophenolic acid
CellCept
• Inhibits IMP dehydrogenase
• Rate-limiting step in purine synthesis in lymphocytes only
• Also, preferentially binds type II isoform IMP dehydrogenase
• Type II Expressed by activated lymphocytes
• ↓ nucleotides → ↓ DNA synthesis in T/B cells
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• Bone Marrow Suppression
• GI: Nausea, cramping, abdominal pain
Inosine-MP Guanosine-MP
IMP
Dehydrogenase
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Cyclophosphamide
• Powerful immunosuppressant (also anti-tumor)
• Used in vasculitis, glomerulonephritis (oral)
• Prodrug: Requires bioactivation by liver
• Converted to phosphoramide mustard
• Metabolized by P450 system
• “Alkylating agent”
• Adds an alkyl group to the N7 position
• DNA strands will cross link
• Inhibits DNA replication → cell death
Cyclophosphamide
Side Effects
• Myelosuppression
• ↓WBC, ↓Hct, ↓Plt
• Hemorrhagic cystitis
• Acrolein metabolite toxic to bladder
• Hematuria +/- dysuria AfraTafreeh.com
• Lower risk with hydration and mesna
• Mesna: sodium 2-mercaptoethane sulfonate
• Mesna binds and inactivates acrolein in the urine
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Cyclophosphamide
Side Effects
• SIADH
• Usually IV dosing for chemotherapy
• Hyponatremia; possible seizures
• Compounded by IVF
• Complex mechanism: More ADH release, less renal response
Azathioprine
• Transplants, autoimmune diseases
• Prodrug converted to 6-Mercaptopurine (6-MP)
• Analog to hypoxanthine (purine like adenine, guanine)
• 6-MP competes for binding to HGPRT
• Hypoxanthine guanine AfraTafreeh.com
phosphoribosyltransferase
• Converts hypoxanthine to inosine monophosphate
• Also guanine to guanosine monophosphate
Hypoxanthine Guanine 6-MP
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Azathioprine
GMP
IMP GMP
AMP
HGPRT
Hypoxanthine Guanine
Guanine
Azathioprine
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↓Purines
HGPRT (A, G)
6-MP Thioinosinic acid
monophosphate
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Azathioprine
Adverse Effects
• Bone marrow suppression
• GI: Anorexia, nausea, and vomiting
• Caution with allopurinol
• Xanthine oxidase inhibitor
• Metabolizes purines → uric acid
• Blunts metabolism of 6-MP/azathioprine
• ↑ risk of adverse effects
Xanthine
Oxidase
6-thiouric acid
6-MP (inactive)
Muromonab-CD3
OKT3
• Monoclonal antibody
• Used in organ transplantation
• Binds to epsilon chain of CD3 (T cells)
• Blocks T-cell activation
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• Leads to T-cell depletion from circulation
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Muromonab-CD3
OKT3
• Key side effect: Cytokine release syndrome
• Occurs after first or second dose
• Fevers, rigors, nausea, vomiting, diarrhea, hypotension
• Sometimes chest pain, dyspnea or wheezing
• Arthralgias and myalgias
• Caused by initial activation of T cells → release of cytokines
• Minimized by pre-medication with steroids, antihistamines
Infliximab
• Antibody against TNF-α
• Used in rheumatoid arthritis, Crohn’s
• “Chimeric”
• Both mouse (murine) and human components
• Antigen-binding portion of molecule: murine
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• Constant Fc domain: human
• Risk of reactivation TB
• PPD screening done prior to treatment
• Risk of other infections: bacterial, hepatitis, zoster
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Other TNF-α Inhibitors
• Adalimumab (monoclonal antibody TNF-α)
• Golimumab (monoclonal antibody TNF-α)
• Etanercept
• Made by recombinant DNA
• Recombinant protein of TNF receptor
• “Decoy receptor”
• Binds TNF instead of TNF receptor
Malaria Drugs
• Chloroquine and hydroxychloroquine
• Malaria drugs with immunosuppressive actions
• Block TLRs in B-cells (↓activation)
• Weak bases: ↑pH in immune cells → ↓ activity
• Other actions AfraTafreeh.com
• Used in rheumatoid arthritis, SLE
