PC 121 Exam 1: Immunosuppressants

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PC 121 Exam 1Immunosuppressants

• Zahra KassamaliPharmD in 2009

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What to know? Dr. Kahl says
Recognize name of drugs from their
structures Assign drugs to classes based on
MOA Understand structural elements that define
commonality and differences between tacrolimus
and sirolimus Recognize DMARDs, name them from
their structures and describe their MOA
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Rapid overview
Sensitization Offending Agent activates T-cells
leading to proliferation
ImmunosuppressantsAntibiotic and other
immunosuppressantsAnti-proliferative
agentsAntimetabolitesIMiDs
Cytokines secreted Chemical activators of
Inflammation TNF-a,IL-2, IL-6.IL-18
Anti-cytokine agents TNF-a receptor TNF-a
antibody IL-1 receptor antagonist CD20
antagonist CD28 antibodyGold
Vasodilation, swelling, Redness, pain
Recruitment of more immune cells)
Symptomatic Treatment NSAIDs Corticosteroids
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arth_diag.jpg2. http//www.nasa.gov/images/conten
t/66769main_tcell2.gif
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Calcineurin Inhibitors Tacrolimus Cyclosporin

• Same MOA, Slightly different pathway

Antigen presenting cell
T cell
Tacrolimus binds FKBP12Cyclosporin binds
cyclophilin
Calcineurin Phosphatase
NFAT cleaved of phosphate active nuclear
transcription factor
Active NFAT binds DNA to initiate transcription
of pro-inflammatory cytokines (IL-2)
http//www.nature.com/ncpgasthep/journal/v3/n11/th
umbs/ncpgasthep0611-f1.jpg
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Tacrolimus Cyclosporine SAR
modified R group slows metabolism due to change
in affinity for CYP 3A4
R
Effector domainbinds calcineurin
Effector domainbinds FRAP (kinase) prevents G1 ?
S
Binds FKBP
Binds FKBP
TacrolimusMacrolide w/2 domains
Sirolimus R -OH Everolimus
R Pimecrolimus R -ClTemsirolimus
R
Cyclosporincyclic peptidemetabolized by CYPs
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Disease-Modifying Antirheumatic Drugs (DMARDs)
SulfasalazineProdrug with 2 active
componentsMesalamine anti-inflammatory
NSAIDSulfapyridine inhibits dihydrofolate
Reductatse (DHFR)--leads to decreased
lymphocytes (immune cells)Inhibits NFkB, txn
factor for inflammatory cytokines
Mesalamine
Sulfapyridine
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Disease-Modifying Antirheumatic Drugs (DMARDs)

• Antimetabolites Cancer chemotherapeutics at
  lower doses

Methotrexate1º rheumatoid arthritis treatment
(1/10 chemo dose)Slow onset 4-6
weeksAntiproliferative to T cells (interferes
with folate metabolism and DNA synthesis)Abortive
agentcontraindicated in pregnancy
Folate
AzathioprineProdrug, converted to
6-mercaptopurinePurine antagonist, inhibits
synthesis of DNA and RNACauses signficant bone
marrow suppression
Purine base
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Alkylating Agents
Chlorambucil
Anti-cancer agents Nitrogen mustards cross-link
DNA, inhibit replication ADE bone marrow
suppression, increased risk of leukemia over long
duration of treatment
Cyclophosphamide
Immunomuodulatory Imides (IMiDs)
Chiral center pka 10
Thalidomide TNF- a synthesis and release
inhibitorOriginally developed as anti-histamine
for pregnancy Teratogenic!! ? Flipper babies
Lenalidomide Modified thalidomide, 2000x more
potentStill teratogenic
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Quinines
Chloroquinine
Hydroxychloroquine
Mostly used in malaria Concentrates in
lysosome Anti-inflammatory MOA unknown Toxicity
Hydroxy lt Chloroquinine Efficacy Hydroxy lt
Chloroquinine
Other Immunosuppressants
Mycophenolate Mofetil Prodrug of mycophenolic
acid (MPA) Inhibits purine biosynthesis Used for
transplant (to prevent rejection) Mycophenolate
Sodium (MPA) Comes in enteric coated formulation
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Syllabus Corrections
R-group missing this O
Page 9
This is NOT a double bond
Temsirolimus
Sirolimus
Azathioprine is a pro-drug metabolized to
6-mercaptopurine, a purine antagonist.
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Lenalidomide Drawn with extra ketone in syllabus
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