21 - Immuno Medchem Flashcards
Cyclosporine / Tacrolimus / Sirolimus
Drug Interactions
- *CYP3A4 Isozymes**
- *Antibiotics = Erythromycin / ketokonazole**
AntiHT = nifedipine / verapamil
- *P-gp Drug Efflux Transporters**
- St. John’s Wort** = INDUCES p-gp –> *reduce CsA levels
Verapamil = inhibits P-gp –> INCREASE CsA levels
What IMS Drugs target:
Signal 3
IL-2 –> IL-2 Receptor
VV
Production of Pro-Inflammatory Cytokines
- *SIROLIMUS**
- *mTOR Inhibitor**
inhibits 2nd messenger signals
induced by IL-2 Ligation
Which IMS drug?
+ MoA
- *AZATHIOPRINE**
- *AntiProliferative Agent**
ProDrug of 6-MP
VVV
rapidly converts under alkaline Conditions
also occurs in the presence of:
SulfHydryl Compounds = Cysteine + Glutathione
Which IMS drug?
MycoPhenolate Mofetil = MMF / Cellcept
Prodrug –> rapidly hydrolyzed to MPA
circled area = increased water solubility
found in BLUE CHEESE
MoA:
Only inhibits DE-NOVO PATHWAY
of Purine Biosynthesis
IMPD
Voclosporin
Semi-synthetic STRUCTURAL ANALOG of CsA
*added a DOUBLE BOND
VV
less NEPHROTOXIC vs CSA
still in clinical trials for:
LN // Psoriasis
What IMS drug?
CYCLOSPORINE A
bunch of AMIDES
CsA - AMIDES
- *Cyclic peptide** from FUNGUS:
- *Tolypocladium Inflatum**
Which IMS drug?
PIMECROLIMUS = Elidel
topical cream used for eczema
Similar to Tacrolimus
- *Binds –> FKBP-12**
- inhibits* Calcineurin
What IMS Drugs target:
Signal 2
- *Co-Stimulatory signals** necessary to optimize:
- *T-Cell IL2 transcription**
- prevent* T-cell Anergy
- inhibit* T-Cell Apoptosis
BELATACEPT
selective co-stimulation blocker
MoA of CsA & FK
Normally:
Signal 1: TCR stimulation –> Calcineurin Activation
VVV
Calcineurin dephosphorylates NFAT
VVV
NFAT –> enters Nucleus –> binds to IL-2 promotor
CsA –> CyP & FK –> FKBP-12
complexes that INACTIVATE CALCINEURIN
so that it can NOT dephosphorylate NFAT
Which IMS Drug?
- *EVEROLIMUS**
- *mTOR inhibitor**
MORE POLAR vs sirolimus
Hydroxyethyl Chain @40
improves the PK characteristics
requires LESS DOSING due to lower half life
Which IMS drug?
TOFACITINIB
selective JAK3 Antagonist
1000x more selective for JAK3 vs other JAK’s
Approved for treatment for RA
genetic inactivation of JAK3 –> SCID
(severe combined immunodeficiency)
Which IMS drug?
FINGOLIMOD
FTY-720
Came from fungus –> kills sugarcane cicada
Structural analog of:
Sphingosine
Which IMS drug?
Prolongs allograft transplant survival
by
inhibiting lymphocyte emigration from lymphoid organs
Structural analog of:
Sphingosine
FINGOLIMOD
FTY -720
Potent Agonist @ 4 Sphingosine Receptors
Approved for Treatment of MS (@low dose)
was D/C’d before due to ADR / poor graft fxn
Which IMS Drug?
Potent inhibitor of:
IMPD = Inosine MonoPhosphate Dehydrogenase
VV
rate limiting step for
De-Novo Synthesis of GUANOSINE
stops production of ATP /GTP
MycoPhenolate = MMF –> MPA
selective due to the fact that:
- *T/B-cells**
- lacks the Salvage Pathway of PURINE biosynthesis*
How does MMF have SELECTIVITY
to one specific pathway of Purine Biosynthesis?
Since T-B-Cells
LACK the SALVAGE PATHWAY
VVV
MMF only targets the
DE-NOVO PATHWAY
of Purine Biosyntesis
IMPD = rate limiting step for Guanosine Nucleotides
Which Part of Tacrolimus (FK)
Binds to CALCINEURIN?
BOTTOM** = **C15 - C22
is invovled in binding to calcineurin
The Top Portion:
Binds to FKBP-12
Pipecolinyl / Pyranose / Cyclohexyl Ring / C-9 Ketone
C24-C26 regoin
Which IMS drug?
Binds FKBP-12 to form a COMPLEX
VVV
interacts with mTOR
VVV
INHIBITS the signal transduction pathway for
the progression of IL-2 stimulated cells from the:
G1 –> S-Phase of the cell cycle
- *SIROLIMUS**
- *mTOR inhibitor**
Rapamycin
Which IMS drug?
Has severe drug interactions with:
ALLOPURINOL
AZATHIOPRINE
Xanthase Oxidase Inhibitors = Allopurinol
Which part of CsA is responsible for
IMS ACTIVITY?
BOTTOM = IMS ACTIVITY
Top –> binds to the CyP
When MeLeu6 –> MeAla6
VVV
Binding to CyP is unchanged
but…
IMS activity is loss
What IMS Drugs target:
Signal 1
TCR stimulation –> Calcineurin Activation
VVV
dephosphorylation of of NFAT
CycloSporine** + **Tacrolimus
CyA + FK
Calcineurin Inhibitors
What IMS drug?
- *TACROLIMUS**
- *LACTONES** = O-C-O
Tacro - Lactones
Macrolide Lactone Antibiotic
from Japaese Soil microorganism
StreptoMyces Tsukubaensis
Which IMS drug?
NON-SELECTIVE
VVV
inhibits Several enzymes with
PURINE Nucleotide Biosynthesis
in BOTH the:
DeNovo & Salvage pathway
AZATHIOPRINE
AntiProliferative Agent
What IMS drug?
SIROLIMUS
mTOR inhibitor - Rapamycin
interrrupts the pathwasy required for the progression of IL-2
t-cells from G1 –> S-phase of the Cell cycle
- *Similar to TAC (FK)**
- instead it targets* TOR, not Calcineurin
Cyclohexyl-residue
