Immune Modulators Flashcards
Action time of prednisone
Intermediate acting
12-36 hrs
Action time of prednisolone and what makes it different from prednisone?
12-36 hours
This one also has parenteral administration
Dexamethasone acting time
Long acting
36 - 72 hours
Differences between prednisone and dexamethasone
Dexamethasone
- Long acting >36 hrs
- Can be given in oral, parenteral, and topical forms
Mechanism of action glucocorticoids + 7 things they decrease
Decrease NF-kB activation
= suppress T cell proliferation and IL-1, IL-6, TNF, IFN
Inhibit macrophage antigen processing
Decrease: PG, leukotrienes, histamine, PAF, bradykinin, NO, IgG
Glucocorticoid uses (4)
- Transplant
- GvHD
- Autoimmune diseases: SLE, RA, SD, psoriasis, asthma
- IBD
Glucocorticoids main side effect
Growth retardation (adeno atrophy) or Cushing’s
Others:
- Avascular bone necrosis
- Osteopenia, osteoporosis
- Cataracts
- Hypertension
- Hyperglycemia
- Hypercholesterolemia
Cyclosporine mechanism of action
- Forms a complex with cyclophilin
- Binds to serine/threonine phosphatase calcineurin and blocks Ca2+ action of activating calcineurin
- Disrupt NF-aT phosphorylation
- NF-aTs don’t translocate to nucleus
= no IL-2 transcription
Immunosuppresor uses (3)
- Transplant
- Autoimmune: RA, Crohn, psoriasis, nephrotic sx, asthma, DM type I, etc.
- GvHD
Cyclosporine ADME
A: 50% available oral or IM
D: 50-60% in RBC or lymphocytes. Highly lipophilic.
M: CYP3A4
E: bile/feces, breast milk
Cyclosporine side effects NHLTG
Nephrotoxicity
Hirsutism
LDL increase
Tremor
Gum hyperplasia
Others: hypertension, hyperK, hyper uric acid, viral infections, hyperglycemia
Meds that decrease cyclosporine concentration (3)
- Phenobarbital
- Phenytoin
- Rifampin
Meds that decrease cyclosporine clearance (3)
- Erythromycin
- Ketoconazole
- Grapefruit
Can cyclosporine and sirolimus be given together?
Yes but with time between.
Between cyclosporine, tacrolimus, and sirolimus, which is more potent?
Tacrolimus
*more toxic also
Tacrolimus mechanism of action
Also known as FK506, it’s an immunophilin that:
1. Binds to FKBP
2. Inhibit calcineurin phosphatase
Tacrolimus ADME
A: food decreases absorption. Oral or IM
D: 75-99% protein bound
M: CYP3A
E: fecal
Tacrolimus side effects
Nephro and neurotoxicity
Hyper K
Hypertension
Hyperglycemia and DIABETES when combined with glucocorticoids
What medication type is rapamycin?
Sirolimus
Sirolimus mechanism of action
- Binds to FKBP12
- Binds to mTOR complex 1 and inhibits pathway
- Stops cell cycle phase between G1 and S
- Inhibit IL-2 RESPONSE
Sirolimus ADME
A: 15% availability oral
D: bound to albumin 40%
M: CYP3A4
E: feces
Which has less renal toxicity: calcineurin inhibitors or proliferation inhibitors (sirolimus)?
Sirolimus
Sirolimus toxicity
Tolerizing effects
- Nephrotox
- HYPERLIPIDEMIA
- Hypertension
- Worsen proteinuria
- Lymphocele
- PANCYTOPENIA
- Mouth ulcers
Methotrexate mechanism of action
FOLATE ANTAGONIM
- Inhibits dihydrofolate reductase
- No folic acid activation
= prevent purine and pyrimidine synthesis
= less cell proliferation
Other: inhibit spermine, cause transmethylation, inhibit release of adenosine
Methotrexate ADME
A: IV, IM, oral
D: bound 50%, distributed to third-space fluids
M: aldehyde oxidase in liver, intestinal flora
E: urine
Methotrexate side effects NABPRT
- Nausea, vomit, diarrhea + ULCERS
- Alopecia
- Bone marrow depression = PANCYTOPENIA
- Pulmonary fibrosis
- Renal and hepatic disorders
- TERATOGENIC folate deficiency
Azathioprine mechanism of action
PRODRUG —> 6-MCP with glutathione
2. —> thio-IMP
3. Converts GMP to GTP
4. Inhibit purine synthesis = less cell proliferation
PURINE ANALOGUE
Azathioprine ADME
A: oral or IV
D: doesn’t cross BBB, bound 30%
M: xanthine oxidase —> 6-MCP (activation)
E: urine
Avoid azathioprine with:
Allopurinol —> blocks xanthine oxidase
Myelosuppressive
ACE inhibitors
Azathioprine side effects BIG A
Bone marrow suppression = PANCYTOPENIA
Increase risk of infections
GI effects
Alopecia
Mycophenolate mofetil mechanism of action
PRODRUG —> MPA
2. Inhibits iosine monophosphate dehydrogenase (IMPDH)
3. Inhibit guanine synthesis
= less lymphocyte proliferation
Mycophenolate mofetil ADME
A: oral or IV
D: extensively bound
M: MPA—> inactive glucuronide
E: urine
Azathioprine uses
- Acute glomerulonephritis
- Autoimmune: SLE, RA
- Crohn
- Transplant
Mycophenolate mofetil side effects
WITH TACROLIMUS: diarrhea and alopecia
- Bone marrow suppression = PANCYTOPENIA
- Vomiting and diarrhea
- Hypertension
- Infections
- PREGNANCY: anomalies, loss
Mycophenolate mofetil avoid with:
- Tacrolimus
- Antiacids
- Cholestyramine
- Aciclovir
Immunosuppresors (10)
- Glucocorticoids
- Cyclosporine
- Tacrolimus
- Sirolimus
- Azathioprine
- Methotrexate
- Mycophenolate mofetil
- Infliximab
- Adalimumab
- Rituximab
Glucocorticoids ____ (increase/decrease) T cell apoptosis
Increase
Short-acting glucocorticoids (2)
Intermediate-acting (3)
Long-acting (2)
Short: hydrocortisone, cortisone
Intermediate: prednisone, prednisolone, methylprednisolone
Long: dexamethasone, betamethasone
Which immunosuppresor should NOT be given to diabetics and why?
Tacrolimus
Toxic to pancreatic b cells
Glucocorticoid ADME
A: oral, IM, IV
D: rapidly removes from blood, distributed everywhere
M: CYP3A4
E: urine
2 medications commonly used for synergistic immunosuppression
Sirolimus + glucocorticoids
Medication used in rheumatic diseases vs glucocorticoids
Mycophenolate mofetil
Methotrexate uses aside from immunosuppression
- Cancer, especially ALL
- Ectopic pregnancy abortion
Infliximab acts against:
TNF-a
Anti TNF-a uses
Refractory therapy for chronic inflammatory sistemic
Ex. RA, Crohn, psoriasis
Anti TNF-a side effects
- Reactivation of prior infections
- Malignancy
- Drug-induced lupus
- Pancytopenia
*heart failure patients
Infliximab ___ (can/can’t) be given with other immunosuppressors
CAN’T
Adalimumab target
TNF-a
Difference between infliximab and adalimumab
Infliximab is chimeric, given IV
Adalimumab is humanized, given subcutaneously
Rituximab uses
- RA
- ITP or TTP
- MS
- B-cell non-Hodgkin lymphoma
Rituximab main side effect
Risk of progressive multifocal leukoencephalopathy PML with latent JC virus
Immunomodulators (5)
- Glatiramer
- Elapegdemasa
- Perixaflor
- Triciclib
- Pagademasa
What is glatiramer acetate used for?
Treatment of relapsing MS
Glatiramer acetate mechanism of action
Acts as target for T cells instead of neuronal myelin
Less Th1 (inflammatory), more Th2 (anti-inflammatory)
Glatiramer acetate ADME
A: subcutaneous
D: doesn’t cross BBB
Perixaflor mechanism of action
Antagonism of CXCR4 —> block binding of SDF-1a
= interfere with HSC retention in bone marrow
= PERIPHERAL LEUKOCYTOSIS
Perixaflor uses
With FILGRASTIM
- Non-Hodgkin’s lymphoma
- Multiple myeloma
Perixaflor ADME
A: subcutaneous
D: <58% bound
M: n/a
E: urine
Trilaciclib mechanism of action
CDK4 and CDK6 (kinase) inhibitor
= decrease in bone marrow suppression caused by chemotherapy
NOTE: teratogen
Elapegademase mechanism of action
Exogenous adenosine deaminase
= reduction of toxic adenosine
= increase lymphocytes
Elapegademase main use
SCID caused by ADA deficiency
Note: IM administration
Pegademase bovine mechanism of action
Enzyme replacement for adenosine deaminase deficiency
Cyclosporine
Immunosuppressor
Tacrolimus
Immunosuppressor
Sirolimus
Immunosuppressor
Methotrexate
Immunosuppressor
Azathioprine
Immunosuppressor prodrug
Mycophenolate mofetil
Immunosuppressor prodrug
Infliximab
TNFa inhibitor
Adalimumab
TNFa inhibitor
Rituximab
CD20 antagonist
Glatiramer
Immunomodulator
(MS)
Elapegdemase
Exogenous ADA enzyme
(SCID)
Perixaflor
Immunostimulant
(NHL and MM)
Trilaciclib
Reduce myelosuppression by chemotherapy
Kinase inhibitor
(SCLC)
Pegademase
ADA enzyme replacement
(SCID)
