Immune Modulators Flashcards by Ana Sofía Caballero Zambrano

Action time of prednisone

Intermediate acting
12-36 hrs

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Action time of prednisolone and what makes it different from prednisone?

12-36 hours
This one also has parenteral administration

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Dexamethasone acting time

Long acting
36 - 72 hours

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Differences between prednisone and dexamethasone

Dexamethasone
- Long acting >36 hrs
- Can be given in oral, parenteral, and topical forms

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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

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Glucocorticoid uses (4)

Transplant
GvHD
Autoimmune diseases: SLE, RA, SD, psoriasis, asthma
IBD

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Glucocorticoids main side effect

Growth retardation (adeno atrophy) or Cushing’s

Others:
- Avascular bone necrosis
- Osteopenia, osteoporosis
- Cataracts
- Hypertension
- Hyperglycemia
- Hypercholesterolemia

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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

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Immunosuppresor uses (3)

Transplant
Autoimmune: RA, Crohn, psoriasis, nephrotic sx, asthma, DM type I, etc.
GvHD

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Cyclosporine ADME

A: 50% available oral or IM
D: 50-60% in RBC or lymphocytes. Highly lipophilic.
M: CYP3A4
E: bile/feces, breast milk

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Cyclosporine side effects NHLTG

Nephrotoxicity
Hirsutism
LDL increase
Tremor
Gum hyperplasia

Others: hypertension, hyperK, hyper uric acid, viral infections, hyperglycemia

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Meds that decrease cyclosporine concentration (3)

Phenobarbital
Phenytoin
Rifampin

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Meds that decrease cyclosporine clearance (3)

Erythromycin
Ketoconazole
Grapefruit

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Can cyclosporine and sirolimus be given together?

Yes but with time between.

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Between cyclosporine, tacrolimus, and sirolimus, which is more potent?

Tacrolimus

*more toxic also

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Tacrolimus mechanism of action

Also known as FK506, it’s an immunophilin that:
1. Binds to FKBP
2. Inhibit calcineurin phosphatase

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Tacrolimus ADME

A: food decreases absorption. Oral or IM
D: 75-99% protein bound
M: CYP3A
E: fecal

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Tacrolimus side effects

Nephro and neurotoxicity
Hyper K
Hypertension
Hyperglycemia and DIABETES when combined with glucocorticoids

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What medication type is rapamycin?

Sirolimus

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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

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Sirolimus ADME

A: 15% availability oral
D: bound to albumin 40%
M: CYP3A4
E: feces

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Which has less renal toxicity: calcineurin inhibitors or proliferation inhibitors (sirolimus)?

Sirolimus

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Sirolimus toxicity

Tolerizing effects
- Nephrotox
- HYPERLIPIDEMIA
- Hypertension
- Worsen proteinuria
- Lymphocele
- PANCYTOPENIA
- Mouth ulcers

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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

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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)