Immunosuppressive Therapy

Front 1

Phases of the Inflammatory Response

Back 1

Phases of the Inflammatory Response
1. Vasodilation - redness and local heat
2. Plasma extravasation - swelling
3. Leukocyte infiltration - very active process
- Vascular recruitment of immune cells
- Migration (chemotaxis)
- Innate or adaptive immunity
4. Wound healing (resolution)

Front 2

Glucocorticoids
Mechanism of action?
Typical Drug of Use?
Clinical Uses?

Back 2

Glucocorticoids

Mechanism of action: Prevent the production of cytokines. Used with other immunosuppressive agents to prevent and treat transplant rejection.

Drug of use:
1. High dose Methylprednisone (i.v.) for acute transplant rejection

Clinical Uses:
1. Efficacious in graft vs. host disease
2. Used in autoimmune disorders
3. Extensive long-term use limited by toxicity

Front 3

Cyclosporine
Class?
Mechanism of action?
Clinical Uses?

Back 3

Cyclosporine
Class: Calcineurin inhibitor - Inhibitor of T cell mediated immunity.

Mechanism of action: Cyclosporin binds to cyclophilin and this inhibits production of IL-2 by blocking dephosphorylation of nuclear factor of activated T-cells (NFAT) by calcineurin, thus NFAT does not enter the nucleus.

Clinical Uses:
1. Organ transplantants and usually in combination with glucocorticoids, antimetabolites
2. Used in severe Rheumatoid arthritis

Front 4

Cyclosporine Toxicity

Back 4

Cyclosporine Toxicity
1. Nephotoxicity occurs in most patients
2. Hypertension
3. Neurotoxicity
4. Hepatoxicity
5. Hyperlipidemia
6. Hirsutism, gum hyperplasia

Front 5

Cyclosporine Pharmacokinetics

Back 5

Cyclosporine Pharmacokinetics

Administered i.v. or orally

Oral absorption slow with 20 – 50% bioavailability

Extensively metabolized by CYP3A, thus drug interactions with other drugs metabolized by CYP3A including glucocorticoids, verapamil, and many more

Note: grapefruit juice inhibits CYP3A

Front 6

Tacrolimus
Class?
Mechanism of Action?
Clinical Uses?
Toxicity?

Back 6

Tacrolimus
Class: Calcineurin Inhibitor

Mechanism: Most potent immunosuppressant with same mechanism as cyclosporine except that it binds to FK binding protein

- Metabolized by CYP3A4 (interactions with Cyclosporine)

Clinical Uses: Used for transplantation and rescue therapy in patients with rejection episodes

Toxicity:
1. Nephrotoxicity, neurotoxicity (headache, tremor, seizures), and other similar to cyclosporine
2. Must monitor due to high potential for nephrotoxicity.

Front 7

Sirolimus (Rapamycin)
Class?
Mechanism?
Clinical Uses?
Toxicity?

Back 7

Sirolimus (Rapamycin)
Class: Lymphocyte Signaling inhibitor

Mechanism: Binds to FKBP but complex does not inhibt calcineurin, rather blocks IL-2 receptor signaling and arrests cell division by blocking the kinase mTOR (molecular target of rapamycin)

Clinical uses:
1. Prophylaxis in organ rejection
2. Other therapies especially in patients with high risk for nephrotoxicity

Note: Metabolized by CYP3A4 so be aware of potential drug interactions

Toxicity:
1. Hyperlipidemia
2. Leukopenia
3. Thrombocytopenia
4. Aggravates cyclosporine renal dysfunction so do not co-administer
5. Typically develops cytotoxicity on its own

Front 8

Azathiopurine
Class?
Mechanism?
Clinical uses?
Toxicity?

Back 8

Azathiopurine
Class: Antiproliferator/antimetabolite

Mechanism: Prodrug of purine analog mercaptpurine which inhibits gene translation
- Azathiopurine is more effective than mercaptopurine as an immunosuppressant (Pharmacokinetics/slow release of 6-MP)

Toxicity:
1. Bone marrow suppression
2. Increased Susceptibility to infection

Front 9

Methotrexate
Class?
Mechanism?

Back 9

Methotrexate
Class: Antiproliferator/antimetabolite

Mechanism: Inhibits DHFR

Clinical Use:
1. Folate analog used as anticancer drug
2. Rheumatoid arthritis
3. Graft vs. host disease

Has cytotoxic and anti-inflammatory activity

Front 10

Mycophenolic Acid, Mycophenolate Mofetil
Class?
Mechanism?
Clinical uses?
Toxicity?

Back 10

Mycophenolic Acid, Mycophenolate Mofetil
Class: Antiproliferators/Antimetabolites

Mechanism:
1. Mycophenolic acid inhibits inosine monophosphate dehydrogenase (IMPDH); rate enzyme in guanosine formation
2. Mycophenolic acid preferentially affects lymphocytes since:
- Lymphocytes depend on IMPDH for purine synthesis
- MA preferentially inhibits IMPDH II which is highly expressed in lymphocytes

Mycophenolate Mofetil is a prodrug for Mycophenolic acid with higher bioavailability

Clinical Use:
1. Transplant rejection with glucocorticoids and calcineurin inhibitors but not Azathiopurine.

Toxicity:
1. Vomiting, Diarrhea
2. Leukopenia
3. Increased risk of infection

Front 11

Anti-thymocyte Globulin
Class?
Mechanism?
Clinical uses?
Toxicity?

Back 11

Anti-thymocyte Globulin
Class: antibody - polyclonal antibodies from rabbit injected with thymocytes.

Mechanism:
1. Contains antibodies to T-cell antigens (CDs) and thus helps to deplete circulating Lymphocytes
2. Used for induction of immunosuppression and acute renal rejection
3. Can be used for delayed graft rejection in renal transplant patients to avoid early use of calcineurin inhibitors or for withdrawal of calcineurin inhibitors.

Toxicity:
1. CYTOKINE RELEASE SYNDROME
- Fever, headache, tremor, nausea/vomiting, malaise, and general weakness
- Cytokine release syndrome looks a lot like sepsis

Front 12

OKT3
Class?
Mechanism?
Clinical uses?
Toxicity?

Back 12

OKT3 (Muromonab-CD-3, anti-CD3)

Mechanism:
1. Mouse monoclonal antibody against human CD-3
2. Depletes available pool of T cells

Clinical Use:
1. Indicated for organ transplant rejcetion

Toxicity:
1. Cytokine Release syndrome
2. Infection
3. Mouse antibody so production of antibodies in host (limits effects)
4. Potentially fatal pulmonary edema, cardiovascular collapse and arrhythmias occur

Front 13

Daclizumab/Basiliximab
Class?
Mechanism?
Clinical uses?
Toxicity?

Back 13

Daclizumab/Basiliximab
Class: Humanize Monoclonal Antibody

Mechanism:
1. Humanized anti-CD25 mouse monoclonal antibodies
2. Binds to IL-2 receptor on activated T-cells

Clinical use:
1. Daclizumab given prophylactically for renal transplants and with other immunsuppressants
2. Basiliximab has higher affinity

Toxicity:
1. Infection
2. Anaphylactic reactions