Immunosupressants

Question 1

Induction Therapy for Organ Transplants

Answer 1

Depleting Agents - rATG or Alemtuzumab

Nondepleting agent - Basiliximab

Question 2

Maintenance therapy for organ transplantation

Answer 2

prevention of acute organ rejection

1. a calcineurin inhibitor
2. an antimetabolite
3. a glucocorticoid

Question 3

General Rx for T cell mediated rejection

Answer 3

Glucocorticoid (high dose pulse followed by tapering dose)

rATG

Question 4

General Rx for Antibody-mediated rejection

Answer 4

Glucocorticoid, high-dose pulse,
then oral taper

IVIG

Question 5

The risk of rejection is highest after transplant, in general it is important to start with a potent anti-lymphocyte agent. There are two exceptions to this protocol, what are they?

Answer 5

Lung transplant - glucocorticoid therapy is delayed for several weeks to allow healing of the bronchial anastomosis

Liver- requires less immunosuppression therapy than other organs

Question 6

rATG [Thymoglobulin]

Answer 6

Purified gamma globulin

bind a variety proteins on the surface of human T lymphocytes

Work by direct cytotoxicity through complement and cell mediated measures and the blockage of lymphocyte function by binding surface molecules.

Question 7

rATG Adverse Effects

Answer 7

Common:
Fever, chills, leukopenia,
thrombocytopenia, headache

Serum sickness

infusion reaction - flu-like symptoms, cytokine release syndrome, local site reactions

infection and malignancy

Question 8

Serum sickness

Answer 8

Type III Hypersensitivity

Rash, pruritus, fever, lymphadenopathy, hypotension

Question 9

Alemtuzumab

Answer 9

Anti-CD52 monoclonal antibody

induces direct antibody dependent cellular cytotoxicity and complement-mediated lysis

Causes depletion of T and B cells

Question 10

Adverse Effects of Alemtuzumab

Answer 10

Common - nausea, vomiting, diarrhea, headache and insomnia

Autoimmune - hemolytic anemia, thrombocytopenia, antiglomerular basement membrane disease

infusion reaction - flu-like symptoms, cytokine release syndrome, local site reactions

Infection and Malignancy

Question 11

Baxiliximab

Answer 11

Anti-IL2Rα (anti-CD-25) Antibodies - binds the IL-2R of T cells preventing T cell activation and proliferation

Used with glucocorticoid and cyclosporine for induction therapy for renal, heart, liver, and lung transplants

2 doses on day 0 and day 4

also used refractory for acute GVHD

potential toxicities - anaphylaxis, infections, lymphoproliferative disorder (EBV+)

There is no cytokine release syndrome or drug interactions

Question 12

Glucocorticoids

Answer 12

Prednisone, Prednisolone, Methylprednisolone, Dexamethasone

Binds to nuclear elements causing transrepression or transactivation of genes

broad anti-inflammatory effects - inhibition of prostaglandin and lipoxygenase synthesis, inhibition of T cell proliferation, humoral immunity dampened but not to a significant degree

↓ IL-1; IL-6; IL-2

Question 13

Therapeutic Uses of Glucocorticoids

Answer 13

Prevention of transplant rejection - induction and maintenance of allograft, Acute Transplant Rejection

GVHD prevention and treatment

management of cytokine release syndrome and infusion reactions

suppression of other immunologically mediated disorders

Question 14

Adverse Effects of Glucocorticoids

Answer 14

Impaired immunity, increased risk of infection, delayed wound healing, hyperglycemia, increased plasma cholesterol, increased BP and salt retention

Delayed effects - peptic ulcers, cushing effects (mood face, nuchal fat, weight gain, muscle wasting and osteoporosis, hirsuitism, cataracts)

Question 15

Calcineurin Inhibitors

Answer 15

Cyclosporine - t½ 10-27 hrs
Tacrolimus - t½ 3-40 hrs

Oral, IV, high protein binding and substrates of CYP3A4 and p-glycoprotein

Requires monitoring plasma concentrations

Question 16

Uses of Cyclosporine / Tacrolimus

Answer 16

High efficacy - prophylaxis of solid organ allograft rejection

treatment of GVHD after bone marrow transplant

also - inflammatory diseases, cyclosporine can be used as ophthalmic drops for uveitis and tacrolimus can be used topically for atopic dermatitis or psoriasis

Question 17

Which calcineurin inhibitor has become the preferred agent and why?

Answer 17

decreased acute rejection rates - more potent and better efficacy

better tolerated

Question 18

Toxicities of calcineurin inhibitors

Answer 18

Nephrotoxicity - vasoconstriction of afferent renal arteriole and interstitial fibrosis of parenchyma

Hypertension

neurotoxicity - tremor, paresthesia, headache, confusion and seizures

hepatoxicity

hyperglycemia - risk for DM with concurrent glucocorticoid use

hyperkalemia, diarrhea, nausea, vomiting

infection and malignancy

cyclosporine specific - hyperuricemia, hyperlipidemia, gum hyperplasia and hirsuitism

Question 19

Calcineurin Inhibitors: Drug Interactions

Answer 19

High potential for drug interactions - interacts with CYP3A4 and P-glycoprotein inducers or inhibitors

With any drug that also causes nephrotoxicity, neurotoxicity

These drugs are not used together

Question 20

CYP3A4 Inducers

Answer 20

• Carbamazepine
• Phenobarbital
• Phenytoin
• Rifampin
• Efavirenz
• St. John’s wort

Question 21

CYP3A4 Inhibitors

Answer 21

• Verapamil, diltiazem
• Azole antifungals
• Macrolide antibiotics
• Dexamethasone
• HIV and HCV protease inhibitors
• Grapefruit juice (CYP3A4 and P-glycoprotein)

Question 22

Cyclosporine + sirolimus

Answer 22

sirolimus must be administured 4 hours after cyclosporin

sirolimus aggravates cyclosporin-induced renal dysfuction

cyclosporin causes increased sirolimus concentration which enhances sirolimus incduced anemia, leukopenia, thrombocyptopenia, hypokalemia and diarrhea

Question 23

Tacrolimus + sirolimus

Answer 23

DO NOT GIVE TOGETHER

They enhance the toxic effects of eachother

Sirolimus decreased serum concentrations of tacrolimus

Question 24

Mycophenolate mofetil

Answer 24

Antimetabolites - Oral, IV prodrug > converted to mycophenolic acid

hepatic glucoronidation with renal excretion, half life 17 hrs

MOA - selective, uncompetitive, reversible inosine monophosphate dehydrogenase inhibition which further inhibits guanine synthesis trapping the cell in G1-S phase leading to apoptosis

Decreases lymphocyte function and T cell mediated and B cell proliferation and function

Question 25

Therapeutic uses of Mycophenolate mofetil

Answer 25

Prophylaxis of organ rejection - renal, cardiac, hepatic used in combination with calcineurin inhibitor and glucocorticoid largely replaced azathioprine in prophylaxis Prophylaxis / treatment GVHD Treatment of psoriasis, lupus, myasthenia gravis etc

Question 26

Toxicities of mycophenolate mofetil

Answer 26

``` Leukopenia pure red cell aplasia increased infection and malignancy risk diarrhea, nausea and vomiting teratogenic ``` antacids and cholestyramine impair absorption probenecid and some antiviral agents compete for tubular secretion any drug with additive toxicities

Question 27

Azathioprine

Answer 27

antimetabolite Oral Prodrug metabolized to 6-mercaptopurine metabolized by xanthine oxidase and thiopurine methyltransferase with renal excretion TPMT def - life-threatening myelosuppression t1/2 of AZA ~10 minutes; t1/2 of 6-MP ~1 hour toxic metabolites inhibits de novo purine synthesis 6-TGTP is incorporated into DNA of proliferating cells and induces strand breaks and base mispairing

Question 28

Therapeutic Uses of Azathioprine

Answer 28

Prophylaxis of organ rejection - combination with calcineurin inhibitor + AZA + glucocorticoid RA IBS Acute glomerulonephritis

Question 29

Azathioprine Toxicities / Drug Interactions

Answer 29

Major effects are bone marrow suppression (leukopenia) and hepatoxicity increased infection and malignancy risk acute pancreatitis skin rashes, diarrhea, nausea, vomiting safe in pregnancy

Question 30

Azathioprine Drug Interactions

Answer 30

Allopurinol / Febuxostat (Xanthine oxidase inhibitors) ↓ AZA inactivation >>> shunt AZA to HGPRT pathway >>> Increased AZA toxicity

Question 31

Belatacept

Answer 31

Selective T cell Costimulation Blocker CTLA4 analog that binds CD80/86 and inhibits T cell activation, cytokine production and proliferation Used for Induction and maintenance therapy / prophylaxis of acute organ rejection in kidney transplant patients who are seropositive for EBV combination therapy - basiliximab, mycophenolate and corticosteroids Adverse effects are post-transplant lymphoproliferative disorders (EBV infection) or progressive multifocal leukoencephalopathy (JC virus)

Question 32

Sirolimus / Everolimus

Answer 32

mTOR Inhibitors - Oral, low bioavailability, required serum level monitoring p-glycoprotein, CYP3A4 with fecal excretion causes cell cycle arrest in G1 phase and inhibition of cell growth, proliferation, angiogenesis, and metabolism drug complexes with FK-binding protein and mTOR

Question 33

Therapeutic Uses of mTOR Inhibitors

Answer 33

Sirolimus / Everolimus Renal transplant -- along with reduced-dose calcineurin inhibitor and glucocorticoids CNI-sparing regimen: Cyclosporine-tapering after 4-8 weeks only (for pts with little risk) cardiac and lung transplantation -- delay treatment until surgical wounds heal prevention and treatment of GVHD Used in drug-eluting coronary stents to inhibit cell proliferation and blood cell occlusion but not hepatic transplants - increased mortality

Question 34

Sirolimus Toxicities

Answer 34

Profound myelosuppression - thrombocytopenia, anemia and leukopenia -impaired wound healing and dehiscence hepatotoxicity - fatal haptic necrosis increases TAGs and cholesterol Peripheral edema, lymphedema, pleural effusion, pericardial effusions; pneuomonitis Diarrhea, nausea, vomiting; headache; arthralgia; aphthous ulcers; acne

Question 35

Sirolimus Drug Interactions

Answer 35

CYP3A4 / P-gp inducers / inhibitors when used with calcineurin inhibitor > renal deterioration, hyperTAGs, hemolytic uremic syndrome and increase in sirolimus concentration Tacrolimus + Sirolimus competition at CYP3A4, P-gp