Immunosupressants Flashcards
Induction Therapy for Organ Transplants
Depleting Agents - rATG or Alemtuzumab
Nondepleting agent - Basiliximab
Maintenance therapy for organ transplantation
prevention of acute organ rejection
- a calcineurin inhibitor
- an antimetabolite
- a glucocorticoid
General Rx for T cell mediated rejection
Glucocorticoid (high dose pulse followed by tapering dose)
rATG
General Rx for Antibody-mediated rejection
Glucocorticoid, high-dose pulse,
then oral taper
IVIG
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?
Lung transplant - glucocorticoid therapy is delayed for several weeks to allow healing of the bronchial anastomosis
Liver- requires less immunosuppression therapy than other organs
rATG [Thymoglobulin]
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.
rATG Adverse Effects
Common:
Fever, chills, leukopenia,
thrombocytopenia, headache
Serum sickness
infusion reaction - flu-like symptoms, cytokine release syndrome, local site reactions
infection and malignancy
Serum sickness
Type III Hypersensitivity
Rash, pruritus, fever, lymphadenopathy, hypotension
Alemtuzumab
Anti-CD52 monoclonal antibody
induces direct antibody dependent cellular cytotoxicity and complement-mediated lysis
Causes depletion of T and B cells
Adverse Effects of Alemtuzumab
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
Baxiliximab
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
Glucocorticoids
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
Therapeutic Uses of Glucocorticoids
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
Adverse Effects of Glucocorticoids
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)
Calcineurin Inhibitors
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
Uses of Cyclosporine / Tacrolimus
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
Which calcineurin inhibitor has become the preferred agent and why?
decreased acute rejection rates - more potent and better efficacy
better tolerated
Toxicities of calcineurin inhibitors
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
Calcineurin Inhibitors: Drug Interactions
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
CYP3A4 Inducers
- Carbamazepine
- Phenobarbital
- Phenytoin
- Rifampin
- Efavirenz
- St. John’s wort
CYP3A4 Inhibitors
- Verapamil, diltiazem
- Azole antifungals
- Macrolide antibiotics
- Dexamethasone
- HIV and HCV protease inhibitors
- Grapefruit juice (CYP3A4 and P-glycoprotein)
Cyclosporine + sirolimus
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
Tacrolimus + sirolimus
DO NOT GIVE TOGETHER
They enhance the toxic effects of eachother
Sirolimus decreased serum concentrations of tacrolimus
Mycophenolate mofetil
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
Therapeutic uses of Mycophenolate mofetil
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
Toxicities of mycophenolate mofetil
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
Azathioprine
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
Therapeutic Uses of Azathioprine
Prophylaxis of organ rejection - combination with calcineurin inhibitor + AZA + glucocorticoid
RA
IBS
Acute glomerulonephritis
Azathioprine Toxicities / Drug Interactions
Major effects are bone marrow suppression (leukopenia) and hepatoxicity
increased infection and malignancy risk
acute pancreatitis
skin rashes, diarrhea, nausea, vomiting
safe in pregnancy
Azathioprine Drug Interactions
Allopurinol / Febuxostat
(Xanthine oxidase inhibitors)
↓ AZA inactivation»_space;> shunt AZA to HGPRT pathway»_space;>
Increased AZA toxicity
Belatacept
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)
Sirolimus / Everolimus
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
Therapeutic Uses of mTOR Inhibitors
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
Sirolimus Toxicities
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
Sirolimus Drug Interactions
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
