Immunosuppressant drugs Flashcards
Induction, maintenance and rejection therapy
Induction therapy –> initial therapy used at the beginning of a transplant
- results in the rapid onset of relatively intense immunosuppression
- typically accomplished with a combo of corticosteroids and antibody-based drugs
Maintenance immunosuppression –> medications taken on a chronic basis to prevent acute rejection
- commonly involves a combo of drugs which have different mechanisms of action
Rejection therapy –> treatment of an episode of acute rejection
- typically involves lymphocyte depleting antibody based drugs or high dose corticosteroids
Non-lymphocyte depleting antibody drugs
Antibodies which block lymphocyte function but do not result in removal of lymphocytes from the circulation
Basiliximab –> anti-CD 25 antibody (CD-25 = IL2 receptor)
- induction therapy
- chimeric antibody
- minimal acute toxicities and is given IV in 2 doses for induction
- results in blockade of immune activation and lymphocyte responses
- long half life
Lymphocyte depleting antibody drugs
Result in the removal of lymphocytes from the circulation
- used for induction or therapy of acute rejection
Thymoglobulin –> rabbit polyclonal AB against human thymus tissue
- results in removal of T lymphocytes from the circulation by the reticuloendothelial system
- contains a variety of AB specificities and cross reacts with platelets and other leukocytes resulting in thrombocytopenia and leucopenia
- infusion related side effects - tachycardia, hypotension, flushing, pulm edema
- infection risks require antimicrobial + antiviral prophylaxis
Alemtuzumab –> humanized monoclonal AB directed at CD-52 = expressed on lymphocytes and monocytes, unknown function
- FDA approved for hematologic malignancies but is used as an induction agent in solid organ transplant
- peripheral and central lymphocyte depletion following a dose is very prolonged
- minimal side effects during infusion
- used for induction
- infection risks require prophylaxis
Calcineurin inhibitors
Tacrolimus + cycosporine –> used for maintenance of immunosuppression
- bind to cyclophyllins = ubiquitous cytosolic proteins –> drug-cyclophyllin complex interacts with calcineurin = a phosphatase that dephosphorylates NFAT
- NFAT translocates to the cell nucleus and controls the production of IL2
- inhibition of this pathway by these drugs interferes with T cell activation
- widely used and the cornerstone of immunosuppression drug regimens
Calcineurin inhibitor side effects
Common to both
- neprhotoxicity
- type 4 RTA
- hyperkalemia
- hypomg
- hypophosphatemia
- thrombotic microangiopathy
Cyclosporin
- hirsutism
- hyperlipidemia
- hyperuricemia/gout
- gingival hyperplasia
Tacrolimus
- neurotoxic
- tremor
- hyperglycemia/new onset DB
- alopecia
- diarrhea
Narrow therapeutic window - blood level must be carefully monitored
mTOR inhibitors
Sirolimus/everolimus –> used for maintenance of immunosuppression
- targets down stream metabolic pathways that control responses to growth factors and interleukins
- also binds to a cyclophyllin –> complex inhibits mTOR = a central enzyme that regulates cell responses to a wide variety of growth factors
- regulates the balance between cell survival signaling and apoptosis signaling –> controls cell cycle progression
- inhibition of mTOR affects lymphocyte responses to immunologic stimulation –> interferes with protein + DNA synthesis, and prevents entry of the cell into the cell cycle
- may result in lymphocyte apoptosis
Sirolimus side effects
- proteinuria
- delayed recovery from ATN
- hyperlipidemia
- delayed wound healing
- lymphoceles
- thrombocytopenia
- pneumonitis
- oral ulcers
Antimetabolites
Azathioprine –> prodrug which is converted to active 6 mercaptopurine
- depletes purine nucleotides + is incorporated into replicating DNA which interferes with DNA synthesis and the proliferative response of lymphocytes to immmunologic stimulation
- now largely replaced by mycophenolate mofetil –> prodrug converted to active form = mycophenolic acid
Mycophenolic acid –> used as a maintenace immunosuppressive drug
- inhibitor of the de novo pathway of purine biosynthesis by inhibiting enzyme inosine monophosphate dehydrogenase
- prevents the generation of purine nucleotides and interferes with DNA synthesis
- lymphocytes are dependent on the de novo pathway of purine synthesis –> most other cell types can also utilize the salvage pathway of purine synthesis, so lymphocytes are uniquely sensitive to the inhibitory effects
Side effects of azathioprine + mycophenolic acid
Azathioprine / 6MP
- myelotoxic - especially leukopenia, thrombocytopenia
- sensitizes to UV radiation
- malignancy risk - esp skin cancer
- important reaction with allopurinol
Mycophenolic acid - Commonly limit dosing
- leucopenia
- anemia
- GI toxicity –> nausea, vomiting, diarrhea
Corticosteroids
Prednisone
- used for induction, maintenance and treatment of acute rejection
- liphophylic and tranverse the cell membrane where they combine with receptors in the cytoplasm –> in combo with the cytoplasmic receptor corticosteroids enter the nucleus where they bind to the promoter regions of various transcription factors
- affect protein synthesis and metabolic functions which control many aspects of the inflammatory response
- block recruitment of inflammatory cells and down regulate adhesion molecules
High, dose related side effect profile
- hyperglycemia
- hypertension
- avascular necrosis of bone
- cataract formation
- weight gain
- adrenal suppression
- cushings
- acne
Belatacept
Newer biologic developed for maintenance of immunosuppression
- recombinant immunoglobulin fusion protein –> combines a modified extracellular portion of CD-152 (CTLA4) with a constant region (Fc) fragment of human IgG
- has affinity for the surface co-stimulatory ligands B7 on APCs –> blocks the B7 interaction with CD28 on T cells = a major pathway of costimulation required for t cell activation
No drug interactions and has a half life of about 8 days
- given as a monthly IV infusion
- not nephrotoxic but has a higher incidence of cellular rejection and post transplant lymphoma compared to cyclosporine or tacrolimus
Special circumstances = rejection
Intense immunosuppression - solumdedrol/prednisone taper, thymoglobulin, IVIg
- reintensify maintenance regimen
Special circumstances - infection
- Life threatening - reduce or cease immunosuppression
- CMV - stop anti-proliferative agent
- polyoma virus - reduce immunosuppression monitoring urine cytology and BK/JC viral load
Prevention is key
- prophylactic ABs
- vaccinations
- early tx
- monitoring for polyoma
Special circumstances - malignancy
- PTLD, hematologic malignancies, malignant melanoma, cervical cancer –> dramatically reduce IS
- solid tumors - reduce IS at least modestly
- skin cancers - azathioprine may be esp. problematic
- sirolimus - antiproliferative/antitumor properties
Prevention
- age appropriate screening
- PAPs
- sun protection
- antivirals/serial EBV viral load monitoring if EBV +
Special circumstances - pregnancy
cyclosporine/tacrolimus, azathioprine and prednisone are generally favored
