Transplant Pharmacology Flashcards by Kyra Porter

induction therapy in transplants

*a short-term course of immunosuppressive drugs given before/during/immediately after a transplant to reduce the risk of rejection

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maintenance therapy in transplants

*immunosuppressive treatment given after a transplant to prevent acute rejection/loss of transplanted organ

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induction therapy agents - classes/examples

non-lymphocyte depleting: well-tolerated
a. IL-2 receptor antagonists = basiliximab
lymphocyte depleting: MORE POTENT
a. polyclonal antibody preparation = rabbit anti-thymocyte globulin or r-ATG (thymoglobulin)
b. monoclonal antibody preparation = alemtuzumab

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maintenance therapy agents - classes/examples

calcineurin inhibitors (CNIs):
-tacrolimus
-cyclosporine
mTOR inhibitors:
-sirolimus
-everolimus
anti-proliferative/antimetabolite agents:
-mycophenolic acid or mycophenolate mofetil
-azathioprine
corticosteroids = prednisone
belatacept (blocks T cell co-stimulation signal)

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corticosteroids - MOA (general)

*widespread anti-inflammatory effects
*ex: prednisone

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azathioprine - drug class, MOA (general)

*prevents lymphocyte proliferation
*class: anti-proliferative / antimetabolite agent
*used to prevent rejection (maintenance therapy) in renal transplantions

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mycophenolic acid / mycophenolate mofetil - drug class, MOA (general)

*prevents lymphocyte proliferation
*class: anti-proliferative / antimetabolite agent
*used to prevent rejection (maintenance therapy) in renal transplantions

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calcineurin inhibitors - MOA, examples (general)

*block IL-2 gene transcription
*ex: tacrolimus, cyclosporine
*used to prevent rejection (maintenance therapy) in renal transplantions

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mTOR inhibitors - MOA, examples (general)

*blocks IL-2 receptor signal transduction
*ex: sirolimus, everolimus
*used to prevent rejection (maintenance therapy) in renal transplantions

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alemtuzumab - drug class, MOA (general)

*anti-CD52 monoclonal antibody
*MOA: depletion of lymphocytes
*used to prevent rejection (induction therapy) in renal transplantions

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maintenance therapy regimen

*agent 1: CALCINEURIN INHIBITORS, mTOR inhibitors, or belatacept
*agent 2: mycophenolic acid, azathioprine, or mTOR inhibitor
*agent 3: prednisone

most common: calcineurin inhibitor + azathioprine or mycophenolic acid + prednisone

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cyclosporine - drug class, MOA, ADEs

*calcineurin inhibitor
*block IL-2 gene transcription (by binding to cyclosporine-binding protein)
*ADEs: nephrotoxicity, HTN, dyslipidemia, hyperglycemia, headache/tremors, gingival hyperplasia, HIRSUTISM

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tacrolimus - drug class, MOA, ADEs

*calcineurin inhibitor
*block IL-2 gene transcription (by binding to FK506 protein)
*ADEs: nephrotoxicity, HTN, dyslipidemia, hyperglycemia, headache/tremors, ALOPECIA

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drug interactions with calcineurin inhibitors - enzyme inducers

*metabolism via Cytochrome P450 3A4
*enzyme inducers → lower levels of calcineurin inhibitors
1. rifampin
2. phenytoin
3. St John’s-wort

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drug interactions with calcineurin inhibitors - enzyme inhibitors

*metabolism of CNIs via Cytochrome P450 3A4
*enzyme inhibitors → raise levels of calcineurin inhibitors
1. NDHP CCBs - diltiazem, verapamil
2. antifungals - fluconazole, ketoconazole
3. antibiotics - erythromycin, clarithromycin, HAART

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mycophenolate mofetil / mycophenolic acid - MOA

*inhibits de novo purine synthesis via IMP dehydrogenase
*blocks proliferation of T cells and B cells
*used to prevent rejection (maintenance therapy) in renal transplantions

note - do NOT take with magnesium or calcium

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mycophenolate mofetil / mycophenolic acid - ADEs

*diarrhea
*leukopenia, anemia
*teratogenic
*increases risk of skin cancer

note - do NOT take with magnesium or calcium

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azathioprine - MOA

*imidazole derivative of 6-mercaptopurine
*gets incorporated into DNA and inhibits synthesis of RNA in T and B cells
*used to prevent rejection (maintenance therapy) in renal transplantions

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azathioprine - ADEs

*bone marrow suppression (esp leukopenia)
*pancreatitis
*INTERACTION WITH ALLOPURINOL

sirolimus - place in therapy

*second-line agent
*potentially less nephrotoxic than the CNIs

sirolimus - MOA

*binds mTOR (a key regulatory kinase in cell division; blocks the G1-S phase transition)
*antiproliferative and anti-neoplastic

*note - in cases of recurrent skin cancer, reduce dose of antimetabolite first (mycophenolate or azothioprine)

sirolimus - ADEs

*anemia, leukopenia, thrombocytopenia
*DELAYED WOUND HEALING
*LYMPHOCELE FORMATION
*increased cholesterol & triglyceride levels
*proteinuria
*edema
*pneumonitis

corticosteroids (prednisone) - MOA

*prevent transcription of cytokine genes and cytokine receptors
*reduces T-cell activation

corticosteroids (prednisone) - ADEs

*GI ulcerations
*hyperglycemia
*osteoporosis
*acne
*CNS effects
*HTN
*increased appetite
*hyperlipidemia
*other

infections after transplantation: 1st month post-transplant

*similar infections to non-immunosuppressed surgical patients: -wound infections -urinary tract infections -line-related infections

infections after transplantation: months 1-6 post-transplant

*cytomegalovirus (CMV) *polyoma virus (BK) *urinary tract infections

infections after transplantation: > 6 months post-transplant

*urinary tract infections, community-acquired pneumonia *BK virus, CMV *OPPORTUNISTIC INFECTIONS & REACTIVATION: Listeria monocytogenes, Nocardia, TB, etc

CMV infection - presentation

*acute viral syndrome with leukopenia *tissue invasive disease: hepatitis, pneumonitis (cough, dyspnea), pancreatitis, colitis (diarrhea)

CMV infection - risk factors

*CMV seronegative (no prior immunity) ***HIGHEST RISK: donor seropositive, recipient seronegative** *recent treatment with lymphocyte-depleting agent (induction phase therapy for transplant)

CMV infection - diagnosis

*demonstration of CMV viremia by PCR

CMV infection - prophylaxis & treatment

*prophylaxis: valganciclovir, letermovir *tx: IV ganciclovir or oral valganciclovir (MOA - inhibits viral DNA synthesis) *resistant CMV infection: foscarnet or MARIBAVIR

polyoma virus (BK virus) - presentation

*typically ASYMPTOMATIC *can cause renal failure, hemorrhagic cystitis

polyoma virus (BK virus) - risk factors

*older age *recent treatment for rejection

polyoma virus (BK virus) - diagnosis

*demonstration of BKV viremia by PCR *demonstration of BK nephropathy (mimics cellular rejection but SV40 stain positive and has inclusion bodies) by allograft biopsy

polyoma virus (BK virus) - treatment

***reduction of immunosuppression** *IVIG, cidofovir?

infection prophylaxis in transplant patients - antifungals

*prevent oral and esophageal candidiasis *fluconazole, clotrimazole *main ADEs = LIVER DYSFUNCTION, HIGH TACROLIMUS LEVEL

infection prophylaxis in transplant patients - vangalciclovir

*prevents CMV infection *high risk (+/-_ vs. low risk donor/recipient serologies = 6 months *letermovir is an alternative / second-line agent *main ADE = LEUKOPENIA

infection prophylaxis in transplant patients - trimethoprim-sulfamethoxazole (TMP-SMX or Bactrim)

*prevents against: -pneumocytsitis jirovecii -Nocardia/toxoplasma -UTIs *alternatives: pentamidine, dapsone, atovaquone *main ADE = HYPERKALEMIA

common malignancies after transplantation

*immunosuppressive medications increase risk of certain malignancies 1. non-melanoma skin cancers (BCC, SCC) - account for > 50% of all malignancies in transplant recipients 2. post-transplant lymphoproliferative disorder (PTLD) - usually arises after primary infection or reactivation of latent EBV infection

causes of early graft dysfunction

*vascular issues *extrinsic compression *acute tubular necrosis *acute pyelonephritis *DRUG TOXICITY - CALCINEURIN INHIBITOR RELATED *acute rejection *urinary obstruction/leaks

causes of later (>3 months) graft dysfunction

1. intrinsic renal process: -chronic rejection, chronic drug toxicity, late acute rejection, BK virus, transplant pyelonephritis, etc 2. mechanical: ureteral obstruction or stricture

features of acute calcineurin inhibitor (CNI) toxicity

*reduced renal blood flow (vasoconstriction) *tubular toxicity (vacuolization) *association with genes controlling intracellular concentration of CNI in kidney

features of chronic calcineurin inhibitor (CNI) toxicity

*stripe-like interstitial fibrosis *secondary FSGS glomerular lesions *renal failure after non-renal solid organ transplant

T-cell mediated rejection (TCMR) - Banff Criteria

*borderline tubulitis *1A/B: tubulitis 5-10 or > 10 inflammatory cells per tubule *2A/B: endothelitis/endovasculitis *3: transmural infarction

T-cell mediated rejection (TCMR) - treatment

*steroids *rabbit antithymocyte globulin (ATG) for stages 1B and above

antibody-mediated rejection (AMR) - diagnostic criteria

*histology: peritubular capillaritis *detection of C4d deposition on biopsy *positive DSA (donor specific antibodies) titers

antibody-mediated rejection (AMR) - treatment

*plasmapheresis/IVIG *rituximab (anti-CD20): targets B lymphocytes *anti C5 antibody (eculizimab)