Organ Transplant

Prophylactic anti-infective medications added to transplant medication regimen

  • Leukocytes provide nonspecific immunity
    • Neutrophils/eosinophils engulf & destroy              basophils /mast cells secrete inflammatory mediators
  • Macrophages & monocytes provide specific immunity by attracting lymphocytes
  • Lymphocytes (T cells & B cells) amplify response, provide specific & memory immunity
  • IgM:  secreted on first exposure to a pathogen
  • IgG:  secreted on first & on subsequent exposures
  • IgA:  found in body fluid excretions & in the mucosa of the GI tract
  • IgE:  combines with mast cells to release inflammatory mediators
  • IgD:  undetermined function

Pharmacology of immunosuppressive agents

  • Calcineurin inhibitors:  cyclosporine A (sandimmune, Neoral), tacrolimus (prograf)
    • “backbone of transplant immunosuppression)
    • MOA:  reversibly inhibits T-lymphocyte (T helper cells) activation & proliferation by ultimately inhibiting the production of IL-2
      • Also has minimal activity against B cells
    • Used for maintenance therapy, NOT acute rejection (little effect on cytotoxic T cells)
    • Time & dose dependent inhibition of T cell proliferation
    • Sandimmune lipophilic oil in water formulation in which bioavailability varies (4-89%)
      • Bile is needed to absorb Sandimmune   & food delays its absorption
      • 5-15 mg/kg in two divided doses
      • Can be mixed with chocolate milk or OJ but need to avoid grapefruit juice  (avoid hot/cold temps, open bottle is good for 2 months)
      • Compliance is an issue
    • Neoral (microemulsion formulation) has much more consistent bioavailability b/c it’s levels aren’t affected by bile or food.  Reaches higher peak concentrations quicker than sandimmune
      • 2-10 mg/kg in 2 divided doses
      • Can be mixed with chocolate milk or OJ but need to avoid grapefruit juice  (avoid hot/cold temps, open bottle is good for 2 months)
      • Compliance is an issue
      • Neoral and Sandimmune are NOT interchangable
    • Cyclosporine is highly lipid soluble and highly protein bound (lots of DDIs) & it undergoes enterohepatic recycling
    • Metabolized by 3A4 & P-GP; Lots of metabolites (& DDIs)
    • Pediatric clearance of cyclosporine is higher than adults
    • IV formulation:  4-6 mg/kg/day given over 206 hours
      • Need to mix in a glass bottle & not use any PVC products as leaching & toxic products may occur
    • Therapeutic trough levels:  100-400 ng/mL  (higher at first right after transplant, monitor whole blood concentrations daily)
    • Cyclosporine-A induced (graft rejection) nephrotoxicity usually occurs at greater than 6 weeks post-transplant
      • The only way to truly distinguish between this drug effect & acute rejection of the kidney is via a renal biopsy
    • 50-90% of patients on cyclosporine will develop HTN
      • The treatment of choice in HTN patients on cyclosporine is CCB (BB are 2nd line)
        • Avoid ACE-I & ARBs b/c of risk of hyperkalemia & decreased GFR
    • Hyperglycemia & hyperlipidemia have both been shown to increase in patients on cyclosporine-A
      • Need to treat hyperlipidemia aggressively due to an increased potential for vessel disease
    • Other SE of cyclosporine A:  tremor & paresthesias (most common CNS symptom of toxicity), dermatological (hirsutism & gingival hyperplasia)
  • Tacrolimus (aka prograf aka FK506) causes immunosuppression similar to cyclosporine A but it also binds to FK binding protein (100x more potent than cyclosporine)
    • Erratic bioavailability (doesn’t require bile for absorption though)
    • Like cyclosporine, tacrolimus is also highly lipophilic & highly protein bound
    • Metabolized by 3A4 (DDIs)
    • IV:  0.03 to 0.1 mg/kg/day as a 24 hours continuous infusion (also mix in glass)
    • PO:  1-10 mg po BID
      • IV to PO conversion isn’t 1:1   (IV dose is roughly 1/3 of oral dose)
    • Like cyclosporine, monitor whole blood rather than [serum]
    • Trough levels = 5-40 ng/mL  (use higher concentration in liver transplant pts)
    • SE:  nephrotoxic (Narrow TI), hepatotoxic (at higher concentrations), HTN (less so than cyclosporine though), CNS–seizures, mental status changes (more so than cyclosporine)
      • Other SE:  more hyperglycemia but less hyperlipidemia than cyclosporine, myocardial hypertrophy that may result in kidney or liver damage
  • Corticosteroids:  prednisone & methylprednisolone
    • MOA:  inhibit CKs, particularly IL-1, 2, 3, 6, & TNF-alpha    (anti-inflammatory mediators)
    • Intraoperatively:  IV methylprenisolong 3 mg/kg    (high dose)
      • Successful in 60-80 % of acute rejections
    • Maintenance:  oral prednisone 1-2 mg/kg/day tapered slowly over 2 months to 5-20 mg/day
    • SE:  CNS (euphoria, depression, psychosis), HTN (Na/H2O retention), infections & impaired wound healing, increased appetite & weight gain, cataracts, osteoporosis, glucose intolerance, hyperlipidemia, Cushing’s
  • mTOR inhibitor:  sirolimus
    • Macrolide immunosuppressant that binds to FK binding protein which binds to mTOR to inhibit T cell proliferation suppress IL-2 & IL-4
    • Also has antifungal & antitumor activity & prevents B cell differentiation into APCs
    • Mainly used in kidney transplants
    • Loading dose:  6 mg PO ASAP after transplant
    • Maintenance:  2 mg PO per day
    • Oral solution (mix with at least 60 mL) that should be kept refrigerated & avoid exposure to light
    • Optimal trough concentration:  16-24 ng/mL
    • SE:  leukopenia, thrombocytopenia, hyperlipidemia
    • Substrate & inhibitor of 3A4 & p-GP
      • Voriconazole & ketoconazole (CYP inhibitors) are CI with sirolimus
  • Antimetabolites or antiproliferatives:  azathioprine (Imuran), mycophenolate mofetil (cellcept)
    • Azathioprine (Imuran) has a black box warning for increased risk of neoplasia, mutogenic potential & hematological toxicity
      • b/c of these toxicities, this drug isn’t used much anymore
      • MOA:  gets converted to 6-MP & interferes with RNA & DNA synthesis thus inhibiting cell division
        • Inhibits T & B cells  (nonspecific immunosuppression)
      • Prevents rejection, not used for acute rejection
      • Major DDI with allopurinol which may result in pancytopenia (abnormal depression of all the blood components) that may be life-threatening
      • SE:  bone marrow suppression (usually starting 1-2 weeks after starting therapy), hepatotoxicity (rare & reversible upon d/c therapy), dermatological (alopecia, significant photosensitivity),
        • Monitor WBC < 3000 cells/mm3   (hold drug & then restart at a lower dose)
    • Mycophenolate mofentil (MMF aka cellcept) is a prodrug that’s metabolized to mycophenolic acid (MPA)
    • Mycophenolate sodium (MPA aka myfortic) is an active drug that’s available as a delayed release tablet
      • MOA:  selective, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH)
        • IMPDH is an enzyme needed for purine synthesis   (more specific at inhibiting T-cells & B-cells than azothioprine)
      • May get an increase in AUC after chronic dosing so a dose adjustment may be needed
      • Metabolized by the liver & eliminated by the kidneys
      • DDIs:  acyclovir & probenecid, bile acid resins (cholestyramine), Al/Mg antacids
      • 1000 mg of cellcept = 720 mg of myfortic
        • Cellcept oral dose:  1-1.5 g BID
        • Myfortic oral dose:  720 mg BID
      • SE:  GI (d/v), progressive multifocal leukoencephalopathy (PML is an infection of the brain that causes a loss of muscle control, confusion, etc), hematological (neutropenia, anemia, thrombocytopenia), teratogenic
  • Antibodies:  polyclonal antibodies (ATGAM, thymoglobulin)    monoclonal antibodies (muromonab-CD3 & IL-2 receptor antagonists–Basiliximab & daclizumab)
    • Used in induction & acute rejection
    • Muromonab CD3 has a black box warning due to pulmonary edema
      • MOA:  binds to CD3 & blocks T cell stimulation by foreign antigens (fights specific immunity–IgG)
      • Uses:  acute rejection, steroid-resistant rejection, sometimes used for induction
      • Dose:  IV push 5 mg/day x 10-14 days for rejection
        • In kids:  2.5 mg/day x 7-14 days for rejection
      • 1st 2 doses need to be administered by a physician & pt needs to be observed for 2 hours after the dose is given
        • Need to have a code cart ready b/c of CK-release syndrome which may result in anaphylaxis
          • CK release syndrome is characterized by flu-life symptoms (fever/chills/n/v/d/myalgias), hypo/hypertension, tachycardia, pulmonary edema, aseptic meningitis/seizures/HA
          • Prophylaxis:  methylprednisolone, benadryl, APAP, Lasix
          • Monitor:  pulse, respiration, temp, BP, fluids q 15 min x 2 hours then q 30 min x 2 hours,
            • Also need to monitor CD3 counts & antibody production
    • RATG (thymoglobulin) is less immunogenic than ATG
      • MOA:  action against T & B cells
      • Used most commonly for induction (kidney) but also for rejection
      • Premedicate w/ APAP & benadryl prior to each infusion
      • Induction:  IV 1.5 mg/kg in 1 L NS for 24 then repeat days 1-4 post-op
      • Rejection:  IV 10-30 mg/kg/day infused over 4-6 hours x 7-14 days
        • Admin in a central line
      • SE:  leukopenia, thrombocytopenia, dermatological, fevers, chills, arthralgia, malaise
    • IL-2-receptor antagonists
      • MOA:  binds to alpha chain CD25 on the surface of T-lymphocytes & prevents the proliferation of T cells
      • Used in induction therapy
      • Very few SE (hypokalemia)
      • Basilizimab (simulect):  chimeric MAB
        • Mostly used in renal transplant induction therapy
        • 20 mg IV within 2 hours prior to transplant surgery followed by 20 mg IV 4 days after transpantation
      • Daclizumab (zenpax):  human MAB used in kidney transplant induction therapy  (less immunogenic)
        • 1 mg/kg IV infusion prior to surgery, then once q 2 weeks x 2 months
        • May cause increased mortality in heart transplants due to an increased risk of infections
  • Infections are a common complication associated with immunosuppressants
    • Highest risk w/in 1st few months after transplant or after treatment of acute rejection episodes
    • CMV prophylaxis:  valganciclovir
      • Also cover HSV
    • CMV treatment:  ganciclovir
    • Want prophylaxis for HSV but not CMV:  acyclovir
    • PCP:  use low dose bactrim (only 2-3x/week) usually used for 6-12 months post transplant
    • Vaccines:  pneumococcal prior to transplant & then 5 years after first dose, inactive influenza q year, possible HBV series prior to liver transplant
      • Don’t give live vaccines while on immunosuppressive therapy
    • Fungal prophylaxis is used in high risk patients  (lung transplant patients, concerned w/ DDIs)
    • HTN:  most often associated with calcineurin inhibitors, corticosteroids, or impaired kidney-graft function
      • Use CCBs (mostly norvasc)
    • Hyperlipidemia is most commonly associated with calcineurin inhibitors, corticosteroids, sirolimus
      • Statins are effective but you need to worry about rhabdo when used in combo w/ calcineurin inhibitors
    • Diabetes mellitus risk factors:  black, hispanic, > 40, pretransplant diabetes status, family history, weight
    • Malignancies:  skin cancers, Post-transplant lymphoproliferative disorders (trxt:  tiruximab) usually occur at more than 5 years after transplant.  Related to overall level of immunosuppression
  • Maintenance therapy usually requires at least 2 immunosuppressive agents
  • Glucocorticcoids (IV methylprednisolone) in high doses are first line rejection therapy
    • Antibodies usually develop to OKT3 so its use is generally limited to one or two uses

ATG & RATG are also used in rejection therapy

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