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Pharmacotherapy VII > Solid Organ Transplant > Flashcards

Solid Organ Transplant Flashcards

1
Q

What three types of diagnostic evidence can be used to detect ABMR?

A
  1. Histologic evidence of acute tissue injury
    • Microvascular injury (glomerulitis or peri-tubular capilaritis)
    • Difference between acute and chronic rejection
  2. Evidence of current/recent antibody interaction with vascular endothelium
    • C4d staining on biopsy (complement activation)
  3. Serologic evidence of donor specific antibodies (DSA)
    • Pre-transplant DSA vs. de novo DSA
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2
Q

What is the time course of antibody-mediated graft damage?

A
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3
Q

What is the “triple whammy” of medication non-adherence when regarding solid organ transplants?

A
  1. Increased risk for antibody mediated rejection = Decreased graft life
  2. Development of DSA leads to elevated PRA and less likelihood of finding a match for next transplant
  3. Increase infection risk due to treatments required for AMR that develops after nonadherence
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4
Q

calcineurin inhibitors

A
  • Cyclosporine (Neoral, Gengraf, Sandimmune)
  • Tacrolimus (Prograf, Envarsus, Astagraf)
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5
Q

antiproliferative agents

A
  • Mycophenolate mofetil/acid (Cellcept/Myfortic)
  • Azathioprine (Imuran)
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6
Q

co-stimulatory blocker

A
  • Belatacept (Nulojix)
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7
Q

inhibitors of late t-cell function

A
  • Sirolimus (Rapamune)
  • Everolimus (Zortress)
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8
Q

monoclonal antibodies

A
  • Basiliximab (Simulect)
  • Alemtuzumab (Campath)
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9
Q

polyclonal antibodies

A
  • Antithymocyte globulin (thymoglobulin)
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10
Q

dosing conversion of calcineurin inhibitors

A
  • IV:PO dosing conversion
    • CYA 1:3
    • TAC 1:4
  • SL:PO dosing conversion
    • TAC 1:2
  • Tacrolimus ER (Astagraf XL) 1:1 conversioν
  • Tacrolimus XR (Envarsus, Tac LCPT) 1: 0.75 – 0.8 conversion
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11
Q

calcineurin side effects

A
  • Hyperglycemia
  • Dyslipidemia
  • Hypertension
  • Hyperkalemia
  • Hemolytic Uremic Syndrome
  • Nephrotoxicity
    • ​Patients may eventually require renal transplant/dialysis
  • Gingival hyperplasia
  • Increase infection/malignancy risk

TAC:

  • Neurotoxicity
  • Tremor
  • Confusion/HA/Cloudiness
  • Hyperglycemia (PTDM)
  • Alopecia

CYA:

  • Hirsutism
  • Gingival hyperplasia
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12
Q

differences in metabolism of CYA and TAC

A

CYA

  • Extensively metabolized by CYP3A
  • Inhibits:
    • CYP3A4
    • P-gp
    • BCRP
    • OATP1B1

Tacrolimus

  • Extensively metabolized by CYP3A
  • Substrate of:
    • CYP3A4/5
    • P-gp
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13
Q

azole interaction with calcineurin inhibitors

A
  • Azoles known inhibitors of CYP 3A4 and p-gp
  • Concomitant administration requires dose decrease of calcineurin inhibitors
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14
Q

grazoprevir/elbasvir interaction with calcineurin inhibitors

A
  • Grazoprevir (GZR)
    • Substrate for OATP1B1/3 transporter, CYP3A, and P-gp
  • Elbasvir (EBR)
    • Substrate of CYP3A4 and P-gp
  • GE is not given with CYA because of 15x increase of GE; however, TAC/GE has minimal interaction
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15
Q

letermovir interaction with calcineurin inhibitor

A

Substrate of drug metabolizing enzymes CYP3A, CYP2D6, UGT1A1, and UGT1A3, and transporters OATP1B1/3 and P-gp

Dose increase of letermovir required with CYA

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16
Q

statin interaction with calcineurin inhibitor

A

Simvastatin and atorvastatin are contraindicated with use of CYA

17
Q

There are many interactions with calcineurin inhibitors. What are potential effects of these interactions?

A
  • Increase creatinine
  • Nephrotoxicity
  • Decrease metabolism
  • Increase metabolism
  • Increase concentration of other agent
18
Q

patient education for calcineurin inhibitors

A
  • Adherence
    • Medication dosed every 12 hours or 24 hours for TAC ER
    • Do not take medication prior to trough draw
    • Follow up with provider for labs
  • DDIs
  • Contact provider if develop any s/sx of infection (i.e., fever, cold/flu symptoms, urinary symptoms)
19
Q

corticosteroid side effects

A
  • Hyperglycemia
  • Dyslipidemia
  • Hypertension
  • Insomnia
  • Psychosis
  • Osteoporosis
  • Weight gain
  • Infection
  • PUD
  • Cataracts
  • Impaired wound healing
20
Q

Findings of Astellas Corticosteroid Withdrawal Study Group

A
  • Corticosteroid Arm
    • More bone fractures + avascular necrosis
    • More serious adverse effects due to DM or infection
    • More ATG for acute rejection
    • Higher fasting triglyceride level
  • Steroid Withdrawal Arm
    • Higher AR rate
    • Higher incidence of hyperkalemia and neutropenia
  • Similarities between 2 arms
    • LDL and HDL cholesterol
    • Blood pressure
    • Mean weight change
    • Cataracts
    • Opportunistic infections
    • Malignancies
    • GI toxicity
    • New onset diabetes (20% incidence)
21
Q

patient education of corticosteroids

A
  • Adherence
    • Dosing in the AM with food
  • Side effects
    • Discuss importance of diet and exercise to minimize some side effects
  • Contact provider if develop any s/sx of infection (i.e., fever, cold/flu symptoms, urinary symptoms)
22
Q

mycophenolate MOA

A
  • inhibits inosine monophosphatate dehydrogenase (IMPDH)
    • inhibits de novo pathway of guanosine synthesis and blockade of lymphocyte proliferation (do not possess salvage pathway)
  • diminishes proliferation of T and B cells
  • decreases generation of CD8 cells

Significantly more effective in combination therapy than AZA

23
Q

mycophenolate side effects

A
  • Leukopenia
  • GI toxicity
    • Diarrhea, nausea
  • Increased risk of infection/malignancy
  • Embryofetal toxicity – 1st trimester
    • Recommend avoiding use if planning pregnancy
    • Any female of childbearing potential must use highly effective contraception 4 weeks prior to starting mycophenolate and continue contraception until 6 weeks after stopping
24
Q

mycophenolate patient education

A
  • Adherence
    • Twice daily dosing. If intolerance can consider TID dosing
    • Take with food (lower Cmax, but no change in AUC)
  • Teratogenicity
  • Contact provider if develop any s/sx of infection (i.e., fever, cold/flu symptoms, urinary symptoms)
25
Q

azathioprine MOA

A
  • Purine antagonist
  • Inhibits DNA and RNA synthesis
26
Q

azathioprine pros/cons

A

PROS

  • Use in pregnancy as substitute for MMF

CONS

  • Not commonly used with new transplants due to toxicity and safer alternative
  • TPMT testing
  • RDA
    • CrCl < 30 ml/min: reduce 25%
    • CrCl < 10 ml/min: reduce 50%
  • CI with allopurinol and febuxostat (decreases AZA dose)
27
Q

azathioprine side effects

A
  • Bone marrow suppression
  • Liver toxicity
  • Pancreatitis
  • Increase infection and cancer risk
  • Alopecia
28
Q

sirolimus/everolimus MOA

A
  • Inhibits cellular response to interleukin-2
  • Immunosuppressive via binding to FKBP and suppression of CD4 t-cell activation and proliferation
  • Anti-proliferative mechanism through blocking kinase activity
29
Q

sirolimus/tacrolimus side effects

A
  • Hyperlipidemia
  • Impaired wound healing
  • Rash
  • Hyperglycemia
  • Proteinuria
  • Oral ulcers
  • Thrombocytopenia
  • Increase risk for infection
  • Arthralgias
  • Pneumonitis
  • Hepatic artery thrombosis
  • ? DVT

Can be used in patients who are at risk of skin cancer

30
Q

belatacept MOA

A
  • Selective T-cell costimulation blocker
    • Binds to CD80/CD86(B7-1/B7-2) on antigen-presenting cells resulting in inhibition of CD28-mediated costimulation of T lymphocytes
    • Similar to 1st-generation blocker abatacept(10x less binding avidity)
  • Fusion protein made of the modified extracellular domain of cytotoxic T lymphocyte antigen 4 (CTLA-4) found on helper T cells
31
Q

calcinurin inhibitor free regimen

A

MMF + prednisone + belatacept

(basiliximab induction)

32
Q

belatacept side effects

A
  • Post Transplant Lymphoproliferative Disorder (PTLD)
    • Contraindicated in EBV neg patients
  • Increased risk for infection
    • CMV and other viral infections
  • Anemia
  • Infusion-related reactions
  • Hypertension
33
Q

Which monoclonal antibody is preferred during EBV infection post-transplant?

A
  • Belatacept binds CD80/CD86 with a higher affinity (500-2500x) than does CD28, thus inhibiting the CD28 co-stimulatory action
  • In immunocompetent setting: EBV infected B cells are balanced by stimulation of cytotoxic t cells.
  • Cancer immunotherapy targets CTLA-4
  • Ipilimumab (Yervoy), a monoclonal antibody against CTLA-4, approved for treatment of melanoma and renal cell carcinoma
34
Q

Difference between belatacept and CYA? Tacrolimus?

A

Belatacept has higher acute rejection rates, but better renal function and lower DSA/improved adherence in the long-term.

TAC has lowest rejection rates.

35
Q

When is belatacept preferred over TAC?

A
  • Adverse effects to calcineurin inhibitor (CNIs) or mTOR inhibitor (mTORi) based regimen
  • Adherence concern
  • CNI nephrotoxicity toxicity
  • “Poor” quality organ (i.e BENEFIT EXT) or patients with lower eGFR post transplant
36
Q

belatacept side effects

A
  • Adherence
    • Every 2-4 week IV infusion
  • Side Effects
    • Infusion site reactions, confusion, new or worsening neurological, cognitive, or behavioral signs and symptoms
  • Contact provider if develop any s/sx of infection (i.e. fever, cold/flu symptoms, urinary symptoms)
37
Q

high-risk patients of acute rejection

A
  • African-American
  • Delayed graft function
  • Previous transplant
  • Multiple transplants
  • High PRA (>40%)
  • Pediatric patients
  • Long cold ischemic time (>24 hours)
38
Q

polyclonal antibodies

A
  • Antibodies derived from non-human sources and targeted to T-lymphocyte cell surface proteins
  • Mechanism of action
    • Antibodies specific for >20 CD receptors and markers involved in the immune response
    • Depletes T-cells opsonization and direct lyses of lymphocytes
  • Indicated for induction therapy and treatment of acute rejection
39
Q

polyclonal side effects

A

Pharmacotherapy VII (6 decks)

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