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850-Exam 2 material > 850- Transplant lecture > Flashcards

850- Transplant lecture Flashcards

1
Q

Indications for Organ Transplant

A
  1. Kidney: Diabetes, hypertension, lupus PCKD
  2. Liver: Alcoholic cirrhosis, NASH, HBV, HCV, HCC, APAP toxicity
  3. Pancreas: Diabetes, Congenital Abnormalities
  4. Heart: Ischemic heart disease, congenital abnormalities, idiopathic cardiomyopathy, valvular diseases
  5. Lung: CF, pulmonary HTN, pulmonary fibrosis COPD, emphysema
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2
Q

Goals of Immunosuppression:

A
  1. Prevent rejection
  2. Avoid complications with high dose immunosuppressants
  3. Patient and graft survival
  4. Patient adherence
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3
Q

Potency of Immunosuppression:

A 
Less Immunosuppressive (lower number)
1. Belatacept
2. Sirolimus/Everolimus
3. Azathioprine
4. Mycophenolate
5. Cyclosporine
6. Tacrolimus
7. Basiliximab
8. Thymoglobulin
9. Alemtuzumab
More Immunosuppressive (higher number)
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4
Q

Induction Therapy Goal:

A
  1. Prevent early acute allograft rejection using intense, prophylactic immunosuppression therapy
  2. This produces profound deficiency on T cells and/or B cells that can last months
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5
Q

Induction Therapy Drugs:

A
  1. Basiliximab
  2. Antithymocyte globulin
  3. Alemtuzumab
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6
Q

Basliximab (Simulect®)

CD25

A

• Mechanism of action:
–Blocks T‐cell proliferation via Interleukin‐2 (IL‐2) reception antagonism (anti‐CD25 antibodies)
• Used in lowest immunologic risk patients
• Decreased infection rates when compared to
other agents
• Does not lead to sustained depletion of lymphocytes and related CD4 helper T cells

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7
Q

Antithymocyte Globulin (Thymoglobulin®)

A

• Mechanism of Action:
–Binds to T‐cell surface antigens leading to the
elimination of T‐cells
• Used in moderate to high immunologic risk
• Increased risk for CMV and BKV
• PJP and other invasive fungal pathogens have been associated with thymoglobulin

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8
Q

Alemtuzumab (Campath®)

CD52 & “AIDS”

A

• Mechanism of Action:
– Binds to CD52 on T‐cells, B‐cells, NK cells, and monocytes/macrophages causing complement activation and antibody‐dependent cellular toxicity
• “AIDS” in a bottle, results to pan T‐cell depletion
• Used as steroid sparing induction
• CD4/CD8 counts nadir at 4 weeks, 1+ years for recovery
• Associated with many opportunistic infections

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9
Q

Maintenance Therapy Goal:

A
  1. Prevent allograft rejection
  2. Maintain an adequate balance of graft function, adverse effects, and prevention of infection

(Lifelong immunosuppression)

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10
Q

Maintenance Therapy Drugs:

A
  1. Corticosteroids
  2. Calcineurin inhibitors
  3. Antimetabolites
  4. mTOR inhibitors
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11
Q

Corticosteroids

A

• OLDEST immunosuppressive agent used in transplantation

• Mechanism of Action:
–Inhibition of cytokine gene expression
–Modification of lymphocyte distribution and function
–Anti‐inflammatory effects

• Dosing:
–Prednisone 5‐10 mg/day (maintenance dose)
(Higher doses are used for induction & rejection therapy)

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12
Q

Corticosteroids: Adverse Effects

• Short Term

A
  1. Mood alterations
  2. Hyperglycemia
  3. Hypertension
  4. Increased appetite
  5. Insomnia
  6. Mood changes
  7. Acne
  8. Leukocytosis
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13
Q

Corticosteroids: Adverse Effects

• Long Term

A
  1. Osteoporosis
  2. Chronic adrenal insufficiency
  3. Ulcerative esophagitis
  4. Hirsutism
  5. Pancreatitis
  6. Amenorrhea
  7. Diabetes mellitus
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14
Q

Calcineurin Inhibitors Drugs:

A
  • Tacrolimus (Prograf, Hecoria, and Astagraf XL)

* Cyclosporine (Neoral, Gengraf, and Sandimmune)

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15
Q

Tacrolimus

T-cell activity

A

• Products:
– Prograf® (capsules, IV)
– Generic tacrolimus (capsules, IV)
– Astagraf XL® (extended release capsules)
– Envarsus XR® (extended release capsules)
– Compounded oral suspension
Also called FK506

• MOA:
– Inhibits T‐cell activity through inhibition of IL‐2 production

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16
Q

Tacrolimus: PK & PD

A

• Absorption: Incomplete and variable
– Best absorbed on an empty stomach
– Bioavailability: 7 ‐ 32%

• Distribution: highly lipophilic
– 99% protein bound (albumin and α1‐acid glycoprotein)

• Metabolism: extensive CYP3A4, p‐glycoprotein
– Half life:
~ 9 hours (immediate release)
~ 34 hours (extended release)

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17
Q

Tacrolimus: Dosing

A
  1. Dosing:
    – Immediate Release: 0.05‐0.1mg/kg/day in divided doses
    ◦ Generally ~1‐4 mg BID
    – Extended Release: 0.1‐0.2 mg/kg/day one time daily
  2. Dose adjusted based on trough concentrations and renal function
    – Goal concentration varies:
    ◦ Time after transplant, type of organ transplanted, infection
  3. Therapeutic range 5 – 15 ng/mL
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18
Q

Tacrolimus: Interactions

A
  1. Primarily through hepatic metabolism CYP3A4: inhibition or induction
    – Examples:
    ◦ Ketoconazole, diltiazem, and grapefruit juice inhibit CYP3A4
    ◦ Phenytoin and rifampin induce CYP3A4
  2. P‐glycoprotein substrate
  3. Antacids
    –Physical interaction –» reduced absorption
    –Separate by at least 2 hours
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19
Q

Tacrolimus: Adverse Effects

*more common in tacrolimus than cyclosporine

A
  1. Hypertension
  2. Diarrhea
  3. Nephrotoxicity
  4. Headache
  5. Hepatotoxicity
  6. Hyperglycemia*
  7. Pruritis
  8. Hyperkalemia
  9. Hypomagnesemia
  10. Infection
  11. Neurotoxicity (tremors)
  12. Alopecia
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20
Q

Cyclosporine

T-cell proliferation

A 
1. Products:
–Modified microemulsion formulation
• Neoral® or Gengraf® 
–Unmodified formulation
• Sandimmune®
–Sandimmune® & Neoral®/Gengraf® are not
equivalent
  1. MOA:
    –Inhibits T‐cell proliferation through inhibition of IL‐2 production
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21
Q

Cyclosporine: PK & PD

A

• Absorption: erratic and incomplete
–Non‐modified: largely dependent on food, bile acids, and GI motility
–Modified: up to 30% increase, less dependent on food, bile acids, and GI motility

• Distribution: highly lipophilic
–98% protein bound (lipoproteins)

• Metabolism: CYP3A4 (extensive), p‐ glycoprotein

22
Q

Cyclosporine: Dosing

A
  1. Dosing:
    – 10‐15 mg/kg/day in divided doses to attain target trough levels
  2. Dose adjusted based on trough concentrations and renal function
    –Goal concentration varies
    • Time after transplant, type of organ transplanted, infection
  3. Therapeutic Range: 50‐200 ng/mL
23
Q

Cyclosporine: Interactions

A
  1. Primarily through hepatic metabolism CYP3A4: inhibition or induction
    – Examples:
    • Ketoconazole, diltiazem, and grapefruit juice inhibit CYP3A4
    • Phenytoin and rifampin induce CYP3A4
  2. P‐glycoprotein substrate
  3. Anticipate and manage –» high inter‐ and intra‐
    patient variability
  4. Nephrotoxic drugs should be used with caution
  5. Consistent administration with or without food
24
Q

Cyclosporine: Adverse Effects

Less Common

A
  1. Migraine
  2. Acne
  3. GI effects
  4. Gynecomastia
  5. Hyperkalemia
  6. Hypomagnesemia
  7. Hepatotoxicity
25
Q

Cyclosporine: Adverse Effects

More Common

A
  1. Hyperlipidemia
  2. Nephrotoxicity
  3. Tremor
  4. Hypertension
  5. Hyperglycemia
  6. Gingival hyperplasia
  7. Hirsutism
26
Q

Calcineurin Inhibitors (Tacrolimus)

A
  • Binds to FKBP12
  • Dosing: 0.05‐0.1mg/kg/day in divided doses to attain target trough levels
  • Monitoring: trough levels
27
Q

Calcineurin Inhibitors (Cyclosporine)

A
  • Binds to cyclophilin
  • Dosing: 10‐15mg/kg/day in divided doses to attain target trough levels
  • Monitoring: trough and C2 levels
28
Q

Antiproliferatives Drugs:

A
  1. Mycophenolate Mofetil (Cellcept®, MMF)
  2. Mycophenolate Sodium (Myfortic ®)
  3. Azathioprine (Imuran®, AZA)
29
Q

Mycophenolate

A

• Products:
– Mycophenolate Mofetil (MMF)
– Mycophenolate Sodium

• Prodrugs for mycophenolic acid (MPA)

• MOA:
– Inhibition of inosine monophosphate dehydrogenase (IMPDH) –» inhibits de novo guanosine nucleotide synthesis
– Prevents T and B lymphocytes proliferation

30
Q

Mycophenolate Dosing:

A

• Dosing:
–250‐1000 mg PO twice daily (MMF)
–180‐720 mg PO twice daily (Myfortic)

• Dosing conversion
–1,000 mg Cellcept® = 720 mg Myfortic®

• Mycophenolate sodium (Myfortic®) is enteric coated for delayed release
–MFG claims this formulation will reduce GI side effects

31
Q

Mycophenolate Adverse Effects:

A 
–Gastrointestinal intolerance:
• Diarrhea 
• Nausea
• Vomiting
–Leukopenia, anemia, thrombocytopenia
32
Q

Mycophenolate Drug Interactions:

A 
1. Aluminum/magnesium containing antacids
• Separate doses by at least 2 hours
2. Cholestyramine
3. Divalent/trivalent cations (iron)
4. Proton pump inhibitors 
5. Oral contraceptives
33
Q

Mycophenolate Teratogenicity:

A
  1. Shown to cause fetal harm
  2. Negative pregnancy test prior to starting medication
  3. Women of child‐bearing age required to use at least two methods of contraception
34
Q

Azathioprine

A

• Prodrug of 6‐mercaptopurine (6‐MP)

• MOA:
– Antagonist of purine metabolism
– Prevents T and B lymphocytes proliferation

• Use (rare):
– Intolerance to mycophenolate
– Women that want to become pregnant

• Dosing:
– 3‐5 mg/kg/day initially, then decrease to 1‐3 mg/kg/day

35
Q

Azathioprine Adverse Effects:

A
  1. GI Intolerance
  2. Leukopenia, anemia, thrombocytopenia
  3. Increased alkaline phosphatase, total bilirubin & transaminases
36
Q

Azathioprine Drug Interactions:

A
  1. Mercaptopurine: profound myelosuppression

2. Allopurinol: inhibits metabolism of azathioprine and 6‐ MP leading to profound myelosuppression

37
Q

mTOR Inhibitors medications:

A
  • Sirolimus (Rapamune®)

* Everolimus (Zortress®, Afinitor®)

38
Q

Sirolimus

A

• Mechanism of Action:
– Binding to FKBP‐12 –» inhibition of mTOR (mammalian
target of rapamycin)
– Suppresses cytokine mediated T‐cell proliferation

• Use:
– May be used to replace mycophenolate or a calcineurin
inhibitor (tacrolimus or cyclosporine)

• Dosing:
– 1‐5 mg/day to attain target trough levels

39
Q

Sirolimus Adverse Effects:

A
  1. Edema
  2. Anemia
  3. Impaired wound healing
  4. Interstitial lung disease
  5. Proteinuria
  6. Hyperlipidemia
40
Q

Sirolimus Interactions:

A

– Metabolized through CYP 3A4

– Similar interactions with cyclosporine and tacrolimus

41
Q

Everolimus

A

• Mechanism of Action:
– Binding to FKBP‐12 –» inhibition of mTOR (mammalian
target of rapamycin)
– Suppresses cytokine mediated T‐cell proliferation

• Use:
– Renal transplant rejection prophylaxis
–Off‐label use: heart transplant rejection prophylaxis

• Dosing:
– 0.75‐1 mg PO twice daily to attain target trough levels

42
Q

Everolimus Adverse Effects:

A
  1. Edema
  2. Anemia
  3. Impaired wound healing
  4. Proteinuria
  5. Hyperlipidemia
43
Q

Everolimus Interactions:

A

– Metabolized by CYP3A4
• Similar drug interactions as cyclosporine and tacrolimus
– Consistent administration in regards to food

44
Q

Belatacept

A
  1. Indication:
    – Maintenance immunosuppression therapy in renal transplant recipients
  2. MOA:
    – Binds to CD80 and CD86 receptors on APCs and blocking the CD28‐mediated costimulation of T‐cells
3. Dosing:
– Initial phase:
• 10 mg/kg IV post‐operative day 0 and 5
• 10 mg/kg IV end of week 2, 4, 8, 12 
– Maintenance phase:
• End of week 16
• 5mg/kg every 4 weeks
45
Q

Belatacept Adverse Effects:

A
  1. Post‐transplant lymphoproliferative disorder
  2. Gastrointestinal disturbances
  3. Hypertension
  4. Peripheral edema
  5. Anemia, leukopenia
  6. NO long term renal toxicity!

• Black‐Box Warning

  1. Increased risk of infections
  2. PTLD associated with EBV seronegative
46
Q

Generic Medications

A

• Generic immunosuppression availability:
– Tacrolimus
– Mycophenolate
– Cyclosporine
– Sirolimus
• Patients are encouraged to maintain consistency with the product they use

47
Q

Immunosuppression Considerations

A
  • Rejection
  • Toxicity
  • Adverse Effects
  • Variability
  • Infection
  • Malignancy
  • Cost
  • Drug‐drug interactions
48
Q

Immunosuppression Complications:

A
  1. Cardiovascular
  2. Infectious
  3. Malignancy
49
Q

Cardiovascular Complications:

A

• Leading cause of mortality in renal transplant recipients
–Hypertension
–Hyperlipidemia
–Diabetes

50
Q

Infectious Complications:

A
  1. Highest risk immediately following transplant and rejection treatment
    – Related to degree of immunosuppression
  2. Opportunistic infections
  3. Atypical organisms
  4. Prophylaxis
51
Q

Malignancy

A

• Related to degree of immunosuppression
– Increased risk with increased survival

  • Lung, breast, colon, and prostate cancer are not increased compared to general population
  • Increased risk of lymphomas and lymphoproliferative disorders, Kaposi’s sarcoma, renal carcinoma, and skin cancers
52
Q

Rejection

A

• Cellular Rejection:
–Hyperacute rejection
–Acute rejection

• Antibody‐mediated rejection (AMR):
–Acute AMR
–Chronic AMR

850-Exam 2 material (19 decks)

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