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Pediatric Pharmacology Exam 2 > Transplant Agents > Flashcards

Transplant Agents Flashcards

1
Q

Transplantation Agents and Rejection (2)

A
  1. Transplantation has progressed rapidly in the past 60 years; Improved survival and rate of acute rejection (AR) due to use of transplant pharmacotherapy
  2. AR risk in kidney transplantation (KTR) currently ≤ 15%
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2
Q

Keys to Success in Transplants (3)

A

Pharmacotherapy:

  1. Immunosuppression
  2. Infection prophylaxis
  3. Supportive medications
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3
Q

Goals of Transplant Therapy (3)

A
  1. Prevent allograft rejection; allograft refers to the transplanted organ
  2. Minimize infection and malignancy
  3. Minimize adverse drug events
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4
Q

Immunosupression Induction therapy

A

Potent agents used early post-transplant

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5
Q

Immunosupression Maintenance therapy

A

Lower intensity, longitudinally used agents

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6
Q

Immunosupression Desensitization therapy

A

Agents used pre-transplant in high risk rejection patients

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7
Q

Allograft injury and dysfunction (2)

A
  1. T-Cell Mediated (cellular rejection)

2. B-Cell Mediated (antibody mediated rejection)

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8
Q

ATG

A

anti-thymocyte globulin

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9
Q

APC

A

antigen presenting cell

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10
Q

AZA

A

azathioprine; CostimAb- belatecept

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11
Q

IL2 R antagonists

A

basiliximab

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12
Q

MPA

A

Mycophenolate

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13
Q

mTOR

A

mammalian target of rapamycin

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14
Q

Determining Immunosupression Regimen Factors (5)

A
  1. Organ type –> Liver < Kidney, Heart < Pancreas < Lung
  2. Patient dependent –> High risk patients > low risk patients
  3. Age
  4. Antibodies present or not present (HLA, etc)
  5. Center specific protocol
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15
Q

Steroid induction agent

A

Solumedrol (methylprednisolone)

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16
Q

Polyclonal antibodies induction agent (2)

A
  1. Thymoglobulin (rabbit antithymocyte globulin)

2. Atgam (horse antithymocyte globulin)

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17
Q

Monoclonal antibodies

A
  1. anti-CD52: Campath (alemtuzumab)

2. anti-CD52 and IL-2 receptor antagonist: Simulect (basiliximab)

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18
Q

Immunosupression pharmacotherapies (6)

A
  1. Steroids
  2. Antithymocyte Globulin
  3. Moncolonal antibodies
  4. Antimetabolites
  5. Calcineurin Inhibitors
  6. mTOR Inhibitors
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19
Q

Corticosteroid pharmacokinetics (3)

A
  1. Good oral biovailability
  2. Methylpred:Prednisolone (4:5)
  3. Hepatic metabolism
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20
Q

Corticosteroid use in immunosupression (5)

A

Used in induction and maintenance

  1. Induction = high dose
  2. Maintenance = lowest dose possible
  3. Given as pre-medications prior to other induction agents
  4. Usually given as high-dose treatment once daily
  5. May be given in divided doses
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21
Q

Steroid ADEs (4)

A

These are mainly for acute (i.e. high doses)

  1. Hyperglycemia
  2. Hypertension
  3. Weight gain
  4. Mood disorders
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22
Q

Steroid withdrawal protocol

A

No continuation of steroids after completion of induction (5-7 days) – taper not needed

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23
Q

Antithymocyte Globulin Agents (2)

A
  1. Rabbit Antithymocyte globulin (Thymoglobulin®)

2. Horse Antithymocyte globulin (Atgam®)

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24
Q

Antithymocyte Globulin Mechanism of Action (2)

A
  1. Polyclonal antibody

2. Binds to Depletes circulating T-cells to depleat CD4 lymphocytes

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25
Q

Antithymocyte Globulin Pharmacokinetics (3)

A
  1. Depletion occurs within 24 hrs
  2. Duration of action can last up to 1 year
  3. Half-life ~ 2 – 3 days
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26
Q

Antithymocyte Globulin ADEs (4)

A
  1. Leukopenia
  2. Thrombocytopenia
  3. Infusion-related reactions; from cytokine release
  4. Serum Sickness
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27
Q

Antithymocyte Globulin Clinical Pearls (5)

A
  1. Pre-medication (steroids, diphenhydramine, and acetaminophen) required to avoid infusion reactions
  2. Dose adjustments MUST be done for leukopenia and thrombocytopenia
  3. Typically administered for 5 days
  4. Also used for cellular rejection; So it can be used for induction and if rejection occurs it can be re-dosed
  5. Use the rabbit
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28
Q

Monoclonal Antibodies Mechanism of Action (2)

A
  1. Binds to surface antigens on the surface of B and T cells to produce antibody-dependent lysis of cells
  2. Cause significant immunosuppression; effects can last up to 1 year
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29
Q

Monoclonal Antibodies Agents (2)

A
  1. Alemtuzumab (Campath®, IV/SQ) – binds to CD52

2. Basiliximab (Simulect®) – binds to CD25, IL-2 receptor antagonist

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30
Q

Azathiprine (Imuran®) Mechanism of Action (2)

A
  1. Converts in the body to active 6-thioguanine to bind to DNA –> inhibiting replication
  2. Empiric testing or test if abnormally low CBC
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31
Q

Azathiprine (Imuran) ADEs (4)

A
  1. D/N/V
  2. Leukopenia, thrombocytopenia (BM suppression)
  3. Hepatoxicity (increased bilirubin and LFTs)
  4. Increased infection risk
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32
Q

Azathiprine (Imuran) Pharmacogenetics (2)

A
  1. TPMT gene mutations

2. Defects in enzyme expression can lead to significant levels of AZA and increased adverse effects

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33
Q

Azathiprine (Imuran) Place in Therapy (3)

A
  1. Renal and heart transplantation
  2. UC/IBD and other immunologic conditions
  3. Leukemia
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34
Q

Azathiprine (Imuran) Dosage Form

A

IV and PO

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35
Q

Mycophenolate moeftil (Cellcept) and Mycophenolate Na+ (Myfortic) Mechanism of Action (2)

A
  1. Binds to inosine mono-phosphate dehydrogenase (IMDH) inhbits activity to synthesize de novo guanosine limiting cell proliferation (guanosine de novo synthesis is required for T and B cells)
  2. Generally always used in combination with a CNI or mTOR +/- steroids
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36
Q

Mycophenolate moeftil (Cellcept) and Mycophenolate Na+ (Myfortic) Absorption and Bioavailability (2)

A
  1. Cellcept = 80 – 90%; tend to use this formulation
  2. Myfortic = 70%; The formulations are not equal!
    * But myfortic may be better tolerated because it is enteric coated
    * Myfortic is an enteric coated-form of Cellcept
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37
Q

Mycophenolate moeftil (Cellcept) and Mycophenolate Na+ (Myfortic) ADEs (4)

A
  1. GI (N/V/D, abdominal pain)
  2. Thrombycytopenia
  3. Anemia
  4. Leukopenia
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38
Q

Calcineurin Inhibitor Agents (2)

A
  1. Tacrolimus (Prograf®, FK506)
    * IV – used more for BMT
    * PO – capsules or suspension
  2. Cyclosporine (Gengraf®, Neoral®, Sandimmune®)
    * Modified
    * Non-modified – older formulation, not used as often
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39
Q

Calcineurin Inhibitor Agents Dosing and Use (2)

A
  1. Dosing based on drug levels
  2. Occasionally used as monotherapy for transplant; also used for a variety of immunologic diseases
    * Crohn’s disease, nephrotic syndrome
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40
Q

Tacrolimus (Prograf, FK506) Mechanism of Action (2)

A
  1. Binds to FKBP preventing calcineurin activity and prevents T-cell proliferation
  2. May lessen B cell production not its main effect
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41
Q

Tacrolimus Oral Absorption (2)

A
  1. Primarily @ small intestine

2. Drug sticks to enteral feeding tubes (and will affect absorption)

42
Q

Tacrolimus Sublingual Absorption (2)

A
  1. Almost complete

2. Capsules can be opened and placed under the tongue

43
Q

Tacrolimus: Factors Affecting Pediatric Absorption (4)

A
  1. Intestinal motility
  2. Intestinal CYP3A4 activity
  3. PgPin intestinal lumen
  4. GI blood flow
44
Q

Tacrolimus Distribution, Metabolism and Excretion (5)

A
  1. Highly protein bound; Albumin and a1-glycoprotein
  2. Distribution may be slightly > in children than adults
  3. Extensively metabolized by CYP3A enzymes; genetic variation may alter metabolism
  4. Excreted via biliary tract
  5. Hepatic blood flow plays a role in metabolism and elimination (increased blood flow in children)
45
Q

Tacrolimus Dosing (4)

A
  1. Dosing is usually q12
  2. Therapeutic monitoring is based on trough levels (~ 11.5 hrs after last dose)
    * Goal range depends on treatment
  3. High goal range: 8 – 12*
  4. Low goal range: 3 – 5*
46
Q

Other indications for tacrolimus (2)

A
  1. Nephrotic Syndrome

2. Crohn’s disease

47
Q

Cyclosporine (Gengraf, Neoral) Mechanism of Action

A

Bind to cyclophilin A which ultimately prevents calcineurin and T cell proliferation through NFAT and IL-2 cell signaling

48
Q

Cyclosporine (Gengra, Neoral) ADME (4)

A
  1. Absorption is increased with modified
  2. Highly protein bound
  3. Metabolized via CYP3A4
  4. Eliminated via biliary excretion
49
Q

Cyclosporine Info (2)

A
  1. Cyclosporine products are not interchangeable

2. Most common formulation today is the modified form

50
Q

Non-Modified Cyclosporine Agents (3)

A
  1. Bile-dependent
  2. Poor absorption
  3. Inconsistent systemic exposure and bioavailability
51
Q

Modified Cyclosporine Agents (3)

A
  1. Not bile-dependent
  2. Better absorption
  3. Reliable systemic exposure and bioavailability
52
Q

Tacrolimus ADEs (5)

A
  1. Nephrotoxicity
  2. Seizures/Tremors*
  3. HTN
  4. Hyperglycemia*
  5. Alopecia
53
Q

Cyclosporine ADEs (7)

A
  1. Nephrotoxicity
  2. Seizures/Tremors
  3. HTN
  4. Hyperglycemia
  5. Hirsutism
  6. Gingival hyperplasia
  7. Hyperlipidemia
54
Q

Agents that inhibit CYP3A4 (what they do and 4 agents)

A

If these drugs inhibit CYP3A4 then Tacrolimus (and other drugs that use the CYP3A4 enzyme) will increase in the body because CYP3A4 cannot metabolize it; if you take CYP3A4 out (because of an inhibitor) the tacrolimus keeps increasing in levels because it isn’t being metabolized

  1. Azole antifungals
  2. Macrolide antibiotics
  3. Diltiazem, Verapamil
  4. Fruit (grapefruit, pomegranate)
55
Q

Agents that induce CYP3A4 (what they do and 4 agents)

A

Enzyme inducers reduce the amount of Tacrolimus in the body because there are more enzymes to metabolize it

  1. Rifampin
  2. Phenytoin
  3. Carbamazepine
  4. Phenobarbitol
56
Q

mTOR inhibitor available agents (2)

A

mTOR = mammalian target of rapamycin

Available agents:

  1. Sirolimus (Rapamune®)
  2. Everolimus (Zortess®) - $$
57
Q

mTOR Inhibitor Mechanism of Action (2)

A
  1. Inhibits T-cell proliferation and activation by inhibiting antibody production and cytokine release
  2. Similar to CNIs but binds at a different binding site to affect mTOR cell signaling pathway
58
Q

mTOR Inhibitor ADEs (5)

A
  1. Hyperlipidemia
  2. Thrombosis
  3. Impaired wound healing
  4. Proteinuria
  5. Require drug level monitoring
59
Q

Sirolimus (Rapimune) Clinical Pearls (4)

PK Pearls (2)

A
  1. Should not be used sooner than 30 days post-transplant (impaired wound healing)
  2. Agent of choice for patients with nephrotoxicity from CNIs and coronary vasculopathy (chronic heart rejection)

PK Pearls
3. Half-life ~ 13 hrs in children

  1. Tablets and oral solution are not bioequivalent (just monitor)
60
Q

Sirolimus (Rapimune) BBWs (2)

A
  1. Liver Transplant: Hepatic Artery Thrombosis

2. Lung Transplant: Pulmonary Fibrosis

61
Q

Everolimus (Zortess) Clinical Pearls (3)

A
  1. Take with low fat meal (increases bioavailability ~ 10%) Infection
  2. CYP 3A4 metabolism
  3. Half-life ~ 30 hours in children
62
Q

Everolimus (Zortess) CX and BBW (4)

A
  1. Use in heart transplant is not recommended
  2. Graft thrombosis (Do not use within 30 days post-transplant)
  3. Infection risk is significant
  4. Risk of malignancy
63
Q

Opportunistic Infections (3)

A
  1. Bacterial (PCP)
  2. Viral (CMV)
  3. Fungal (Thrush)
64
Q

Pneumonia (PCP) Signs and Symptoms (4)

A
  1. Shortness of breath
  2. Sputum production
  3. ‘Ground glass opacities’ on chest x-ray
  4. Highest risk: 1 month to 1 year post transplant
65
Q

PCP Prophylaxis (4)

A
  1. TMP/SMZ (Bactrim®)
  2. Dapsone
  3. Atovaquone
  4. Pentamidine
66
Q

SMX/TMP Mechanism of Action and Dosing (4)

A
  1. Sulfamethoxazole: inhibits folic acid synthesis
  2. Trimethoprim: dihdyrofolic acid reduction inhibiting enzymes of folic acid pathway
  3. FIRST LINE AGENT for prophylaxis and treatment
  4. Dose based on trimethoprim component (given three times weekly M/W/F)
67
Q

Dapsone mechanism of action (3)

A

1, Competitive antagonist of para-aminobenzoic acid (PABA) → lack of PABAprevents folic acid synthesis

  1. AGENT OF CHOICE for sulfa-allergic patients
  2. MUST test G6PD before starting therapy
68
Q

Pentamidine Mechanism of Action

A

Interferes with RNA/DNA, phospholipids, and protein synthesis

69
Q

Pentamidine Dosing (3)

A
  1. Available IV and inhaled
  2. Inhaled dosed every 14-21 days
  3. IV dosed every 21-30 days
70
Q

Pentamidine ADEs (4)

A
  1. Cough/dyspnea/wheeze (inhaled)
  2. Fatigue
  3. Fever
  4. Appetite suppression
71
Q

Cytamegalovirus Info (

A
  1. Majority of population infected at some point during life
  2. > 80% positive by age of 50
  3. Increased risk of graft failure and viral co-infections (Epstein Barr Virus – EBV)
  4. Highest risk: 2 weeks to 6 months post transplant
72
Q

CMV Low Risk Category

A

Donor CMV Status: negative

Recipient CMV Status: negative

73
Q

CMV Intermediate Risk Category

A

Donor CMV Status: negative or positive

Recipient CMV Status: positive

74
Q

CMV High Risk Category

A

Donor CMV Status: Positive

Recipient CMV Status: Negative

*Will need a longer course of prophylaxis

75
Q

CMV Prophylaxis (2)

A
  1. Universal Prophylaxis: All patients receive prophylaxis
  2. Preemptive Prophylaxis
    * Patients do not receive prophylaxis
    * CMV PCRs monitored and treated when positive
76
Q

CMV Prophylaxis Agents (3)

A
  1. Ganiclovir/Valganciclovir
  2. Acyclovir
  3. CMV-IVIG (Cytogam®)
77
Q

Thrush

A
  1. Yeast infection of the mouth and/or esophagus
  2. Leads to painful ulcers → blood stream infections → endocarditis
  3. Highest risk: immediate to 6 months post transplant
  4. Risk increased for patients on steroids
78
Q

Thrush Prophylactic Agents (3)

A
  1. Mycostatin (Nystatin); agent of choice, swish swallow
  2. Clotrimazole
  3. Difuclan (Fluconazole)
79
Q

Thrush Prophylaxis Mechanism of Action and Info (3)

A
  1. MOA: Binds to sterols in cell membrane → leaks contents of cell
  2. Swish/Swallow 3-4 times daily
  3. Do not eat/drink for 20-30 minutes after each dose
80
Q

Clotrimazole MOA and Pertinent Info (4)

A
  1. MOA: Binds to sterols in cell membrane → leaks contents of cell
  2. Available as a troche
  3. CAUTION in younger kids (choking hazard)
  4. CYP3A4 interactions
81
Q

Fluconazole MOA and Pertinent Info (3)

A
  1. MOA: Interferes with fungal cytochrome P450 activity → decrease ergosterol synthesis → inhibits cell wall formation
  2. Agent of choice for systemic prophylaxis
  3. MAJOR drug interactions (CYP450)
82
Q

Hyperacute Allograft Rejection

A

Minutes to hours after transplantation

83
Q

Acute Cellular Rejection (ACR) Allograft Rejection (3)

A
  1. Days to weeks aftertransplantation
  2. Primarily due to T cell mediated injury; T-Cell related
  3. Therapy targets T cell activation and T lymphocytes
84
Q

Antibody Mediated Rejection (AMR) Allograft Rejection (3)

A
  1. Days to weeks after transplantation

Acute/chronic antibody mediated rejection (AMR)
1. Primarily due to antibody mediated injury

  1. Therapy targets antibody production and B lymphocytes; More B-Cell related
85
Q

Chronic Rejection allograft rejection

A

Usually develops over months to years

*Acute rejection may develop during chronic rejection (acute-on-chronic)

86
Q

Mixed ACR/AMR

A

Can present simultaneously

87
Q

Rejection severity banff grade 1,2,3

A

Higher grade rejection require higher intensity therapy regimens

88
Q

Risk factors for allograft rejection (4)

A
  1. Histocompatibility
    * ABO-Blood type mismatches
    * HLA mismatches
  2. Long organ ischemic times pre-transplant
  3. Non-compliance
  4. Opportunistic infections
89
Q

ACR vs. AMR

A

ACR: Target T lymphocytes, Inhibit T cell activation, Deplete T lymphocyte

AMR: Target DSA/plasma cells, Remove circulating DSA, Target plasma cells and pre-cursor B cells

90
Q

ACR Therapeutic Agents (4)

A
  1. rATG
  2. Corticosteroids
  3. Increase maintenance immunosuppression
  4. Alemtuzumab (not utilized at UVA)
91
Q

AMR Therapeutic Agents (6)

A
  1. Plasmapharesis(PLEX)
  2. IVIG
  3. Rituximab
  4. Corticosteroids
  5. Bortezomib*
  6. Eculizumab*
92
Q

Biopsy proven ACR (4)

A
  1. Empiric corticosteroid therapy optional prior to biopsy
  2. Avoid empiric pulse corticosteroids in Hepatitis C patients
  3. Pulse steroids associated with worsening Hepatitis C recurrence and severity
  4. Confirm ACR vs. Hepatitis C recurrence (liver transplant)
93
Q

Clinically suspected ACR (3)

A
  1. Biopsy may not be an option due to bleeding or procedural risk
  2. Utilize signs, symptoms, lab results
  3. Pancreas: clinical diagnosis at UVA (no biopsyreads)
    * Enteric drained: serum amylase, lipase, glucose, c-peptide
    * Bladder drained: urinary amylase, serum glucose, c-peptide
94
Q

Documenting Biopsy Proven ACR

A
  1. Documentation of biopsy results
  2. Preliminary results emailed to transplant team
  3. Transplant team progress notes (next days note)
  4. Not available in EPIC until read finalizes
95
Q

Plasmapharesis (PLEX) (2)

A
  1. Antibody removal
    * Extra-corporeal protein ultrafiltration
    * Plasma exchange
  2. Catheter goes in → blood comes out → filters the antigens → blood goes back into the body
96
Q

IVIG: immunomodulation (6)

A
  1. Regulation of antibody production
  2. Saturate Fc receptors on macrophages
  3. Suppress inflammatory mediator production
  4. Modulate complement
  5. Decrease proliferation and induce apoptosis in B cells
  6. Giving yourself other immunoglobulins to further suppress inflammatory mediator production, modulate complement antibody process and decrease proliferation of cytokines and induce apoptosis (modulating the immune system to give you certain immunoglobulins)
97
Q

Rituximab

A

Anti-CD20 monoclonal antibody; Profound B cell depletion

98
Q

Bortezomib (3)

A

Part of AMR therapy

  1. Proteasome inhibitor; Selective reversible inhibition of 26s proteasome
  2. Induces plasma cell apoptosis
  3. Not used as often
99
Q

Eculizumab (4)

A
  1. Monoclonal antibody against complement protein C5
  2. Prevents formation of membrane attack complex
  3. Prevents ongoing complement dependent injury
  4. Super $ and big guns
100
Q

Corticosteroids for AMR therapy (6)

A
  1. Generalized immunosuppression
  2. Anti-inflammatory
  3. Decrease in circulating T lymphocytes
  4. Bind intracytosolic steroid receptor
  5. Decrease cytokine and receptor expression
  6. Inhibit IL-1,IL-2,IL-3,IL-6,INF-γ, TNF-α

Pediatric Pharmacology Exam 2 (9 decks)

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