Transplant Agents Flashcards

Question

Antithymocyte Globulin Pharmacokinetics (3)

Answer 1

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

Answer 2

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

Answer 3

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

Answer 4

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

Answer 5

1. Alemtuzumab (Campath®, IV/SQ) – binds to CD52 | 2. Basiliximab (Simulect®) – binds to CD25, IL-2 receptor antagonist

Answer 6

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

Answer 7

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

Answer 8

1. TPMT gene mutations | 2. Defects in enzyme expression can lead to significant levels of AZA and increased adverse effects

Answer 9

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

Answer 10

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

Answer 11

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

Answer 12

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

Answer 13

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

Answer 14

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

Answer 15

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

Answer 16

1. Primarily @ small intestine | 2. Drug sticks to enteral feeding tubes (and will affect absorption)

Answer 17

1. Almost complete | 2. Capsules can be opened and placed under the tongue

Answer 18

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

Answer 19

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)

Answer 20

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*

Answer 21

1. Nephrotic Syndrome | 2. Crohn's disease

Answer 22

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

Answer 23

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

Answer 24

1. Cyclosporine products are not interchangeable | 2. Most common formulation today is the modified form

Answer 25

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

Answer 26

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

Answer 27

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

Answer 28

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

Answer 29

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)

Answer 30

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

Answer 31

mTOR = mammalian target of rapamycin Available agents: 1. Sirolimus (Rapamune®) 2. Everolimus (Zortess®) - $$

Answer 32

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

Answer 33

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

Answer 34

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 4. Tablets and oral solution are not bioequivalent (just monitor)

Answer 35

1. Liver Transplant: Hepatic Artery Thrombosis | 2. Lung Transplant: Pulmonary Fibrosis

Answer 36

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

Answer 37

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

Answer 38

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

Answer 39

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

Answer 40

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

Answer 41

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)

Answer 42

1, Competitive antagonist of para-aminobenzoic acid (PABA) → lack of PABAprevents folic acid synthesis 2. AGENT OF CHOICE for sulfa-allergic patients 3. MUST test G6PD before starting therapy

Answer 43

Interferes with RNA/DNA, phospholipids, and protein synthesis

Answer 44

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

Answer 45

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

Answer 46

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

Answer 47

Donor CMV Status: negative Recipient CMV Status: negative

Answer 48

Donor CMV Status: negative or positive Recipient CMV Status: positive

Answer 49

Donor CMV Status: Positive Recipient CMV Status: Negative *Will need a longer course of prophylaxis

Answer 50

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

Answer 51

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

Answer 52

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

Answer 53

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

Answer 54

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

Answer 55

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

Answer 56

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)

Answer 57

Minutes to hours after transplantation

Answer 58

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

Answer 59

1. Days to weeks after transplantation Acute/chronic antibody mediated rejection (AMR) 1. Primarily due to antibody mediated injury 2. Therapy targets antibody production and B lymphocytes; More B-Cell related

Answer 60

Usually develops over months to years | *Acute rejection may develop during chronic rejection (acute-on-chronic)

Answer 61

Can present simultaneously

Answer 62

Higher grade rejection require higher intensity therapy regimens

Answer 63

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

Answer 64

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

Answer 65

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

Answer 66

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

Answer 67

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)

Answer 68

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

Answer 69

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

Answer 70

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

Answer 71

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)

Answer 72

Anti-CD20 monoclonal antibody; Profound B cell depletion

Answer 73

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

Answer 74

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

Answer 75

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