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Transplant Flashcards

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1
Q

Explain the 3 signals

A
  1. antigen recognition by APC, process w/ MHC ; naive T cell recognizes MHC1 through CD3 complex and T cell receptor
  2. costimulation: CD28 upregulation, combine with B7 on APC
  3. Responds to transcription factors –Upregulates receptors on comitted T cell –> IL2, CD25 upregulation, T cell clones, proliferation
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2
Q

Signal 1 drugs

A

Blocks antigen binding
* muronomab-CD3
* CNI
* Thymoglobulin: block the CD2, CD3, CD4 and CD8

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3
Q

Signal 2 drugs

A

costimulation binding inhibited by
Belatacept
Abatacept (CTLA-4-Ig)

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4
Q

Signal 3 drugs

A

DNA replication, upregulation of CD25, IL2, T cell proliferation
* inhibit nuceltodie synthesis: mycophenolic acid
* block CD25, prevent activation of T cell: basiliximab
* Block internal cell signaling: sirolimus/everolimus
* Cell cycle arrest: Azathioprine
* moab block CD52 on mature lymphocytes= cell lysis/depletion: Alemtuzumab

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5
Q

MPA mechanism

A

Interferes with nucleotide synthesis, prevent proliferation of cell (T cell clones)
“Inhibits inosine phosphate dehydrogenase”

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6
Q

Calcineurin inhibitor mechanism

A

preventing the creation of IL-2 → T cell block

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7
Q

Alemtuzumab mechanism

A

MoAB against CD52 surface antigen on mature lymphocytes (T cell> B cell), NK cells, macrophages, monocytes, eosinophils –> causes cell lysis

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8
Q

Cyclosporine PK info

A

Trough goal 50-400 ng/ml
Bioavailability ~30%
Half life: 6-12 hours
Linear kinetcs, trough directly related to drug concentration

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9
Q

Tacrolimus PK info

A

Trough goal 3-20 ng/mL (more potent)
Bioavailability: ~25%
Half life: 8-12 hours
Linear kinetcs, trough directly related to drug concentration

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10
Q

Neoral

A

Cyclosporine microemulsion capsule/solution
BID (every 12 hour)
can dilute with orange/apple juice
can sub with gengraf (bioequivalent)

modified CYA

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11
Q

Gengraf

A

Cyclosporine emulsion capsule/solution
bioequivalent to Neoral

modified CYA

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12
Q

Sandimmune IV

A

Anaphylaxis may occur, short term use
contains castor oil (cremphor EL)
Use when PO not tolerated
Discard after 24 hours

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13
Q

Sandimmune

A

Cyclosporine castor oil capsule/solution
QD dosing (every 24 hours)
DAW! do not sub, erratic bioavailability
Use glass to administer, prone to flocc
Dilute with milk or orange juice

non modified CYA

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14
Q

CNI TDM

A

Frequent montioring of CNI trough and renal function
Weekly/First 3 months/Prolonged period
Verify last 2 doses/formulation/regimen
Troughs based on time post-transplant
Once stable:
Less frequent CNI trough monitoring ok
Unless acute clinical change occurs

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15
Q

cyclosporine ADR

A

Nephrotoxicity
Hyperlipidemia
Hypertension
Hyperglycemia
Tremor, headache
Gingival hyperplasia
Hirsutism
Diarrhea, vomiting

Kidney, fat, BP, sugar, gums, hair, GI, cns

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16
Q

Tacrolimus ADR

A

Diarrhea, nausea
Nephrotoxicity
Tremor, headache
Insomnia
Hyperglycemia
Hyperlipidemia
Hypertension

GI, kidney, sleep, sugar, fat, bp, cns

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17
Q

Calcineurin Inhibitor DDI

Drugs that inhibit CYP450/pgp (increase CNI AUC)

A
  1. CCB (verapamil, diltiazem, nicardipine)
  2. antifungals (ketoconazole)
  3. antibiotics (clarithromycin, quinuprisitin)
  4. protease inhibitors (ritonavir, indinavir, etc)
  5. Gastric acid supressants (PPI, magnesium, etc)
  6. Grapefruit juice (naringin)

BP, azole, mycin, pristin, VIRALS, GERD, grapefruit

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18
Q

Calcineurin inducer DDI

Drugs that induce CYP450/pgp (decrease CNI AUC)

A
  1. antibiotics (naficillin, rifampin, rifabutin)
  2. Antifungal (caspofungin, terbinafine)
  3. Anticonvulsants (carbamazepine, phenytoin, phenobarbital)
  4. Other (octreotide, orlistat)
  5. Herbals (st. john’s wort, echinacea)

penicillins, rifampin, fungin/fine, seizure drugs, orli/oct, HERBS

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19
Q

Prograf (PO)

A

IR tacrolimus capsules
dosed BID (Q 12 H)
DAW

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20
Q

Prograf (IV)

A

ER tacrolimus; DAW
QD (Q 24 H)
Hydrogenated castor oil
Continuous infusion, use glass or polyethylene containers, anaphylaxis may occur

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21
Q

Astagraf XL

A

ER tacrolimus polymer
trough may be lower than IR
QD (Q 24 H)

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22
Q

Envarsus

A

ER tacrolimus meltdose controlled release
QD (Q 24 H)
Dose is 70% of IR daily dose

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23
Q

PK of CNI are affected by

A

Fat content in meals and bile
Time post transplant
Early post-OP more absorption
Compromised GI func
Diarrhea
Gastroparesis
Overall bioavailability
Dosage form variation
Drug interactions

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24
Q

Mycophenolic acid mechanism

A

interferes with nucleotide synthesis, prevent proliferation of cell (T cell clones)
“Inhibits inosine phosphate dehydrogenase”

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25
Mycophenolate Mofetil (MMF)
Cell cept prodrug 1000mg 94% bioavailability
26
Enteric coated Mycophenolic Acid
Myfortic delayed release, enteric coated active drug 720mg F= 72%
27
MPA and CNI DDI
Cyclosporine: MRP2 transporter inhibited - no enterohepatic recycling - decreases MPA AUC and MPA EHC Tacrolimus: minimal inhibition - enterohepatic recycling occurs still - Higher MPA AUC than cyclosporine MPA can be used to lower CNI dose, switch between CNI, and for pt with high risk
28
MPA DDI
Decreased MPA AUC * * Cholestyramine/bile acid sequestrants * antibiotics: norfloxacin, metronidazole, ciprofloxacin, amox/clav, rifampin
29
MPA ADR
1. GI adr most notable (chronic N/V/D/Dyspepsia) -- more prevalent with tacrolimus + MPA 2. Hematologic: low wbc/neutrophil/platelets, anemia 3. opportunistic infections 4. CNS: insomnia, dizziness, severe headache 5. Cardiovascular
30
Renal elimination of MPA vs DDI
Acyclovir/ganciclovir Co-trimoxazole (bactrim) competes with metabolite MPAG for tubular secretion, notable when GFR < 60 ml/min
31
MPA vs COC DDI
Levonorgestrel AUC decreased counsel patients on using barrier method MMF -- associated with birth defects
32
Glucocorticoids x MMF DDI
GC may increase MPA metabolism by enhancing UGT enzymes = lowers the AUC of MPA
33
MMP DDI: protein binding
a potential DDI may alter drug binding to albumin
34
MMF monitoring
Controversial, used on occasion if renal GFR <20-25 ml/min; adjust or stop drug
35
Glucocorticoid mechanism
ortisol level is highest in the morning HPA: mononuclear cells release cytokines (IL1, TNFa) to stimulate cortisol release from hypothalamus and pituitary
36
Short acting GC equivalent conversions
25mg cortisone (pro) 20mg hydrocortisone
37
Intermediate acting GC equivalent conversions
5mg prednisone (pro) 5mg prednisolone 4mg triamcinolone 4mg methylprednisolone
38
Long acting GC equivalent conversions
0.75mg dexamethasone 0.60 mg betamethasone
39
rank GC in terms of MC effect
MC effect: water retention - HTN Most MC effect: short acting -intermediate acting * cortisone, hydrocortisone > Predisone, prednisolone No MC effect: intermediate - Long acting * triamcinolone, methylprednisolone, dexamethasone, betamethasone
40
GC principles of use
1. Assess risk 2. check evidence for use 3. short term vs long term 4. time of use: morning better due to circadian 5. monitor/minimize ADR 6. evaluate outcomes for disease responses
41
GC dosing regimen adjustment
Daily morning dose (5mg) or alternate daily dosing if possible (difficult titration) Taper schedule: start high to control inflammation, divide into multiple doses Once disease controlled, reduce dose and frequency; (physiologic of 5mg prednisone) Supraphysiologic dosing: 5-7.5mg/day of prednisone
42
Disease states to consider in GC use
1. decreased albumin states (liver disease increases drug conc) 2. hypothyroidism (increased therapeutic effect) 3. pregnancy (avoid use in first trimester, or lowest effective dose/short acting) 4. surgery (stress dose, then wean off) 5. Diabetes (GC increases gluconeogensis, decreases insulin secretion, increase BG) 6. Peptic ulcer disease: 2x increase risk in GC patients , avoid NSAID dual use
43
GC DDI
inhibitors of GC * oral contraceptives * conjugated estrogens * macrolide antibiotics **-mycin** * ketoconazole * isoniazid * naproxen * **cyclosporine** Inductors of GC * phenytoin * phenobarbital * rifampin * carbamazepine * ephedrine (dexamethasone) Decreased absorption * cholestyramine * antacids
44
GC is an inducer of other drugs
Tacrolimus (dec auc) cyclosporine (high dose methylpred) Mycophenolic acid MPA (UGT enzymes enhanced)
45
DDI GC hypokalemia risk
Diuretic x GC = low potassium Amphotercin B x GC = low potassium
46
Tissue side effects of prolonged GC
striae on arm/abdomen Avascular necrosis **thin pelvic bones** Ecchymoses (bruise,blue,mark) cararacts in young patients , glaucoma - adrenal atrophy, cushings, HTN, vasculitis, thrombosis, hyperlipidemia - CNS changes, increased mood, behavior/memory change - retention of sodium, loss of potassium (Na/K) - delayed wound healing, acne, GI bleed, pancreatitis, PUD -broad immunosupression
47
Tissue side effects of prolonged GC
striae on arm/abdomen Avascular necrosis **thin pelvic bones** Ecchymoses (bruise,blue,mark) cararacts in young patients , glaucoma - adrenal atrophy, cushings, HTN, vasculitis, thrombosis, hyperlipidemia - CNS changes, increased mood, behavior/memory change - retention of sodium, loss of potassium (Na/K) - delayed wound healing, acne, GI bleed, pancreatitis, PUD -broad immunosupression
48
Induction therapy
More intense immunosuppression, blunt the immune system Initiates just prior and during the acute post-transplant period 1. Induction agent 2. IV bolus MEPN 3. MPA dose
49
Maintenance therapy
Achieve less intense suppression but over a longer duration Prophylaxis against acute rejection Things to consider: deceased/living donor, prior transplants, ADR, HLA mismatch, acute rejections, compliance, drug costs 1. Calcineurin inhibitors (CYA,TAC) 2. Lymphocyte proliferation inhibitors (MPA,MMF, azathio) 3. Non-specific: Glucocorticoids
50
Rejection therapy
Management of immunologic rejection process Can be acute or chronic in order to preserve organ function Acute responds better to drug therapy
51
high risk Induction therapy drugs
1. polycolonal ab (thymoglobulin, atgam) 2. monoclonal ab (alemtuzumab)
52
Low risk induction therapy
IL2 receptor blocker (basiliximab --simulect)
53
MPA monitoring based on CYA
MMF + CYA = MPA 1-3.5 mg/L or AUC 30-60 mg/h/L
54
MPA monitoring based on TAC
MMF + TAC = MPA 1.9 - 4.0 mg/L or AUC 30-60 mg/h/L
55
what drugs require DAW?
All MPA Generic vs brand CNI IR vs ER tacrolimus nonmodified CYA (sandimmune)
56
Thymoglobulin therapy
Rabbit antibody 1.5 mg/kg/day
57
ATGAM
horse antibody **requires skin test before use** 10-15 mg/kg/day
58
polyclonal induction infusion rate
IV infusion 4-6 hours x 2-4 daily doses
59
Polyclonal AB ADR
First dose: flu like syndrome due to cytokine release **premedicate with benadryl** Leukopenia, lymphopenia, thrombocytopenia, pruritus, erythema Serum sickness
60
Alemtuzumab therapy
use is restricted for high risk pt, not approved in kidney transplant 1.single dose 2.two dose
61
Single dose Alemtuzumab
Precede with IV methylprednisolone 250 mg 30 min before infusion Give MoAB 20-30 mg IV over 2-3 hours 2 months of anti-infective prophylaxis after d/c drug or until CD4+ >= 200 cells/uL
62
two dose alemtuzumab
Precede w/ IV methylprednisolone 500 mg 30 min before infusion Dose 1: 0.3mg/kg/dose intra-operatively on day of transplant (D-0) Dose 2: 0.3mg/kg/dose 24 hrs post transplant (D-1) after 1st dose, or on D-4 2 months of anti-infective prophylaxis after d/c drug or until CD4+ >= 200 cells/uL
63
effect of alemtuzumab on immune system (cells)
B cells return in 3-12 months T cells can be depressed for up to 3 years average half life = 11 hours chronic dosing half life = 6 **DAYS**
64
monoclonal antibodies ADR
1. hama reaction (initial) - fever,rigor,N/D, hypotension (low BP) 2. GI disorders N/V/D 3. profound lymphopenia, neutropenia 4. increased risk of malignancy, infection, or autoimmune reactions ^requires anti-infective prophylaxis after d/c drug or until CD4+ is greater than 200 cells/microLiter
65
basiliximab adr
minimal, no increase in infections some GI effects: N/V/D

Immunology (6 decks)

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