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Immunology > Transplant > Flashcards

Transplant Flashcards

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
Q

Mycophenolate Mofetil (MMF)

A

Cell cept
prodrug
1000mg
94% bioavailability

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26
Q

Enteric coated Mycophenolic Acid

A

Myfortic
delayed release, enteric coated
active drug 720mg
F= 72%

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27
Q

MPA and CNI DDI

A

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
Q

MPA DDI

A

Decreased MPA AUC
* * Cholestyramine/bile acid sequestrants
* antibiotics: norfloxacin, metronidazole, ciprofloxacin, amox/clav, rifampin

29
Q

MPA ADR

A
  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
Q

Renal elimination of MPA vs DDI

A

Acyclovir/ganciclovir
Co-trimoxazole (bactrim)
competes with metabolite MPAG for tubular secretion, notable when GFR < 60 ml/min

31
Q

MPA vs COC DDI

A

Levonorgestrel AUC decreased
counsel patients on using barrier method
MMF – associated with birth defects

32
Q

Glucocorticoids x MMF DDI

A

GC may increase MPA metabolism by enhancing UGT enzymes
= lowers the AUC of MPA

33
Q

MMP DDI: protein binding

A

a potential DDI
may alter drug binding to albumin

34
Q

MMF monitoring

A

Controversial, used on occasion
if renal GFR <20-25 ml/min; adjust or stop drug

35
Q

Glucocorticoid mechanism

A

ortisol level is highest in the morning
HPA: mononuclear cells release cytokines (IL1, TNFa) to stimulate cortisol release from hypothalamus and pituitary

36
Q

Short acting GC equivalent conversions

A

25mg cortisone (pro)
20mg hydrocortisone

37
Q

Intermediate acting GC equivalent conversions

A

5mg prednisone (pro)
5mg prednisolone
4mg triamcinolone
4mg methylprednisolone

38
Q

Long acting GC equivalent conversions

A

0.75mg dexamethasone
0.60 mg betamethasone

39
Q

rank GC in terms of MC effect

A

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
Q

GC principles of use

A
  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
Q

GC dosing regimen adjustment

A

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
Q

Disease states to consider in GC use

A
  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
Q

GC DDI

A

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
Q

GC is an inducer of other drugs

A

Tacrolimus (dec auc)
cyclosporine (high dose methylpred)
Mycophenolic acid MPA (UGT enzymes enhanced)

45
Q

DDI GC hypokalemia risk

A

Diuretic x GC = low potassium
Amphotercin B x GC = low potassium

46
Q

Tissue side effects of prolonged GC

A

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
Q

Tissue side effects of prolonged GC

A

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
Q

Induction therapy

A

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
Q

Maintenance therapy

A

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
Q

Rejection therapy

A

Management of immunologic rejection process
Can be acute or chronic in order to preserve organ function
Acute responds better to drug therapy

51
Q

high risk Induction therapy drugs

A
  1. polycolonal ab (thymoglobulin, atgam)
  2. monoclonal ab (alemtuzumab)
52
Q

Low risk induction therapy

A

IL2 receptor blocker (basiliximab –simulect)

53
Q

MPA monitoring based on CYA

A

MMF + CYA = MPA 1-3.5 mg/L or AUC 30-60 mg/h/L

54
Q

MPA monitoring based on TAC

A

MMF + TAC = MPA 1.9 - 4.0 mg/L or AUC 30-60 mg/h/L

55
Q

what drugs require DAW?

A

All MPA
Generic vs brand CNI
IR vs ER tacrolimus
nonmodified CYA (sandimmune)

56
Q

Thymoglobulin therapy

A

Rabbit antibody
1.5 mg/kg/day

57
Q

ATGAM

A

horse antibody
requires skin test before use
10-15 mg/kg/day

58
Q

polyclonal induction infusion rate

A

IV infusion 4-6 hours x 2-4 daily doses

59
Q

Polyclonal AB ADR

A

First dose: flu like syndrome due to cytokine release premedicate with benadryl
Leukopenia, lymphopenia, thrombocytopenia, pruritus, erythema
Serum sickness

60
Q

Alemtuzumab therapy

A

use is restricted for high risk pt, not approved in kidney transplant
1.single dose
2.two dose

61
Q

Single dose Alemtuzumab

A

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
Q

two dose alemtuzumab

A

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
Q

effect of alemtuzumab on immune system (cells)

A

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
Q

monoclonal antibodies ADR

A
  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
Q

basiliximab adr

A

minimal, no increase in infections
some GI effects: N/V/D

Immunology (6 decks)

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