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PDAT4 > 22/23 - Transplant Therapeutics > Flashcards

22/23 - Transplant Therapeutics Flashcards

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1
Q

3 Mechanisms for IMMUNOSUPPRESSION

A

IMS is achieved by:
DEPLETION of Lymphocytes

DIVERSION of lymphocyte Traffic

BLOCKING of lymphocyte proliferation & response

Combination works best:
typically 3 maintanence Drugs
or AB induction + 2 maintanence druge

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2
Q

Induction Overview
Strategy for ImmunoSuppression: INDUCTION

A

Acute & Potent IMS

Used in PERI-operative Period

Goals:
induce allograft acceptance by Supressing T-Cells
BRIDGE to Maintenance Agents

Agents:
Corticosteroids
Lymphocyte Depleting & Non-Depleting ANTIBODY AGENTS

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3
Q

Corticosteroids: Pharmacology
Strategy for ImmunoSuppression: INDUCTION

A

NON-Depleting Agent
universally used for ALL xplants @ time of engraftment

  • *Action on T-cells**
  • *inhibit the TRANSLOCATION of NFkB & AP-1** –> nucleus
  • INHIBITION of CYTOKINE GENE EXPRESSION*

Act on Other Leukocytes

Anti-inflammatory Effects

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4
Q

Corticosteroids: Dosing / Admin
Strategy for ImmunoSuppression: INDUCTION

A

HIGH DOSE METHYLPREDNISOLONE

250-100mg IVPB
or
Followed by IV MP or PO prednisone taper

Supresses lymphocyte production for 24 hours
allows for QD dosing

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5
Q

Corticosteroids: ADRs
Strategy for ImmunoSuppression: INDUCTION

A

SHORT TERM EFFECTS
most resolved after 1-2 days

  • impaired*
  • *Glucose Tolerance /** Wound Healing

INCREASED
Appetite / BP / Fluid Retention

Mood Disturbance

Leukocytosis

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6
Q

Depleting Agents: Pharmacology
Strategy for ImmunoSuppression: INDUCTION

A
  • *Polyclonal Antibodies**
  • *ThymoGlobulin // Atgam**

AB’s directed against T-Cell surface AG’s –> Binding
VVV
Opsonization & elimination
VVV
T-Cell Lysis + Cytokine Release
VV
T-CELL DEPLETION

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7
Q

Thymoglobulin & Atgam
Dose & Admin
Strategy for ImmunoSuppression: INDUCTION

A

DEPLETING AGENTS

Thymoglobulin
30 day half life // IV for 3-7 days // 1 IgG Subtype
Binds to lymphocytes with GREATER AFFINITY
–> Greater/longer T-cell Depletion

Atgam
Same, but with 2 subtypes
Different binding affinities

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8
Q

Polyclonal AB’s: ADR’s
Thymoglobulin / Atgam
Strategy for ImmunoSuppression: INDUCTION

A

Leukopenia / Thrombocytopenia / Anemia
Some AB’s recognize AG’s on NON-lymphoid Cells

MAY trigger T-cell Activation
foreign protein / pro-inflammatory cytokines / POLYclonal response

Cytokine Release Syndrome
first dose effect

Serum Sickness
type 3 hypersensitivity, 5-15 days after admin, may use coritocosteroids

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9
Q

Polyclonal AB’s - MONITORING
Thymoglobulin / Atgam
Strategy for ImmunoSuppression: INDUCTION

A

EFFICACY - GOALS
Absolute Lymphocyte Count (ALC) of < 200 cells/uL
(better surrogate marker vs CD3)
CD3 < 50 cells/uL

TOXICITY
WBC < 5k
Platelets <100k
due to nonspecificity of AB –> non-lymphoid cells

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10
Q

Alemtuzumab: Pharmacology
Strategy for ImmunoSuppression: INDUCTION

A

Monoclonal AB // DEPLETING AGENT

Humanized AB against CD52

CD52 found on nearly ALL T+B cells
+ most monocytes / macrophages / some granulocytes

AB-Dependent LYSIS after Cell surface binding

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11
Q

Basiliximab: Pharmacology
Strategy for ImmunoSuppression: INDUCTION

A

Monoclonal AB // NON-DEPLETING AGENT

Chimeric AB against CD25 // aka IL-2 Receptor Antagonist

CD25 = A-Chain on ACTIVATED T-cells only
VVV
blocks signal 3 & T-cell proliferation

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12
Q

Alemtuzumab: Dose / ADRs
Strategy for ImmunoSuppression: INDUCTION

A

single 30mg Dose on day 0
12 day half life
prolonged lymphopenia

Infusion Reactions
fevers / chills / HypoTension / Rash / NVD
use APAP / DPH / MP to limit ADR

Hematologic
Due to targetting OTHER cell lines
anemia / neutropenia / thrombocytopenia
Use: Erythropoetin / filgrastim / transfusion

Infections
opportunistic // sepsis

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13
Q

Basiliximab: Dose / ADRs
Strategy for ImmunoSuppression: INDUCTION

A

20mg IVPB on Day 0 + 4
7 day half life

IL-2 Receptor saturation for 30-45 days

  • *EXTREMELY WELL TOLERATED**
  • no Cytokine release syndrome or first dose reaction*

RARE Hypersensitivity Reactions

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14
Q

Calcineurin Inhibitors (CNIs): Pharmacology
Strategy for ImmunoSuppression: MAINTENANCE

A

FORMULATIONS are NOT INTERCHANGABLE
medication errors result in serious ADRS –> graft rejection

Tacrolimus = TAC or FK506
Binds FKB-12 –> complex

Cyclosprine = CSA
Binds -> Cyclophilin

INHIBIT CALCINEURIN –> prevent NFAT from entering nucleus
VV
Inhibition of IL-2 synthesis –> Prevention of T-cell Proliferation

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15
Q

Tacrolimus Dosing
Strategy for ImmunoSuppression: MAINTENANCE

A

Dose adjustments are based on TROUGH LEVELS (C0)

  • *Prograf**
  • *IR** 0.05-0.1 mg/kg/dose PO q12 hr
  • *Astagraf-XL**
  • *ER** 0.1-0.2 mg/kg/dose –> 1:1 conversion
  • *Envarsus-XR**
  • *ER, but with better absorption (throughout GI tract**)
  • *1:0.8 conversion**
  • reduced daily IR dose by 20%*
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16
Q

Cyclosporine: Dose
Strategy for ImmunoSuppression: MAINTENANCE

A

Cyclosporine dose adj based on
TROUGH (C0) or 2-hr PEAK level (C2)

Cyclosporine -> Cyclophilin

3-5 mg/kg/dose PO q12h

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17
Q

CNIs: Routes of Administration
Strategy for ImmunoSuppression: MAINTENANCE

A

IV Formulation
↑Risk for NEPHROtoxicity, avoid formulation
used for bone marrow xplant w/ severe Mucositis

Suspension
given via NG tube

Sublingual
admin of IR TAC only –> decrease dose by 50%

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18
Q

CNI: Drug Interactions
Strategy for ImmunoSuppression: MAINTENANCE

A
  • *CYP3A4 inducers** reduce levels of CNI
  • phenytoin / carbamazepine / rifampin*
  • *CYP3A4 inhibitors** INCREASE levels of CNIs
  • *Azole antifungals / -mycins** / diltiazem / verapamil / ritonavir

p-GP substrate

NSAIDS –> added nephrotoxicity

ACE-I / ARB –> renal sparing / nephroprotective effects

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19
Q

TAC vs CSA
in ADRs

A

Both still have 5-yr risk of CHRONIC RENAL FAILURE = 7-21%

TAC is WORSE at almost ALL, except HTN

Acute Nephrotoxicity
generally similar in ACUTE setting
vasospasms of glomerular arteriole –> reduction in GFR
reversible

Chronic Nephrotoxicity
IRREVERSIBLE
ischemia due to hemodynamic changes -> scaring/fibrosis

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20
Q

When to choose or switch
CSA > TAC ?

Every time you switch IMS agents you increase risk of rejection
Check levels 7 days after change and then monthly!

A

RISK FOR DM
Post Transplant DM (PTDM) / New Onset Diabetes after transplant (NODAT)
TAC has dose dependent REDUCTION in INSULIN secretion

PEDS < 5 YEARS
use CSA, not TAC

Hair Loss

Tremors or Falls

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21
Q

When to choose or switch
TAC > CSA?

Every time you switch IMS agents you increase risk of rejection
Check levels 7 days after change and then monthly!

Study These Flashcards
A

GREATER POTENCY
​REJECTION

  • *Hair Growth (hirutism**)
  • caused by CSA*

Gingival HyperPlasia

22
Q

AntiMetabolites: Pharmacology
Strategy for ImmunoSuppression: MAINTENANCE

Study These Flashcards
A

Stop the CELL-CYCLE for T-cell Proliferation

Mycophenolic Acid = MPA
INHIBITS IMPDH –> inhibits DE-NOVO synthesis of Guanosine
MORE SPECIFIC, only blocks the DE-NOVO pathway
higher affinity to IMPDH of ACTIVE T-cells

Azathioprine = AZA
prodrug, same de-novo inhibition but for BOTHadenine + guanine
TPMT + Xanthine Oxidase for inactivation

23
Q

AZA: Pharmacology
Strategy for ImmunoSuppression: MAINTENANCE

Study These Flashcards
A

AntiMetabolite Maintenance Agent // PRODRUG

INHIBITION of DE-NOVO Purine Synthesis
(both ADENINE + GUANINE)

Need for TPMT SCREEN (genotyping / enzyme activity test)
since this is responsible for activation & deactivation of 6MP

  • *TPMT genetic Polymorphisms**
  • SLOWS inactivation of 6MP* –> accumulation of myelosuppressive metabolites –> death!
24
Q

Mycophenolate: Dose / Admin / ADR
Strategy for ImmunoSuppression: MAINTENANCE

Study These Flashcards
A
  • *PO: 1000-1500mg BID**
  • 720mg EC-MPS = 1000mg MMF (**dose conversion)*

IV: 1000mg BID over 2 hours

  • *MPA has SECOND PEAK** due to ENTEROHEPATIC RECIRCULATION
  • BUT –>* CSA INHIBITS that –>
  • decreased AUC of MPA when taken with CSA*

ADR:
GI Upset // Hematologic

25
**Azathioprine: Dose / Admin / ADR** Strategy for ImmunoSuppression: MAINTENANCE
**PO: 1-3 mg/kg/day** IV: EQ to oral dose, but lower end * *_AVOID WITH XANTHINE OXIDASE INHIBITORS_** * Uloric / Allopurinol* * NOT as potent as MPA* * *_HEMATOLOGIC EFFECTS_** (not as specific) **Pancreatitis / Hepatoxicity / Squamous Cell Cancer**
26
**MPA: GI ADR Amelioration**
**MPA = GI ADR's** **Take W/ FOOD** // use **Anti-motility agents or Anti-emetics** Change to **EC formulation** (for upper GI ADR) *SWITCH TO AZA? (rejection risk, not as potent)* **TID-QID Dosing Intervals** * **reduce MPA dose*** * but increased incidence of rejection*
27
**CorticoSteroids for Maintanence** Strategy for ImmunoSuppression: MAINTENANCE
**Prednisone: 5-15mg/day** (*low dose)* Reserved for: * *Pts w/ multiple rej** on steroid-free regimin * *High-Risk xplant Patients (sensitized**) or **+xmatch** * *No-Induction - 3 drug regimen** **_ADR's Associated w/ CHRONIC USE_** **Diabetes / Osteoporosis / HYPERLipidemia / Cateracts** Acne / Infection / Weight Gain
28
**Risks & Benefits** of **Steroid Minimization / Avoidance** Strategy for ImmunoSuppression: MAINTENANCE
_BENEFITS_ **Reduction of PTDM/NODAT (**Diabetes from Steroids / CNIs) less weight gain, *no diff in infxn rates* *_RISKS_* Need for **higher doses of other immunospression (^TAC/CSA) More Potent Induction**
29
**mTOR inhibitors: Pharmacology** Strategy for ImmunoSuppression: MAINTENANCE
**_Sirolimus**_ // _**Everolimus_** * unlike CNI's who block IL-2 Production* * *mTORi block _IL-2 Signal Transduction_** mTOR inhibits binds to **FKBP-12** the complex ***inhibits phosphorylation of proteins*** ***Inhibits _smooth muscle proliferation_*** ***inhibits _VEGF activity_*** possible benefit in reducing malignancies
30
**Sirolimus / Everolimus** **Dose & Admin** Strategy for ImmunoSuppression: MAINTENANCE
*both mTORi's have NO IV formulation* **_Sirolimus_** **QD**, LD of **6mg** or 0.2mg/kg MD of **2mg** or 0.1mg/kg **62 hour Half Life** **_Everolimus_** **_BID Dosing_** , *NO loading dose* MD of **0.75mg q12 hr** Half life of 30 hours
31
**mTORinhibitors: ADR's Sirolimus / Everolimus** Strategy for ImmunoSuppression: MAINTENANCE
**_Hematologic_** Thrombo / Anemia **_Mouth Ulcers / *Decreased* Wound Healing_** Since inhibition of **VEGF healing** --\> delay initiation / if recurrent DC **_Proteinuria / Nephrotoxicity_** GFR decreased by 15% in setting of Full dose CNI (CSA\>\>FK506) Lower CNI through,***conversion of CNI -\> Sirolimus not recommended*** _HYPERTg's // Interstitial Pneumonitis_
32
**mTORinhibitors: Drug Interactions Sirolimus / Everolimus** Strategy for ImmunoSuppression: MAINTENANCE
**_P-Glycoprotein Competition_** **CYCLOSPORINE** --\> resulting in **INCREASED BV/Levels** admin **4 hours after CSA** _**CYP3A4 Inducers** --\> *decrease mTORi levels*_ Phenytoin / carbamazepine / rifampin / nafcillin **_CYP3A4 inhibitors_** _--\> INCREASE levels_ Azole antifungals / -mycins / diltiazem / ritonavir
33
**Belatacept: Pharmacology** Strategy for ImmunoSuppression: MAINTENANCE
**_Selective Costimulation Blocker_** Signal 2 Blocker **Fusion Protein --\> _B7 on APCs_** promotes T-cell **anergy & apoptosis** Benefit: **Preserve RENAL FUNCTION** (CNI avoidance)
34
**Belatacept: Dose & Admin** Strategy for ImmunoSuppression: MAINTENANCE
**_IV Dosing over 30 minutes_** Month 0-1: 10mg/kg --\> Month 2-3: 10mg/kg --\> Month 4-12: 5mg/kg **_EBV Seropositive Virus Patients ONLY_** Epstein-Barr Virus ***_DO NOT USE in LIVER XPLANT patients_*** due to an INCREASED risk of graft loss & death
35
**Belatacept: ADRs**
**_PTLD_** only used in **EBV Positive** because of this B-cell proliferation due to induced immunosupression **_Myelosuppression_** **_GI Upset_** **_Neuropathy_** Acute Infusion Related ADR's
36
**Triple Regimen** Immunusppressive Therapy
*If deviating from golden Triad* **MUST compensate for increased REJ RISK VVV 3 Maintenance Drugs** **AB Induction + 2 Maintanence Drugs**
37
**Patient Factors in OPTOMIZING IMS**
Perceived **Immunologic risk** for rejection Expected/existing **drug toxicities** **Infectious Risk** **Co-morbidities** H/O of **non-adherence**
38
**Antibody Induction Choice** **HIGH RISK**
High Risk: **African / Re-Transplant / High PRA ABOi / Positive XM** use: **_LYMPHOCYTE DEPLETING AGENTS_** **Thymoglobulin / Atgam / Alemtuzumad**
39
**Antibody Induction Choice** ***LOW RISK***
**_No Antibody_** need to stay on the **3 drug regimen** **_Basiliximab_** can be 2 drug Therapy **_High Risk for ATN/DGF_** upgraded to **depleting agents**
40
**Acute Tubular Necrosis = ATN** Who is at risk?
**ATN** --\> damage to **kidney tubules** caused by a **lack of oxygen** to kidney tissue = **ischemia** Risk Factors: * *Donor Age \>50 or \<12** yo * *Recipient \>55** * *Cold Ischemic time \> 24 hours** * *Donor SrCr \> 1.8mg/dL** prior to procurement * *DCD** (donation after cardiac death) *_IF AT RISK for TBN:_* Use **depleting agent** --\> result in *decreased inflammatory response & improved outcomes*
41
**Thymoglobulin vs Atgam** For **AB Induction in KIDNEY**
* *_THYMOGLUBULIN_** \> Atgam * less rejection* & **improved graft survival**
42
**Thymoglobulin vs Alemtuzumab** for **AB induction for KIDNEY**
**HIGH RISK = similar** * *_Alemtuzumab_ * LESS rejection* in EARLY rejection** * BUT* * *MORE LATE-acute rejections** * *"Alem is MORE late"** both beneficial in ATN/DGF prevention following kidney transplant
43
* *Alemtuzumab vs Basiliximab** * *AB Induction for KIDNEY**
* low risk:* * *_ALEMTUZUMAB_** * **LESS rejection*** ## Footnote **but more _LATE-acute_ rejections w/ alemtuzumab** **"Alem is MORE LATE"**
44
* *Thymoglobulin vs Basiliximab** * *AB Induction for KIDNEY**
HIGH RISK: * *_THYMOGLOBULIN_** * **LESS rejection*** ## Footnote **more overall infections with thymoglobulin though**
45
**CSA vs TAC Maintenance Selection**
* *_TAC is better for all organs_** * but EQUAL for **HEART*** _Cyclosporine_ **higher LDL / hirsutism / gingival HYPERplasia / HT** _Tacrolimus_ higher incidence of **NODAT, Alopecia, Neurotoxicity** *no consistance differences in mortality / infection / delayed graft fxn*
46
* *Belatacept vs CNI** * *Maintenance Selection**
**Bela** allows for **avoidance of _CNI nephrotoxicity_** * *_for Kidney:_** * *Bela is EQUAL in survival of graft** **_BELA \> CNI_** for **LONG-TERM** **renal fxn** (**GFR)** *but has **increased risk of ACUTE rejection***
47
**Steroid Minimization / Avoidance** What is the best **ADJUNC agent combination?**
**_Steroids_** **additional safety** in case of **nonadherence** allows for a **SAFER dose de-escalation** of CNI and MPA in case of **ADRs** *_if STEROID-FREE_* use **AB-induction** * _if deviating from TAC/MPA combo_* * *consider steroids**, esp for high-risk
48
**MMF (MPA prodrug) vs AZA** Maintenance Selection
***_NO difference in patient survival or graft function_*** _**MMF** (MPA prodrug) is...._ ***less ACUTE rejection*** **improved GRAFT survival** more **diarrhea** / *similar other side effects*
49
**MMF vs EC-MPS (Enteric Coated)** Maintenance Selection
* **_NO DIFFERENCE IN:_*** * *Acute rejection** / **pt or graft survival** * *malignancy / infection / GI ADR** * some studies show:* * **reduced* GI intolerance in EC-MPS \> MMF**
50
**When to use mTORi** instead of **Antimetabolite (MPA\>AZA)**
Generally considered ***NOT* suitable replacement for CNIs** _Used as an alternative for_ **_MPA intolerant patients_** w/ **significant toxicities (intolerable)** _Also for:_ **patients at risk for _TUMOR RECURRENCE_** or those with **_SKIN CANCERS_**
51
**What 2 drugs does CSA affect and HOW? Drug Interactions**
**_AZAthioprine_** **CSA** --\> _***INHIBITS*** **enterohepatic reciculation**_ stops SECOND PEAK --\> ***reduced AUC* of AZA** **_Sirolimus / Everlimus_** **P-Gp substrate competition** VVV **INCREASED Sirolimus levels** **Admin Sirolimus _4 hours_ _after_ CSA**
52
**Steroid Avoidance Considerations**
_Late Steroid Withdrawal:_ **High Incidence of Chronic Rejection ADRs already manifesting** _3-6months post-transplant_ **15-20% Acute Rejection** / ***↑CVD Risk*** _Early, 5-14 days post-txp_ ***↑Acute Rejection*** ↓***CVD Risk***, long term graft fxn stays the same

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