Transplant Drugs

Front 1

Brand/generic names of calcineurin inhibitors

Back 1

1. Sandimmune (Cyclosporine USP)
-Injection, oral soln, caps

2. Neoral (Cyclosporine USP, modified)
-Oral soln, caps

3. Prograf (Tacrolimus)
-Injection, caps

Front 2

What is the frequency of administration of calcineurin inhibitors?

Back 2

Q 12 hours

Front 3

How do you administer cyclosporine capsules/oral soln?

Back 3

Capsules: Administer the daily dose as 2 equally divided doses Q 12 hours WITH MEALS

Oral soln: Administer the daily dose as 2 equally divided doses Q 12 hours WITH MEALS. May dilute soln with CHOCOLATE MILK or ORANGE JUICE in a GLASS CONTAINER. Additional diluent should be used to rinse container to assure admin. of total dose.

Front 4

What medications interact with cyclosporine?

Back 4

CYP 3A4 inhibitors/inducers

CYP3A4 substrates: Lovastatin, Simvastatin, Atorvastatin
-Co-administration of these agents w/ CsA results in significant increases in statin exposure and may increase risk of rhabdomyolysis.

Mycophenolate mofetil (CellCept)
-Co-admin. w/ CsA inhibits MPAG excretion via hepatocytes, thus interfering w/ MPA enterohepatic recycling, leading to reduced exposure of the active metabolite, MPA.

Front 5

Name common CYP3A4 inducers.

Back 5

Anticonvulsants:
1. Phenytoin (Dilantin)
2. Phenobarbital (Solfoton)
3. Carbamazepine (Tegretol)

Antimicrobial agents:
1. Rifampin
2. Rifabutin

Antiviral agents:
1. Nevirapine (Viramune)
2. Efavirenz (Sustiva)

Herbal products:
1. St. John's Wort

Front 6

Name common CYP3A4 inhibitors.

Back 6

Antidepressants:
1. Nefazodone (Serzone)

Antiviral agents:
1. Delavirdine (Rescriptor)
2. Indinavir (Crixivan)
3. Nelfinavir (Viracept)
4. Ritonavir (Norvir)
5. Saquinavir (Invirase)

Azole antifungal agents:
1. Ketoconazole
2. Fluconazole
3. Itraconazole
4. Clotrimazole

CCBs:
1. Diltiazem
2. Verapamil
3. Nicardipine

Macrolides:
1. Erythromycin
2. Clarithromycin
3. Troleandomycin (Tao)

Food:
1. Grapefruit juice

Front 7

What is the MOA of calcineurin inhibitors?

Back 7

1. Forms complex:
-Cyclosporine w/ cytostolic protein (cyclophilin) of T-lymphocytes.
-Tacrolimus w/FKBP-12 & a calcium-calmodulin-calcineurin complex

2. The complex inhibits calcineurin, which normally translocates NFAT (the promoter gene for IL-2) and activates transcription of IL-2.

Bottom-line: Inhibits TRANSCRIPTION & synthesis of IL-2, thereby inhibiting IL-2 mediated T-CELL PROLIFERATION and polyclonal T-cell activation.

Front 8

Drug-disease interactions of calcineurin inhibitors

Back 8

1. Altered biliary flow (Cyclosporine)- diversion of biliary flow can decrease adsorption (more for Sandimmune than Neoral)

2. DM- Worsens glycemic control

3. Vaccinations- Avoid live vaccines

Front 9

Calcineurin inhibitor ADRs by body system

Back 9

CNS:
1. Seizure
2. Hallucinations
3. Insomnia
4. Tremor
5. Paresthesias (Cyclosporine)
6. Depression (Tacrolimus)
7. Psychosis (Tacrolimus)
8. Anorexia (Tacrolimus)

HEENT:
1. Gingival hyperplasia (Cyclosporine)
2. Alopecia (Tacrolimus)

CV:
1. HTN

GI:
1. Hepatoxicity

Renal:
1. Nephrotoxicity

Endocrine/metabolic:
1. DM
2. Hyperlipidemia
3. Hyperuricemia (Cyclosporine)
4. HyperK+
5. HyperCa++ (Tacrolimus)
5. HypoMg++
6. Hypophosphatemia (Tacrolimus)

Dermatologic (Cyclosporine)
1. Hirusitism
2. Hypertrichosis
3. Acne

Hematologic (Tacrolimus):
1. Anemia

Front 10

How is tacrolimus administered?

Back 10

IV: Dilute w/ NS or D5W and admin. as a CI via PVC-FREE container and tubing

PO: Q12 H CONSISTENTLY with or without food

Front 11

Tacrolimus DDIs

Back 11

CYP3A4 inducers and inhibitors

Front 12

Calcineurin inhibitor monitoring

Back 12

Cyclosporine:
Trough
C2: 2 hours post-dose

Tacrolimus:
Trough goal 5-20 ng/mL

Front 13

mTOR inhibitor brand/generic names and product availability

Back 13

Rapamune (Sirolimus)
-soln/tabs

Front 14

mTOR inhibitor MOA

Back 14

Forms complex w/ FKBP-12 that binds and inhibits activation of mTOR (mammalian target of rapamycin), a kinase that is critical in IL-2- mediated cell cycle progression, thereby BLOCKS ACTIVATION OF T- & B-CELLS.

Front 15

mTOR inhibitor advantage over calcineurin inhibitors

Back 15

mTOR inhibitors are not nephrotoxic like calcineurin inhibitors

Front 16

Sirolimus administration

Back 16

-Once daily
-Consistently with or without food

Oral soln:
Dilute in 2 ounces of H2O or orange juice, stir vigorously and drink at once, then refill container with 4 ounces of the chosen fluid and stir vigorously and drink.

Front 17

Sirolimus DDIs

Back 17

1. CYP3A4 inhibitors/inducers

2. CYP3A4 substrates (e.g., CYCLOSPORINE)
- Simultaneous admin. increases Cmax and AUC of sirolimus by 120-500% and 140-200% , respectively.
Administration 4 hours apart increased Cmax and AUC of sirolimus by 30-40% and 35-80%, respectively.

Front 18

Sirolimus Drug-Disease Interactions

Back 18

1. Liver Txp- assoc. w/ increased incidence of mortality, graft loss, hepatic artery thrombosis.

2. Lung txp: fatal bronchial anastomotic dihiscense

3. Vaccinations

Front 19

Sirolimus ADRs

Back 19

CNS:
1. Anorexia

HEENT:
1. Oral ulcers

GI:
1. Diarrhea
2. Esophagitis
3. Gastritis
4. Gastroenteritis
5. Hepatoxicity
4. Hepatic artery thrombosis

Renal:
1. Synergistic nephrotoxicity w/calcineurin inhibitors

CV:
1.HTN

Endocrine/metabolic:
1. Hyperlipidemia
2. HyperK

Dermatologic:
1. Rash
2. Acne

Hematologic:
1. Leukopenia
2. Thrombocytopenia
3. Pancytopenia
4. Thrombosis

Other:
1. Lymphocele pneumonitis
2. Bronchial anastomotic dehiscence in de novo lung txp

Front 20

Sirolimus Monitoring

Back 20

Trough goal 5-20 ng/mL

Front 21

Sirolimus PK

Back 21

Tablet F=27%
Oral soln F=15%

t1/2: 57-63 hours (INCREASED with hepatic dysfx)

Front 22

Antiproliferative Agents Brand/Generic Names, Availabilty

Back 22

1. Azathioprine (Imuran)
-Injection, tabs

2. Mycophenolate mofetil (CellCept)
-injection, suspension, tabs, caps

3. Mycophenolate sodium (Myfortic)
-Tabs

4. Leflunomide (Arava)
-Tabs

Front 23

Azathioprine (Imuran) MOA

Back 23

-Purine analogue prodrug
-Purine synthesis inhibitor
-Inhibits proliferation of leukocytes
-Cleaved to 6-Mercaptopurine which is activated intracellularly to several active metabolites which are incorporated directly into DNA as thiopurine and also interfere with RNA & DNA biosynthesis directly and via feedback inhibition.

Front 24

Azathioprine Drug-Drug Interactions

Back 24

1. Allopurinol: Xanthine oxidase is responsible for elimination of active metabolites of azathioprine. Concomitant use results in sig. increased azathioprine.
REDUCE DOSE OF AZATHIOPRINE BY 65-75%!

Front 25

Azathioprine Drug-Disease Interactions

Back 25

1. Renal insufficiency- BA is significantly reduced in uremic patients

2. Vaccinations

Front 26

Azathioprine ADRs

Back 26

HEENT: Retionopathy

GI:
1. N/V/D
2. Anorexia
3. Pancreatitis
4. Hepatotoxicity

Dermatologic:
1. Rash
2. Skin cancer

Hematologic:
1. Leukopenia
2. Thrombocytopenia
3. Pancytopenia

Front 27

Azathioprine Administration

Back 27

IV: Dilute dose in NS or D5W, CI over 50-60 min.

PO: Once a day, consistently with or without food

Front 28

Azathioprine PK

Back 28

F=41-47%
F=17% in uremic pts

Front 29

Mycophenolate mofetil (CellCept) MOA

Back 29

Metabolized in the liver to mycophenolic acid (MPA), which inhibits inosine monophosphate dehydrogenase, the enzyme that controls the rate of GMP synthesis in the de novo pthwy of purine synthesis used in the proliferation and activation of B and T lymphocytes.

Front 30

Mycophenolate mofetil administration

Back 30

IV: D5W, CI over at least 2 hours

PO: Q8-12 hours CONSISTENTLY with or without food

Front 31

Mycophenolate Drug-Drug Interactions

Back 31

1. Cyclosporine (Cellcept ONLY)- CsA inhibits MPAG excretion via hepatocytes, thus interfering w/enterohepatic recycling leading to decreased MPA exposure.

2. Cholestyramine (Prevalite): Interrupts enterohepatic recirculation, thereby decreasing MPA exposure.

3. Colestipol and colesevelam (Cellcept ONLY): Decreases MPA exposure

4. Antacids: Reduced absorption

5. Efficacy of oral contraceptives may decrease. Recommend additional BC.

Front 32

Mycophenolate Drug-Disease Interactions

Back 32

1. Severe renal impairment reduces protein binding of MPA

2. Vaccinations

Front 33

Mycophenolate ADRs

Back 33

GI:
1. N/V/D
2. Abdominal pain

Hematologic:
1. Leukopenia
2. Pancytopenia
3. Thrombocytopenia
4. Anemia

Front 34

Myfortic Administration

Back 34

PO: Q 12 h consistently WITHOUT food (30 minutes before or 2 hours after a meal)

Front 35

Myfortic versus Cellcept

Back 35

Myfortic is extended release (less frequent dosing)

Myfortic must be taken without food.


Cellcept comes injection, oral solution, tabs and caps. Myfortic only comes in tablets.

Front 36

Leflunomide (Arava) MOA

Back 36

Metabolized in liver to A77 1726 which inhibits de novo PYRIMIDINE synthesis by inhibition of dihydro-orotate dehydrogenase (DHODH)

Front 37

Leflunomide (Arava) Administration

Back 37

PO: QD

Front 38

Leflunomide (Arava) Drug-Drug Interactions

Back 38

1. Cholestyramine: Reduces biliary recycling and sig. shortens t1/2
DO NOT use w/ leflunomide

Front 39

Leflunmide (Arava) Drug-Disease Interactions

Back 39

1. Renal insufficiency- BA reduced
2. Vaccinations

Front 40

Leflunomide (Arava) ADRs

Back 40

CNS:
1. HA
2. Dizziness
3. Neuralgia
4. Neuritis

HEENT:
1. Alopecia

GI:
1. N/V/D
2. Anorexia
3. Gastroenteritis
4. Esophagitis
5. Colitis

Endocrine/metabolic:
1. DM
2. Hyperlipidemia
3. Hyperthyroidism

Front 41

Leflunomide (Arava) PK

Back 41

Highly protein bound
F=80%
Elimination t1/2= 11-14 days

Front 42

Leflunomide (Arava) Drug-Drug Interactions

Back 42

1. Cholestyramine: Reduces biliary recycling and sig. shortens t1/2
DO NOT use w/ leflunomide

Front 43

Leflunmide (Arava) Drug-Disease Interactions

Back 43

1. Renal insufficiency- BA reduced
2. Vaccinations

Front 44

Leflunomide (Arava) ADRs

Back 44

CNS:
1. HA
2. Dizziness
3. Neuralgia
4. Neuritis

HEENT:
1. Alopecia

GI:
1. N/V/D
2. Anorexia
3. Gastroenteritis
4. Esophagitis
5. Colitis

Endocrine/metabolic:
1. DM
2. Hyperlipidemia
3. Hyperthyroidism

Front 45

Leflunomide (Arava) PK

Back 45

Highly protein bound
F=80%
Elimination t1/2= 11-14 days

Front 46

Glucocorticoid

Back 46

Ex. Cortisol
Controls carbohydrate, protein and fat metabolism and are anti-inflammatory by preventing phospholipid release, decreasing eosinophil action and a number of other mechanisms.

Front 47

Mineralocorticoid

Back 47

Ex Aldosterone
Control electrolyte and water levels mainly by promoting sodium retention in the kidney

Front 48

Corticosteroids Intravenous

Back 48

1. Methylprednisolone
2. Prednisolone

Front 49

Corticosteroids oral

Back 49

1. Prednisone
2. Prednisolone
3. Dexamethasone

Front 50

Steroids glucocorticoid potency ranking

Back 50

Dexamethasone> Betamethasone > Methylprednisolone > Prednisolone > Prednisone> Hydrocortisone

Front 51

Corticosteroid MOA

Back 51

Downregulate expression of HLA and numerous cell adhesion molecules as well as decrease synthesis of numerous lymphokines responsible for activation, proliferation and migration (IL-1, IL-2, IL-6, IL-8, IFN gamma, TNF alpha)

Front 52

Corticosteroid Drug-Drug Interactions

Back 52

CYP3A4 inhib/inducers

Front 53

Corticosteroid Disease Interactions

Back 53

1. DM
2. Osteopenia/osteoporosis
3. Vaccinations

Front 54

Corticosteroid ADRs CNS

Back 54

CNS
1. Seizure
2. Psychosis
3. Delirium
4. Hallucinations
5. Mood swings
6. Insomnia
7. Pseudomotor cerebri

Front 55

Corticosteroid ADRs HEENT

Back 55

1. Cataracts
2. Glaucoma

Front 56

Corticosteroids ADRs CV

Back 56

1. HTN
2. Cardiomyopathy

Front 57

Corticosteroid ADRs GI

Back 57

1. Increased appetite
2. GERD
3. PUD
4. Pancreatitis

Front 58

Corticosteroids ADRs Renal

Back 58

1. Edema
2. Alkalosis
3. Hyperkalemia

Front 59

Corticosteroids ADRs Endocrine/Metabolic

Back 59

1. DM
2. Hyperlipidemia
3. HPPA Axis Suppression
4. Growth suppression

Front 60

Corticosteroids ADRs
Dermatologic

Back 60

1. Hirusitism
2. Acne
3. Skin atrophy
4. Impaired wound healing

Front 61

Corticosteroids ADRs
Hematologic

Back 61

Transient leukocytosis

Front 62

Corticosteroids ADRs
Musculoskeletal

Back 62

1. Arthralgia
2. Myopathy
3. Osteoporosis
4. Avascular necrosis

Front 63

Corticosteroids Administration

Back 63

Take in the morning with food

Front 64

Monoclonal Antibodies
Brand/generic names, availability

Back 64

1. Orthoclone OKT3 (Muromonab CD3)
-injection

2. Basiliximab (Simulect)
-Injection

3. Daclizumab (Zenapax)
-injection

Front 65

Orthoclone OKT 3 (Muromonab CD3) MOA

Back 65

Murine monoclonal IgG
-Binds to and facilitates removal of cell lines expressing CD3 (part of TCR complex)
CD3 is important in antigen recognition and antigen-specific signal transduction

Front 66

Orthoclone OKT 3 (Muromonab CD3)
Administration

Back 66

-Administered as an IV bolus over less than a minute.

-Premedications
DOSE 1:
-IV steroids
-APAP
-Antihistamines
(1 hour before dose)

Subsequent doses: APAP and antihistamines PRN 1 hour prior with steroids for infusion-related rxns

Evaluate volume status prior to admin.

Do not give to those with volume overload or uncompensated CHF

Front 67

Orthoclone OKT 3 (Muromonab CD3) Drug-Drug Interactions

Back 67

NONE

Front 68

Orthoclone OKT 3 (Muromonab CD3) Drug-Disease Interactions

Back 68

1. Uncomp. CHF/volume overload- Risk of FATAL PULMONARY EDEMA

2. Vaccinations

Front 69

Orthoclone OKT 3 (Muromonab CD3) ADRs

Back 69

CNS:
1. Dizziness
2. HA

HEENT:
1. Photophobia

CV
1. Tachycardia

Hematologic
1. Transient lymphopenia
2. Pancytopenia

Musculoskeletal
1. Rigor
2. Tremor

Other
1. Fever
2. Chills
3. Dyspnea
4. PULMONARY EDEMA

Front 70

Orthoclone OKT3 (Muromonab CD3)
Monitoring

Back 70

CD3- suppression of CD3<25 cells/cubic mm

Front 71

Basiliximab (Simulect)
MOA

Back 71

Chimeric (murine/human), monoclonal IgG that binds to CD25 of the human high affinity IL-2 receptor which is only expressed on activated lymphocytes.

Competitively inhibits IL-2 and facilitates preferential elimination of activated lymphocytes.

Front 72

Basilixumab (Simulect) Admin.

Back 72

Dilute in NS or D5W.
CI or bolus over 20-30 min.

NO PREMEDS

Front 73

Basilixumab (Simulect) DDIs

Back 73

Vaccinations

Front 74

Basilixumab (Simulect) Monitoring

Back 74

NONE

Front 75

Basilixumab (Simulect) Pharmacodynamics

Back 75

CD25 saturation at or above serum concentrations of 0.2 mcg/mL

Front 76

Daclizumab (Zenapax) MOA

Back 76

Humanized monoclonal IgG that specifically binds to CD25 which is only expressed on activated lymphocytes.

Competitively inhibits IL-2
Facilitates preferential elimination of activated lymphocytes

Front 77

Daclizumab (Zenapax) Administration

Back 77

IV- NS, Centrally or peripherally as CI over 15 min.

No PreMeds

Front 78

Daclizumab (Zenapax) DDIs

Back 78

Vaccinations

Front 79

Daclizumab (Zenapax) ADRs

Back 79

Severe hypersensitivity rxns including anaphylaxis within the first 24 hours

Front 80

Daclizumab (Zenapax) Pharmacodynamics

Back 80

CD25 saturation at 5-10 mg/mL
Adults
-at rec. dosing saturation occurs for 120 d
Peds
-at rec dosing, sat occurs for 90 d

Front 81

Polyclonal antibodies
Brand/Generic

Back 81

1. Antithymocyte globulin (equine) (Atgam)

2. Antithymocyte globulin (rabbit)
(Thymoglobulin)

Front 82

Antithymocyte globulin MOA

Back 82

Polyclonal IgG directed against cell surface markers such as:
Atgam- CD2, CD3, CD4, CD8, CD11a, CD18
Thymoglobulin- CD2, CD3, CD4, CD5, CD6, CD7, CD8, CD11a, CD18, CD28, CD45, CD49, CD54, CD58, CD80, CD86, HLA Class1 and Beta2 microglobulin

Antithymocyte globulin targets multiple phases of immunity including T cell activation, homing and cytotoxic activities

Front 83

Antithymocyte globulin (Atgam and Thymoglobulin) Administration

Back 83

NS or D5W
Administer CENTRALLY over 4-6 hours
PreMeds:
Dose 1- IV steroids, APAP, antihistamines 1 hour prior to first dose and use in subsequent doses PRN

Front 84

Antithymocyte globulin DDI

Back 84

Vaccinations

Front 85

Antithymocyte globulin ADRs

Back 85

Infusion related reactions (fever, chills, dyspnea)
Leukopenia
Thrombocytopenia
Rash

Front 86

Antithymocyte globulin Monitoring

Back 86

CD2 goal <50 cells/cubic mm

Front 87

Atgam v. Thymoglobulin PK

Back 87

Atgam elim. t1/2=36 hours to 12 days
Thymoglobulin- 2 compartment model, terminal elim. t1/2 for 1st dose=2-3d,
14-45 d with mult. doses