Unit 2 - Transplants 2

Question 1

How long does it take for Basiliximab to become effective?

Answer 1

36 +/- 14 days

Question 2

What is the terminal half-life of basiliximab?

Answer 2

7.2 +/- 3.2 days

Question 3

What are the adverse effects of basiliximab?

Answer 3

Chimeric nature decreases risk of hypersensitivity/adverse effects associated with full murine antibodies
Severe acute hypersensitivity reactions are rare but have included anaphylaxis:
- hypotension
- tachycardia
- dyspnea
- wheezing
- pulmonary oedema
- respiratory failure
- urticaria
- rash
- pruritis
- sneezing

Question 4

What is the dosing of basiliximab?

Answer 4

Adult dosage:

• the first dose should be given within 2 hours PRIOR to transplantation
• the second dose should be give 4 days AFTER transplantation

Question 5

How is basiliximab administered?

Answer 5

Via a peripheral or central vein over 20 - 30 minutes

Question 6

Why is maintenance immunosuppressive therapy administered to all renal transplant recipients?

Answer 6

To prevent acute rejection

Question 7

What medications are given as maintenance immunosuppression?

Answer 7

Calcineurin inhibitors
- cyclosporin
- tacrolimus
mTOR inhibitors
- sirolimus
Steroids
- prednisolone
Purine nucleotide modulators
- mycophenolate
- azathioprine

Question 8

Why is the level of chronic immunosuppression slowly decreased over time?

Answer 8

Lower the overall risk of infection and malignancy as the risk of acute rejection decreases

Question 9

How long does immunosupressive therapy last?

Answer 9

Life-long

Question 10

What are CNIs?

Answer 10

Calcineurin inhibitors

Question 11

What are the two licenced calcineurin inhibitors?

Answer 11

• cyclosporin

- tacrolimus

Question 12

What is the function of cyclosporin?

Answer 12

• blocks T-cell cytokine gene transcription

Question 13

What is the main target of cyclosporin?

Answer 13

IL-2 gene

- T-cell growth factor

Question 14

What is tacrolimus?

Answer 14

Macrolide antibiotic extracted from microorganism

Question 15

What are the side effects of calcineurin inhibitors?

Answer 15

Both associated with nephrotoxicity?

• cyclosporin - hirsutism, hypertension, MARKED NEPHROTOXICITY
• tacrolimus - glucose intolerance, GREATER INCIDENC OF NEPHROTOXICITY, hyperlipidaemia

Question 16

How are calcineurin inhibitors metabolised?

Answer 16

CYP450 3A4 enzymes

Question 17

Which drugs lead to increased levels of calcineurin inhibitors?

Answer 17

CYP450 inhibitors

• fluconazole
• erythromycin
• clarithromycin
• verapamil
• diltiazem

Question 18

Which drugs lead to decreased levels of calcineurin inhibitors?

Answer 18

CYP450 inducers

• rifampocom
• phenytoin
• carbamazapine
• St. John’s wort
• warfarin

Question 19

What is mTOR?

Answer 19

mammalian Target of Rapamycin

Question 20

What is the function of sirolimus?

Answer 20

Impairs ability of lymphocytes to replicate

- target is mTOR

Question 21

What are the advantages of sirolimus over tacrolimus or cyclosporin?

Answer 21

Sirolimus is not nephrotoxic

As effective as cyclosporin in preventing acute rejection and prolonging graft survival

Question 22

What are the disadvantages of sirolimus?

Answer 22

Can delay wound healing so generally reserved for use after 3 months of surgery and only where intolerance or withdrawal of calcineurin inhibitors

Question 23

What are the side effects of sirolimus?

Answer 23

• hyperlipidaemia
• leucopenia
• delayed wound healing

Question 24

How is sirolimus metabolised?

Answer 24

CYP450 3A4 enzymes

Question 25

Why is the co-administration of cyclosporin and sirolimus be separated by at least 4 hours?

Answer 25

Cyclosporin can markedly increase oral bioavailability of sirolimus

Question 26

Give two examples of a purine nucleotide modulator

Answer 26

Azathioprine - prodrug which gives rise to 6-mercaptopurine (6-MP)
Mycophenolate Mofetil

Question 27

What is the function of azathioprine?

Answer 27

Purine antagonist

- inhibits conversion of inosine monophosphate to adenine and guanine nucleotides and terminates DNA synthesis

Question 28

What is the function of Mycophenolate mofetil?

Answer 28

Inhibits inosine monophosphate dehydrogenase
- an enzyme that catalyses synthesis of guanine nucleotides
Lymphocytes do not have alternative pathways for producing guanine nucleotides
- prevents T-cell proliferation

Question 29

What is a more widely used alternative to Azathioprine?

Answer 29

Mycophenolate

Question 30

What is mycophenolate licenced for?

Answer 30

Use in renal, liver and heart transplants at oral doses of 1 to 2g twice daily

Question 31

What are the advantages of mycophenolate?

Answer 31

Reduces acute rejections from 36% (azathioprine) to 20% (MPA) when used in renal immunosuppressive regiments
Some evidence that chronic rejection is also reduced

Question 32

Why is there less infection risk with mycophenolate compared with azathioprine?

Answer 32

Incidence of leukopenia is slightly less than with azathioprine

Question 33

Give examples of steroids used in transplant patients?

Answer 33

Methylpredisolone is given at induction to all patients
- IV 500mg to 1g
Prednisolone is used for maintenance (~20mg per day reduced over 3-6 months with a maintenance dose of ~10mg per day)

Question 34

What are the side effects of giving steroids to transplant patients?

Answer 34

Cushing’s syndrome
Diabetes
Hyperlipaemia

Question 35

What percentage of patients will suffer an episode of rejection?

Answer 35

Approximately 20%

Question 36

What percentage of transplant rejections can be treated successfully?

Answer 36

90%

- 2% of all renal transplant patients will suffer rejection that is not treatable

Question 37

How can transplant rejection be diagnosed?

Answer 37

Biopsy

Rising creatinine levels

Question 38

What is antithymocyte globulin?

Answer 38

Purified gamma globulin (serum of rabbits immunised with human thymocytes)