Question 20

College answer

Aim: To explore the side effects of immune suppression drugs commonly seen in the ICU.
Key sources include: Common scenarios in clinical practice with solid organ transplants. TE Oh Ed 8. Chapters on Heart, Liver and Lung transplants, sections on post-transplant management. CanMEDS Medical Expert.
Discussion:
A)    A high level of detail in the mechanism of action and monitoring was not required to pass. Despite this many candidates did not attempt the question including indications or the requirement for monitoring. Candidates are strongly advised to attempt every question.

B)    A structured approach to the non-infectious complications distinguished the better answers. For an example of a successful systems-based approach see below:
Tacrolimus:
Renal: nephrotoxicity and AKI
CNS: headache, seizures, tremors, confusion Haematological: Bone marrow suppression causing anaemia
Endocrine and metabolic- Diabetes after transplant, hyperkalaemia, hypomagnesaemia CVS: HTN
GI: N+V+D anorexia Increased Malignancy risk.
 

Discussion

Considering they took immunosuppressants out of the First Part exam between the 2014 and 2017 versions of the syllabus, the inclusion of this First Part pharmacodynamics question in the Second Part exam must have caught 86.4% of the exam candidates somewhat off-guard. Those who might use this as an argument for the development of a comprehensive Second Part syllabus are reminded that a syllabus mainly helps the exam-writers by providing a conceptual map for the exam, and is usually not an effective defence against esoteric questions. 

• Mechanism of action
  • Prednisolone: a corticosteroid; influences protein synthesis to produce widespread anti-immune/antiinflammatory "immune anergy", including dendritic cell apoptosis, decreased immunoglobulin synthesis and decreased B and T lymphocyte numbers and function.
  • Mycophenolate: a purine synthesis inhibitor; decreases the activity of inosine-5'-monophosphate dehydrogenase which is the rate-limiting enzyme in de novo synthesis of guanosine nucleotides. B and T lymphocytes are dependent on this pathway and therefore mycophenolate decreases their numbers. 
  • Tacrolimus: a calcineurin inhibitor; inhibits the synthesis of IL-2 which is necessary for the maturation and proliferation of T-lymphocytes. 
• Monitoring
  • Prednisolone: no drug level monitoring is directly required; patients should still have regular blood glucose and electrolyte monitoring to watch for insulin resistance and mineralocorticoid side effects
  • Mycophenolate: drug levels are only necessary in solid organ (mostly renal) transplant patients when dosing is being adjusted early in the course of therapy. Subsequent monitoring consists of FBCs only (looking for neutropenia).
  • Tacrolimus: drug levels need to be done regularly because the therapeutic window is narrow (for example, 8 to 12 ng/mL for liver transplant recipients in the first few weeks)
• Non-infectious complications
  • Prednisolone:
    • Hyperglycaemia, weight gain, CNS disturbances (eg. mania and psychosis), hyponatremia, hypokalemia, fluid retention, adrenal suppression, osteopenia, myopathy, gastritis, and cataracts
  • Mycophenolate: 
    • Hypoglycemia, pancytopenia, back pain, headache, hypertension,  vomiting, nausea, acne, increased risk of malignancy (especially skin) and an inflammatory syndrome which resembles sepsis but which is aseptic. 
  • Tacrolimus: 
    • Hypertension,  nephrotoxicity, neurotoxicity (eg. confusion and psychosis), cardiac arrhythmia, hyperkalemia, hypomagnesemia, increased risk of malignancy, nausea and vomiting, and diarrhoea

Zachary, Andrea A., and Mary S. Leffell. "Transplantation Immunology." 2nd ed, (2013). Humana press

Zdanowicz, Martin M. "The pharmacology of immunosuppression." American journal of pharmaceutical education 73.8 (2009).

Dambrin, Camille, Jochen Klupp, and Randall E. Morris. "Pharmacodynamics of immunosuppressive drugs." Current opinion in Immunology 12.5 (2000): 557-562.

Hussain, Yaseen, and Haroon Khan. "Immunosuppressive drugs." Encyclopedia of infection and immunity (2022): 726.