Pharmacology of immunosuppressants

Immunosuppressants have not appeared in the CICM Second Part exam until Question 20 from the cursed first paper of 2023, which took the candidates by surprise when it asked for some considerable amount of detail about the mechanism of action monitoring and side effects of mycophenolate, tacrolimus and prednisolone. The pass rate was predictably dismal. There is no mechanism to defend against these sorts of questions in the future, and one can generally guess that this one (like the one about the endothelial glycocalyx) will never be repeated and recede into well-deserved obscurity. At the same time it feels like CICM trainees should have a resource they could refer to when they look back on this exam paper to work out what kind of answer was expected. 

For those who would like to dive deeper, there are great free papers by Zdanowics (2009), Hussain & Khan (2022) and Dambrin et al (2000), as well as the excellent 427-page Transplantation Immunology by  Zachary & Leffell (2011). For those who emphatically would not like to dive deeper, the following bullet list contains all the material required to answer Question 20 from the forsaken first paper of 2023, and nothing more. Additionally, there is a short entry at the end which deals with the choices one is forced to make about immunosuppressants in septic patients, to answer the little 2-marks section on this topic which appeared at the end of Question 8 from the first paper of 2024.

Mechanisms of action of immunosuppressants

• 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 of immunosuppressants

• 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 of immunosuppressants

• 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

Classification of immunosuppressants

The immense complexity of the human immune system is a massive attack surface for drug agents, and moreover each agent may have several overlapping mechanisms of action, which means that any attempt to group them by some kind of common physiological effect is likely to be pointless and cumbersome. Fortunately, "pointless and cumbersome" is what we do here at Deranged Physiology. 

Suthanthiran et al (1996) classified immunosuppressants by final mechanism of suppression, as follows:

"inhibitors of transcription (cyclosporine, tacrolimus), inhibitors of nucleotide synthesis (azathioprine, mycophenolate mofetil, mizoribine, leflunomide), inhibitors of growth factor signal transduction (sirolimus, leflunomide), and inhibitors of differentiation (15-deoxyspergualin)."

But what about interferon, methotrexate, the various mibs and mabs? And why include something weird and unheard of as a whole separate class? Some go even further along this road; eg. this, from Xu & Chu (2022):

"Immunosuppressive agents commonly used in clinical practice can be broadly classified into the following categories: 1). Glucocorticoids; 2). Cytotoxic drugs (e.g., cyclophosphamide); 3). Calmodulin inhibitors (e.g., cyclosporine, tacrolimus); 4). Macrolamines (e.g., macrolimus ethyl ester); 5). Chinese herbal immunosuppressive agents (e.g., total ginseng)."

Total ginseng. Hussain & Khan (2022) do it slightly differently, bu separating the agents by what appears to be chemical structure:

"Immunosuppressive drugs or immunosuppressant are mainly categorized into four major classes’ i.e., Glucocorticoids, Protein drugs, Intravenous gamma globulin and Protease inhibiter. Each class is further classified into subclasses"

Except they group things together which clearly do not belong together, eg. "glucocorticoids are further divide into small molecule drugs that include immunophilins binding drugs like calcineurin inhibiters, cyclophilin binding drugs including cyclosporine, " and so on. Perhaps the model by Meneghini et al (2021) could be viewed as a more chemically accurate representation, but only because it is simpler, dividing the spectrum into "small molecules", "polyclonal biological preparations" and "monoclonal or fusion proteins", where "small molecules" catches everything from steroids to cyclophosphamide.

Unfortunately, the reader waiting for a comprehensive resource to base their classification will be disappointed. One must either make their peace with this and learn the properties of a few select drugs without trying to scaffold them cognitively, or join the abovelisted authors in creating a system which fails at the fundamental premise of classification, which is to give meaning and structure to our conceptualisation of reality and permit learning of general characteristics rather than individual facts.

Still, one ought to try. 

• Corticosteroids, as a class of their own, because they Do All The Things and are nonspecific
• Inhibitors of specific immune functional elements
  • Cytokines
    • Infliximab (anti TNF-α)
    • Tocilizumab (anti IL-6)
    • Anakinra (anti IL-1)
  • Complement 
    • Eculizumab (anti CD5)
  • Neutrophils (Chiang et al, 2020)
    • Activity inhibitors 
      • Pentoxyphylline
  • Macrophages
    • Direct macrophage killing toxins
      • Etarnercept
  • All lymphocytes
    • Activation suppressors
      • Leflunomide
      • Thalidomide
      • Barciticinib
    • Proliferation inhibitors
      • Methotrexate
    • Direct lymphocyte killing toxins 
      • Alemtuzumab (anti CD25)
  • T cell specific agents
    • Activation suppressors

      • Cyclosporine

      • Tacrolimus

      • Sirolimus

      • Everolimus
      • Dasatinib
      • Daclizumab and basiliximab (anti IL-2 receptor )
    • Proliferation inhibitors
      • Azathioprine
      • Mycophenolate
    • Direct T-cell killing toxins
      • Antithymocyte Globulin: anti CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44 and CD45, as well as HLA class I and II
  • B cell specific agents
    • B-cell proliferation suppressors
      • Cyclophosphamide
    • Direct B-cell killing toxins
      • Rituximab (anti CD20)

This is imperfect, as it does not collect these agents into classes which are chemically or pharmacologically alike, and instead joins them by their specific indication, as it is possibly valuable to know what they are for. 

What to do with immunosuppressants if the solid organ transplant patient is floridly septic

What indeed. The body of knowledge is broiad but largely empty of good data, with a small number of great review articles and trials towering over a flat barren expanse of expert opinion. The reader is invited to behold a three-dimensional grid table, where in on one axis we list the possible immunosuppressants, on the other their possible indications, and on the third the variants of infectious illness these people are susceptible to. As the permutations are therefore impossibly numerous, some kind of individualised approach based on broad principles is suggested.  Any CICM exam answer dealing with something like this would therefore have to incorporate some humility and acknowledgement that this extends beyond the expertise of the intensivist and into the wild evidence-free frontier of transplant and immunology medicine.

Thus:

• Consultation:
  • Discussions with transplant physicians are essential. 
  • ICU specialists are usually not also experts on solid organ transplant and therefore would share decisionmaking with the relevant specialist service
  • The balance of sepsis severity vs. graft dysfunction needs to be debated and a considered decision needs to take into account:
    • The toxicity of a long course of antibiotics to the transplant
    • The threat to life from transplant failure, vs from sepsis (eg. it is very different when the transplanted organ is the heart, vs. the kidneys)
    • The length of time since transplantation (as often long term grafts have a lower requirement for immunosuppression and can tolerate longer interruptions to antirejection agents)
• Risk assessment
  • Determine the role of the immunosuppression in the origin of the sepsis (eg. do some levels; was the patient inadvertently overdosed with tacrolimus, or did the graft function sabotage their clearance of the drug)
  • Determine whether the infection is likely to resolve in the presence of ongoing immunosuppression (eg. is there an effective therapy, like with S.pneumoniae, or are we entirely dependent on the immune system to handle it, like with the BK virus)
  • Is the infection an opportunistic one, i.e. would lifting the immunosuppression create an unfavourable environment for this pathogen (eg. Candida or Pneumocystis)
  • Is the immunosuppression keeping a destructive immune response at bay (eg. tuberculosis meningitis, which classically gets worse before it gets better with treatment)

One can be guided by these broad generic statements about infectious diseases:

• Viral illnesses require T-cell mediated immunity to defeat.
  • Eg. CMV risk is increased when anti-T-cell agents are used, eg. tacrolimus
  • Reducing these agents while treating the virus is possible, but also wherever the virus is susceptible to an effective treatment, they can also be continued
• Fungal diseases require good innate immunity to defeat
  • Corticosteroids have greatest effect here, i.e. taper steroids in severe bacterial disease
  • Except if the CNS is involved, immune reconstitution can exacerbate the clinical course, so perhaps instead reduce the dose of a calciuneurin inhibitor instead
  • Some opportunistic fungi (eg. PJP) can call for an escalation of corticosteroids instead 
• Bacterial illness requires B-cell humoral responses as well as innate immunity
  • Weaning off as much of the corticosteroids as possible while avoiding adrenal suppression is the key
  • Reducing antiproliferative agents should also help (to assist the recovery of the innate cell response). This class includes:
    • cyclophosphamide
    • azathioprine
    • cyclosporine A
    • mycophenolate
  • Enhance humoral immunity passively: replace immunoglobulin, rather than wait for the effects of  rituximab or alemtuzumab to wear off
  • T-cell related agents can be 
• Good to know:
  • "Acute graft rejection is uncommon with temporary cessation of immunosuppression other than steroids in sepsis" - Roberts & Fishman (2021) suggest that in fact survival is potentially improved, even when the early post-transplant period is considered.

For the reader with interest that extends beyond passing CICM exams,  Kim et al (2024) and Bafi et al (2017) give good overviews of this complex topic, and Roberts & Fishman (2021) offer an excellent summary of the evidence, such as it is.