30th August 2024

Immunosuppressants

Immunosuppressant medications are essential for treating chronic inflammatory diseases, autoimmune disorders, and preventing organ rejection post-transplantation. Examples include azathioprine and mercaptopurine, ciclosporin, methotrexate, mycophenolate and tacrolimus. However, their use increases susceptibility to infections by suppressing the innate, cellular and humoral immune response.

Azathioprine

Azathioprine is converted to its active form, 6-mercaptopurine, which disrupts nucleic acid production as a purine analogue. Adverse effects include bone marrow suppression, nausea, vomiting, and pancreatitis. Testing for thiopurine methyltransferase (TPMT) activity before treatment is recommended, as individuals with low enzyme activity are at greater risk of developing myelosuppression from thiopurine therapy.

Ciclosporin

Ciclosporin, an immunosuppressive drug, works by inhibiting T-cell activation. A key step in this process is the influx of calcium into T-cells, which activates the enzyme calcineurin. Calcineurin then dephosphorylates transcription factors like NF-AT, which triggers the production of interleukin-2 (IL-2) and other cytokines that regulate T-helper cells and inflammation. Ciclosporin binds to cyclophilin, forming a complex that blocks calcineurin activity. This inhibition reduces IL-2 synthesis, thereby suppressing the immune response.

Ciclosporin use is associated with numerous side effects, including gingival hyperplasia, hirsutism, convulsions, hypertension, immunosuppression, gastrointestinal disturbances, liver and kidney problems, hyperkalaemia and peripheral neuropathy. Of particular concern is the increased risk of skin cancers due to its immunosuppressive effects.

Methotrexate

Methotrexate, classified as an antimetabolite, acts distinctly in neoplastic and inflammatory conditions. In neoplasms, it functions as a potent inhibitor of dihydrofolate reductase, crucial for converting dihydrofolate to tetrahydrofolate—a cofactor essential for nucleotide synthesis. This inhibition halts DNA and RNA synthesis, effectively suppressing the proliferation of cancer cells.

In inflammatory disorders, it inhibits DNA and RNA synthesis, suppresses immunoglobulins crucial for immune responses, reduces B lymphocytes, and dampens cytokine production. These mechanisms collectively modulate inflammation.

Methotrexate therapy carries a range of potential adverse effects, such as macrocytic anaemia from folate deficiency, immunosuppression, mucositis, leukopenia, gastrointestinal disturbances, and possible impacts on renal and hepatic function. Additionally, it is teratogenic, increasing the risk of birth defects and additional neoplasms. Pulmonary fibrosis is also a significant concern associated with its use.

Mycophenolate

Mycophenolic acid, also known as mycophenolate, is a compound of fungal origin that exerts its pharmacological effects as a prodrug. Central to its mechanism of action is the inhibition of inosine monophosphate dehydrogenase (IMPDH), an enzyme critical to the de novo synthesis of purines. Given that purines can be acquired through two distinct pathways – de novo synthesis and the salvage pathway – and that leukocytes predominantly rely on de novo synthesis for their purine requisites, the inhibition of IMPDH by mycophenolic acid effectively impairs purine biosynthesis, resulting in the downregulation of inflammatory cells, particularly T and B lymphocytes, through the inhibition of DNA synthesis.

Despite its therapeutic benefits, the use of mycophenolic acid requires careful monitoring due to potential adverse effects. Common side effects include gastrointestinal disturbances, nausea, anaemia, agranulocytosis, metabolic acidosis and immunosuppression, which has led to the association with progressive multifocal leukoencephalopathy.

Tacrolimus

Tacrolimus is a potent immunosuppressant that targets T-cells by interacting with the protein FKBP12 to form a complex that blocks calcineurin activity. This blockade prevents T-cell activation and interleukin-2 (IL-2) Tacrolimus is a crucial immunosuppressant in post-transplant care. It presents with a spectrum of potential adverse effects across various physiological systems. Cardiovascular effects, notably hypertension and arrhythmias, are critical concerns post-transplant. Central nervous system impacts such as headaches and tremors can significantly affect daily functioning. Dermatologically, tacrolimus may induce acne and pruritus. Endocrine and metabolic effects include the development of new-onset diabetes mellitus after transplantation (NODAT) and electrolyte imbalances like hyperkalaemia and hypomagnesemia, necessitating meticulous management. Gastrointestinal side effects such as nausea and diarrhoea can lead to dehydration and exacerbate electrolyte disturbances if not properly controlled. Tacrolimus also heightens susceptibility to infections, including urinary tract infections and opportunistic infections, requiring vigilant monitoring. Renal function is particularly vulnerable to tacrolimus-associated nephrotoxicity, necessitating continuous assessment and careful dosage adjustment.

Corticosteroids

Corticosteroids exert their therapeutic effects by activating cytoplasmic receptors, which then translocate to the nucleus to modify transcription. This process leads to the downregulation of pro-inflammatory molecules and the upregulation of anti-inflammatory proteins. One notable complication is oral candidiasis, resulting from immunosuppression that predisposes the oral mucosa to fungal colonisation. Prolonged corticosteroid use can also suppress the Hypothalamic-Pituitary-Adrenal (HPA) axis, reducing endogenous cortisol production and requiring careful tapering to avoid adrenal crisis.

Long-term use may also compromise skeletal integrity, increasing the risk of osteoporosis and avascular necrosis. The pathogenesis involves decreased bone formation and enhanced resorption, with avascular necrosis particularly affecting the femoral head. Metabolic derangements, such as glucose intolerance, heighten the risk of iatrogenic diabetes mellitus. Psychiatric manifestations, ranging from mood alterations to psychosis, necessitate thorough psychiatric assessment in predisposed individuals. Gastrointestinal complications, notably peptic ulceration, are exacerbated by concurrent NSAID use. Additionally, the immunosuppressive effects increase susceptibility to fungal, mycobacterial, and viral infections.