U01.02.036 Immunosuppressants

Immunosuppressive agents are crucial in managing autoimmune diseases and preventing transplant rejection. They work by blocking lymphocyte activation and proliferation, reducing cellular immunity. While these agents provide critical therapeutic benefits, they also come with risks such as chronic infection, malignancy, and various side effects.

Mechanism of Action, Indications, and Toxicity of Common Immunosuppressive Agents

Drug	Mechanism of Action	Indications	Toxicity	Notes
Cyclosporine	Calcineurin inhibitor; binds cyclophilin. Blocks T-cell activation by preventing IL-2 transcription.	Psoriasis, rheumatoid arthritis	Nephrotoxicity, hypertension, hyperlipidemia, neurotoxicity, gingival hyperplasia, hirsutism	Highly nephrotoxic, especially in higher doses or in patients with decreased renal function.
Tacrolimus (FK506)	Calcineurin inhibitor; binds FK506 binding protein (FKBP). Blocks T-cell activation by preventing IL-2 transcription.	Similar to cyclosporine. Increases risk of diabetes and neurotoxicity.	No gingival hyperplasia or hirsutism. Risk of diabetes, neurotoxicity.	Similar to cyclosporine but with fewer cosmetic side effects.
Sirolimus (Rapamycin)	mTOR inhibitor; binds FKBP. Blocks T-cell activation and B-cell differentiation by preventing response to IL-2.	Kidney transplant rejection prophylaxis, especially for “Sir Basil’s kidney transplant.”	Pancytopenia, insulin resistance, hyperlipidemia. Not nephrotoxic.	Synergistic with cyclosporine. Also used in drug-eluting stents.
Basiliximab	Monoclonal antibody; blocks IL-2R.	Prevents transplant rejection.	Edema, hypertension, tremor.	Works specifically by targeting IL-2 receptor on T-cells.
Azathioprine	Antimetabolite precursor of 6-mercaptopurine. Inhibits lymphocyte proliferation by blocking nucleotide synthesis.	Rheumatoid arthritis, Crohn’s disease, glomerulonephritis, other autoimmune conditions.	Pancytopenia. Increased toxicity when used with allopurinol.	6-MP is degraded by xanthine oxidase. Be cautious when using with allopurinol.
Mycophenolate Mofetil	Reversibly inhibits IMP dehydrogenase, preventing purine synthesis of B and T cells.	Lupus nephritis, transplant rejection prophylaxis.	GI upset, pancytopenia, hypertension, hyperglycemia.	Less nephrotoxic and neurotoxic. Associated with invasive CMV infection.
Glucocorticoids	Inhibit NF-κB. Suppress B- and T-cell function by decreasing transcription of many cytokines. Induce T-cell apoptosis.	Autoimmune and inflammatory disorders, adrenal insufficiency, asthma, CLL, non-Hodgkin lymphoma.	Cushing syndrome, osteoporosis, hyperglycemia, diabetes, amenorrhea, adrenocortical atrophy, peptic ulcers, psychosis, cataracts, avascular necrosis (femoral head).	Demargination of WBCs causes artificial leukocytosis. Adrenal insufficiency may develop if stopped abruptly after chronic use.

Points to Remember

Cyclosporine and Tacrolimus: Both are calcineurin inhibitors, but Tacrolimus has a lower risk of cosmetic side effects (e.g., no gingival hyperplasia or hirsutism).
Sirolimus (Rapamycin): Unlike other immunosuppressants, it is not nephrotoxic and is synergistic with cyclosporine.
Azathioprine: It is metabolized to 6-Mercaptopurine, which can be toxic when combined with allopurinol.
Mycophenolate Mofetil: Associated with a lower nephrotoxic and neurotoxic risk but can cause invasive CMV infections.
Glucocorticoids: While highly effective for many conditions, they come with significant long-term risks like osteoporosis and adrenal insufficiency if stopped abruptly.

Learning Objective

Students should be able to identify the mechanisms of action, clinical indications, and toxicity profiles of the most commonly used immunosuppressive agents in the context of organ transplantation and autoimmune diseases.

USMLE Step 1 Review Series

Curriculum

U01.02.036 Immunosuppressants

Mechanism of Action, Indications, and Toxicity of Common Immunosuppressive Agents

Points to Remember

Learning Objective

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