PharmacologyTier 1Medical Sciences concept

Immunosuppressant mechanisms of action (calcineurin inhibitors, mTOR inhibitors, antimetabolites)

Core concept

T-cell activation needs three signals - each class blocks a different one
- Signal 1 TCR/MHC-peptide -> calcineurin -> NFAT -> IL-2 transcription
- Signal 2 CD28-CD80/86 costimulation
- Signal 3 IL-2 -> IL-2R -> mTOR -> G1-S progression, clonal expansion

Calcineurin inhibitors

Ciclosporin binds cyclophilin; tacrolimus binds FKBP12
- Complex inhibits calcineurin (a Ca-calmodulin phosphatase)
- dec NFAT dephosphorylation -> dec IL-2, IL-4, IFN-gamma transcription
- Greatest effect on naive T cells

mTOR inhibitors

Sirolimus, everolimus bind FKBP12 (same immunophilin as tacrolimus) but inhibit mTOR, not calcineurin
- Blocks signal 3 -> G1 arrest of IL-2-stimulated T cells
- Shifts effector -> memory phenotype, inc Tregs, inc apoptosis
- dec neoangiogenesis (anti-VEGF effect) -> antitumour

Antimetabolites

Azathioprine - prodrug -> 6-MP -> TIMP -> 6-TGN incorporated into DNA/RNA
Mycophenolate - inhibits IMPDH -> blocks de novo guanosine synthesis
- Lymphocytes lack a purine salvage pathway -> selectivity
- Also dec glycosylation of adhesion molecules

Drug	Target	Signature toxicity
Ciclosporin	Cyclophilin-calcineurin	Gingival hyperplasia, hirsutism, HTN, nephrotox, tremor
Tacrolimus	FKBP12-calcineurin	NODAT, neurotox/tremor, PRES, alopecia, dec Mg, inc K
Sirolimus/everolimus	FKBP12-mTOR	Hyperlipidaemia, poor wound healing, proteinuria, pneumonitis, mouth ulcers, anaemia
Azathioprine	Purine synthesis/DNA	Myelosuppression, hepatotox, pancreatitis
Mycophenolate	IMPDH	Diarrhoea, leukopenia, anaemia; teratogenic

Tacrolimus vs ciclosporin - more diabetes and neurotoxicity, less hirsutism/gum hypertrophy; both nephrotoxic (afferent arteriolar vasoconstriction, chronic interstitial fibrosis)
Both CNIs are CYP3A4 + P-gp substrates with narrow therapeutic index
- inc levels: azoles, macrolides, diltiazem/verapamil, grapefruit, protease inhibitors
- dec levels: rifampicin, phenytoin, carbamazepine, St John's wort
Azathioprine + allopurinol/febuxostat -> xanthine oxidase blocked -> shunt to 6-TGN -> profound myelosuppression; reduce AZA to 25-33% or avoid
Check TPMT (and NUDT15) before azathioprine
mTOR inhibitors potentiate CNI nephrotoxicity and impair wound healing - avoid de novo peri-transplant

Maintenance transplant immunosuppression = CNI + antimetabolite + prednisolone
- Liver transplant: CNI + steroid, MMF as third agent or CNI/steroid-sparing; induction benefit less established than in kidney
Switch CNI -> mTOR inhibitor where interstitial fibrosis/tubular atrophy or malignancy develops
Malignancy risk with sustained immunosuppression - non-melanoma skin cancer, and PTLD/non-Hodgkin lymphoma (EBV-driven)
Pregnancy - tacrolimus, ciclosporin and azathioprine are continued; mycophenolate and mTOR inhibitors are contraindicated
- Avoid breastfeeding on tacrolimus
Tacrolimus toxicity presentation: tremor, headache, seizures, cortical blindness -> think PRES, check level and MRI
Chronic dec Mg and inc K with CNIs - CNI inhibits NCC and impairs distal K secretion (a phenocopy of Gordon syndrome)

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