SN7 SHORT NOTE 5M

Classify the immunosuppressant drugs. Describe the calcineurin inhibitors and the complications of immunosuppression.

Pharmacology · 2nd Professional — Para-Clinical

Classification of Immunosuppressants

Class	Drugs	Mechanism
Calcineurin inhibitors	Ciclosporin, tacrolimus	Bind cyclophilin and FKBP respectively, and the complex inhibits calcineurin, so NFAT cannot activate IL-2 transcription — T-cell activation fails. The backbone of transplant immunosuppression
MTOR inhibitors	Sirolimus (rapamycin), everolimus	Block the mTOR pathway and so IL-2-driven T-cell proliferation; not nephrotoxic, so useful where renal function is a concern
Antiproliferative	Azathioprine, mycophenolate mofetil	Azathioprine is converted to 6-mercaptopurine and inhibits purine synthesis; mycophenolate inhibits inosine monophosphate dehydrogenase, on which lymphocytes depend selectively for purine synthesis
Corticosteroids	Prednisolone, methylprednisolone	Broad suppression of cytokine transcription; used for induction, maintenance and rejection episodes
Cytotoxic	Cyclophosphamide, methotrexate	Vasculitis, lupus nephritis, and severe autoimmune disease
Biologicals	Basiliximab (anti-IL-2 receptor), antithymocyte globulin, rituximab (anti-CD20), belatacept, anti-TNF agents, tocilizumab	Induction therapy, steroid-resistant rejection, and autoimmune disease
JAK inhibitors	Tofacitinib, baricitinib	Autoimmune disease

Calcineurin Inhibitors in Detail

Narrow therapeutic index requiring level monitoring — too little causes rejection, too much causes nephrotoxicity, and the window between them is small
Nephrotoxicity is the central problem — both acute (reversible afferent arteriolar constriction) and chronic (irreversible interstitial fibrosis); paradoxically, the drug that saves a transplanted kidney also damages it
Ciclosporin — additionally causes gum hypertrophy, hirsutism, hypertension, hyperlipidaemia, hyperkalaemia, hypomagnesaemia and tremor
Tacrolimus — more potent, and now generally preferred; causes less hirsutism and gum change but more diabetes (post-transplant diabetes mellitus), neurotoxicity and alopecia
Both are metabolised by CYP3A4, so interactions are numerous and clinically serious — levels are raised by azoles, macrolides, diltiazem, verapamil and grapefruit juice, and lowered by rifampicin, phenytoin, carbamazepine and ST JOHN wort

CLINICAL PEARL

An interaction that changes a calcineurin inhibitor level can cost the patient the graft. Add rifampicin and the level collapses, and rejection follows; add an azole antifungal and the level soars, and the kidney is damaged. This is why every new prescription for a transplant patient — including antibiotics, antifungals and herbal preparations — must be checked against the immunosuppressant, and why patients are told never to take anything without asking.

Complications of Immunosuppression

Infection — the dominant risk: bacterial, and opportunistic organisms including cytomegalovirus, Pneumocystis, fungi, tuberculosis, and reactivation of hepatitis B and herpes viruses. Prophylaxis with co-trimoxazole and valganciclovir is routine
Malignancy — particularly skin cancer and post-transplant lymphoproliferative disease (EBV-driven); the risk relates to the total burden and duration of immunosuppression
Drug-specific toxicity — nephrotoxicity, diabetes, hypertension, dyslipidaemia, bone loss, marrow suppression
Mycophenolate is teratogenic, causing characteristic malformations; pregnancy must be excluded and contraception used, and it is switched to azathioprine before a planned pregnancy
Live vaccines are contraindicated; inactivated vaccines should be given before transplantation wherever possible

Applied Aspects

Check every new drug against the immunosuppressant before prescribing for a transplant patient, and warn them explicitly about over-the-counter and herbal preparations
Screen for tuberculosis and hepatitis B before starting any prolonged immunosuppression — essential in India, where the background prevalence makes reactivation a real and frequently fatal event
Never allow a transplant patient to run out of medication; a few missed days can cause irreversible rejection, and cost or supply interruption is a genuine cause of graft loss in India
Take fever seriously and investigate broadly; the usual inflammatory signs are blunted and the differential includes organisms that would not trouble a normal host
Advise sun protection and annual skin examination, given the substantially raised risk of skin malignancy
Check TPMT before azathioprine and never combine it at full dose with allopurinol, which blocks its inactivation by xanthine oxidase and causes profound marrow suppression

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