Immunosuppressants

Immunosuppressants are drugs that blunt the immune response to prevent or treat transplant rejection, control autoimmune disease, and suppress graft-versus-host reactions. For NEET PG, the highest-yield axis is the mechanism + signature toxicity + monitoring triad — calcineurin inhibitors, mTOR inhibitors, antimetabolites, biologicals and glucocorticoids. This is a "match-the-mechanism" goldmine.

Classification

Immunosuppressants are best grouped by where they hit the T-cell activation cascade and clonal expansion pathway.

Class	Prototype drug(s)	Molecular target	Net effect
Calcineurin inhibitors (CNIs)	Ciclosporin, Tacrolimus	Calcineurin phosphatase	↓ IL-2 gene transcription
mTOR inhibitors	Sirolimus (rapamycin), Everolimus	mTOR kinase (raptor)	↓ IL-2-driven proliferation (G1→S arrest)
Antiproliferative / antimetabolites	Azathioprine, Mycophenolate mofetil (MMF)	Purine synthesis	↓ Lymphocyte DNA synthesis
Glucocorticoids	Prednisolone, Methylprednisolone	NF-κB, cytokine genes	Broad anti-inflammatory + immunosuppressant
Biologicals (antibodies)	Basiliximab, ATG, Rituximab, Belatacept, Muromonab-CD3	Surface receptors / co-stimulation	Depletion or blockade
Others	Cyclophosphamide, Methotrexate, Leflunomide, Fingolimod	Various	Disease-specific

High-yield: The classic three-signal model — Signal 1 = antigen via TCR; Signal 2 = co-stimulation (CD28–B7); Signal 3 = IL-2 → mTOR proliferation. CNIs block Signal 1's downstream IL-2 transcription, belatacept blocks Signal 2, basiliximab blocks the IL-2 receptor, and sirolimus blocks Signal 3.

The T-cell activation cascade — where each drug acts

The flow of T-cell activation and the drug targets along it:

TCR engages antigen → ↑ intracellular Ca²⁺ → calmodulin activates calcineurin → calcineurin dephosphorylates NFAT → NFAT enters nucleus → IL-2 gene transcription → IL-2 binds IL-2R (CD25) → mTOR pathway → clonal proliferation

• Ciclosporin / Tacrolimus → block calcineurin (the dephosphorylation step).
• Basiliximab → blocks IL-2 receptor (CD25).
• Sirolimus / Everolimus → block mTOR (the proliferation step).
• MMF / Azathioprine → block purine synthesis needed for DNA replication during proliferation.
• Glucocorticoids → suppress cytokine genes broadly.

Calcineurin inhibitors (CNIs)

Ciclosporin (Cyclosporine A)

A cyclic polypeptide of fungal origin (Tolypocladium inflatum). It binds the cytoplasmic immunophilin cyclophilin; the ciclosporin–cyclophilin complex inhibits calcineurin, preventing dephosphorylation of NFAT and thereby blocking IL-2 (and other cytokine) gene transcription. Net result: selective inhibition of T-helper cell activation with relative sparing of bone marrow.

Key pharmacokinetics: lipophilic, highly variable oral absorption (microemulsion form = Neoral improves it), metabolised by CYP3A4 and is a P-glycoprotein substrate → abundant drug interactions. Therapeutic drug monitoring (TDM) is mandatory.

Adverse effects (very high-yield):

Toxicity	Notes
Nephrotoxicity	Dose-limiting; afferent arteriolar vasoconstriction; both acute (reversible) and chronic (interstitial fibrosis)
Gingival hyperplasia	Classic; also seen with phenytoin and nifedipine
Hirsutism / hypertrichosis	Distinguishes it from tacrolimus (which causes alopecia)
Hypertension	Common
Hyperkalaemia, hypomagnesaemia, hyperuricaemia (gout)	Metabolic
Neurotoxicity (tremor)	Milder than tacrolimus
Hyperlipidaemia, hepatotoxicity	—

High-yield: Triad to remember for ciclosporin — Nephrotoxicity + Gingival hyperplasia + Hirsutism. It does NOT cause significant myelosuppression (unlike azathioprine/MMF), and does NOT cause diabetes the way tacrolimus does.

Mnemonic — ciclosporin toxicity "GHN": Gingival hyperplasia, Hirsutism/Hypertension/Hyperkalaemia/Hyperlipidaemia, Nephrotoxicity.

Tacrolimus (FK506)

A macrolide from Streptomyces tsukubaensis. Binds FKBP-12 (FK-binding protein); the complex also inhibits calcineurin — same downstream effect as ciclosporin but roughly 10–100× more potent. Now the preferred CNI in most solid-organ transplant protocols (especially liver and kidney).

Adverse effects overlap with ciclosporin but with a different flavour:

Feature	Ciclosporin	Tacrolimus
Immunophilin bound	Cyclophilin	FKBP-12
Potency	Lower	10–100× higher
Diabetogenic	Less	More (new-onset diabetes after transplant)
Hair	Hirsutism	Alopecia
Gingival hyperplasia	Yes	No / minimal
Neurotoxicity	Less	More (tremor, headache, seizures)
Nephrotoxicity	Yes	Yes
Hyperlipidaemia	More	Less

High-yield: Tacrolimus is more diabetogenic and more neurotoxic than ciclosporin, and causes alopecia rather than hirsutism, with no gingival hyperplasia. Both share nephrotoxicity as the dose-limiting toxicity. Topical tacrolimus and pimecrolimus are used for atopic dermatitis.

mTOR inhibitors — Sirolimus & Everolimus

Sirolimus (rapamycin), isolated from Streptomyces hygroscopicus on Rapa Nui (Easter Island), also binds FKBP-12 — but unlike tacrolimus, the sirolimus–FKBP-12 complex does NOT inhibit calcineurin. Instead it inhibits mTOR (mammalian target of rapamycin), blocking IL-2-driven progression from G1 to S phase of the cell cycle → arrests lymphocyte proliferation (Signal 3 blockade).

Distinguishing toxicity profile (the examiner's favourite):

• NOT nephrotoxic — this is the key contrast with CNIs; often used to spare the kidney.
• Hyperlipidaemia / hypertriglyceridaemia — prominent.
• Myelosuppression — thrombocytopenia, anaemia, leucopenia.
• Impaired wound healing and mouth ulcers (anti-proliferative on fibroblasts).
• Interstitial pneumonitis.

High-yield: Sirolimus binds the same FKBP-12 as tacrolimus but acts on mTOR, not calcineurin — hence it is not nephrotoxic. Remember it for drug-eluting coronary stents (sirolimus/everolimus coating prevents neointimal proliferation/restenosis). Everolimus is also used in renal cell carcinoma and subependymal giant cell astrocytoma (SEGA) in tuberous sclerosis.

Because sirolimus and tacrolimus compete for FKBP-12, combining them is pharmacologically interesting but managed carefully.

Antiproliferative agents (antimetabolites)

Azathioprine

A prodrug converted to 6-mercaptopurine (6-MP) and then to thioinosinic acid, which inhibits purine synthesis → suppresses proliferating B and T lymphocytes. Used in transplant, SLE, IBD, rheumatoid arthritis, and steroid-sparing regimens.

High-yield — the allopurinol interaction (extremely tested): 6-MP is degraded by xanthine oxidase. Allopurinol (and febuxostat) inhibits xanthine oxidase → 6-MP accumulates → severe myelosuppression. If co-administration is unavoidable, reduce azathioprine dose to ~25–33% of normal. This is a frequent single-best-answer item.

Pharmacogenetics: patients deficient in thiopurine methyltransferase (TPMT) cannot inactivate 6-MP → life-threatening bone-marrow suppression. TPMT testing is recommended before starting. Other adverse effects: hepatotoxicity, GI upset, increased malignancy/infection risk.

Mycophenolate mofetil (MMF)

A prodrug hydrolysed to mycophenolic acid (MPA), which reversibly and non-competitively inhibits inosine monophosphate dehydrogenase (IMPDH) — the rate-limiting enzyme of de novo guanosine nucleotide synthesis.

High-yield: Lymphocytes (B and T) depend almost exclusively on the de novo purine pathway and lack the salvage pathway, so MMF is relatively selective for lymphocytes. This selectivity, plus a better profile than azathioprine, makes MMF the standard antimetabolite in modern transplant regimens (typically CNI + MMF + steroid).

Adverse effects: GI toxicity (diarrhoea, the dose-limiting effect; enteric-coated mycophenolate sodium reduces it), myelosuppression, increased infection (CMV) and malignancy. Teratogenic — first-trimester pregnancy loss and congenital malformations; contraindicated/avoided in pregnancy.

Glucocorticoids

Prednisolone and methylprednisolone bind the cytoplasmic glucocorticoid receptor → modulate gene transcription, inhibit NF-κB, suppress cytokine production (IL-1, IL-2, IL-6, TNF-α), and cause lympholysis/redistribution. Used for induction, maintenance, and first-line treatment of acute rejection (high-dose pulse methylprednisolone). Long-term toxicity: Cushingoid features, osteoporosis, diabetes, infection, growth retardation, cataract — hence "steroid-sparing" strategies built around CNI/MMF.

Biological agents

Agent	Target	Use / notes
Basiliximab	IL-2 receptor α-chain (CD25)	Induction; blocks Signal 3 at receptor; well tolerated
Antithymocyte globulin (ATG)	Polyclonal anti-T-cell	Induction & steroid-resistant rejection; serum sickness, cytokine release
Muromonab-CD3 (OKT3)	CD3	Historic; severe cytokine release syndrome
Belatacept	CTLA-4-Ig → blocks CD80/86 (B7)	Blocks Signal 2 (co-stimulation)
Rituximab	CD20 (B cells)	Antibody-mediated rejection, lymphoma, autoimmune disease
Alemtuzumab	CD52	Profound depletion

High-yield: Basiliximab = anti-CD25 (IL-2R) for induction. Belatacept = co-stimulation blocker (Signal 2). Muromonab-CD3 is associated with cytokine release syndrome.

Therapeutic drug monitoring (TDM)

CNIs and mTOR inhibitors have a narrow therapeutic index, wide interpatient variability, and serious dose-related toxicity → TDM is essential.

• Ciclosporin / Tacrolimus / Sirolimus all require trough (C0) whole-blood level monitoring.
• All are CYP3A4 + P-glycoprotein substrates → watch for interactions:
  • Levels ↑ (toxicity risk) with: ketoconazole/azoles, macrolides (erythromycin, clarithromycin), diltiazem/verapamil, grapefruit juice, HIV protease inhibitors.
  • Levels ↓ (rejection risk) with: rifampicin, phenytoin, carbamazepine, phenobarbitone, St John's wort.

High-yield: Adding rifampicin to a transplant patient on ciclosporin/tacrolimus can precipitate acute rejection (enzyme induction lowers drug levels); adding an azole antifungal can cause CNI toxicity (enzyme inhibition raises levels).

Clinical use — transplant regimens & autoimmune disease

Induction (peri-transplant): Basiliximab or ATG ± high-dose steroids.

Maintenance (the classic triple regimen): Calcineurin inhibitor (tacrolimus) + Antimetabolite (MMF) + Glucocorticoid (prednisolone)

Acute cellular rejection: First line = high-dose pulse methylprednisolone; steroid-resistant rejection → ATG.

Antibody-mediated rejection: plasmapheresis, IVIG, rituximab.

Autoimmune / non-transplant uses: SLE and lupus nephritis (MMF, azathioprine, cyclophosphamide), rheumatoid arthritis (methotrexate, leflunomide), IBD (azathioprine), psoriasis and atopic dermatitis (ciclosporin, topical tacrolimus), multiple sclerosis (fingolimod — S1P receptor modulator).

Complications common to all immunosuppressants

1. Infection — opportunistic: CMV, Pneumocystis jirovecii (PCP prophylaxis with co-trimoxazole), BK virus nephropathy, reactivation TB, fungal infections.
2. Malignancy — especially post-transplant lymphoproliferative disorder (PTLD, EBV-driven), skin cancers (squamous cell), and Kaposi sarcoma.
3. Drug-specific organ toxicity — see individual profiles above.

High-yield: Long-term immunosuppression markedly raises risk of skin cancers and EBV-associated PTLD. CMV is the classic opportunistic infection — give valganciclovir prophylaxis in high-risk recipients.

Key differentials / "spot-the-drug" comparisons

Nephrotoxic vs renal-sparing: Ciclosporin & tacrolimus = nephrotoxic; sirolimus = renal-sparing (used to reduce CNI exposure).

Hirsutism vs alopecia: Ciclosporin → hirsutism; tacrolimus → alopecia.

Gingival hyperplasia: Ciclosporin (also phenytoin, nifedipine) — tacrolimus does NOT.

Diabetogenic CNI: Tacrolimus > ciclosporin.

Same FKBP-12, different target: Tacrolimus → calcineurin; Sirolimus → mTOR.

Antimetabolite selectivity: MMF (IMPDH, de novo purine pathway, lymphocyte-selective) vs azathioprine (general purine synthesis, xanthine-oxidase-dependent metabolism, allopurinol interaction, TPMT pharmacogenetics).

Recently asked / exam angle

• Mechanism matching: "Drug that binds cyclophilin and inhibits calcineurin" → Ciclosporin; "binds FKBP-12 but inhibits mTOR" → Sirolimus.
• "Immunosuppressant + allopurinol → dangerous myelosuppression, reduce dose" → Azathioprine (via xanthine oxidase / 6-MP).
• "Enzyme inhibited by mycophenolate" → Inosine monophosphate dehydrogenase (IMPDH).
• "Gingival hyperplasia in a renal transplant patient" → Ciclosporin.
• "Drug coating drug-eluting stents" → Sirolimus / Everolimus.
• "Anti-CD25 / IL-2 receptor monoclonal for induction" → Basiliximab.
• "Most common opportunistic infection / prophylaxis with co-trimoxazole" → PCP / CMV considerations.
• "Drug causing new-onset diabetes after transplant (NODAT)" → Tacrolimus.
• "Co-stimulation (Signal 2) blocker / CTLA-4-Ig" → Belatacept.
• Pharmacogenetic test before azathioprine → TPMT.

Rapid revision

1. Ciclosporin binds cyclophilin; tacrolimus binds FKBP-12; both inhibit calcineurin → ↓ NFAT → ↓ IL-2 transcription.
2. Ciclosporin signature: nephrotoxicity + gingival hyperplasia + hirsutism; no myelosuppression.
3. Tacrolimus is 10–100× more potent, more diabetogenic & neurotoxic, causes alopecia, no gingival hyperplasia.
4. Sirolimus binds FKBP-12 but inhibits mTOR (G1→S arrest); not nephrotoxic; causes hyperlipidaemia, myelosuppression, poor wound healing; coats drug-eluting stents.
5. Azathioprine → 6-MP → inhibits purine synthesis; allopurinol (xanthine oxidase inhibitor) → toxic accumulation → cut dose to ~25%.
6. Check TPMT before azathioprine to avoid fatal marrow suppression.
7. MMF → mycophenolic acid → inhibits IMPDH (de novo purine pathway); lymphocyte-selective; main toxicity diarrhoea; teratogenic.
8. Basiliximab = anti-CD25 (IL-2R); belatacept = CD80/86 (Signal 2) blocker; rituximab = anti-CD20.
9. Standard maintenance triple therapy: tacrolimus + MMF + prednisolone.
10. Acute cellular rejection → pulse methylprednisolone; steroid-resistant → ATG.
11. CNIs & mTOR inhibitors are CYP3A4/P-gp substrates: azoles/macrolides ↑ levels (toxicity); rifampicin/phenytoin ↓ levels (rejection).
12. Long-term risks: opportunistic infection (CMV, PCP, BK virus), PTLD (EBV), and skin cancers.