IMMUNOSUPPRESSANTS
OVERVIEW:
- Can broadly be categorised into THREE CLASSES:
o S-Phase Inhibitors: MTX, TPs, Mycophenolate (AKA Anti-metabolites)
o Calcineurin Inhibitors: Ciclosporin, Tacrolimus
o Corticosteroids (see endocrine chapter)
S-PHASE INHIBITORS – Thiopurines, Mycophenolate, Methotrexate
OVERVIEW:
- MOA: inhibit/interfere with DNA synthesis (mainly purines) less cell division of rapidly
dividing cells (e.g. WBCs) immunosuppression
- INDICATIONS:
o Crohn’s & Ulcerative Colitis
o Rheumatoid arthritis
o Extreme psoriasis
o Prevent transplant rejection (taken LIFELONG to prevent rejection after surgery)
THIOPURINES (TPs) – Azathioprine, Mercaptopurine (DMARDs)
MOA:
- Azathioprine is a PRODRUG – gets metabolised to Mercaptopurine (active drug)
gets metabolised further via different pathways DIFFERENT EFFECTS:
o Mercaptopurine inhibits S-phase of B&T lymphocytes (immunosuppression)
o Mercaptopurine degraded by Thiopurine Methyltransferase (TPMT)
o Mercaptopurine degraded by Xanthine oxidase (inhibited by Allopurinol)
- If pt lacks TPMT or is taking a Xanthine Oxidase Inhibitor/XOis (e.g. Allopurinol) –
more Mercaptopurine available for immunosuppression increased TOXICITY
PRE-TREATMENT SCREENING:
- Pts must have their TPMT levels measured BEFORE treatment (via blood test)
- If they have little-no TPMT activity – TPs are CONTRAINDICATED
- TPs can still be used even if TPMT activity is low – requires SPECIALIST SUPERVISION
SIDE EFFECTS:
- Myelosuppression (Bone-marrow suppression): unexplained bruising/bleeding, any
signs of infection (fever, sore throat) – STOP & REPORT
- Hypersensitivity reactions: urticaria, hypotension, dizziness – STOP & REPORT
- Severe nausea: NO NEED TO STOP – normally clears w/in a few weeks of starting
INTERACTIONS:
- XOis (Allopurinol, Febuxostat): inhibit mercaptopurine-breakdown (reduce TP dose)
- ACEis: (Ramipril): increased anaemia-risk (also due to myelosuppression)
MONITORING REQUIREMENTS: TPs CAN be used in pregnancy (under
- Pre-treatment TPMT test specialist supervision) – but not
- Full blood count (blood test): generally recommended (although
o WEEKLY for 1st 4 WEEKS NOT known to be teratogenic)
o Then reduced to ONCE every 3 MONTHS
, MYCOPHENOLATE (CellCept)
MOA:
- Inhibits S-phase of B&T lymphocytes (like TPs do)
- Better at preventing TRANSPLANT REJECTION than TPs (INDICATION)
- Often combined with Ciclosporin & Steroids for transplant rejection
SIDE EFFECTS:
- MYELOSUPRRESION: same as TPs – STOP & REPORT
- BRONCHIECTASIS:
o Ectasis = dilation/widening of tubular structure
o Bronchiectasis: permanent widening of bronchi XS mucus secretion
impairs mucociliary escalator bacterial colonization & infection
PREGNANCY:
- TERATOGENIC: should NOT be used during pregnancy – should STOP 3 MONTHS
before wanting to get pregnant (like Statins)
- CONTRACEPTION: 6 weeks for women, 90 days for men after stopping
METHOTREXATE
MOA:
- Inhibits the use of folic acid (FA) by dihydrofolate reductase (DHFR) less
nucleotide production inhibition of S-phase of rapidly dividing cells
immunosuppression
- MTX is structurally similar to FA – MTX competes with FA for DHFR
- FA is given alongside MTX (NOT on the same day) to offset MTX-toxicity
INDICATIONS:
- Severe IBDs (UC, Crohn’s) where other agents have failed/not suitable
- Rheumatoid arthritis
- Severe psoriasis (specialist use only)
- CANCER (hospital use)
SIDE EFFECTS:
- Myelosuppression: same as others – STOP & REPORT
- Hepatoxicity: jaundice, pale stools – STOP & REPORT
- Pulmonary Toxicity: dyspnoea - STOP & REPORT
- Oral mucositis: inflamed mucosa dysphagia, bleeding gums, xerostomia
- Extreme GI-discomfort: N&V, epigastric pain, diarrhoea
FA 5mg supplementation helps reduce ADRs but does NOT help w/ myelosuppression
INTERACTIONS:
- NSAIDs: cause renal impairment MTX build-up & TOXICITY
- Penicillins: same as NSAIDs
- Trimethoprim: also inhibits folate-use MORE myelosuppression
COUNSELLING POINTS:
- MTX taken ONCE WEEKLY – dispense using 2.5mg tablets (do NOT mix with 10mg)
- Do NOT take FA on same day as MTX dose – FA may be taken ONCE WEEKLY or DAILY
- Pt MUST attend BLOOD TESTS (for FBC, renal & liver testing) every 2-3 months
- Do NOT use in pregnancy or BF (EXTREMELY TERATOGENIC)
BOTH men & women need effective contraception during & 6 months after finishing MTX
OVERVIEW:
- Can broadly be categorised into THREE CLASSES:
o S-Phase Inhibitors: MTX, TPs, Mycophenolate (AKA Anti-metabolites)
o Calcineurin Inhibitors: Ciclosporin, Tacrolimus
o Corticosteroids (see endocrine chapter)
S-PHASE INHIBITORS – Thiopurines, Mycophenolate, Methotrexate
OVERVIEW:
- MOA: inhibit/interfere with DNA synthesis (mainly purines) less cell division of rapidly
dividing cells (e.g. WBCs) immunosuppression
- INDICATIONS:
o Crohn’s & Ulcerative Colitis
o Rheumatoid arthritis
o Extreme psoriasis
o Prevent transplant rejection (taken LIFELONG to prevent rejection after surgery)
THIOPURINES (TPs) – Azathioprine, Mercaptopurine (DMARDs)
MOA:
- Azathioprine is a PRODRUG – gets metabolised to Mercaptopurine (active drug)
gets metabolised further via different pathways DIFFERENT EFFECTS:
o Mercaptopurine inhibits S-phase of B&T lymphocytes (immunosuppression)
o Mercaptopurine degraded by Thiopurine Methyltransferase (TPMT)
o Mercaptopurine degraded by Xanthine oxidase (inhibited by Allopurinol)
- If pt lacks TPMT or is taking a Xanthine Oxidase Inhibitor/XOis (e.g. Allopurinol) –
more Mercaptopurine available for immunosuppression increased TOXICITY
PRE-TREATMENT SCREENING:
- Pts must have their TPMT levels measured BEFORE treatment (via blood test)
- If they have little-no TPMT activity – TPs are CONTRAINDICATED
- TPs can still be used even if TPMT activity is low – requires SPECIALIST SUPERVISION
SIDE EFFECTS:
- Myelosuppression (Bone-marrow suppression): unexplained bruising/bleeding, any
signs of infection (fever, sore throat) – STOP & REPORT
- Hypersensitivity reactions: urticaria, hypotension, dizziness – STOP & REPORT
- Severe nausea: NO NEED TO STOP – normally clears w/in a few weeks of starting
INTERACTIONS:
- XOis (Allopurinol, Febuxostat): inhibit mercaptopurine-breakdown (reduce TP dose)
- ACEis: (Ramipril): increased anaemia-risk (also due to myelosuppression)
MONITORING REQUIREMENTS: TPs CAN be used in pregnancy (under
- Pre-treatment TPMT test specialist supervision) – but not
- Full blood count (blood test): generally recommended (although
o WEEKLY for 1st 4 WEEKS NOT known to be teratogenic)
o Then reduced to ONCE every 3 MONTHS
, MYCOPHENOLATE (CellCept)
MOA:
- Inhibits S-phase of B&T lymphocytes (like TPs do)
- Better at preventing TRANSPLANT REJECTION than TPs (INDICATION)
- Often combined with Ciclosporin & Steroids for transplant rejection
SIDE EFFECTS:
- MYELOSUPRRESION: same as TPs – STOP & REPORT
- BRONCHIECTASIS:
o Ectasis = dilation/widening of tubular structure
o Bronchiectasis: permanent widening of bronchi XS mucus secretion
impairs mucociliary escalator bacterial colonization & infection
PREGNANCY:
- TERATOGENIC: should NOT be used during pregnancy – should STOP 3 MONTHS
before wanting to get pregnant (like Statins)
- CONTRACEPTION: 6 weeks for women, 90 days for men after stopping
METHOTREXATE
MOA:
- Inhibits the use of folic acid (FA) by dihydrofolate reductase (DHFR) less
nucleotide production inhibition of S-phase of rapidly dividing cells
immunosuppression
- MTX is structurally similar to FA – MTX competes with FA for DHFR
- FA is given alongside MTX (NOT on the same day) to offset MTX-toxicity
INDICATIONS:
- Severe IBDs (UC, Crohn’s) where other agents have failed/not suitable
- Rheumatoid arthritis
- Severe psoriasis (specialist use only)
- CANCER (hospital use)
SIDE EFFECTS:
- Myelosuppression: same as others – STOP & REPORT
- Hepatoxicity: jaundice, pale stools – STOP & REPORT
- Pulmonary Toxicity: dyspnoea - STOP & REPORT
- Oral mucositis: inflamed mucosa dysphagia, bleeding gums, xerostomia
- Extreme GI-discomfort: N&V, epigastric pain, diarrhoea
FA 5mg supplementation helps reduce ADRs but does NOT help w/ myelosuppression
INTERACTIONS:
- NSAIDs: cause renal impairment MTX build-up & TOXICITY
- Penicillins: same as NSAIDs
- Trimethoprim: also inhibits folate-use MORE myelosuppression
COUNSELLING POINTS:
- MTX taken ONCE WEEKLY – dispense using 2.5mg tablets (do NOT mix with 10mg)
- Do NOT take FA on same day as MTX dose – FA may be taken ONCE WEEKLY or DAILY
- Pt MUST attend BLOOD TESTS (for FBC, renal & liver testing) every 2-3 months
- Do NOT use in pregnancy or BF (EXTREMELY TERATOGENIC)
BOTH men & women need effective contraception during & 6 months after finishing MTX
