Pharmacology of major drug classes used to manage gastroenterological conditions
IBD drug classes
| Class | Agents | Target |
|---|---|---|
| 5-ASA | Mesalazine, sulfasalazine, olsalazine, balsalazide | Local mucosal PPAR-gamma / NF-kB |
| Corticosteroid | Prednisolone; budesonide (ileal-release, MMX) | Broad |
| Thiopurine | Azathioprine, 6-mercaptopurine | Purine synthesis; Rac1 -> T-cell apoptosis |
| Antimetabolite | Methotrexate | DHFR; adenosine release |
| Calcineurin inhibitor | Ciclosporin, tacrolimus | IL-2 transcription |
| Anti-TNF | Infliximab, adalimumab, golimumab | TNF-alpha |
| Anti-integrin | Vedolizumab | alpha4beta7 - gut-selective |
| Anti-IL-12/23 | Ustekinumab | p40 subunit |
| Anti-IL-23 | Risankizumab, mirikizumab, guselkumab | p19 subunit |
| JAK inhibitor | Tofacitinib, upadacitinib, filgotinib | JAK1 +/- 3 |
| S1P modulator | Ozanimod, etrasimod | Lymphocyte egress from nodes |
Acid suppression and motility
| Class | Agents | Note |
|---|---|---|
| PPI | Esomeprazole, pantoprazole, omeprazole, rabeprazole | Irreversible H+/K+ ATPase. 30-60 min pre-meal - needs active pumps |
| H2RA | Famotidine, nizatidine | Tachyphylaxis within days |
| Prokinetic | Metoclopramide, domperidone, erythromycin | Metoclopramide - extrapyramidal, esp. young/female |
| Antiemetic | Ondansetron (5-HT3), metoclopramide (D2), aprepitant (NK1) | |
| Antispasmodic | Hyoscine butylbromide, peppermint oil | |
| Laxative | Osmotic (macrogol, lactulose), stimulant (senna, bisacodyl), softener |
Use
- PPIs among the most prescribed drug classes in Australia; a large fraction have no ongoing indication
- Biologic and small-molecule use in IBD rising steeply; earlier positioning replacing step-up
- Thiopurine monotherapy declining as advanced therapies move earlier
Thiopurine metabolism - the examinable pathway
- Azathioprine -> 6-MP -> three competing routes:
- HPRT -> 6-TGN = active metabolite (efficacy + myelosuppression)
- TPMT -> 6-MMP = inactive but hepatotoxic
- XO -> thiouric acid (why allopurinol matters)
- TPMT activity sets the starting dose
| TPMT | Metaboliser | Action |
|---|---|---|
| <5 units/mL RBC | Homozygous low | Avoid, or very low dose |
| 5-8 | Heterozygous intermediate | ~1/3 standard dose |
| >8 | Homozygous wild-type | Standard 2-3 mg/kg (AZA) |
- Also check NUDT15 - the dominant cause of thiopurine myelosuppression in East Asian ancestry, missed by TPMT alone
Metabolite levels explain non-response
| 6-TGN | 6-MMP | Interpretation |
|---|---|---|
| Low | Low | Underdosing or non-adherence |
| Low | High | Shunter - preferential TPMT metabolism |
| Normal | Normal | Thiopurine-refractory - switch class |
- Shunter -> add low-dose allopurinol (100 mg) + reduce thiopurine to ~25-33%
- Blocks XO -> shifts flux to 6-TGN, drops 6-MMP
- -> better efficacy, less hepatotoxicity. Requires close FBE monitoring - profound myelosuppression if the dose is not reduced
Why combination therapy works
- Immunomodulator + biologic:
- dec anti-drug antibody formation
- inc trough drug levels -> better outcomes
- dec infusion reactions and loss of response
- Independent additive effect
Monitoring
| Drug | Monitor | Interval |
|---|---|---|
| 5-ASA | FBE, UEC, LFT, urinalysis | 1 month, then ~monthly initially, then periodically |
| Thiopurine | FBE, LFT | Weekly-fortnightly x 8 wks, then 3-monthly. Lifelong |
| Methotrexate | FBE, LFT, UEC | 2-4 weekly initially, then 3-monthly |
| Ciclosporin | Level, BP, UEC, Mg, cholesterol | Frequent |
| Anti-TNF | Trough level + antibody on loss of response; TB/HBV before starting | |
| JAK inhibitor | FBE, lipids, LFT, CK | Baseline, 4-8 wks, then periodic |
| PPI | Mg, B12 if long-term |
- Before any biologic or JAK: TB (IGRA + CXR), HBsAg + anti-HBc, HCV, HIV, VZV serology, vaccination, cervical screening
Adverse effects by class
5-ASA
- Common (1-10%): watery diarrhoea, rash, headache, nausea, fever
- Acute intolerance reaction - bloody diarrhoea mimicking a flare. Stop the drug, do not escalate immunosuppression
- Less common: interstitial nephritis, pneumonitis, pericarditis, thrombocytopenia, hepatitis, pancreatitis
Sulfasalazine (5-ASA + sulfapyridine - the sulfa moiety causes most of the toxicity)
- Dose-related: nausea/vomiting, headache, folate malabsorption, alopecia
- Idiosyncratic: rash, fever, reversible reduction in sperm motility
- Rare serious: haemolysis (G6PD), agranulocytosis, hepatitis, pancreatitis
Thiopurines
- Dose-related: hepatitis, leucopenia (2-5%), nausea
- Idiosyncratic: fever, rash, arthritis
- Pancreatitis - dose-independent, never rechallenge
- Infection risk even with a normal white cell count
- Malignancy: lymphoma, non-melanoma skin cancer, AML
- Rare: nodular regenerative hyperplasia, cholestatic jaundice
Anti-TNF
| Event | Rate |
|---|---|
| Infusion/injection-site reaction | 3-20% |
| Psoriasiform skin reaction | ~5% |
| Serious infection | ~3% |
| TB reactivation | ~0.05% |
| Drug-induced lupus | ~1% |
| Non-Hodgkin lymphoma | ~0.06% |
- Also: demyelination, worsening of NYHA III-IV heart failure
Hepatosplenic T-cell lymphoma
- Combined thiopurine + anti-TNF, almost exclusively males <35. Aggressive, usually fatal
- -> stop the thiopurine after ~1 year of combination therapy in young men, or use methotrexate instead
JAK inhibitors - herpes zoster, hyperlipidaemia, VTE, MACE, malignancy (age >65, smokers, CV risk factors)
Vedolizumab - gut-selective, best safety profile; slow onset, no EIM benefit
S1P modulators - first-dose bradycardia/AV block, macular oedema, lymphopenia, LFT rise
Corticosteroids (prolonged)
- Growth retardation in children, adrenal suppression, cataracts, osteopenia, glucose intolerance, infection, mood disturbance, striae/acne/moon facies
- Budesonide has ~90% first-pass metabolism - lower systemic exposure, but not zero
PPI (long-term)
- Hypomagnesaemia, B12 and iron malabsorption, C. difficile and enteric infection, fundic gland polyps, interstitial nephritis, fracture risk
- Rebound acid hypersecretion on cessation - wean, do not stop abruptly
Fertility and pregnancy
Fertility and pregnancy
| Contraindicated | Methotrexate, thalidomide, 6-thioguanine |
| Safe | Oral/topical 5-ASA, sulfasalazine (+ folate), corticosteroids, azathioprine, 6-MP |
| Probably safe | Infliximab, adalimumab, ciclosporin, tacrolimus, budesonide, metronidazole, ciprofloxacin |
- Active disease is more dangerous to the pregnancy than the drugs - do not stop maintenance therapy
- Infants exposed to anti-TNF in utero: no live vaccines for 12 months (placental transfer, mainly third trimester)
- Male fertility: sulfasalazine -> reversible dec sperm motility; methotrexate -> reversible oligospermia; ileal pouch surgery -> impotence or retrograde ejaculation in ~10% of men
Interactions that matter
- Allopurinol + thiopurine -> life-threatening myelosuppression unless the thiopurine dose is cut to ~25-33%
- Febuxostat + thiopurine - contraindicated
- Methotrexate + trimethoprim/sulfamethoxazole -> pancytopenia
- Ciclosporin - CYP3A4: azoles, macrolides, grapefruit inc levels; nephrotoxic with NSAIDs
- PPI + clopidogrel (CYP2C19 - pantoprazole preferred); PPI reduces absorption of ketoconazole, atazanavir, iron
- Live vaccines contraindicated on any biologic, JAK inhibitor, thiopurine or prednisolone >=20 mg/day
- 5-ASA + azathioprine -> mild TPMT inhibition, inc 6-TGN
Loss of response
- Loss of response to anti-TNF ~20%/year - immunogenicity is the commonest mechanism
- Low trough + high antibody -> switch agent; low trough + no antibody -> dose intensify
- Thiopurine takes 8-12 weeks to full effect - not an induction agent
- 5-ASA benefit is largely UC-specific; minimal in Crohn
- Steroid dependence at 1 year ~20-30% of IBD patients - a marker to escalate, not to continue steroids
- Malignancy risks are cumulative and dose-dependent -> annual skin checks, sun protection, up-to-date cervical screening
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