RA

Question 1

Aminosalicylates

Mesalazine

Common indications

Answer 1

1. Mesalazine is used first-line in the treatment of mild-to-moderate UC. Sulfasalazine is an alternative but has largely been replaced by mesalazine for this indication
2. Sulfasalazine is one of several options for the management of RA, in which it is used as a DMARD (Disease Modifying Anti-rheumatic Drugs), usually as part of combination therapy

Question 2

Aminosalicylates

Mesalazine, Sulfasalazine

MOA

Answer 2

• In ulcerative colitis (UC), mesalazine and sulfasalazine both exert their therapeutic effects by releasing 5-aminosalicylic acid (5-ASA).
• The precise mechanism of action of 5-ASA is unknown, but it has both anti-inflammatory and immunosuppressive effects and appears to act topically on the gut rather than systemically.
• For this reason, 5-ASA preparations are designed to delay delivery of the active ingredient to the colon.
• The oral form of mesalazine comprises a tablet with a coating that resists gastric breakdown, instead of releasing 5-ASA further down the gut.
• Sulfasalazine consists of a molecule of 5-ASA linked to sulfapyridine.
• In the colon, bacterial enzymes break this link and release the two molecules. Sulfapyridine does not contribute to its therapeutic effect in UC, but it does cause side effects, and for this reason, it has largely been replaced by mesalazine for this indication.
• By contrast, sulfapyridine is probably active in rheumatoid arthritis, though its mechanism is unclear. Mesalazine has no role in rheumatoid arthritis.

Question 3

Aminosalicylates

Mesalazine, sulfasalazine

Adverse effects

Answer 3

• Mesalazine generally causes fewer side effects than sulfasalazine.
• Most commonly, these are gastrointestinal upset (e.g. nausea, dyspepsia) and headache.
• Both drugs can cause rare but serious blood abnormalities (e.g. leucopenia, thrombocytopenia) and renal impairment.
• In men, sulfasalazine may induce a reversible decrease in the number of sperm (oligospermia).
• It can also cause a serious hypersensitivity reaction comprising fever, rash and liver abnormalities.

Question 4

Mesalazine, sulfasalazine

Warnings

Answer 4

• Mesalazine and sulfasalazine are salicylates, like aspirin. Patients who have aspirin hypersensitivity should not take these drugs.

Question 5

Mesalazine, sulfasalazine

Interactions

Answer 5

• Mesalazine tablets with a pH-sensitive coating (e.g. Asacol® MR) may interact with drugs that alter gut pH.
• For example, proton pump inhibitors increase gastric pH so may cause the coating to be broken down prematurely.
• Lactulose lowers stool pH and may prevent 5-ASA release in the colon.

Question 6

MTX

Common indications

Answer 6

1. DMARD for RA
2. As part of chemotherapy regimens for leukaemia, lymphoma and solid tumours
3. Severe psoriasis that is resistant to other treatments

Question 7

MTX

MOA

Answer 7

• Methotrexate inhibits dihydrofolate reductase, which converts dietary folic acid to tetrahydrofolate (FH4).
• FH4 is required for DNA and protein synthesis, so lack of FH4 prevents cellular replication.
• Actively dividing cells are susceptible to the effects of methotrexate, accounting for its efficacy in cancer.
• Methotrexate also has anti-inflammatory and immunosuppressive effects.
• These are mediated in part by inhibition of inflammatory mediators such as interleukin (IL)-6, IL-8 and tumour necrosis factor (TNF)-α, although the underlying mechanisms are not fully understood.

Question 8

MTX

Adverse effects

Answer 8

• Dose-related adverse effects of methotrexate include mucosal damage (e.g. sore mouth, gastrointestinal upset) and bone marrow suppression (resulting in most significantly in neutropenia and an increased risk of infection).
• Rarely, hypersensitivity reactions including cutaneous reactions, hepatitis or pneumonitis may occur.
• Long-term use can cause hepatic cirrhosis or pulmonary fibrosis.
• As methotrexate is usually administered once weekly (see Prescription), there is a risk of accidental overdose if patients take treatment daily.
• Overdose causes severe dose-related adverse effects with renal impairment and hepatotoxicity.
• Neurological effects such as headache, seizures and coma may also occur.
• Treatment is with folinic acid, which ‘rescues’ normal cells from methotrexate effects, and with hydration and urinary alkalinisation to enhance methotrexate excretion.

Question 9

MTX

Warnings

Answer 9

• Methotrexate is teratogenic and must be avoided in pregnancy.
• Both men and women taking the drug should use effective contraception during and for 3 months after stopping treatment.
• As methotrexate is renally excreted, it is contraindicated in severe renal impairment.
• As it can cause hepatotoxicity, methotrexate should be avoided in patients with abnormal liver function.

Question 10

MTX

Interactions

Answer 10

• Methotrexate toxicity is more likely if it is prescribed with drugs that inhibit its renal excretion, e.g. NSAIDs, penicillins.
• Co-prescription with other folate antagonists, e.g. trimethoprim and phenytoin, increases the risk of haematological abnormalities.
• The risk of neutropenia is increased if methotrexate is combined with clozapine.

Question 11

MTX

Communication

Answer 11

• Explain that methotrexate treatment should cause improvement in, for example, swollen painful joints, but that this may take some time to reach maximal effect.
• Emphasise that methotrexate should be taken once a week (not every day) by prompting the patient to consider on what day they will take it.
• Warn patients to seek urgent medical advice if they develop a sore throat or fever (infection), bruising or bleeding (low platelet count), nausea, abdominal pain or dark urine (liver poisoning) or breathlessness (lung toxicity).
• Give advice regarding contraception (see Warnings) to all patients (men and women) who have the potential to have a child.

Question 12

MTX

Monitoring

Answer 12

• Efficacy should be monitored by symptoms, examination (e.g. of inflamed joints) and blood tests (e.g. inflammatory markers).
• Safety monitoring is essential as adverse effects can be life-threatening, but may be reversible if detected early and treatment is stopped.
• Patients should be advised to report unexpected symptoms (see above). Measure full blood count, liver and renal function before starting treatment, then 1–2 weekly until treatment is established and 2–3 monthly thereafter.
• Treatment should be stopped immediately if abnormalities develop or if the patient becomes breathless.