DMARDs Flashcards
Name the conventional synthetic DMARDs (csDMARDs)
Methotrexate
Hydrochloroquine
Sulfosalazine
Leflunomide
What are the indications for methotrexate?
Rheumatoid arthritis
Tx of psoriasis that has not responded to topical, steroids or phototherapy
Psoriatic arthritis
Crohn’s disease
Ectopic pregnancies
Neoplastic disease
What is the pharmacodynamic of methotrexate?
Inhibits dihydrofolate reductase, essential for the synthesis of purines and pyrimidines (i.e., nucleotides)
This prevents cell division and leads to anti-inflammatory action
What is the pharmacokinetic of methotrexate?
Bioavailability = 64-90%
Protein binding = 46.5-54% plasma proteins
Half-life = 3-10 hours (low dose), 8-15 hours (high dose)
Metabolism = hepatic (via folylpolyglutamate synthase)
Excretion = kidney (via urine), some in bile (8.7-26%) with IV administration
N.B: methotrexate has a narrow therapeutic index and should not be taken everyday
What are the contraindications for methotrexate?
Acute infection
Pregnancy and breastfeeding
Ascites
Immunodeficiency syndrome
Significant pleural effusion
Severe hepatic impairment
What are the side-effects of IV/Oral methotrexate?
Anaemia
Liver cirrhosis
Decreased appetite
Pulmonary fibrosis
GI symptoms (i.e., vomiting, diarrhoea)
Nausea
Leucopenia/bone marrow disorders/agranulocytosis
What are the side-effects specific to IV methotrexate?
Necrotising demyelinating leukoencephalopathy
Neurotoxicity
According to NICE guidelines what monitoring should be done for patients with blood dyscrasias (i.e., any disorder of the blood e.g., leukaemia etc) or liver cirrhosis on low-dose methotrexate?
FBCs + Us&Es every 1-2 week until therapy is stabilised then every 2-3 months thereafter
Also patients should be advised to report all symptoms and signs suggestive of infection, especially sore throat
How is methotrexate monitoring done at the Royal Sussex?
Once a week for 6 weeks
Then once a month for 3 months
Then 3 monthly thereafter
What are the significant drug interactions for methotrexate?
Methotrexate + trimethoprim = depletion of folic
Methotrexate + PPIs = increased clearance of Methotrexate
Methotrexate + NSAIDs = increased risk of toxicity
Methotrexate + Phenoxymethylpenicillin/Piperacillin/Piroxicam/Pivmecillinam = increased risk of toxicity
Methotrexate + live vaccines (e.g., infleunza, MMR) = increased risk of generalised infection (possibly life threatening)
Methotrexate + Levetiracetam = decreased clearance of Methotrexate (this can cause toxicity as Methotrexate has a narrow therapeutic window)
Methotrexate + Nitrous oxide = increased risk of toxicity
What other supplement should be prescribe in conjunction with methotrexate and why?
Folic acid
Decreases mucousal and GI side-effects (no evidence it reduced haematological side effects)
When should methotrexate be withdrawn?
If the patient has:
ulcerative stomatitis
diarrhoea
Suggests GI toxicity
What drug may be required in acute methotrexate toxicity?
Folinic acid (as calcium folinate)
A patient has moderate-severe active rheumatoid arthritis. What dose of methotrexate would they be given?
7.5g once weekly
(max dose = 20mg)
A patient has severe active rheumatoid arthritis. What dose of methotrexate would they be given?
Initially 7.5mg
Then increase in steps of 2.5mg once weekly
Max 25mg per week
A patient has severe Crohn’s. What dose of methotrexate would they be given?
Initially 25mg once weekly until remission
Maintenance = 15mg once weekly
What dose of methotrexate would be given for maintenance of remission of severe Crohn’s?
10-25mg once weekly
A patient has severe psoriasis not responding to conventional treatments. What dose of methotrexate would they be given?
Initially 2.5–10 mg once weekly
Then increased in steps of 2.5–5 mg, adjusted according to response
dose to be adjusted at intervals of at least 1 week
What is the usual dose of methotrexate for severe psoriasis not responsive to conventional treatment?
Usual dose 7.5–15 mg once weekly
Stop treatment if inadequate response after 3 months at the optimum dose
Maximum 30 mg per week.
TRUE OR FALSE
Methotrexate is not licenced for use in severe Crohn’s disease
TRUE
What investigations should you do before starting methotrexate?
Chest X-ray (look for latent TB)
Renal function
Liver function
What are the indications for sulfasalazine?
Tx of acute attack of mild to moderate and severe UC
Maintenance of remission of mild to moderate and severe UC
Active Crohn’s disease
Active Rheumatoid arthritis (on expert advice)
Sources for sulfasalazine
https://bnf.nice.org.uk/drugs/sulfasalazine/
https://go.drugbank.com/drugs/DB00795
https://en.wikipedia.org/wiki/Sulfasalazine
A patient is being treated for an acute attack of mild to moderate and severe UC. What dose of sulfasalazine would they be given?
By mouth
1-2g QDS until remission occurs (corticosteroids may also be given if necessary)
By rectum
0.5-1g BD (given alone or with oral therapy, morning and night after a bowel movement)
A patient is being treated for active Crohn’s. What dose of sulfasalazine would they be given?
By mouth
1-2g QDS until remission occurs (corticosteroids may also be given if necessary)
By rectum
0.5g-1g BD (can be given alone or with oral therapy, morning and night after bowel movement)
What dose of sulfasalazine would be given for maintenance of remission of mild to moderate and severe UC?
By mouth
500mg QDS
By rectum
0.5-1g BD (given alone or with oral therapy, morning and night after a bowel movement)
What dose of sulfasalazine would be given for Tx of active RA?
By mouth
Initially 500mg daily
Increased in steps of 500mg every week
Increased to 2-3g daily in divided doses
Enteric coated tablets to be administered
What is the pharmacodynamic of sulfasalazine?
Anti-inflammatory
Broken down into 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP) whose mechanism of action are still being studied
What is the pharmacokinetic of sulfasalazine?
Bioavailability = <15%
Protein binding = not available
Half-life = 5-10 hours
Metabolism = colon by bacteria
Excretion = faeces (but majority of 5-ASA stays in the colonic lumen)
What are the contraindications for sulfasalazine?
CAUTIONS include:
- acute porphyrias
- G6PD deficiency
- Hx of allergy
- Hx of asthma
- maintain adequate fluid intake
- risk of haematological toxicity
- risk of hepatic toxicity
- slow acetylator status
What are the common/very common side-effects of sulfasalazine?
Insomnia
Stomatitis
Altered taste
Tinnitus
Urine abnormalities - can colour the urine
What are the uncommon side-effects of sulfasalazine?
Face oedema
Seizure
Vasculitis
Vertigo
What are the frequency unknown side-effects of sulfasalazine?
Hepatic failure
Anaemia
Decreased appetite
Ataxia
Cyanosis
Encephalopathy
Haematuria
Hallucination
Hypoprothrombinaemia
Lymphadenopathy
Macrocytosis
Aseptic meningitis
Methaemoglobinaemia
Nephrotic syndrome
Severe cutaneous adverse reactions (SCARs)
Smell disorders
SLE
Yellow discolouration of body fluids
If haematological abnormalities occur usually in the first 3 to 6 months of treatment on sulfasalazine, what should you do?
Discontinue sulfasalazine
What should you advice patients receiving aminosalicylates (which includes sulfasalazine) and their carers to report?
Any unexplained:
- bleeding
- bruising
- purpura
- sore throat
- fever
- malaise
that occurs during Tx
What monitoring should be done for all patients on aminosalicylates (including sulfasalazine)?
Renal function
Before starting
At 3 months of Tx
Then annually during Tx
What monitoring should be done for all patients on sulfasalazine?
Bloods
Close monitoring of FBC (inc. differential WCC and platelet count) initially
Then at monthly intervals during the 1st 3 months
Renal function
Although recommended by the manufacturer, evidence of practical value is unsatisfactory
LFTs
Should be done at monthly intervals for the 1st 3 months
What are the significant drug interactions for sulfasalazine?
Sulfasalazine + darolutamide (new type of hormone therapy for men whose prostate cancer has stopped responding to other types of hormone therapy - an androgen receptor inhibitor) = increased exposure to Sulfasalazine
Sulfasalazine + tepotinib (kinase inhibitor used in treating small cell lung cancer) = could increase exposure to sulfasalazine
Sulfasalazine + voxilaprevir (reversible inhibitor of the NS3/4A protease an important protein in HCV) = increases [sulfasalazine]
