RA Drugs Flashcards
What is the aim of RA drug treatment?
- Control symptoms
- Stop progress of disease
- Restore & maintain normal function
What is the treatment for rheumatoid arthritis?
Treatment for localised problem in joints:
- Physiotherapy, occupational therapy
- DMARD’s- 1st line- methotrexate (15 mg weekly, escalated up to max 25g weekly) given w/ prednisolone (30 mg daily reducing in 5mg increments every 2 weeks until therapy is removed after 12 weeks.)
- Can also give NSAIDs w/ paracetamol
- Biologics e.g. TNF (Monoclonal antibodies)
- Local joint injection (corticosteroids) - triamicinolone, methylprednisoline
- Oral tablets - prednisolone (acute flares - daily for 2 weeks)
- IV - hydrocortisone, methylprenisolone (serious flares - daily for 3 days)
- Surgery
^Usual order- learn this order!
What are NSAIDs? Use of NSAIDs in treating RA? Examples of NSAIDs you could prescribe for RA? Dosage?
What are they?
- Anti-inflammatory
- Acts to inhibit COX —> thus inhibiting prostaglandin production= increases pain threshold
- Improve joint pain & stiffness
In RA:
- Improve joint pain and stiffness
- Effective anti-inflammatory
- Have no effect on disease activity or progression
E.g.
- Naproxen
- Aspirin
- Ibuprofen
- Celecoxib
Dosage:
- High dose needed for a few weeks
- Ibuprofen 400-800mg tds
- Naproxen 750mg stat then 250mg tds for 7 days
What is the mechanism of NSAID action?
Increases pain threshold by reversibly- inhibiting COX-1 & COX-2
COX-1= produces prostaglandin to maintain secretion of gastric mucus, platelet-initiated blood clotting & maintaining renal blood flow
COX-2= only active during inflammatory response- produces PG that mediates pain & inflammation. Responsible for anti-inflammatory action of NSAID.
During trauma, immune cells convert phospholipid cell membrane into arachidonic acid (AA)
- AA is converted to prostaglandin
- Prostaglandin is responsible for pain & inflammation
NSAIDs:
- reversibly Inhibit COX enzymes > AA not converted to prostaglandin > pain relief & anti-inflammation
i.e NSAID Prevent cycloxegenase (COX) from making prostaglandins
What are the side effects of NSAIDs & why? What could you co-prescribe to reduce side effects of NSAID?
Side effects:
1. Peptic ulcer, bleeding & perforation
- COX-1enzyme is responsible for producing prostaglandins that maintain gastric mucosal integrity & platelet initiated blood clotting
- This is why inhibition of COX-1 can lead to serious GIT side effects.
2.Increased risk of ischaemic heart disease
Co-prescribe:
- Proton Pump Inhibitors
- e.g. Lansoprazole
Contraindications of NSAIDs- who can’t have them?
- Allergy to NSAIDs or salicyate
- GI bleeding or ulcer (past or present)
- History of recurrent GI haemorrage or ulcer
- Severe heart faliure
- Severe liver impairment
- Severe renal impairment
Why do you not give aspirin to children?
Increases ammonium production in liver
leads to brain & liver damage= Reyes disease
What are DMARDS? Examples? Safety?
What are they?
- Disease Modifying Anti-Rheumatic Drugs
- Suppress inflammation & prevent permanent damage
- Used alongside corticosteroids as bridging therapy’ (short-term)
- Main therapy for RA
Examples:
- Methotrexate
- sulfasalazine
- Leflunomide,
- hydroxychloroquine,
- gold (not used)
Safety:
- Sulfasalazine - GI upset, raised liver enzymes, bone marrow suppression
- Hydroxychloroquine - retinal damage
- Leflunomide - hypertension, GI upset, bone marrow suppresion
- Gold - rash, proteinuria, bone marrow suppresion
What is Methotrexate? Safety- what is it given with? Indications of use?
What is it?
- Antimetabolite - slows growth of cells
- Folic acid antagonist- acts on folate pathway
- Best established DMARD in RhA
Safety:
- Given once a week!
- Folic acid given on another day to reduce toxicity (Methotrexate on Monday, Folic acid on friday)
- Regular monitoring required - every 2 weeks (FBC and LFT’s every 1-2 weeks until therapy is stabilised, thereafter patients should be monitored every 3-4 months)
Indications of use:
- Rheumatoid arthritis
- Psoriatic arthritis
- Reactive arthritis - only for rare occasions w/ recurrent disease or severe Kertaoderma Blennorrhagia.
- Chemotherapy
Mechanism of action of Methotrexate?
1st line drug for RA
Folic acid/ folate= important for DNA replication & repair
MOA- FOLATE PATHWAY:
- Inhibits dihydratefolate reductase (enzyme)!
- enzymes is responsible for converting to active tetrahydrofolate
- Tetrahydrofolate is needed for synthesis of nucleoside thymidine & is part of synthesis of purine & pyrimidine
- therefore, methotrexate inhibits synthesis of DNA & RNA
Why is methotrexate not given w/ trimethoprim?
Trimethoprim also acts on folate pathway
if taken together= increases risk of bone marrow suppression
- fewer blood cells in bone marrow-less oxygen= anaemia
Also reduces cells that provide immunity (leukocytes, erythrocyte)= increased risk of infection
Side effects of methotrexate?
Folic Acid deficiency!
- blood tests- all results will appear low (e.g. wcc)- pancytopenia
- therefore regular blood tests required
Avoid for following:
Pregnancy
- Shouldn’t use methotrexate- it can damage the unborn child.
Bone marrow failure
- Anaemia - fatigue!
- Thrombocytopenia - low platelet count. Presents with bruising of skin.
- Leukopenia = infections. Patients told to seek medical attention if developed severe sore throat.
- Severe bone marrow failure is rare but can be fatal.
GI side effects
- Nausea & vomitting- main side effects! (GI upset)
- Oral ulceration
- Co-prescribing folic acid or other anti-sickness meds may help w/ nausea.
- Giving methotrexate subcutaneously may help too.
Liver damage
- Hepatic cirrhosis - scarring (fibrosis) of the liver leading to long-term liver damage.
- Hepatitis- associated w/ hyper sensitivity reaction.
- Minimise alcohol!!
- Blood test monthly
Pulmonary complications
- Pneumonitis
- Pulmonary fibrosis- Presents as shortness of breath & dry cough
- Methotrexate stopped
needed- as this is more common in adults w/ pre-existing lung disease - screen for TB.
Infections
- Shingles
- Herpes
- Particularly in diabetic patients & people in steroids.
Nodulosis
- Found in pressure points or in lung
- Exacerbated by methotrexate
Drug interactions of methotrexate? What monitoring does methotrexate need?
Drug interactions
- Trimethoprim- used to treat UTIs- also acts on folate pathway !
- Septrin - antibiotic
- Both can lead to bone marrow failure after one dose.
Monitoring:
1. Monthly blood test - looks at LFT & U&E to see if liver & kidney are happy. Look at WWC & platelets to see how bone marrow is doing.
2. Baseline chest x-ray to check for lung problems and TB
Routes & frequency of administration of methotrexate?
Given WEEKLY - Methotrexate on a Monday (7.5-20 mg)
Given w/ Folic acid - given on a Friday (5 mg)
- Also advised to eat a diet high in folate e.g. beans, peanuts, fresh fruit, whole grains, green veg.
- Folic acid reduces GI side effects e.g. nausea & vomitting
- as methotrexate inhibits folate absorption- folic acid is taken- folic acid= needed in DNA synthesis
Routes of administration:
- Orally - 2.5mg or 10 mg tablets - dose is increased by increasing number of tablets.
- Subcutaneous injection - can increase efficacy by increasing bioavailability
Who should avoid Sulphasalazine?
- Anyone w/ Sulphonamide allergy
- Anyone w/ Aspirin allergy may also react.
What are the 7 most common side effects that occur within 6 months of taking Sulphasalazine?
- Nausea
- Muscocutaneous reactions - rash
- Diarrhoea & abdominal pain
- Neuropsychiatric
- Haematological - low WWC or platelet count
- Liver abnormalities
- Pneumonitis - extremely rare
Is Sulphasalazine safe during pregnancy & breastfeeding?
- Safe in pregnancy
- Caution when breastfeeding
- Azospermia in men i.e. reversible low sperm count
What warning does Sulphasalazine need?
- Less monitoring than methotrexate
- Requires blood tests
- NOTE: can cause orange body fluids due to orange tablet - warn patients!
Leflunomide- indications of use?
- RA
- Psoriatic arthritis
- Rarely lupus
Side effects of Leflunomide
- GI upset - especially diarrhoea & weight loss
- Deranged LFTs
- Mild hypertension
- Rash & alopecia (hair loss)
- Bone marrow suppression
Monitoring for Leflunomide
- Blood tests
- Needs blood pressure checks
Is Leflunomide safe to take during pregnancy & does it affect fertility?
- New drug
- Most data comes from animal studies.
- Safer than methotrexate but shouldn’t be taken in pregnancy.
- Pregnancy still needs planning.
- Needs to be flushed out of body if trying for baby because has long half-life.
Hydroxychloroquine- indications for use?
- Mild to moderate SLE
- Rheumatoid arthritis
- Sjögren’s
Toxicity problems & side effects of Hydroxychloroquine?
Ocular toxicity
- Vision loss
- Typical bulls eye appearance on back of eye (NOTE- view image on note)
- GI side effects- nausea & vomiting.
- Increase in seizures in epileptic patients
- Some report increase in psorias
Is Hydroxychloroquine safe to use during pregnancy?
Yes
Safest DMARD overall
Monitoring for Hydroxychloroquine?
- No need to for blood monitoring
- Eye monitoring at opticians required.
How is gold used for RA? Side effects?
- Old treatment - v. v. rarely used
- Water soluble compound of sodium aurothiomalate
- Modulates B cell & macrophage function
- Can stay w/in synovium for up to 25 years
Side effects:
- Very toxic
- Chrysiasis - blue discolouration in skin.
- Colitis & lung disease
- Unsafe in pregnancy
What are biologic drugs? Which cytokine do they act on? Examples? MOA?
Produced in living systems
- Recombinant protein- target parts of human system that cause inflammation
- More specific & targeted than DMARDs
- Less side effects than DMARDs
cytokines:
- TNF-⍺- main target
- IL-6
- IL-1- not used yet - under development
Examples:
- TNF-a inhibitors
- B-cell inhibitors
- Interleukin inhibitors
- T-cell therapy
Specific example:
- Rituximab
- Etanercept
- Abatacept
MOA:
- Target cytokines
- TNF alpha is main target!!
What are the 5 anti-TNF drugs available? What are the 4 different patterns of failure seen?
Examples:
- Adalimumab
- Infliximab
- Etanercept
- Certilizumab
- Golimumab
- Etanercept a soluble TNF-Alpha receptor
- Infliximab - monoclonal antibodies against TNF-alpha
- Adalimumab - monoclonal antibodies against TNF-alpha
Patterns of failure seen:
- No response = primary failure.
- Initial response but then loss of response = secondary failure.
- Incomplete response- don’t go into complete remission.
- Toxicity
Side effects of Anti-TNF? Contraindications?
- Increased risk of infection - doubles risk of infection compared w/ traditional DMARDs.
- Increased TB risk= screen for TB.
- Increased risk of cancer recurrence - particularly melanoma.
Contraindications
- Previously had cancer - particularly those who’ve had a melanoma.
- Heart failure - should not receive anti-TNFs - they make heart failure worse.
- MS- shouldn’t receive drugs.
- Therapy has to be stopped prior to surgery because they reduce your immune response- immunesupression. Only restarted after the wound has healed.
NICE guidelines for anti-TNF for RA?
- Active RhA disease activity
- Tried at least 2 DMARDs (including methotrexate for >6 months)
- Should normally be used together w/ methotrexate
What are B-cell inhibitors used for? Example of a drug? MOA?
Used for:
- Rheumatoid arthritis
- Vasculitis
- SLE
- Malignancy
Examples:
- Rituximab
MOA:
- Rituximab is an IgG1 monoclonal antibody
- It targets CD20 which is expressed on B cells
- Results in cell lysis of B cells
NOTE: learn what each drug targets in immune system- very important!
Safety for B cell inhibitors?
- Infection risk similar to anti-TNF
- No issue w/ malignancy
- Chest infections
- PML - reactivation of JC virus - v. rare. Usually fatal viral disease characterised by progressive damage.
- Given by infusion
- Lasts - average is 9-12 months but can be up to 2 years.
How does T cell therapy work? Example? What should it be co-prescribed? Safety?
How does it work:
- T cells require 2 signals for activation
- Abatacept interferes w/ the second signal that switches on the T cell.
- Blocks the CD28 on Helper T cells binding to B7 on APCs.
Example:
- Abatacept
Co-prescribed w/ Methotrexate
Safety- infection risk
