Lec 41- DMARDs Flashcards
1
Q
DMARDS act to
A
- Ameliorate symptoms
- Slow progress of RA and other arthritic disease including psoriatic arthritis, juvenile arthritis
- May be used for other chronic inflammatory condition e.g. UC, Chrons and psoriasis
- Heterogeneous group of compounds
2
Q
Modification of disease process
A
- Radiological evidence, symptoms and quality of life improvements support early aggressive management of RA
- Slow onset- therapeutically active after 3-6 months, usually response within 6 months
- Frequently found by chance to be effective
- Mechanism of action poorly understood
- DMARD toxicity> NSAIDs
- Require haematological monitoring
3
Q
Common mechanism of DMARDS (NB link with inflammation, go and look at the different actions)
A
Mechanism of action are varied -Decrease macrophage activity; -Decrease T cell activation -Decrease nucleotide synthesis -Decrease free radical scavenger No evidence for decrease in bone erosion but decrease rheumatoid factor
4
Q
Evidence
A
- Monotherapy with methotrexate effective- 1st line treatment
- If methotrexate fails, other DMARDs less likely to work
- Combination therapy more effective
- Combinations tolerated as well as mono therapies
- Drug choice less important than speed and intensity of DMARDs introduction
- Start within 3 months of symptoms (doesn’t have it because most patient put the symptoms down to older age)
5
Q
NICE GUIDANCE: RA- the management of RA in adults
A
-In people with newly diagnosed active RA, offer a combination of DMARDs (including methotrexate and at least one other DMARD, plus short term glucocorticoids)
+As first line treatment as soon as possible, ideally within 3 months of the onset of persistent symptoms
-In people with newly diagnosed RA for whom combinations DMARD is not appropriate
+Start DMARD monotherap ,placing greater emphasis on fast escalation to a clinically effective dose rather than on the choice of DMARD
-In people with recent-onset RA receiving combination DMARD therapy and in whom sustained and satisfactory levels of disease control have been achieved, cautiously try to reduce drug doses to level that still maintain disease control
6
Q
What DMARDs and cytotoxic are available for RA
A
Anti-malarial (Chloroquine): mild to early active RA
- Sulphasalazine (UC treatment) - Active RA
- Gold compounds- Active, progressive RA
- Methotrexate- Moderate to severe RA
- Penicillamine- Severe active RA
- Leflunomide- Severe active RA
- Azathioprine- Severe active RA
- Cyclosporin- Severe active RA
- Cyclophosphamide- RA with systemic complications
7
Q
Methotrexate
A
- MOST effective DMARD available
- Dihydrofolate reductase inhibitor (DHFR-I): blocks folate synthesis; for severe RA
- Its main therapeutic effect is inhibition of DNA synthesis but is also impairs RNA and protein synthesis
- Decrease the secretion of pro-inflammatory cytokines such as tumour necrosis factor (TNF)
- While increasing the secretion of the inhibitory cytokine IL-10
8
Q
Methotrexate (MTX) pathway
A
- MTX 50-90% renally excreted and 6-7%, hepatically excreted –> Remainder travels to bone marrow –> Haematopoietic pro-generator cells
- As MTX is an analogue of folate –> Modified MTX by polyglutamation (this extends the persistence and activity within the cell); enhances the effect of MTX on cell –> Folate pathway
- Haematopoiesis, MTX polymlutamate effects de-novo purine synthesis –> Effects AICAR transformas; effects GMP and AMP; Compromising DNA synthesis –> reducing cell proliferation (number of WBC): reduce titre of leucocytes moving to RA sites= slowing of inflammatory response
9
Q
MTX applications (dosage and when to use it)
A
- Once weekly dosage regimen doses used in RA are lower than those used in cancer chemotherapy
- Onset of action (6wks- 3 months)
- Started at a dose of 7.5mg orally once weekly and this is increased slowly to a max of 25mg Once weekly
- First-line DMARD, especially if disease is severe, progressing quickly and or the patient cannot tolerate sulphasalazine
10
Q
MTX- side effects
A
- Nausea and stomatitis- successfully managed with folic acid supplementation without the need for dosage reduction
- The appears to be no clear guidance on the optimal dosage regimen of folic acid
- Some rheumatologist recommend a dose of 5mg daily, some use 5mg Once weekly (72 hours after MTX) and others advocate 5mg dd for 6 days each week, with the dose withheld on the day MTX is take
- Hepatic and pulmonary ADRs
11
Q
MTX- side effects
A
- Hepatic fibrosis or cirrhosis is rare in the absence of previously abnormal liver function tests
- The risk of hepatic toxicity is also greater if theres an excess alcohol intake
- MTX is also teratogenic to ova and sperm
- Haematological
- renal
- Others
12
Q
Pulmonary side effects
A
- Pulmonary complications in the form of pneumonitis (inflammation of the lung) are rare idiosyncratic reactions and are potentially lethal
- Classical presentation is with rapid onset dyspnoea (shortness of breath) which may result in death after a few days
- Patients should be advised to stop MTX if they experience dyspnoea or cough and to seek immediate attention
13
Q
Monitoring
A
- Pre-treatment aassessment: FBC, U and E, creatinine, LFTs and CXR
- Monitoring requirements: FBC and LFTs fortnightly until 6 weeks after last dose increase, and monthly thereafter
- U&E 6-12 monthly (more frequently if there is any reason to suspect deteriorating renal function)
14
Q
Hydroxychloroquine
Plaquenil
A
- An anti-malarial drug, which is also effective in RA and systemic lupus erythematosus
- Mode of action may be related to inhibition of cellular lysosomal enzyme release and interference with intracellular function through inhibition of IL-1 release
- Drug interactions: antacids decrease absorption cimetidine increases drug level. Hydroxychloroquine antagonises anti-convulsants (epilepsy)
15
Q
Hydroxychloroquine applications
A
- May be prescribed with other DMARDs
- Typical dosage regimen: 200-400 mg daily, aiming for a maintenance dose of 3-5mg/Kg/day, depending on response
- Base dose on ideal bodyweight risk of toxicity in obese patients
- Time to response: Approximately 3-6 months
- Lower toxicity than most DMARDS
