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locomotor > Pain & Analgesia: Disease Modifying Anti Rheumatic Drugs (DMARDS) > Flashcards

Pain & Analgesia: Disease Modifying Anti Rheumatic Drugs (DMARDS) Flashcards

1
Q

What are the important disease affecting the joints?

A
  • OA= degenerative, ‘wear and tear’, very common, experienced by most elderly people
  • Crystal arthropathies= uric acid deposition (gout), calcium pyrophosphate deposition (pseudogout)
  • Inflammatory joint diseases= immunologically-led pathology, inflammation central feature
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2
Q

What are the inflammatory joint diseases?

A 
-RA
Connective tissue disease:
-Systemic lupus erythematosus
-Systemic sclerosis
-Mixed connective tissue disease
Seronegative spondylarthropathies- axial skeleton
-Psoriatic arthritis (men> women)
-Ankylosing spondylitis
-Enteropathic arthritis (IBD)
-Reactive arthritis (infections)
-Behcet's disease
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3
Q

What is the pathophysiology of inflammatory joint diseases?

A
  • Immune system mistakenly attacks the tissue that lines and cushions the joints (synovium)
  • Joint becomes stiff, swollen and painful
  • Cartilage wears away- release of destructive enzymes
  • RA= pannus (thickened synovium), white cells
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4
Q

Describe RA

A
  • Chronic inflammatory disease= 1-3% population, women 2-3 x men
  • Joints primarily involved early= synovial joints simultaneously (polyarthritis), small joints of hands and feet (symmetrical), painful, swollen and stiff and deformed joints
  • Systemic (extra-articular) manifestations later= heart, small vessels, lungs, kidneys, eyes, spleen
  • Younger onset than OA= 25-50, disability more severe, systemic
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5
Q

How does RA present?

A

-Joint stiffness (morning and after rest)
=Joint pain (difficulties with daily activities)
-Flare-ups and remissions
-Joint structure damages= weak ligaments, tendons and muscles around hands decrease grip and manual dexterity
-Disuse atrophy (wasting of muscles)

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6
Q

What is the aetiology of RA?

A
  • Unknown
  • Probably multifactorial= inappropriate immune-mediated inflammatory response
  • Genetic predisposition (HLA-DR4 increase risk by 5x)
  • Environmental factors may trigger immune response= infectious (parvovirus), diet
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7
Q

What are the stages of RA?

A
  • Inciting agent
  • Immune system activation
  • Immune complexes deposition (synovium)
  • Complement activation
  • Inflammatory response= T cells, B cells, macrophages, cytokines, antibodies, complement
  • Joint destruction
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8
Q

Describe the pathogenesis of RA

A
  • Inflammation and oedema of synovium (T cells)
  • Synovial hypertrophy and proliferation increases fluid
  • Pannus formation (granulation tissue)
  • Destruction of cartilage and bone by pannus= pro-inflammatory cytokines (TNFa, IL-1, interferon x), metalloproteases (collagenases)
  • Muscles wasting
  • Joint deformity and ankylosis (fuse bony ends)
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9
Q

What are the clinical features of RA?

A
  • Onset insidious in 70% (may be abrupt)
  • Often begins with ache and morning stiffness (>30 mins)
  • Early symptoms may be the thought ‘age-related’
  • Most commonly presented: polyarticular and symmetrical
  • Typically small joint of feet and hands
  • Tenderness in all joints affected, swelling of joints
  • Early afternoon fatigue and malaise also occur
  • Deviation of fingers/ Z deformity of thumb/ weakening of muscles/ subluxation of joints
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10
Q

What are the extra-articular manifestations of RA?

A

-General= weight loss; malaise and fever, lymphadenopathy
-Skin= ‘rheumatoid’ nodules
-Eye= keratoconjuctitis, scleritis, episcleritis
-Respiratory= pleurisy, pleural effusions, interstitial fibrosis, rheumatoid nodules, bronchiolitis
-Cardiac= pericarditis, myocarditis, endocarditis, valvular heart disease
-GI= adverse effects from drugs
-Renal= amyloidosis, drug induced nephropathy, renal tubular acidosis
-Neurological= entrapment syndrome (carpal tunnel), peripheral neuropathy from vasculitis- sensory and motor, mononeuritis multiplex
-Haematological= anaemia, leucopoenia, lymphoma, thrombocytosis
More likely in RF factor/ HLA-DR4 positive

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11
Q

What are the x-ray investigations used to diagnose RA?

A
  • Soft tissue swelling and widening of joint space (early)
  • Osteoporosis and uniform narrowing of joint space (later)
  • Bone erosions and cysts (due to pannus destruction)
  • High-resolution ultrasound and MRI
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12
Q

What laboratory tests are used to aid diagnosis?

A
  • ESR raised (90%)
  • Anaemia (normochromic normocytic)
  • Synovial fluid (cloudy, sterile, decreased viscosity, increased white cells)
  • Rheumatoid factor (75%) decreased prognosis
  • Other autoantibodies
  • Anti-citrullinated protein antibodies (ACPAs)
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13
Q

What are the goals for pharmacological management of RA?

A
  • Relieve symptoms early
  • Put disease into remission early
  • Prevent joint-damage long-term
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14
Q

Describe early stage RA management

A
  • Analgesic drugs (paracetamol, codeine)

- Non-steroidal anti-inflammatory drugs= ibuprofen, diclofenac, COX-2 selective drugs (celecoxib)

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15
Q

Describe RA treatment management after diagnosis

A
  • DMARDs= disease-modifying anti-rheumatic drugs, more powerful but adverse effects
  • Corticosteroids/ immunosuppressants= intra-articular injections, occasionally systemic oral treatment
  • Biological therapies if failure to respond to DMARDs
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16
Q

Why do we use DMARDs?

A
  • Reduce underlying disease activity
  • Reduce pain and disability
  • Achieve remission
  • Reduce inflammatory destruction of joints
  • Prevent progression
17
Q

What are the initial choices of DMARD?

A

-Methotrexate
-Sulfasalazine
Plus corticosteroid
-Immunosuppressant drugs= LEFLUNOMIDE, azathioprine, ciclosporin, cyclophosphamide
-Older DMARDs= HYDROXYCHLOROQUINE, penicillamine, gold salts

18
Q

What happens to DMARD choice when disease becomes refractory/ aggressive/ systemic?

A 
-Cytokine modulators
=infliximab (TNFa inhibitors)
=etanercept (TNFa i)
=adalimumab (TNFa i)
-Other new biologics
=abatacept (T cells)
=rituximab (B cells)
=anakinra (IL-1)
=toclizumab (IL-6)
19
Q

What are the general points about DMARDs?

A
  • Not analgesics
  • Target immune-mediated inflammatory activity
  • No immediate therapeutic effect (2-6 months for full response)
  • Response should allow NSAID dose to be reduced
  • No objective benefit= discontinue= try another
  • Retard erosive damage as judged radiologically
20
Q

What is mechanism of action of methotrexate?

A
  • Dihydrofolate reductase inhibitor
  • Enzyme important in regenerating folic acid
  • Generation in thymidine bases in DNA
  • Inhibit chances of rapidly dividing cells can replicate contributing to further damage
21
Q

Describe methotrexate

A

-Immunosuppressant= blocks DNA synthesis in proliferating cells by binding with and blocking the action of folic acid reductase
-Indications= RA, psoriasis, Crohn’s disease, malignancy
-By mouth once weekly with food (can also be given by injection)
-Usually prescribed with folic acid
-GI upset (sickness, diarrhoea, mouth ulcers), hair loss, skin rashes, blood cell formation disruption, teratogenic, infections, liver, pulmonary toxicity
-Contra-indications= pregnancy, immunosuppression, liver disease
Bone marrow disruption

22
Q

What are the dangers of immunosuppressant drugs?

A

-Viruses (herpes zoster)
-Fungi (candida)
-Tuberculosis
-Malignancy
Cellular immune system > humoral

23
Q

What is the structure of sulfasalazine?

A
  • Combination of sulphonamide (antibiotic) and 5-ASA (amino salicylic acid)
  • Joined by azo bond, cleaved in the colon
24
Q

Describe sulfasalazine

A

-Aminosalicylate= combination of 5-ASA and sulfapryridine
-Anti-inflammatory, systemic immunosuppressant activity
-Indication= active RA, IBD (UC, Crohn’s)
-By mouth as enteric-coated tablets (initially 500 mg to 2-3 g daily)
-Rashes, GI upset, decreased WBCs (neutrophils) and platelets (monitor FBC), reversible azoospermia, anaphylaxis, photosensitivity, decreased folate
Bone marrow disruption

25
Q

Describe corticosteroids

A
  • Action at nuclear receptors, immunosuppression, anti-inflammatory
  • Up to 15 mg daily often given with bisphosphonate
  • Intra-articular injections may help settle a flare
  • Osteoporosis, weight gain, infections, skin changes, hyperglycaemia
26
Q

Describe how Gold was used as a DMARD

A
  • Sodium aurothiomalate/ auranofin
  • Given by intramuscular injection weekly (also oral)
  • Mouth ulcers, rashes, haematological, proteinuria
  • Monitor blood count and urine
27
Q

Describe how penicillamine was used as a DMARD

A
  • Dimethylcysteine
  • Related to penicillin, also used as a chelating agent
  • Taste disturbance (Zn), haematological, proteinuria
  • Monitor blood count and urine
28
Q

Describe how hydroxychloroquine was used as a DMARD

A
  • Also used for SLE and malaria
  • Retinal damage (blurred vision)= eye tests
  • Hydroxychloroquine retinopathy
29
Q

How do we assess the DMARD response?

A 
Clinical:
-Joint inflammatory activity (synovitis)
-Pain (score)
-Disability (score)
Investigations:
-Markers of inflammation (ESR, CRP)
-Anaemia
-Rheumatoid factor= an IgM Ab against host IgG?
30
Q

What is the role of TNFa in RA?

A

Leads to synovitis/pannus

  • Osteoclasts= bone resorption= bone erosion
  • Synoviocytes= articular inflammation= pain, swelling
  • Chondrocytes= cartilage degradation= joint space narrowing
31
Q

Describe the action of TNFa antagonsist

A
  • infliximab= monoclonal antibody= directly recognise TNFa

- etanercept= receptor analogue (soluble;) would normally interact with- circulating TNFa binds

32
Q

Describe infliximab

A
  • Cytokine inhibitor- blocks the pro-inflammatory action of TNFa
  • Indications= RA, treated with at least 2 DMARDs, active disease (2 visits one month apart)
  • Intravenous infusion every 8 weeks (etanercept/ adalimumab s.c. injection)
  • Given with methotrexate)
  • Hypersensitivity reactions, latent tuberculosis reactivation, skin cancer and lymphoma
  • Contra-indications= severe infections, pregnancy, breast feeding
33
Q

Describe the action of other immunosuppressant drugs

A
  • Leflunomide= decreased de novo pyrimidine synthesis/ oral, well-tolerated, rapid activity, bone marrow toxicity
  • Azathioprine= oral, GI upset, bone marrow toxicity
  • Cyclophosphamide= alkylating agent (mutagenic), oral, bone marrow toxicity)
  • Ciclosporin= inhibits kinase signalling cascade (calcineurin inhibitor), renal impairment, hypertension
34
Q

Describe non-drug management of RA

A
  • Patient education and motivation
  • Exercise- mobile joints
  • Physiotherapy
  • Joint protection= splinting and braces
  • Occupational therapy (aids to help grip)
  • Good nutrition (counteract weight loss)
  • Complementary/ alternative therapies?
  • Surgical (joint fusion/ replacement)

locomotor (20 decks)

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