day 2 - drugs for bones and joints Flashcards
difference between COX1 and 2
Cox 1 is constitutive (activity is increased as part of inflammatory response also 2-4 fold). Cox 2 is inducible by inflammatory stimuli in many cells including macrophages, syniviocytes, chondrocytes, fibroblasts and endothelial cells.
Analgesia in RA
Paracetamol
Paracetamol-opioid combinations
Non steroidal anti-inflammatory drugs
Do not change natural history of disease, used for symptom control only
Disease Modifying Agents - RA
DMARDs (disease modifying anti-rheumatic drugs)
Immune modulators - restore ‘normal’ immune environment within synovium
Alter disease activity, outcome and progression, and provide symptom relief
Slow onset of action: weeks-to-months
Comparisons of efficacy based on functional indices reduction in joint swelling and lab markers e.g. ESR/CRP
All require regular monitoring for adverse effects
Should be started soon after diagnosis, or can have worse outcomes
DMARDs- RA
Methotrexate Sulfasalazine Gold salts Azathioprine D-Peniciallamine Hydroxychloroquine Ciclosporin Lefluonamide Biological agents
Methotrexate moa and dose
Competitive inhibition of dihydrofolate reductase. Also has other anti-inflammatory and cytokine modulating effects
Used in RA, psoriatic arthritis, and as a steroid sparing agent in other AI conditions
Low dose used in RA and other AI disease (high doses in haematological malignancies)
Dose:
Weekly dose (7.5 mg-20mg- per week).
Often taken in conjunction with folic acid (5mg, other 6days/week)
Coverts dietary folic acid to tetrahydrofolate – required for DNA and protein synthesis. Thus impairs cellular replication.
Cytokine modulation less understood
Methotrexate- adverse effects
Usually well tolerated. BUT requires monitoring
SE related to inhibition of cellular replication
Mouth ulcers / nausea – Rx with folic acid
Bone marrow suppression inc. neutropaenia
Others:
Acute cutaneous reactions, hepatitis, pneumonitis (temporary discontinuation)
Chronic use can rarely lead to interstitial pneumonitis and hepatic cirrhosis
Renally excreted so care with CRF or agents that impair GFR
Teratogenic (3 month washout)
Hydroxychloroquine moa and toxicity
Accumulates in cells – appears to block TLR signalling, phagocytic functions, and DC activation however exact mode of action poorly understood
Efficacy unclear but commonly used in SLE and RA
Toxicity based on cumulative dose
Eye: corneal (reversible) and macular retinopathy. Need baseline eye exam (peripheral and colour vision) and monitoring. Note – G6PD lysis
Common: GI upset
Sulphasalazine moa and tox
Aminosalicylate (in common with mesalazine)
= 5-ASA linked to sulfapyridine.
Poorly absorbed, orally cleaved to 2 active components by colonic bacteria
5-ASA – anti-inflammatory/immunosuppressive effects
Sulfapyridine – (purported) anti-folate activity
SE:
Common: GI upset, headache
Rare: haematological dyscraisias, renal impairment, oligospermia, hypersensitivity reactions
use of biologicals in RA
Natural substances, chemically altered used as therapeutic agents
Used in patients who have Active disease (DAS28 >5.1) on 2 occasions, 1 month apart Not responded to at least 2 DMARDs (including methotrexate) after 6months, 2 months at standard dose
Target chronic inflammatory pathway
Aim
Improvement in DAS28 >1.2points at 6months
Biological Agents- RA
Anti TNF
Infliximab, chimeric antibody of part mouse (variable region) part human antibody (Fc region) . Inhibits TNF by binding in the joint cavity, infusion with methotrexate once a week
Etanercept, recombinant human TNF fusion protein, competitively inhibits TNF binding to cell surface receptor, subcut injection twice a week
Adalimumab, recombinant human monoclonal antibody, subcut injection
Others: Golimumab, Tocilizumab, Abatacept, Certolizumab
Rituximab
Monoclonal antibody to CD20 Depletes B cells Used to treat moderate to severe RA patients who have failed anti TNF therapy Given max 6-monthly No long term data
Osteoarthritis treatment goals
Age or injury related cartilage damage
Leads to joint damage
Presents with pain and swelling
Cellular mechanisms of disease poorly understood- therapeutic goals are reduction of pain and symptom control
Osteoarthritis- Treatment
Simple analgesia (paracetamol, NSAIDS) Physiotherapy Exercise Patient education Avoid weight gain Bone protection -Bisphosphonates -Calcium supplementation +/- VD3 Joint injection Joint replacement
what is Gout
precipitation of monosodium urate crystals in tissues, imbalance between production and secretion of uric acid.
Hyperuricaemia associated with obesity, diabetes, hypertension, CAD, renal insufficiency, and increased triglycerides.
uric acid excretion
UA: filtered at glomerulus. In hyperuricaemia large loads filtered, UA
re-absorption increases to avoid dumping of poorly soluble urate
into urinary tract (secretion impaired).
Uricosuric agents (probenicid, sulfinpyrazone and high dose aspirin) block re-sorption of filtered and secreted UA in the renal tubules.
Thiazide diuretics and low dose aspirin reduce renal clearance of
uric acid-90%) may precipitate gout.
Gout- acute treatment
AIM: relieve pain and inflammation.
NSAIDs e.g. high dose indomethacin
NOT allopuinol or probenicid acutely as cause mobilisation of uric acid stores as serum levels fall & will prolong acute attack.
Colchine: inhibits leukocyte micro-tubular formation and migration
must be given early until good pain relief or G.I side effects (nausea, vomiting , diarrhoea, abdo pain) t1/2=30hrs clearance reduced in renal impairment.
Steroids may be useful.
Gout- Chronic treatment
Aim: control symptoms and prevent renal damage. Long –term hypouricaemic agents for those with recurrent attacks (>2/yr)
Allopurinol: Competitively binds xanthine oxidase which converts adenine & guanine (purines) to UA. Reduces precipitation in joints and kidneys.
Reduce dose in renal and hepatic failure.
S.E. headaches, dyspepsia, diarrhoea. Gout flare!
Rarely fever, renal failure, allopurinol hypersensitivity (Stevens-Johnson Syndrome and TEN). Note interaction with mercaptopurine and azathioprine
Other uses: prevention of tumour lysis syndrome
Osteoporosis- treatment aims
Prevent further bone loss
Improve bone mineral density
Reduce fracture risk
Osteoporosis- treatment
Calcium/ vitamin D
Bisphosphanates- inhibit bone resorbtion (osteoclasts):
- Alendronate, etidronate
Reduce vertebral and non vertebral fractures
Daily/ weekly tablets
Can cause :
oesphageal ulceration and hypophosphataemia (commonly)
Osteonecrosis of the jaw, atypical femoral fracture (rarely)
Denosumab (anti-RANKL)
SERM’s (selective estrogen receptor modulators e.g. raloxifene)
Strontium
Recombinant PTH (teriparatide)
NOTE - HRT is no longer used as increased risk of coronary events and breast cancer
Ankylosing spondylitits
Ankylosing spondylitis (AS), a form of spondyloarthritis (SpA), is a chronic inflammatory disease of the axial skeleton manifested by back pain and progressive stiffness of the spine; it can also involve the hips, shoulders, and peripheral joints. Extraarticular manifestations, including uveitis, may also be seen in patients with AS and other forms of SpA. AS typically develops in young adults, with a peak age of onset between 20 and 30 years.
The name “ankylosing spondylitis” is derived from the Greek root “ankylosis,” meaning stiffening of a joint, and “spondylos,” which refers to a vertebra. “Ankylosing spondylitis” thus refers to the inflammatory disorder associated with fibrous or bony bridging of joints in the spine, including the bridging of intervertebral discs.
Psoriatic arthropathy
INTRODUCTION — Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis [1]. It was initially considered a variant of rheumatoid arthritis, but subsequently emerged as a distinct clinical entity [2]. Historically, seronegativity for rheumatoid factor (RF) had been a requirement for the diagnosis; however, over 10 percent of patients with uncomplicated psoriasis and up to 15 percent of the normal population have RF present in their serum. As a result, the term “usually seronegative” arthritis is most suitable for PsA [3,4].
Patients with psoriatic arthritis (PsA) present with pain and stiffness in the affected joints. Morning stiffness lasting more than 30 minutes occurs in one-half of patients. The stiffness is accentuated with prolonged immobility and is alleviated by physical activity. A history of psoriasis is present in about 70 percent of patients presenting with arthritis.
