Download OAHKS radiology learning guide - Section 5 (1.7mb, ppt)

LEARNING GUIDE 5:
PHARMACOLOGY FOR
ARTHRITIC CONDITIONS
Cathy Senserrick and Sophie Rodier 2011
Commonly Used drugs
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OSTEOARTHRITIS
Simple analgesics- panadol
 NSAIDs- COX inhibitors- different types
 Opiods- what are the risks
 Natural therapies- what is the evidence?
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RHEUMATOID/INFLAMMATORY ARTHRITIS
As above plus
 Glucocorticoids- steroids
 DMARDs
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OSTEOPOROSIS medications
GOUT medications
Paracetamol
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Paracetamol, acetaminophen (USA-Tylenol)
No effect locally. Decrease hyperalgesic effects of the prostoglandins At the spinal
cord / decrease neurotransmission of pain signal. Also? Increase inhibitory
descending pathways from the brain via COX 3 enzyme. ? Cannabinoid receptor
activation (ie .mechanism is central not local). Analgesic and antipyretic but not
antiinflammatory.
Panadol Osteo is a larger dose so taken less often- ususally 3xday vs 4.
Side effects-potential hepatotoxicity with overdose due to paracetamol metabolite
NAPQI, increased risk if taken with ETOH. Upper GI irritation and risk of renal
toxicity long term use>4g/day. OASRI recommend<4g/day
Drug interactions- Warfarin- potential to increased effect of warfarin esp with
prolonged panadol osteo use- controversial but be aware.
Benefits- regular paracetamol reduces the dose of stronger drugs required, so less
side effects from these. Only mild analgesia when used alone. No effect on
stiffness/ function (OASRI guidelines 2010)
NSAIDs
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Naproxen, ibuprofen , diclofenac (Voltaren)available over counter. Stronger NSAIDS eg
Indomethacin (Indocid) Meloxicam (Mobic) require prescription. Slow release formulas available
Suppress formation of prostoglandins and thromboxane- by blocking COX enzyme which is
involved in conversion arachidonic acid released from the cell membrane in response to
mechanical trauma/presence of cytokines or other inflammatory mediators– anti inflammatory,
antipyretic and analgesia( ie. Local role of prostoglandins and bradykinin on C fibres)
Protective role of prostoglandins in upper GIT (suppress gastric acid production)- risk of GIT
irritation/ diarrhoea/dyspepsia 20% pts, ulcer perforation/GIT bleeding and death103,000hospitilisations, 16,500 deaths/yr in US (dose dependent)
Prostoglandins also play a role in the release of thromboxane (clotting factor) from platelets
during injury, thus use of NSAIDs prolongs bleeding time.
COX-2 selective drugs- work on COX 2 enzyme which is implicated more in prolonged
inflammation/ less effect on protective prostoglandins (activated by COX 1)but still some.
The key activators of COX 2 in prolonged inflammatory conditions are Interleukin-1 and TNF
Prostoglandins act synergistically with other mediators eg histamine and bradykinin – effect is
hyperalgesia of C fibres, increased chemotaxis, increased pain responses and increased vascular
permeability/ oedema). NSAIDs target these issues in chronic inflammatory states
Prostoglandin PGE 2 stimulates increase temp via the hypothalamus. NSAIDS “reset” the
thermostat.
COX 2 inhibitors (Coxibs)- one serious side effect is the increased throboxane production/ cardiac
risk eg Rofecoxib (Vioxx) was withdrawn from the market. Celecoxib (celebrex) etc still in use.
NSAIDs
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Evidence give superior pain relief to paracetamol ( up to 2x)- OASRI guidelines
Main issue is upper GI tract irritation, bleeding etc. Greater risk when combined
with high doses paracetamol (OASRI)
To reduce risk, COX-2 selective NSAIDs are used or non-selective NSAIDs with a
proton pump inhibitor eg Omeprezole (Losec)(halves risk hospitalisation for GIT
complications-OASRI) or prostoglandin analogue eg Misoprostol (Cytotec). These
drugs have superceded the old H2 receptor antagonists eg Ranitidine (Zantec)histamine 2 recptor stimulates gastric acid production and release.
Other risks are cardiac risk esp if history IHD, congestive heart failure and atrial
flutter and renal toxicity (beware elderly). Prostoglandins involved in renal blood
flow- vasodilators. Beware fluid retention, hypertension- signs of altered renal
function. Also may effect liver enzymes- look for rash, dizziness, headaches. Not to
be taken in pregnancy.
Topical NSAIDs can give moderate relief knee OA( up to 40%)- OASRI. No
evidence supporting one brand over another.
NB. One advantage- Using NSAIDs post op can reduce the need for opiods by 1/3
Opiods- Codeine
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Natural derivative from morphine (from poppies)
Weak binding to µ-opiod receptors (spinal cord
and brain)- mild analgesia, anti-tussive and antidiarrhoea
Can be combined with paracetamol and ibuprofen
(panadeine, nurofen-plus)
Side effects- constipation, nausea, dry mouth, rash,
drowsiness. Risk OD/ hepatic toxicity/respiratory
depression, antitussive at subanalgesic doses (
cough med)
Opiods- Tramadol
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Centrally acting synthetic opiod analgesic- mild-moderate pain. Brand
names Tramal,Ultram)
Parent drug and metabolite bind to µ-opiod receptors. Also weak inhibition
of reuptake of nor adrenaline and serotonin( which is how antidepressants
work)
Side effects- dizziness, drowsiness, nausea, constipation, sweating, rashes
Caution- not for pts with liver disease (extensively metabolised there). Risk
OD esp if taken with alcohol/ other opiods- respiratory depression
Increased risk of seizure esp if used with antidepressants
Risk serotonin syndrome esp if taken with SSRIs (class of antidepressants)
Can get combined paracetamol and tramadol preps but don’t take both
(risk OD- liver damage)
Stronger Opiods
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Oxycodone (Oxycontin- slow release, Endone fast), fentanyl (Durogesic),
buprenorphine (norspan) ,morphine sulphate. Can get slow release most
types, and patches. Some patches last 7 days but may take 3 days to take
full effect on first dose. Different types bind more stongly to receptor or
unbind slower etc
Stronger activation of µ opiod receptor- mimics activity of endogenous
enkephalins and B endorphins. Decreased release of glutamate neurotransmitter/ excitatory/action potential formation at spinal cord.
Activates descending inhibitory pathways from brain (GABA)/ euphoria/
decreases affective component pain
Often prescribed for moderate- severe pain. No convincing evidence gives
greater relief of pain than NSAIDs (OASRI). Significant side effects: greater
degree of nausea and vomiting, drowsiness, dizziness,
constipation,respiratory depression, antitussive (decreased cough reflex),
constricts pupils, urinary retention, histamine release (rashes), tolerance(
larger doses required to give same effect- becomes a problem if need
surgery/ have a flare etc), physical dependence (withdrawal symptoms)
Glucocorticoids- Steroids- local
injection
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OASRI- short term ,4 weeks, relief good. No
evidence to support long term relief even when
given at regular intervals(OASRI)
See later on for mechanisms
Intra-articular hyaluronic acid
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Knee OA- less pain relief compared with
corticosteroid injection at 2 weeks, but superior
results at 4, 8, 12 and 26 weeks (OASRI)
No major adverse effects-mild local pain,
inflammation at injection site
Glucosamine
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Glucosamine sulphate and glucosamine
hydrochloride both break down to active ingredient
in stomach- glucosamine, so neither is superior
1500mg day 12 months associated with moderate
pain relief and decreased medial joint space
narrowing and rate TKR (OASRI). Issues studies
discussed in document
Chondroitin Sulphate
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Early evidence of reduced joint space narrowing.
Limited evidence of significant pain relief
(OASRI)
Avocado Soybean Unsponifiables
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Early evidence for mild- moderate pain relief- more
research required
(OASRI)
Vitamin E, Selenium, other antioxidants
etc
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Trials have been poor, no conclusions can be drawn
at this time. Includes green lipped mussel extracts,
rosehip powder
Only one good trial 150 knee OA pts with
nutritional supplement methylsofonylmethane
(MSM)- significant improvement in function and pain
on WOMAC after 12 week trial (OASRI)
Doxycycline
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Vibramycin-antibiotic!
Early studies showed it was structure modifying for
knee OA however recent triple blinded, placebo
controlled trial of 232 patients showed No effect on
reducing symptoms, increasing function over 24
week trial (short) but increased risk of adverse
effects
Annals Rheumatic Diseases (2011) 70(7) 1191-6
NICE Guidelines
Rheumatoid Arthritis/ Inflammatory
Arthritis
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NHRMC guidelines 2009
Worth mentioning that in top guidelines are EARLY
REFERRAL to specialist if: persistent joint swelling and
pain beyond 6 weeks> 3 joints, symmetrical involvement
of MCP or MTP joints or early morning stiffness >30
minutes. This ensures EARLY DIAGNOSIS and BEST
CLINICAL OUTCOME
NB like OA, this presentation only covering drug
treatments
Early treatment reduces risk of errosive damage to
joints  reduces risk of systemic complications (ie
atherosclerosis, lymphoma)
EARLY RA
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Simple analgesia- paracetamol, OMEGA 3 and
Gamma- linolenic acid supplementation
NSAIDs or selective COX 2 inhibitors where these
prove ineffective. NB risk vs benefit needs to be
explained to pt
Corticosteroids should be considered next- short
term, low dose oral course. This should be done with
consultation of Rheumatologist, and considering comorbidities, side effects etc
Glucocorticoids- steroids
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Glucocorticoids have an antiinflammatory and immunosuppressive action.
Short course orals eg. prednisolone prescribed in acute phases of
autoimmune disorders eg reactive arthritis, Lupus, RA, etc
These drugs work by interacting with intracellular receptors which then
move into the nucleus of the cell and interact with a superfamily of
receptors in the DNA that control gene transcription- they will increase
production of some proteins and decrease production of others. For
instance, inhibit genes for COX 2 enzyme/ decreased production of
prostoglandins involved in chronic inflammation. Inhibit genes for cytokine
release (eg Interleukins, NO)- so decreased response to inflammation.
Inhibit genes for adhesion to/ activation of inflammatory and immune cells.
Inhibit Vitamin D 3 mediated induction of osteocalcin gene in osteoblasts
and modification of transcription of collegenase genes( risk osteomalacia/
osteoporosis). Increase synthesis of Annexin-1 which is important in negative
feedback to hypothalamus and anterior pituitary so supresses release of
endogenous glucocorticoids- this may slow wound healing etc).
Glucocorticoids
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Metabolic effects- decreased uptake and utilisation
of glucose, increased gluconeogenesis so tendency
towards hyperglycemia. Consider diabetics etc.
Increased catabolism and decreased anabolism of
proteins- consider effects on growth in children/
tissue repair/muscle wasting/ thin skin. Fatspermissive effect on lipolytic hormones and
redistribution of fat to the abdomen.
Behavioural effects- increased aggression
Increased risk cataracts and glaucoma
Glucocorticoid injections
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Rapid relief target joints. Current recommendations
no more than 3 per year for a specific joint
DMARDs
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Disease Modifying Anti-Rheumatic Drugs
Act on the immune system or suppress the disease
process (chemotherapeutic agents)
Only under supervision of Rheumatologist due to
potential toxicity
Traffic light scheme for prescribing
Types of DMARDs
Drugs that suppress the
disease process
Drugs which affect the
immune process
Biological agents
Gold
Methotrexate
Infliximab
Penicillamine
Chloroquine
Etanercept
Sulfasalazine
Azathiorprine
Adalimumab
Ciclosporin
Abatacept
Lefluniomide
Anakinra
Rituximab
DMARDS- Methotrexate
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First line for moderate to severe disease or where high risk
of erosive disease “gold standard”
Anti-inflammatory and immunosuppressant activity
Antimetabolite cytotoxic agent
Folic acid antagonist
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inhibits DNA synthesis, antiproliferative agent
Inhibits inflammatory cells and enzymes like steroids
Inhibits immune cell proliferation ( immunosuppressive)
Increased production of adenosine-anti-inflammatory actions.
Fewer side effects than steroids
Can give folate as an adjunct and still works on disease.
DMARDs- Gold compounds
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Eg auranofin- oral, sodium aurothiomalate- IM
3-4 months to work
Mechanism unclear
Decreases joint swelling and pain
Slows progression joint damage
Side effects- 1/3 pts. Rashes, mouth ulcers,
polyneuropathy
DMARDs- Sulphasalazine
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Can cause remission in acute RA
Also used for chronic inflammatory bowel disorders
Scavenges toxic oxygen metabolites produced by
neutrophils in inflammation
Side effects- GIT irritation, malaise, headache,
rashes
DMARDS- Penicillamine
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Weeks to take effect
Decreases interleukin-1 production, decreases
collagen synthesis (NB thin skin, wound healing etc),
full mechanism unknown
Side effects- nausea and vomiting, decreased taste,
rashes
DMARDS- Cloroquinine
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Anti-malarial drug. Takes greater than 1 month to
work
Can cause remission in RA and SLE, but doesn’t stop
bony damage long term
Mechanism unclear
DMARDS- Biologicals
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Also called Therapeutic Monoclonal Antibodies
“imabs,omabs,iximabs,zumabs”- ending depends on source
of antibodies- mice, humans
Antibodies to TNF cytokines. Bind to Interleukin-1 and TNF
and inhibits effect on T cells. Also target gene signalling
pathways. Inhibits Interleukin 2 production.
Side effects- few. Rarely blood dyscrasias and
demyelinating CNS disorders, kidney toxicity
NB long term use- decreased host defence/ increased risk
of infections and malignancies.
$20,000/year, lifelong, need to have failed methotrexate
+ one other drug for 6 months to be eligible
NICE Guidelines
Osteoporosis
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ANTIREABSORPTIVE AGENTS
 Biphosphonates
 SERMS
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Selective Oestrogen Receptor
Modulators
BONE ANABOLIC AGENTS
 Parathyroid
Hormone
 Oral calcium Salts
 Vitamin D- Calcitriol
 Calcitonin Hormone
 Strontium
Biphosphonates
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Eg Alendronate (Fosamax)
These drugs are enzyme resistant analogues of pyrophosphate (P-O-P) not hormones
Incorporated into the bony matrix and ingested by osteoclasts there. Accumulate at the sites of
bone mineralisation and remain there for some time (usually a weekly dose)
Inhibit the recruitment of more osteoclasts
Promote apoptosis of osteoclasts
Also used for bone pain from metastases eg breast cancer, multiple myeloma and Pagets Disease
NB Poor oral absorption therefore very important to take on an empty stomach. Pts encouraged
to stay upright after taking to avoid oesophageal and gastric irritation. Other drugs must be
taken at least 30 minutes before as they can interfere with this drug’s absorption, including
calcium supplements
Proven efficacy in decreasing #risk at hip and spine
Contraindications- renal insufficiency, oesophagitis, motility disorders, gastric ulcers
Side effects- nausea, vomiting, gastric irritation, constipation
NB. Ongoing monitoring- read Schilcher et al (2011). Biphosphonate use and atypical fractures
of the femoral shaft. N Eng J Med 364(18)1728-1737 and Park-Wyllie et al (2011).
Biphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women.
JAMA 305(8)783-789.
SERMS
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Eg Raloxifene (Evista)
These drugs prevent accelerated bone loss in the immediate post menopausal period and
at least transiently increase bone density
Decrease bone reabsorption by decreasing osteoclast proliferation and activation/
recruitment
Increase osteoclast apoptosis
Increase lifespan of osteoblasts and osteocytes
Old “HRT” oestrogens were associated with an increased risk of uterine and breast
cancer. Newer selective type are agonists at oestrogen receptors in bone and
cardiovascular tissue, antagonists at breast and uterine receptors (ie reduced risk here).
NB Not absolutely risk free. Largely replaced traditional “HRT” in treatment of post
menopausal osteoporosis
Daily tablet. Encouraged to take at same time every day
Common side effects- often settle in first 6 months- hot flushes, leg cramps, swelling of
hands, feet and ankles, joint pains, insomnia. DVT-rare but may be advised to stop taking
before overseas flights, operations etc
Contraindications- liver disease
May be taken with Vitamin D and Calcium but NOT with alendronates and Strontium. Not
to be taken with other oestrogens (except some patches)
Parathyroid hormone
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Eg Teriparatide (Forteo)- recombant parathhyroid hormone
Anabolic agent that activates osteoblasts and stimulates bone
formation. Used in combination with calcium and Vitamin D as
required
PBS for pts at very high risk of # (BMD T score –0.3)or develop 1or
more #s despite 12 months of anti-reabsorptive agents or 2 or more
#s with minimal trauma
Daily injection- 18 months max treatment as risk of osteosarcoma
(avoided if history Pagets, hyperparatyhroid, XRT, sarcoidosis etc).
Initiated by specialist but can be continued by GP
Side effects- nausea, headache, joint pain, dizziness, injection site
reactions, transient hypercalcemia first dose (CNS depression)
Oral Calcium Salts
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Eg Caltrate
For treatment of low serum calcium- symptoms- tetany, cramps
Conditions- hypothyroid, kidney disease etc can predispose to this as
well as poor diet etc
Adjunctive treatment in osteoporosis- not as effective as SERMS plus
weight bearing exercise/ weights in preventing bone loss. Often
given with Vitamin D and phosphates
Side effects- gastric irritation. Take with meals or milk for maximum
absorption. Drug interaction- digoxin. Take 30 mins after
biphosphonates(impairs absorption of these)
Calcium levels must be monitored- hypercalcemia may cause
vascular and other soft tissue calcification
Vitamin D- Calcitriol
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If deficient in Vitamin D in blood tests eg Ricketts,
osteomalacia, dark skinned people, poor light exposure,
hypoparathyroid, chronic renal impairment AND
demonstrated reduced bone density- proven benefit
Taken with calcium salts if deficient
Overdose- hypercalcemia- muscle aches and weakness,
nausea, constipation,CNS depression, coma. This can happen
when pts are given an initial large loading dose then don’t
turn up for follow up monitoring/ blood tests
Vitamin D 3 in cod liver oil tablets, however often combined
with Vitamin A which has been associated with higher # risk
in epidemiological studies and is also toxic in large doses
Examples- ergocalciferol (Ostelin), cholecalciferol
Calcitonin
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Hormone- bone anabolic agent. Natural hormone produced in thyroid
Extra calcitonin can be given as a treatment- can be porcine or synthetic
Subcutaneous or intramuscular injection, nasal spray preparations eg
miacalcin
Decreases calcium mobilisation from bone so decreases serum calcium ( also
used for hypercalcemic states associated with thiazide treatment,
hyperparathyroid, neoplasms, sarcoidosis)
May also relieve pain of vertebral osteoporotic #s
Inhibits osteoclasts so used in osteoporosis, however long term INHIBITS
bone formation AND bone reabsorption- regular monitoring required eg
blood tests, bone density scans etc
Side effects- allergy type- rash, dizziness etc
Drug interactions- Lithium
Strontium
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Eg Protos- sachet in water at least 2 hours after milk/food.
Usually taken at bedtime
Increases bone formation and decreases bone reabsorption
SOTI and TROPOS trials
Over 1000 pts in each trial
Significantly reduces the incidence of vertebral and hip
fractures in at risk populations
30% reduction risk >80 yrs population
Side effects- nausea, diarrhoea,? Slight increased risk DVT
Gout
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ACUTE PHASE
 NSAIDs-
usually indomethacin (indocid)
 Glucocorticoids
 Colchicine
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CHRONIC PHASE
 Colchicine
 Allopurinol
 Probenecid
and sulfinpyrazone
Colchicine
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(colcrys)
Prevents leucocyte migration into joints. The leucocytes engulf the
uric acid crystals in the synovium by phagocytosis to form tophi
Effective in acute flares of gouty arthritis
Also used as a preventor- decreases number of flares
Drug interactions- several drugs ( including common antibiotics and
blood pressure meds) interfere with clearance of colchicine- inhibit
the enzymes that break it down. So these patients may require a
smaller dose of the drug and titrate up.
Side effects- muscle breakdown (rhabdomyolosis) combining with
statins will increase risk of muscle aches, nausea and vomiting ,
diarrhoea initially, hair loss, anaemia and low white blood count
(affects bone marrow), increased risk of infection
Allopurinol
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(zyloprim)
Decreases synthesis of uric acid by inhibiting xanthine oxidase
enzyme (converts hypoxanthine derived from purines in diet to
xanthine then to uric acid). It decreases formation of tophi and can
decrease number of flares (preventor). Increased uric acid levels can
also cause kidney stones
Side effects- rash ( increased risk if taken with penicillins)/ drug
allergy
Drug interactions- immunosuppressive drugs (eg azathioprine,
mercaptopurine) are metabolised by xanthine oxidase, so there will
be decreased clearance- the dosage of these drugs is decreased
accordingly if given with allopurinol
Probenecid, Sulfinpyrazone
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Uricosuric agents- increase uric acid excretion by
the kidneys
Probenecid- benuryl,benemid,probalan
Drug interactions- dercreased clearance of many
NSAIDs, antibiotics and some BP medications
Side effects- may initially cause flares, so used in
chronic conditions when on preventors, increased risk
kidney stones so drink plenty of fluids with
References
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Osteoarthritis Research Society International
(OARSI) guidelines 2010- based on current
evidence available. Updated annually. Available
on-line
(NICE) National Institute for Clinical Excellence OA
guidelines 2008 (UK)
NICE RA guidelines 2009 (UK)
NHRMC (National Health and Medical research
Council)- Australian guidelines