Muskuloskeletal - Gout Flashcards
Describe gout.
Gout is an arthritic condition characterised by the precipitation of monosodium urate crystals at joints leading to inflammation and pain
What is the drug related aetiology of gout?
ACEi/ARB
Diuretics
Immunosuppressants: ciclosporine, tacrolium
Abx used for TB: pyrazinamide, ethambutol
Levodopa
Salt restriction
Nicotinic acid
What is the pathophysiology of gout?
Gout is poorly soluble at physio pH - 6.8mg/dL –> predisposes to ppt
Imbalance in purine meta –> uric acid
1. Overpdtn of uric acid
- Primary: inborn errors of meta
- Secondary: conditions that increase cell turnover and purine generation
2. Under excre of uric acid (90%)
At physio pH, it deprotonates, binds to sodium to form monosodium urate crystals
MSU crystals mobilise from joints to synovial fluid
MSU crystals are a DAMP –> sensed by body, immunce cells activated
Phagocytes (macrophages, monocytes, neutrophils) phagocytose MSU crystals
- Lysis and activation of neutrophils –> release lysosomal enzymes –> destroy neutrophils –> damage joints
- Phagocytosis by monocytes results in release of TNF, IL-1, IL-6
+ve feedback loop (more & more neutrophils recruited to phagocytose crystals, intense acute inflamm resp & pain)
What are the risk factors for gout?
Age
Male
Purine rich diet
High fructose corn syrup
HTN
DM
Alc
Smoking
Sedentary lifestyle
Obesity
Drugs
Describe the epidemiology of gout
Most common in dev countries
Common in >40y.o.
M:F=5:1
Occurrence in male <30y.o. & premenopausal women REFER
- Suggest inherited enzyme defect or presence of renal disease
What are the signs and symptoms of gout?
Asymptomatic hyperuricaemia does NOT equate to gout
Signs:
MSU crystals in joint aspirate
Tophi = tissue growth ard MSU crystal dep in soft tissue near joints
Serum uric acid >6.8 mg/dL
Asymmetrical monoarthritis
- Usually @ first MTP of big toe, possible midfoot, ankle, knee, hand, wrist, elbow
Joint destruction
Nerve compression syndrome
Kidney stones
Gouty nephropathy
Symptoms:
Waking w severe pain
Erythema +++
Warmth
Tenderness +++
Joint swelling+++
More likely in wee hours of morning (when it’s cold)
At joints with poorer blood flow to clear uric acid (commonly first MTP of big toe)
What are the goals of therapy?
Rapid, safe, effective pain relief
Reduce the recurrence of acute gout flares
- Lower uric acid levels
Prevent joint destruction and tophi formation
Increase QoL
Address assoc comorbidities
What are the principles of pharmacological management?
Acute gout flare:
1st line - Colchicine (leukocyte motility inhib)
- Most specific and potent for acute gout flare
- Give within 24-36h of onset of acute gout flare otherwise give adjunct
Adjunct - NSAIDs, intraarticular glucocorticoid
- Good for anti-inflamm and analgesic (NSAIDs only) but not most potent and specific agent
If already on ULT at time of gout flare, continue.
ULT:
Criteria for ULT
->=2 flares a year
- Presence of tophi
- Clinical imaging or radiographic evi of MSU crystals
-
When to initiate
- 2-4 weeks after resolution of acute gout flare
- UNLESS no good time to start (flares too freq), pt unlikely to return to collect tx, pt highly motivated for tx
Target
- Non-tophaceous gout: <360 micromol/L (<6 mg/dL)
- Tophaceous gout: <300 micromol/L (<5 mg/dL)
1st line: Uric acid synth inhib/xanthine oxidase inhib
- Allopurinol > Febuxostat
- Allopurinol higher risk of SCAR
- Febuxostat a/w MACE
- Add on colchicine/low dose PO NSAID or coxib/low dose PO corticosteroid (to manage ppt of gout flare) - for 6mo
Colchicine 0.5 mg once daily
Celecoxib 200mg once daily
Prednisolone 5-7.5 mg once daily
2nd line Uricosuric agents
- Probenecid
- Rarely used nowadays
- Initiate w same combi for acute gout flare as xanthine oxidast inhib
What is the typical duration of ULT?
Clinical remission >= 1y without flares and no tophi
Only 13% w SU<7mg/dL hv no recurrent flares during 5y follow up after stopping ULT
If pt is tolerable to ULT, not bothersome, can hv pref to cont or stop (shared decision making)
What are the non-pharm recommendations for gout?
Limit purine rich food
Limit high fructose corn syrup
- E.g. juice, soda
Maintain healthy diet
- Include more veg e.g letuce, radish
- Include more low fat dairy pdts
Drink plenty of fluids (>=2L, unless on fluid restriction)
Wt management
Limit alc
Smoking cessation
Exercise reg except during acute flare (rest)
Ice during acute flare
List some purine rich food
Meats: Red meat, meat extract (broth), organ meats
Seafood: Sardines, mackerel, salmon, herring, anchovies (ikan bilis), prawn, cockles, mussels, clams, scallop, fish roe
Fruits: strawberry, durian
Others: asparagus, cauliflower, mushroom, peanuts, bean cake
What are some med review considerations?
Switch thiazides to diff anti-HTN (it decreases urate excre)
Losartan is the preferential anti-HTN
- ACEi & ARBS are uricosuric
Do NOT stop low dose aspirin if indicated (despite it increasing urate reabsorption)
Do NOT switch anticholesterol med to fenofibrate (despite fenofibrates uricosuric effect)
Describe the MOA of colchicine
Colchicine is a leukocyte motility inhibitor. It blocks tubulin polymerisation into microtubules. Inhib leukocyte migration and phagocytosis. Inhib pdtn of leukotriene B4 (LTB4) and PG
What are the S/E assoc w colchicine?
Common
GI: NVD, abdo cramping
Rare but srs
MSK: muscle weakness, paresthesia
Haem: unexplained bleeding, pale lips
Endocrine: change in urine output
Hepatic: dark coloured urine, jaundice
What is the recommended dosing w colchicine
Acute
1mg loading dose, f/b 0.5mg one hour later OR
0.5 mg BD-TDS until flare resolves
ULT
0.5 mg once daily
What are the DDI assoc w colchicine?
CYP3A4 inhib:
Macrolides, azole antifungals, antivirals, non-DHP CCB, grapefruit juice
CYP3A4 inducers:
CBZ, PHT, PB, rifampicin, St John’s wort
Statins: (bidirectional increase in serum [ ]), potentiate rhabdomyolysis
What are the cautions assoc w colchicine?
Hepatic impairment
Renal impairment
- Reduce dose, prolong interval
Pregnancy and lactation XX
Blood dyscrasias
Describe the PK of colchicine.
A:
- F ~45%
D:
- Vd: 5-8L/kg
- Protein binding ~39%
M:
- Substrate of CYP3A4, P-gp
E:
- t1/2: 27-31h
- 40-65% xcre in urine as unchanged drug
- Enterohepatic recirc
Describe the MOA of allopurinol and febuxostat
Allopurinol and febuxostat are xanthine oxidase inhibitors, the enzyme involved in conversion of purine to uric acid –> decrease uric acid pdtn
Allopurinol is a competitive inhib (purine analogue) while febuxostat does not resemble purines
Describe the dosing of allopurinol
Ini: <=100 mg once daily
Titration: Increments of 50-100mg Q2-8 weeks
Usual maintenance: >300mg/d (ok for renal impairment)
Max: 800-900 mg/d (normal renal fn)
Describe the dosing of febuxostat
Ini: 40mg/d
Titration: 80mg/d if not at target after 2-4 weeks
What are the S/E of the uric acid synth inhib?
Common
GI: NVD, abdo cramping
Rare but srs:
SCAR-SJS, TEN, DRESS
Hepatotoxicity: dark urine, jaundice, pale stools
Febuxostat:
- CNS: headache
- MSK: muscle weakness, joint pain
- a/w MACE
What are the risk factors of SCAR?
Onset: usually within first 3mo of ini
Renal impairment <60mL/min
Agent concomitant w diuretics
Starting dose (high)
HLA-B*58:01 positive
Escalation (rapid)
Seniority
What are the cautions w the uric acid synth inhib?
CI: concomitant pegloticase
Hypersensitivity
Pregnancy and lactation XXX
Hepatic impairment
Renal impairment
What are the DDI assoc w uric acid synth inhib?
Increase bone marrow suppression: 6-Mercaptopurine, Azathioprine, cyclophosphamide
Increase hypersensitivity w:
ACEi, diuretics Ampicillin, amoxicillin
Increase serum [ ] levels of:
CBZ, warfarin, theophylline
Pegloticase - CI
Describe the MOA of probenecid
Inhib of solute carrier 2 and 22
Inhib PCT anion reabsorption –> inhib uric acid xcre
Describe the dosing of probenecid
Ini: 250 mg BD x1/52, f/b 500mg BD
Titration: 500 mg increments Q4 weeks as tolerated if sx persist
Usual maintenance: <=2 mg/d
Max: 3000 mg/d
What are the S/E assoc w probenecid?
Common
GI: NVD, abdo cramping
CNS: headache
Skin: flushing
Endocrine: Urolithiasis
Rare but srs
Hypersensitivity: angioedema, rash
Haem: hemolytic anaemia
What are the DDI assoc w probenecid?
Paracetamol
- Probenecid increases paracetamol [ ]
Increases serum [ ] of:
Methotrexate, beta-lactam abx, NSAIDs
Pegloticase CI
Decrease probenecid efficacy:
salicylates
What are the cautions w probenecid?
Urolithiasis
Hypersensitivity
Blood dyscrasias
Children <2y.o.
Caution:
Renal impairment <50mL/min NOT reco
CKD NOT effective
G6PD def
PUD
