Pharmaco: Gout Flashcards
Drugs used for acute gouty arthritis:
- NSAIDs (e.g., Naproxen, Indometacin)
- COX-2 selective NSAIDs (e.g., Celecoxib)
- Glucocorticoid (e.g., Prednisolone)
- Colchicine
No role for paracetamol in gout
Drugs used for prevention of gouty arthritis:
Urate-lowering therapy:
- Xanthine-oxidase inhibitors (Allopurinol, Febuxostat)
- Uricosuric agents (Probenecid)
NSAIDs use in acute gouty attack:
- Indication
- Inhibit production of prostaglandins and urate crystal phagocytosis
- Begin within 24-48h of flare onset
NSAIDs use in acute gouty attack:
- Choice of NSAID
Choice of NSAID:
- Naproxen (may be preferred due to long half-life 12-24h, dose 1-2 times daily)
- Indomethacin (additional benefit due to broader spectrum of anti-inflammatory action via additional steroid-like phospholipase A2 inhibition which can reduce pdn of leukotrienes)
- Celecoxib (COX-2 selective NSAID)
NSAIDs use in acute gouty attack:
- Which NSAID is contraindicated
Low-dose aspirin, salicylates are CONTRAINDICATED due to anti-uricosuric action (dcr uric acid excretion, incr chance of hyperuricemia)
NSAIDs use in acute gouty attack:
- Renal impairment
Not suitable for patients with CrCl <30ml/min or for prolonged duration (not for prophylaxis use)
Glucocorticoids use in acute gouty attack:
- dosage form
Prednisolone can be used oral or intra-articular injection
IM injection may be considered as well
Glucocorticoids use in acute gouty attack:
- Renal impairment
May be choice of drug for acute gouty attack in renal impairment since NSAIDs not suitable, Colchicine need to reduce dosing/increase dosing interval
Colchicine use in acute gouty attack:
- MOA
- Binds to tubulin
- Prevent tubulin polymerization into microtubules, disrupt cytoskeletal structure of cells, therefore disrupts cell division/proliferation (not just affect immune cells)
- Inhibit leukocyte migration and phagocytosis of urate crystals
- Inhibit leukotriene B4 (LTB4) and prostaglandin (PG) production, therefore reducing the positive feedback of inflammation
Colchicine use in acute gouty attack:
- Indication
Reduces pain and inflammation in acute gouty attack within 24-36h
If >36h, colchicine becomes less effective because phagocytosis has already started, too many cytokines and lysosomal enzymes released (NSAIDs and steroids might be better options)
Onset of colchicine may take some time, can give 1-2 doses of corticosteroids first
Colchicine use in acute gouty attack:
- Side effects
- GI SEs: Diarrhea, nausea, vomiting, abdominal pain
- Muscle weakness
- Unusual bleeding
- Pale lips
- Change in urine amount
- Hair loss
Colchicine use in acute gouty attack:
- Explain the mechanism of Colchicine SEs
- Thus, the SEs are ________
Inhibition of microtubule polymerization, at higher conc. affect cell division and proliferation of rapidly proliferating cells (cells along walls of GIT are rapidly proliferating cells)
- Therefore, cause GI SEs such as diarrhea, nausea, vomiting, abdominal pain
Similar mechanism with the other SEs (e.g., changes in proliferation of blood cells cause unusual bleeding, pale lips)
Thus the SEs are dose-limiting adverse effects - higher doses and longer duration of use cause stronger inhibition of microtubule polymerization, and hence increase frequency of adverse effects
Colchicine use in acute gouty attack:
- DDIs
Colchicine is a major substrate of CYP3A4 and P-glycoprotein
- Macrolides - CYP3A4 inhibitor, Pgp Inhibitor (incr serum conc. of colchicine)
- Azoles - CYP3A4 inhibitor, Pgp Inhibitor
- Statins - CYP3A4 substrate (incr serum conc. of each other)
- Verapamil - CYP3A4 inhibitor, Pgp Inhibitor
- Diltiazem - CYP3A4 inhibitor
Colchicine use in acute gouty attack:
- Renal impairment
- Hepatic impairment
Renal or hepatic impairment:
- Both renal and hepatic impairment increase risk of colchicine toxicity including myopathy, neuropathy, pancytopenia (low RBC, WBC, and platelets)
- Consider reducing colchicine dose or increasing dosing interval in renal impairment as it increases the risk of colchicine toxicity
What combination of drugs may be used in acute gouty attack?
- Colchicine + NSAID/Coxib/Prednisolone
- Avoid NSAID + Steroids (due to incr risk of PUD/GI bleed)
Xanthine oxidase inhibitors use in prevention of gouty attack:
- Difference between Allopurinol and Febuxostat
Both are 1st line, allopurinol more often use due to familiarity and cost
Allopurinol:
- Purine analog (imidazole in hypoxanthine/xanthine to pyrazole), competitive inhibitor of XO
Febuxostat:
- Synthetic non-competitive inhibitor of XO
MOA: decrease uric acid synthesis/production (anti-hyperuricemic agents)
Xanthine oxidase inhibitors use in prevention of gouty attack:
- Indications
- Debilitating gout attacks
- Chronic erosive arthritis
- Urate nephrolithiasis (kidney stones)
Xanthine oxidase inhibitors use in prevention of gouty attack:
- Side effects (Allopurinol and Febuxostat)
- Skin rash
- N/V
- Diarrhea
- Fever
- Sore throat
- Stomach pain
- Liver injury (rare) - dark urine, light stools, jaundice
- Febuxostat: headache, edema, muscle pain, joint pain
Xanthine oxidase inhibitors use in prevention of gouty attack:
Allopurinol metabolism and implications
- Renal metabolism, therefore lower dose used in renal impairment
Xanthine oxidase inhibitors use in prevention of gouty attack:
Safety concerns for Allopurinol
- What are the risk factors?
Hypersensitivity syndrome: risk of severe cutaneous adverse reaction (SCAR), most occur within first few weeks to 3 months after initiation
- SJS, TEN: fever + mucocutaneous lesions leading to necrosis and sloughing of the epidermis
- DRESS: rash + fever + multiorgan failure (e.g., liver, kidneys, heart lungs)
Risk factors: RASHES
- Renal impairment (CrCl <60ml/min)
- Agent (e.g., concomitant diuretic - loop/thiazide, ACEi, ampicillin/amoxicillin)
- Starting dose (high starting dose)
- HLA-B*5801 genotype (common in Hans Chinese, Thai, Korean popln) - not routinely tested due to low PPV and lack of alternative cost-effective ULT option
- Escalation (rapid dose escalation)
- Seniority (older age)
Testing of the allele may be more useful for pt alr at higher risk of SCAR
Xanthine oxidase inhibitors use in prevention of gouty attack:
Safety concerns for Allopurinol
- What should be counseled to the patient?
Patient education and monitoring esp in the first 3 months, look out for:
- Flu-like symptoms: fever, body ache, unwell
- Mouth ulcers, sore throat
- Red or sore eyes
- Rash
*Stop the med
*Photograph the rash
*Inform Dr
Pt started on Febuxostat should be counseled on this as well
Xanthine oxidase inhibitors use in prevention of gouty attack:
Contraindication for Allopurinol
Contraindicated in pt with previous hypersensitivity to allopurinol
Xanthine oxidase inhibitors use in prevention of gouty attack:
DDI with Allopurinol
Increase bone marrow suppression due to incr conc. of:
- 6-mercaptopurine
- Azathioprine
- Cyclophosphamide
Increase hypersensitivity rxn/toxicity of allopurinol with: (Agents)
- ACEi
- Loop diuretics
- Thiazide/thiazide-like diuretics
- ampicillin/amoxicillin
Monitor treatment due to increase conc of:
- Carbamazepine (incr ADR)
- Warfarin (incr bleeding)
- Theophylline (incr ADR)
Increase adverse/toxic effect of:
- Pegloticase (not used in Sg)
What to do?
- Consider removing the agent/switch to alternative
- Consider switching from Allopurinol to Febuxostat
- Consider monitoring therapy (if neither can be done)
Xanthine oxidase inhibitors use in prevention of gouty attack:
Febuxostat metabolism and implications
Liver metabolism
Xanthine oxidase inhibitors use in prevention of gouty attack:
Safety concerns for Febuxostat
Lower risk of SCAR than Allopurinol
- Still need to educate patient to monitor for S&S
Higher risk of death in patient with gout AND major cardiovascular disease
- Use with caution if patient has major CVD (previous MI, stroke, unstable angina, HF, CHD)
- (Healthhub) Blood clot in the vessels - possible symptoms include severe chest pain with extreme sweating, severe headache, severe giddiness, passing out, change in strength on different sides of the body, difficulty speaking or thinking. These suggest heart attack and stroke.
Probenecid (uricosuric agent) use in prevention of gouty attack:
- MOA
Solute carrier family 2 and 22 inhibitor; URAT1 and GLUT9 inhibitor
- Inhibits proximal tubule anion transport
- Inhibits uric acid reabsorption
- Increase uric acid excretion
Probenecid (uricosuric agent) use in prevention of gouty attack:
- Indications
Start 2-4 weeks after an acute attack
May be used if allopurinol is contraindicated in tophaceous gout, or in increasingly frequent gouty attacks
Probenecid (uricosuric agent) use in prevention of gouty attack:
- Side effects
- Nausea and vomiting
- Painful urination
- Lower back pain
- Allergic reactions
- Rash
Probenecid (uricosuric agent) use in prevention of gouty attack:
- Safety concerns
- Risk of hemolytic anemia in pt with G6PD deficiency
- Renal impairment (not recc in pt with CrCl <50ml/min)
- Not effective in pt with CKD
Probenecid (uricosuric agent) use in prevention of gouty attack:
- Precautions
- Take plenty of fluid (>=2L of water) to prevent kidney stones (urolithiasis) from forming
- Keep urine pH >6.0 to reduce risk of kidney stone formation by coadministration of alkalinizing agent e.g., potassium citrate
this is conditionally recommended against, need not coprescribe alkalinizing agent due to lack of evidence for efficacy
Probenecid (uricosuric agent) use in prevention of gouty attack:
- Contraindication
Contraindicated in pt with hx of urolithiasis
Not effective in CKD, not recommended in pt with CrCl <50ml/min
