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Gout - Coggle Diagram
Gout
Colchicine
MOA:
Inhibits β-tubulin polymerization into microtubules, preventing activation, degranulation, and migration of neutrophils associated with mediating some gout symptoms
PK/PD:
A: Onset of action - (oral) - 18-24h
D: Concentrates in liver, spleen, kidney and leukocytes. NOT in heart, skeletal muscle and brain; Vd - 5-8 L/kg
Protein binding - ~39%
M: Hepatic metabolism - CYP3A4 + glucuronidation
Bioavailability: ~45%
Half-life - 27-31h
E: Urine (40-65% unchanged)
Special Population:
Dosage adjustment needed in elderly + use with caution; colchicine crosses the placenta and present in breast milk
Pearls:
Hazardous drug; narrow therapeutic range - close monitoring needed for toxicity
Monitoring:
CBC; renal; hepatic functions; adverse reaction related to toxicity
DDI:
(Class X: Avoid Combo) - Abametapir; Antihepaciviral Combination Products; Conivaptan; CYP3A4 inhibitors; Fusidic Acid; Idelalisib; Lasmiditan;
(Class C: Monitor Therapy) - Choline C 11; Clofazimine; Cyanocobalamin; Digoxin; Erdafitinib; Fibric Acid Derivatives; Fosaprepitant; HMG-CoA Reductase inhibitors; Larotrectinib; Lumacaftor and Ivacaftor; Multivitamins; Palbociclib; Tacrolimus
Class D (Consider Therapy Modification) - Tipranavir; Stiripentol; P-glycoprotein/ABCB1 Inhibitors; MiFEPRIStone; Fosamprenavir;
AE:
diarrhea, nausea, vomiting (all dose-related with fast onset)
Dosing/Indication:
For gout ppx and tx at first sign of flare
Dose (ppx): 0.6 mg once or twice daily (maximum: 1.2 mg/day). In patients with GI intolerance, some experts give 0.6 mg every other day
Duration:
Patients without tophi:
3 to 6 months after achieving target serum uric acid levels with urate-lowering therapy
Patients with ≥1 tophi
: Optimal duration is unclear; some experts continue colchicine therapy for 6 to 12 months after achieving target serum uric acid levels with urate-lowering therapy and resolution of tophi, unless it is clear that tophi will not resolve despite persistent normal urate levels
Dose (Tx):
Day 1
- 1.2 mg at the first sign of flare, followed in 1 hour with a single dose of 0.6 mg OR 0.6 mg 3 times daily on the first day of flare; maximum total dose: 1.8 mg
Day 2 + thereafter
- 0.6 mg once or twice daily until flare resolves
Xanthine Oxidase Inhibitors
Allopurinol
MOA
: reduce uric acid by Impairing ability of xanthine oxidase to convert hypoxanthine to xanthine and xanthine to uric acid
AEs
: allopurinol hypersensitivity syndrome, skin rash, leukopenia, GI problems, headache, uticaria
Significant!!
Acute gout attacks
possible during early stages of allopurinol administration. When initiating urate-lowering therapy such as allopurinol, anti-inflammatory prophylaxis is generally recommended for 3 to 6 months to reduce risk of gout attacks.
Acute hepatotoxicity
with allopurinol are associated with drug reaction with eosinophilia and systemic symptoms (DRESS) and allopurinol hypersensitivity syndrome
Hypersensitivity reactions (delayed)
- ranging from mild maculopapular rash to severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS)
adherence Is low
risk of allopurinol hypersensitivity reaction (HLA-B*5801 allele positive)
severe rash, hepatitis, Interstitial nephritis, eosinophilia
1:1000 patients, 20-25% mortality
HLA-B*5801 screening in patients at elevated risk of SCAR, including patients of Asian descent (eg, Korean, Han Chinese, Thai) and African American patients
Initial dose
: Initiate 100 mg daily; titrated every 2-5 weeks to achieve desired serum uric levels;
Maintenance dose
: ≥300 mg/day needed to reach the desired uric acid target; doses up to 800 mg/day may be required
Renal Impairment
eGFR >60 mL/minute: No dosage adjustment necessary
eGFR ≤60 mL/minute: Initial: <100 mg daily; to lower the risk of AHS, some experts recommend not exceeding an initial dose of ~1.5 mg of allopurinol per mL/minute of eGFR (eg, for an eGFR of 50 mL/minute/1.73 m2, the initial dose should not exceed 75 mg daily)
Monitoring
: CBC; serum uric acid levels after every dose titration until desired level, then every 6-12 months, LFTs, renal function (BUN, serum creatinine, or creatinine clearance [prior to initiation and periodically]), prothrombin time. Monitor hydration status, signs/symptoms of hepatotoxicity, and signs/symptoms of hypersensitivity reactions, including severe cutaneous adverse reactions (SCAR). Consider HLA-B*5801 testing prior to initiation of therapy in patients of Southeast Asian descent
Goal during therapy for gout: <6 mg/dL; <5 mg/dL in patients with severe gout (eg, tophi, frequent attacks, chronic arthropathy)
PK
Onset of action: 2 to 3 days; peak effect: 1 week or longer; normal serum urate levels achieved typically within 1 to 3 weeks
A: Oral: 90% from GI tract
M: Rapidly oxidized to active metabolites, primarily oxypurinol
t1/2: Parent drug: ~1 to 2 hours; Oxypurinol: ~15 hours
E: Urine (76% as oxypurinol, 12% as unchanged drug); feces (~20%)
Febuxostat
MOA
: reduce uric acid by Impairing ability of xanthine oxidase to convert hypoxanthine to xanthine and xanthine to uric acid
Dosing
: Initial: 40 mg once daily; increase to 80 mg once daily in patients who do not achieve a serum uric acid level <6 mg/dL after 2 weeks. The dose may be increased further to 120 mg once daily
Renal Impairment
Mild to moderate impairment (CrCl 30 to 89 mL/minute): No dosage adjustment necessary.
Severe impairment (CrCl <30 mL/minute): Maximum dose: 40 mg once daily.
Warnings
: BBW for CV deaths compared to allopurinol, hepatic failure (fatal and nonfatal), Hypersensitivity and serious skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS) have been reported, particularly in patients with prior skin reactions to allopurinol
Monitoring
: LFTs at baseline and periodically; serum uric acid levels (as early as 2 weeks after initiation, after each dosage titration), then every 6-12 months; signs/symptoms of cardiovascular events; signs/symptoms of hypersensitivity or severe skin reactions
Goal during therapy: <6 mg/dL; <5 mg/dL in patients with severe gout (eg, tophi, frequent attacks, chronic arthropathy)
BBW
: Cardiovascular death
PK
A: ≥49%
D: ~50 L
Protein binding: ~99%, primarily to albumin
M: Extensive conjugation via (UGTs) 1A1, 1A3, 1A9, and 2B7 and oxidation via cytochrome P450 (CYP) 1A2, 2C8, and 2C9 as well as non-P450 enzymes. Oxidation leads to formation of active metabolites
E: Urine (~49% mostly as metabolites, 3% as unchanged drug); feces (~45% mostly as metabolites, 12% as unchanged drug)
t1/2: ~5 to 8 hours
Management of hyperuricemia In gout
Goals
terminate acute attack
prevent recurrent attacks
prevent complications associated with chronic deposition of urate crystals in tissues
IL-1 Inhibitors
Kineret (anakinra)
MOA
: Block IL-1 alpha/beta to reduce inflammation, degradation of cartilage, and stimulation of bone resorption
Dosing
(off label use when conventional therapy is ineffective, contraindicated, or not tolerated) 100 mg subq once daily (most patient received therapy for 3 days)
Special Populations
Administer every other day in ESRD; no hepatic dose adjustment; Increased risk of serious infection in RA patients; screen for TB prior to initiation; up to date vaccinations prior to initiation; Discontinue once pregnancy is confirmed
Side Effects
Headache, vomiting, antibody development, infection, injection site reaction
Monitoring Parameters
CBC w/ differential (baseline, monthly for 3 months, then q3 months for up to 1 year); TB test (baseline); SCr; S/s of infection
PK/PD
highly bioavailable; T1/2 4-6h
Ilaris (canakinumab)
Special Populations
: crosses the placenta; screen for TB prior to initiation; up to date vaccinations prior to initiation; no renal/hepatic dose adjustments
PK/PD
: onset of action ~week; T1/2 ~26 day
MOA
: Block IL-1 beta to reduce inflammation by preventing interactions with cell surface receptors
Side Effects
: weight gain, diarrhea, gastroenteritis, nausea, upper abdominal pain
Dosing
(off label use when conventional therapy is ineffective, contraindicated, or not tolerated) 150 mg subq as a single dose
Monitoring Parameters
CBC w/ differential; CRP; serum amyloid protein A (SAA); signs of infection; TB test (baseline)
Uricosurics
Probenecid
MOA
: competitively inhibits active reabsorption of irate at the proximal renal tubule to increase the urinary excretion of uric acid and lowers serum rate concentrations
AEs
: SJS, aplastice anemia, leukopenia, neutropenia, thrombocytopenia, hepatic necrosis, anaphylaxis, nephrotic syndrome (rare), flushing, dizziness, HA, alopecia, rash, GI upset, polyuria
PK/PD
: rapid & complete systemic absorption; hepatic metabolism; renal excretion
DDIs
may increase serum acetaminophen, and may reduce clearance of acetaminophen to one of its non-toxic metabolites which may increase risk for acetaminophen toxicity, even at lower doses.
Consider limiting acetaminophen use with probenecid
May affect the serum concentrations of several ABX, NSAIDs, sulfonylureas, and other, so check for interactions
may increase serum concentrations of methotrexate. Try to avoid concomitant use, but if use together, consider lower MTX doses and monitor for MTX toxicity
Dosing
: 250mg PO BID x 1 week; may increase to 500mg BID; if needed, may increase to max of 2 g/day (increase dosage in 500 mg incrememnts every 4 weeks. If serum concentrations of uric acid levels are wnl and goat attacks have been absent for 6 months, daily dosage may be reduced by 500 mg every 6 months
Monitoring
: serum and urinary uric acid levels, renal function, CBC
Warnings
: DC therapy if rare, severe hypersensitivity rxn occurs
May cause exacerbation of acute gouty attack
Use in caution in its with PUD
Monotherapy may not be effective if CrCl <30 mL/min
Contraindications
: hypersensitivity rxns to probenecid; any aspirin therapy; uric acid kidney stones; children <2 y/o; initiation during acute gout attack
Special Pops
: Not recommended if CrCl <50 mL/min; avoid use in CrCl <30 mL/min (other agents preferred in pts with mod-severe CKD (stage 3+))
Pearls
: also FDA approved as adjunct therapy for prolongation and elevation of beta-lactam plasma levels
Lesinurad
BBW:
Nephrotoxicity; should be used in combo with xanthine oxidase inhibitor
Dosing:
Oral: 200 mg once daily (in combination with a xanthine oxidase inhibitor, including allopurinol or febuxostat); maximum dose: 200 mg once daily
Contraindicated in CrCl < 30 ml/min; not recommended in severe hepatic impairment
Used to treat hyperuricemia associated with gout
AE:
Headache, GERD, Influenza, Increased SCr, Renal failure
Contraindication:
Severe renal impairment (CrCl <30 mL/minute), end-stage renal disease (ESRD), dialysis, kidney transplant recipients, tumor lysis syndrome, or Lesch-Nyhan syndrome
Warning/Precautions:
Major CV events have occurred in clinical trials; gout flare-ups; nephrotoxicity
Special Population:
Use with caution in poor CYP2C9 metabolizers
DDI:
Class C (Monitor Therapy): Alpelisib; Aspirin; Clozapine; CYP2C9 inducer/inhibitor; Lumacaftor and Ivacaftor; Nimodipine; Rifapentine; Selpercatinib; Tacrolimus;
Class D ( Therapy modification): Ubrogepant; Progestin; Estrogen
Class X (Avoid): Valproate products
Monitoring:
SCr + CrCl at tx initiation and periodically; serum uric acid
MOA:
inhibits the function of transporter proteins involved in renal uric acid reabsorption [URAT1] and organic anion transporter 4 [OAT4], and lowers serum uric acid levels and increases renal clearance and fractional excretion of uric acid in patients with gout.
PK/PD:
A: Rapid
Protein binding: >98% primarily to albumin
Vdss: ~20L
M: primarily by CYP2C9
Bioavailability: 100%
Half-life: ~5 hours
E: Urine (63%; ~30% as unchanged drug); Feces (32%)
Goal Monitoring
monitor uric acid levels every 2-5 weeks then every 6 months after
evaluate need for risk reduction therapy based on comorbidities
Non-pharm
Local Ice application to affected joints (adjuvant therapy)