Gout

Learning Outcomes and Objectives

• Describe the doses, mechanism of actions (MOA), indications, adverse effects, drug interactions, and contraindications of drug classes used in the treatment of gout.

• Identify Drug-Related Problems (DRPs) in a gout prescription through reference to clinical practice guidelines.

• Dispense gout prescriptions in a legally and clinically accurate manner.

• Counsel patients effectively on the proper use of gout medications.

• Provide non-pharmacological advice to patients with gout to help manage the condition.

Introduction to Gout

• Definition: Gout is a form of musculoskeletal (MSK) disorder caused by the deposition of monosodium urate (MSU) crystals in the joints, leading to inflammatory arthritis.

• Phases of Chronic Gout: Gout is considered a chronic MSK condition that transitions between two specific phases:

  • Phase of Calamity: General chronic state.

  • Phase of Flares: Characterized by intense localized joint inflammation, pain, swelling, and tenderness that limits movement.

Pathophysiology of Gout

• Uric Acid (Urate): A natural metabolic waste product of purine metabolism in the body with no known physiologic purpose.

• Serum Concentration Balance: Physiological processes balance the rate of urate production against elimination by the kidney, usually maintaining levels between $4 \text{ to } 6\,mg/dL$.

• Hyperuricaemia: Occurs when serum urate levels exceed the solubility threshold of $6\,mg/dL$. This is caused by either overproduction or underexcretion of uric acid.

• Crystal Formation: Accumulation leads to the precipitation of fine, needle-like MSU crystals in areas with low blood flow (e.g., distal limbs), causing localized inflammation.

Overproduction and Underexcretion of Uric Acid

• Sources of Purines (Adenine and Guanine):

  • Dietary intake: Seafood, offal (liver and kidney), and red meat.

  • Metabolism of DNA: Breakdown of nucleotides.

  • Physiological synthesis: Endogenous purine production.

• Overproduction Mechanisms: Pathological changes to DNA metabolism, increased purine synthesis, or high intake of purine-rich foods.

• Underexcretion Mechanisms: Primarily seen in patients with Chronic Kidney Disease (CKD), where weakened renal function compromises the ability to eliminate uric acid.

Risk Factors

• Non-Modifiable Factors:

  • Gender: Males are more likely to be affected.

  • Age: The elderly population is at higher risk.

  • Family History: Heredity and genetic similarities increase the likelihood of experiencing the condition.

• Modifiable Factors:

  • Dietary Preference: High consumption of alcohol or purine-rich foods.

  • Loop Diuretics: Drugs such as $hydrochlorothiazide$ and $frusemide$ increase fluid loss via urination, concentrating urate and risking MSU precipitation.

  • Obesity: Associated with a twofold ($2\times$) increased risk of gout.

Complications of Gout

• Recurrent Gout Flares (Tophaceous Gout): Tophi (singular: tophus) are bulbous, swollen growths on joints due to MSU crystal accumulation. This can lead to permanent joint damage and functional impairment.

• Gouty Nephropathy: Persistently elevated urate leads to the formation of urate kidney stones in the nephron (urate nephrolithiasis), which can cascade into CKD.

Signs and Symptoms of Gout

• Diagnosis Criteria: A patient identifies as having gout only if they fulfill two criteria:

  • Elevated serum urate level ($\ge 6\,mg/dL$).

  • Development of MSU crystal deposition in joints with clinical signs.

• Subjective (Symptoms):

  • Monoarticular condition (usually affecting the big toe).

  • Onset often occurs at night and lasts for several days.

  • Progresses to feet, ankles, heels, or knees if poorly managed.

  • Five Cardinal Signs of Inflammation: Redness, warmth, pain, swelling, and stiffness (loss of function).

• Objective (Signs):

  • Laboratory Tests: Serum uric acid $\ge 6\,mg/dL$ ($360\,mmol/L$); Presence of uric acid in synovial fluid via knee aspiration.

  • Scans: X-Ray showing joint swelling with MSU crystals or tophus.

• Asymptomatic Hyperuricaemia: Patients with high urate levels ($\ge 6\,mg/dL$) but no clinical signs or crystal deposition.

Non-Pharmacological Management

• Dietary Changes: Reduce alcohol and purine-rich food consumption to lower urate production.

• Weight Reduction: Lower BMI from obese/overweight status to a normalized level ($18.5 - 23.9\,kg/m^{2}$).

• Ice Packs: Applied to affected joints to reduce pain and inflammation; used as adjuvant therapy with medication.

Pharmacological Management Phases

• Acute Gout Flares: Focuses on treating intense pain and inflammation episodes.

• Chronic Gout Management: Uses Urate Lowering Therapies (ULT) to prevent crystal formation in patients with recurrent flares.

• Treatment Rule: Patients with asymptomatic hyperuricemia generally do not require active pharmacological treatment.

Classification of Gout Medications

• Anti-Inflammatory Drugs:

  • NSAIDs: $Diclofenac$, $Indomethacin$.

  • Colchicine: $Colchicine$.

• Glucocorticoids (Corticosteroids): $Prednisolone$.

• Xanthine Oxidase Inhibitors (XOI): $Allopurinol$ .

• Uricosuric Agents: $Probenecid$.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• Mechanism of Action: NSAIDs inhibit constitutive COX-2 enzymes to prevent the conversion of arachidonic acid to prostaglandin.

• Subclasses:

  • Non-Selective: Bind to both COX-1 and COX-2 ($Diclofenac$, $Indomethacin$).

  • Selective COX-2: Bind selectively to COX-2 to reduce GI side effects ($Celecoxib$, $Etoricoxib$).

• Dosing:

  • $Diclofenac$: $100 - 150\,mg/day$ divided into BD to QDS.

  • $Indomethacin$: $50\,mg$ TDS.

  • $Celecoxib$: $100\,mg$ BD.

  • $Etoricoxib$: $120\,mg$ OM (maximum).

• Adverse Drug Reactions (ADRs) & Cautions:

  • GI intolerance and increased risk of bleeds.

  • Abnormalities in renal functions and bronchospasms.

  • Indomethacin specific: CNS effects including drowsiness and dizziness; avoid tasks needing mental alertness.

  • Selective COX-2 specific: Increased risk of cardiovascular events (e.g., heart attack, stroke).

  • Hypersensitivity: Ranges from swollen eyes to Steven Johnson Syndrome (SJS).

Colchicine

• Mechanism of Action: Binds to tubulin to disrupt the formation of microtubules. This inhibits the migration of white blood cells (WBCs) and prevents phagocytosis, thereby reducing inflammation.

• Dosing for Healthy Adults:

  • Acute Flare (with Loading Dose): Day 1: $1\,mg$ load followed by $500\,\mu g$ after 30 minutes. Day 2 onwards: $500\,\mu g$ OM or BD.

  • Acute Flare (without Loading Dose): $500\,\mu g$ TDS.

  • Prophylaxis (Chronic): $500\,\mu g$ OM or BD.

  • Max Dose: $1.8\,mg/day$ for treatment; $1.2\,mg/day$ for prophylaxis.

• ADRs & Cautions:

  • Gastrointestinal irritant: Nausea, vomiting, diarrhea, abdominal pain.

  • Rare effects: Blood dyscrasias (bone marrow suppression leading to low platelets/WBCs), Neuromuscular toxicity (neuropathy, rhabdomyolysis), and renal failure.

• Drug Interactions (CYP3A4):

  • Inducers (Decrease levels): $Phenytoin$, $Carbamazepine$, $Rifampicin$.

  • Inhibitors (Increase levels): $Clarithromycin$, $Itraconazole$, $Grapefruit\,Juice$, $Ritonavir$.

Prednisolone

• Physiological Role: Synthetic glucocorticoid mimicking endogenous cortisol. Regulates homeostasis via the Hypothalamus–Pituitary–Adrenal (HPA) axis.

• Mechanism of Action: Passively crosses into cytoplasm to form a drug-receptor complex with glucocorticoid receptors (GR). The complex alters transcription to increase proteins that inhibit the enzyme Phospholipase A2 (PLA2), preventing the formation of Arachidonic Acid (AA) and subsequent prostaglandins.

• Dosing:

  • Gout: $30 - 40\,mg$ divided into once or twice daily for $3 \text{ to } 7$ days.

  • Rheumatoid Arthritis: $\le 15\,mg/day$ once daily for approximately 3 months (tapering as DMARDs take effect).

• Common ADRs: Nausea/Vomiting, abdominal pain, insomnia (awakening effect).

• Uncommon/Rare ADRs:

  • Metabolic: Moon face, hyperglycemia, osteoporosis, water retention.

  • Haematological: Decreased WBC (infection risk) and platelets (bleed risk).

  • Ophthalmological: Glaucoma, cataracts.

  • Psychiatric: Mood changes.

  • Dermatological: Easy bruising, skin thinning, hirsutism.

• Steroid Withdrawal: Patients on high doses ($> 30\,mg/day$) or prolonged use ($\ge 2\,weeks$) must not discontinue suddenly. Abrupt cessation leads to near-zero cortisol levels, causing fatigue, N/V, diarrhea, and weight loss.

Allopurinol (Urate Lowering Therapy)

• Mechanism of Action: Competitively inhibits xanthine oxidase (XO), preventing the hydrolysis of purine into uric acid.

• Dosing Strategy: "Start low, go slow." Initiate at $50 - 100\,mg/day$. Increase gradually to the clinically effective dose of approximately $300\,mg/day$ (Maximum: $900\,mg/day$).

• ADRs:

  • Common: Nausea, vomiting, diarrhea; precipitation of acute gout attacks early in treatment.

  • Rare: Hepatotoxicity, drug fever, and Severe Cutaneous Adverse Reactions (SCAR) such as SJS and Toxic Epidermal Necrolysis (TEN).

• SCAR Risk Factors (RASHES):

  • R: Renal impairment.

  • A: Agent concomitant use (e.g., diuretics).

  • S: Starting dose (high starting doses increase risk).

  • H: HLA-B*5801 presence (allele found more in Chinese/Korean populations; PPV is approx $2\%$).

  • E: Escalation (rapid dose titration).

  • S: Seniority (older age).

Probenecid (Uricosuric Agent)

• Mechanism of Action: Inhibits the organic anion transporter (OAT) at the proximal convoluting tubule (PCT). This blocks urate reabsorption, allowing urate to stay in the nephron and be excreted in urine.

• Dosing: $250\,mg$ BD for 1 week, then $500\,mg$ BD for 1 week, then increase by $500\,mg$ every 4 weeks (Maintenance: $\le 2\,g/day$). Must be taken after food.

• ADRs & Cautions:

  • Common: Nausea, vomit, loss of appetite, stomach irritation, headache, dizziness.

  • Rare: Nephrolithiasis (kidney stones) due to increased urate concentration in the nephron. Patients must drink at least eight glasses of water daily to mitigate this.

• Drug Interactions: Probenecid competes with other drugs for tubular secretion. Concomitant use with $meropenem$, $ertapenem$, and $aspirin$ is contraindicated.

Questions & Discussion

• Q: How do underexcretion and overproduction lead to gout?

  • A: Both lead to urate levels exceeding the solubility threshold ($\ge 6\,mg/dL$), causing MSU crystals to precipitate in joints and trigger inflammatory responses.

• Q: What is the mechanism of NSAIDs in gout?

  • A: They inhibit COX-2 to stop the production of prostaglandins from arachidonic acid, reducing pain and swelling.

• Q: What is the significance of the "Start low, go slow" strategy in ULT?

  • A: It minimizes the risk of SCAR and reduces the likelihood of precipitating an acute gout flare during the initiation of therapy.

• Q: What are the contraindications for probenecid?

  • A: Drugs that use the same OAT secretion pathway, specifically $meropenem$, $ertapenem$, and $aspirin$.