Pharmacology & Therapeutics

Rheumatic & Inflammatory Disorders

Comprehensive study notes covering rheumatoid arthritis, gout, and glucocorticoid pharmacology — mechanisms, side effects, and clinical decision-making.

🦴 Rheumatoid Arthritis

  • Definition
    • Chronic, systemic, autoimmune inflammatory disorder
    • Primarily affects synovial joints → progressive joint destruction
    • Extra-articular manifestations may involve skin, eyes, lungs, and vasculature
  • Pathophysiology overview
    • Autoimmune attack directed against self-antigens in synovium
    • Activated T cells and B cells drive chronic inflammation
    • Proinflammatory cytokines (TNF-α, IL-1, IL-6) promote synovial hyperplasia
    • Pannus formation → cartilage erosion and bone destruction
  • Treatment goals
    • Relieve pain and reduce swelling
    • Slow or halt radiographic disease progression
    • Preserve joint function and quality of life
    • Induce remission when possible
  • DMARDs are the cornerstone of RA management — they modify the disease course, unlike NSAIDs which provide only symptomatic relief.
  • Initial management approach
    • NSAIDs for rapid symptomatic control of pain and swelling
    • NSAIDs do NOT alter disease progression or prevent bone erosion
    • High-dose NSAIDs often required → significant adverse effect burden
    • DMARDs initiated concurrently if symptoms are severe at diagnosis
    • DMARDs have delayed onset of action: 2 weeks to 6 months
  • Refractory RA strategies
    • Combination DMARD therapy for inadequate response to monotherapy
    • Addition of biologic agents (TNF inhibitors, IL-1 antagonists)
    • Targeted synthetic DMARDs (JAK inhibitors) for refractory cases
    • Consider switching between agents with different mechanisms

🦶 Gout

  • Overview
    • Inflammatory arthritis caused by monosodium urate crystal deposition
    • Hyperuricemia is the underlying metabolic disturbance
    • Acute flares alternate with asymptomatic periods
    • Chronic tophaceous gout if undertreated
  • Acute gout treatment
    • NSAIDs are first-line therapy for acute flares
    • Colchicine is an alternative for acute episodes
    • Intra-articular glucocorticoids for monoarticular flares
    • Systemic glucocorticoids for polyarticular or refractory cases
  • Colchicine — key facts
    • Mechanism: binds tubulin → inhibits microtubule polymerization
    • Reduces leukocyte migration and LTB4 production
    • Acute side effects: diarrhea, GI pain (dose-limiting)
    • Chronic toxicity: hematuria, alopecia, myelosuppression, peripheral neuropathy
    • Narrow therapeutic index — caution in renal/hepatic impairment
  • Colchicine toxicity is enhanced by CYP3A4 and P-glycoprotein inhibitors — dose reduction required with drugs like clarithromycin or cyclosporine.
  • Chronic gout prevention — urate-lowering therapy
    • Goal: reduce total body uric acid pool
    • Indicated for recurrent flares, tophi, or radiographic joint damage
    • Initiate after acute flare has resolved
  • Allopurinol
    • Mechanism: xanthine oxidase inhibitor
    • Blocks conversion of purines → uric acid
    • Also useful in tumor lysis syndrome prophylaxis
    • Side effects: rash, hypersensitivity, xanthine stones
    • Interaction: inhibits 6-mercaptopurine metabolism
  • Febuxostat
    • Mechanism: xanthine oxidase inhibitor (non-purine analog)
    • More potent than allopurinol in some patients
    • Useful in allopurinol-allergic patients
    • Cardiovascular risk warning (black box)
    • Hepatotoxicity monitoring required
  • Other urate-lowering agents
    • Pegloticase — recombinant urate oxidase; rapidly degrades uric acid to allantoin; used for refractory gout; risk of anaphylaxis and infusion reactions
    • Rasburicase — recombinant urate oxidase; used for tumor lysis syndrome; rapidly lowers uric acid
    • Probenecid — uricosuric agent; inhibits proximal tubular reabsorption of urate; ineffective when GFR < 50 mL/min; inhibits secretion of weak acids (penicillins, cephalosporins)
  • Treatment algorithm summary
    Acute flare → NSAID / Colchicine / Steroid → Resolved → Urate-lowering therapy → Allopurinol / Febuxostat / Probenecid

🧬 Glucocorticoids

  • Overview
    • Synthetic derivatives of cortisol with variable glucocorticoid and mineralocorticoid potency
    • Potent anti-inflammatory and immunosuppressive effects
    • Used across multiple inflammatory and autoimmune conditions
  • Relative potencies
    DrugGlucocorticoid ActivityMineralocorticoid ActivityDuration
    Cortisol / Hydrocortisone11Short
    Prednisone40.3Intermediate
    Triamcinolone50Intermediate
    Betamethasone250Long-acting
    Dexamethasone300Long-acting
  • Cellular mechanisms
    • Reduced leukocyte migration to sites of inflammation
    • Stabilized lysosomal membranes → decreased phagocytosis
    • Decreased capillary permeability → reduced edema
  • Biochemical actions
    • Inhibit PLA2 via lipocortin induction → reduced prostaglandin and leukotriene synthesis
    • Downregulate COX-2 expression
    • Suppress platelet-activating factor (PAF)
    • Reduce interleukin production (e.g., IL-2, IL-6)
  • Therapeutic uses
    • Anti-inflammatory: RA, gout, asthma, IBD, dermatitis
    • Immunosuppressive: transplant rejection, autoimmune disease
    • Replacement therapy: adrenal insufficiency
  • Glucocorticoids act via genomic pathways (hours to days) and non-genomic pathways (minutes) — the rapid effects are mediated by membrane-bound receptors.
  • Adverse effects — systemic
    • Endocrine
      • ACTH suppression → adrenal cortical atrophy
      • Iatrogenic Cushing syndrome: fat deposition, muscle weakness, bruising, acne
      • Withdrawal syndrome: malaise, myalgia, arthralgia, fever, shock
    • Metabolic
      • Hyperglycemia via increased gluconeogenesis
      • Increased insulin resistance
      • Electrolyte shifts: Na+/water retention, hypokalemia, hypocalcemia
    • Musculoskeletal
      • Osteoporosis → vertebral fractures
      • Aseptic necrosis of femoral head
      • Myopathy and muscle atrophy
    • GI & other
      • Peptic ulcer disease, GI bleeding
      • Impaired wound healing
      • Increased infection risk (thrush, opportunistic)
      • Ocular: glaucoma, cataracts (sorbitol pathway)
      • Neuropsychiatric: mood changes, psychosis
  • Minimizing toxicity
    • Alternate-day therapy to reduce HPA axis suppression
    • Local application (topical, inhaled, intra-articular) when possible
    • Gradual dose tapering — never abrupt withdrawal
    • Monitor bone density and supplement calcium/vitamin D
    • Screen for hyperglycemia and infection
  • Withdrawal considerations
    • Abrupt cessation after prolonged use → adrenal crisis
    • Tapering schedule depends on dose and duration
    • Stress-dose steroids required during surgery or illness

💊 DMARDs — Detailed Pharmacology

  • Methotrexate (MTX) — first-line DMARD
    • Mechanism: folate antagonist; inhibits dihydrofolate reductase
    • Cytotoxic to rapidly dividing lymphocytes
    • Dose: once weekly (low-dose for RA)
    • Side effects: hepatotoxicity, hematotoxicity, pulmonary fibrosis
    • Folic acid supplementation reduces toxicity
    • Contraindicated in significant renal or hepatic disease
  • Hydroxychloroquine
    • Mechanism: stabilizes lysosomal membranes; reduces chemotaxis
    • Slower onset; milder efficacy than MTX
    • Side effects: GI distress, visual dysfunction (cinchonism), hemolysis in G6PD deficiency
    • Retinal toxicity risk → baseline and annual eye exams
  • Sulfasalazine
    • Mechanism: sulfapyridine inhibits B-cell function; 5-ASA inhibits COX
    • Used in mild-moderate RA and inflammatory bowel disease
    • Side effects: hemolysis in G6PD deficiency, rash, GI upset
  • Leflunomide
    • Mechanism: inhibits dihydro-orotate dehydrogenase (DHODH)
    • Reduces pyrimidine synthesis → arrests lymphocytes in G1 phase
    • Side effects: alopecia, rash, diarrhea, hepatotoxicity
    • Teratogenic — contraindicated in pregnancy
  • All DMARDs require regular monitoring: CBC, liver function tests, renal function. MTX specifically requires monitoring for interstitial pneumonitis.
  • Biologic DMARDs — TNF inhibitors
    • Etanercept
      • Recombinant TNF receptor fusion protein
      • Binds soluble TNF-α
      • Subcutaneous administration
    • Infliximab
      • Chimeric monoclonal antibody to TNF-α
      • IV administration
      • Often combined with MTX
    • Adalimumab
      • Fully human monoclonal antibody to TNF-α
      • Subcutaneous administration
      • Lower immunogenicity than chimeric agents
  • Other biologic and targeted agents
    • Anakinra — IL-1 receptor antagonist; shorter half-life; injection site reactions common
    • Tofacitinib — JAK inhibitor (targeted synthetic DMARD); oral administration; risk of infections, lymphomas, and thromboembolism
  • Infection risk — biologic class effect
    • All TNF inhibitors and IL-1 antagonists increase susceptibility to infections
    • Tuberculosis screening required before initiating therapy
    • Avoid live vaccines during treatment
    • Hold biologics during active serious infections

⚕️ Clinical Pearls & Exam Traps

  • Rheumatoid arthritis
    • Start DMARDs early — even during the first visit if symptoms are significant
    • NSAIDs are symptomatic only; they do not protect against joint erosion
    • Combination therapy is often needed for refractory disease
    • MTX is the anchor drug; add biologics or JAK inhibitors if inadequate response
  • Gout
    • Do NOT start urate-lowering therapy during an acute flare — it can worsen symptoms
    • Colchicine is most effective when started within 24 hours of flare onset
    • Allopurinol dose must be adjusted in renal impairment
    • Probenecid requires adequate renal function (GFR > 50 mL/min)
    • Pegloticase is reserved for severe, refractory chronic gout
  • Glucocorticoids
    • Always taper after prolonged use to avoid adrenal crisis
    • Alternate-day therapy reduces HPA suppression
    • Inhaled and topical routes have fewer systemic effects
    • Stress-dose steroids are essential during major illness or surgery
    • Monitor for osteoporosis, hyperglycemia, and infections
  • On USMLE, the most common cause of death in RA is cardiovascular disease, not the arthritis itself. Screen and manage CV risk factors aggressively.
  • High-yield drug interactions
    • Allopurinol + 6-mercaptopurine / azathioprine → increased myelotoxicity
    • Probenecid + penicillins / cephalosporins → reduced renal clearance of the antibiotic
    • NSAIDs + glucocorticoids → increased GI bleeding risk
    • Colchicine + CYP3A4 inhibitors → toxicity risk
  • Monitoring parameters
    • MTX: CBC, LFTs, creatinine, pulmonary symptoms
    • Hydroxychloroquine: annual ophthalmologic exam
    • Biologics: TB screening, infection surveillance
    • Glucocorticoids: blood glucose, bone density, blood pressure

📊 Comparison Tables

  • DMARDs at a glance
    DrugMechanismKey Side EffectsMonitoring
    MethotrexateFolate antagonistHepatotoxicity, myelosuppressionCBC, LFTs, Cr
    HydroxychloroquineLysosomal stabilizationRetinopathy, GI distressEye exam
    SulfasalazineB-cell inhibition, COX inhibitionHemolysis (G6PD), rashCBC, G6PD screen
    LeflunomideDHODH inhibitionHepatotoxicity, alopeciaLFTs
    TNF inhibitorsTNF-α blockadeInfections, infusion reactionsTB screen, infection
    JAK inhibitorsJAK-STAT inhibitionInfections, lymphomas, thrombosisCBC, infection
  • Gout therapies compared
    AgentIndicationMechanismKey Limitation
    ColchicineAcute flareMicrotubule inhibitionDiarrhea, narrow TI
    AllopurinolChronic preventionXanthine oxidase inhibitorRash, 6-MP interaction
    FebuxostatChronic preventionXanthine oxidase inhibitorCV risk, hepatotoxicity
    PegloticaseRefractory goutUrate oxidaseAnaphylaxis, cost
    ProbenecidChronic preventionUricosuricRequires GFR > 50
  • Glucocorticoid potency summary
    DrugEquivalent Dose (mg)Anti-inflammatory PotencyNa+ Retention
    Hydrocortisone201++
    Prednisone54+
    Methylprednisolone45+
    Dexamethasone0.75300
    Betamethasone0.6250
  • Dexamethasone and betamethasone have zero mineralocorticoid activity — preferred when sodium retention must be avoided.