34.4 Cutaneous and Musculoskeletal Pharmacology: Cellulitis and Abscess, Drug-Induced Skin Reactions (SJS/TEN), Pain Management (Paracetamol, NSAIDs, Opioids), Osteoporosis, Rheumatoid Arthritis and Osteoarthritis, Septic and TB Arthritis, Gout, SLE and Psoriasis

Why this area matters

Skin and soft-tissue infections, drug eruptions, pain, arthritis and osteoporosis are everyday problems. Severe cutaneous adverse reactions to drugs such as carbamazepine and allopurinol are particularly relevant in Southeast Asian patients because of HLA associations. The TOS asks for drug choice, adverse effects, interactions and monitoring.

Cellulitis, abscess and other skin infections

• Non-purulent cellulitis and erysipelas (streptococci): cephalexin, dicloxacillin or amoxicillin-clavulanate. Use clindamycin for penicillin allergy, and IV cefazolin for severe cases.
• Abscesses:
  • incision and drainage is the main treatment;
  • add antibiotics for large or multiple abscesses, systemic signs or immunosuppression;
  • for CA-MRSA, use TMP-SMX, doxycycline or clindamycin; for serious MRSA, vancomycin or linezolid.
• Animal bites: amoxicillin-clavulanate.
• Necrotizing fasciitis: surgery plus broad-spectrum antibiotics including clindamycin.
• Impetigo: topical mupirocin or fusidic acid if limited; oral cephalexin if extensive.
• Superficial fungal infections:
  • topical azoles or terbinafine;
  • oral terbinafine (liver function, taste disturbance) or itraconazole for onychomycosis and tinea capitis, with griseofulvin as an alternative for tinea capitis in children.
• Scabies: permethrin 5% for the patient and contacts, or oral ivermectin.

Drug-induced skin reactions

• Management:
  • stop the culprit drug immediately;
  • give supportive care in a burn unit or ICU (fluids, wound care, eye and mucosal care, infection control, nutrition);
  • document the allergy and avoid re-challenge;
  • systemic steroids or cyclosporine are sometimes used for SJS/TEN.
• Genetic screening:
  • HLA-B*15:02 predicts carbamazepine SJS/TEN in many Asian populations;
  • HLA-B*58:01 predicts allopurinol SJS/TEN and DRESS, especially in East and Southeast Asians, and is screened where available;
  • start allopurinol at a low dose.

Analgesic Pharmacology & Toxicology: Acetaminophen, NSAIDs & Opioids

Acetaminophen (Paracetamol)

• Mechanism: Centrally acting reversible inhibitor of cyclooxygenase-1 and COX-2; acts on central TRPA1 channels and the endocannabinoid system. Effective analgesic and antipyretic; lacks significant peripheral anti-inflammatory activity and does not impair platelet aggregation or gastric mucosa.
• Metabolic Pathway & Overdose Pathophysiology:
  • At therapeutic doses, $90\text{--}95\%$ of acetaminophen is safely conjugated in the liver via Phase II glucuronidation and sulfation into non-toxic water-soluble metabolites.
  • Approximately $5\text{--}10\%$ is shunted through Cytochrome P450 (predominantly CYP2E1) to generate the highly reactive, cytotoxic electrophile N-acetyl-p-benzoquinone imine (NAPQI).
  • At normal doses, NAPQI is instantaneously detoxified by conjugation with endogenous hepatic glutathione ($GSH$) to form harmless mercapturic acid and cysteine conjugates excreted in urine.
  • In acute overdose ($> 150\text{ mg/kg}$ in children or $> 7.5\text{--}10\text{ g}$ in adults), Phase II glucuronidation and sulfation pathways become overwhelmed and saturated. Shunting through CYP2E1 generates massive quantities of NAPQI, which rapidly depletes hepatic glutathione reserves.
  • Once hepatic glutathione falls below $30\%$ of baseline, free unconjugated NAPQI covalently binds nucleophilic macromolecules and sulfhydryl groups on hepatocytes, causing mitochondrial permeability transition, ATP depletion, and massive centrilobular (Zone 3) hepatic necrosis and fulminant liver failure.
• Antidote: N-Acetylcysteine (NAC):
  • Supplies cysteine as an essential substrate to replenish hepatic glutathione stores, and directly binds/reduces NAPQI as a glutathione substitute. Most effective when initiated within 8 hours of acute ingestion.
  • The Rumack-Matthew Nomogram: Evaluates hepatotoxicity risk following a single acute ingestion. Serum acetaminophen concentration must be measured at least 4 hours post-ingestion (to ensure completed absorption). A 4-hour concentration above $150\text{ mcg/mL}$ ($1,000\ \mu\text{mol/L}$) warrants immediate initiation of the full course of intravenous or oral NAC.

NSAIDs: Non-Selective vs. COX-2 Selective

• Non-Selective NSAIDs (Ibuprofen, Naproxen, Ketorolac, Indomethacin, Mefenamic Acid):
  • Reversibly inhibit both COX-1 (constitutively expressed in gastric mucosa, platelets, and kidneys) and COX-2 (inducible at sites of inflammation).
  • Gastric Toxicity: Inhibiting COX-1 halts mucosal synthesis of cytoprotective prostaglandins ($PGE_2, PGI_2$), which normally stimulate protective mucus and bicarbonate secretion and maintain mucosal blood flow. Results in erosive gastritis, peptic ulcer disease, and severe upper GI bleeding.
  • Renal Hemodynamic Toxicity: Prostaglandins dilate the afferent arteriole of the renal glomerulus. NSAIDs block prostaglandin synthesis, causing afferent arteriolar vasoconstriction, reduced GFR, acute prerenal azotemia, sodium and water retention (worsening hypertension and heart failure), and analgesic nephropathy / papillary necrosis with chronic use.
• Selective COX-2 Inhibitors (Celecoxib):
  • Selectively inhibits inducible COX-2 without blocking constitutive gastric COX-1. Significantly lowers upper GI ulceration and bleeding rates.
  • Cardiovascular Thrombotic Hazard: Vascular endothelial cells synthesize prostacyclin ($PGI_2$) via COX-2, which promotes vasodilation and inhibits platelet aggregation. In contrast, platelets synthesize thromboxane $A_2$ ($TXA_2$) exclusively via COX-1, which promotes vasoconstriction and platelet aggregation. Celecoxib selectively suppresses endothelial $PGI_2$ without inhibiting platelet $TXA_2$. This unopposed platelet aggregation and vasoconstriction significantly elevates the risk of myocardial infarction and ischemic stroke (FDA boxed warning).

Opioid Analgesics & Reversal

• Mechanism: Agonists at presynaptic and postsynaptic mu ($\mu$) opioid receptors ($G_i$-protein coupled). Presynaptically, they close voltage-gated calcium channels, inhibiting exocytosis of excitatory neurotransmitters (substance P, glutamate, CGRP). Postsynaptically, they open potassium channels, hyperpolarizing the dorsal horn nociceptive neuron to block pain transmission.
• Classic Opioid Overdose Triad:
  1. Central Nervous System Depression (coma, stupor, somnolence)
  2. Respiratory Depression (respiratory rate $< 12/\text{min}$, shallow breathing, apnea; primary cause of fatal overdose)
  3. Miosis (symmetric pinpoint pupils; Exception: Meperidine produces normal or dilated pupils due to intrinsic antimuscarinic atropine-like properties)
• Antidote: Naloxone:
  • Pure competitive antagonist at $\mu$, $\kappa$, and $\delta$ opioid receptors. Administered IV, IM, subcutaneous, or intranasally. Reverses respiratory arrest within 1 to 2 minutes.
  • The Rebound Toxicity Danger: Naloxone has a short elimination half-life of 30 to 90 minutes. Many long-acting opioid agonists (Methadone, extended-release Oxycodone or Morphine) have durations of action spanning 12 to 36 hours. When naloxone wears off, circulating opioid agonist molecules reoccupy receptors, causing recurrent rebound respiratory depression. Patients must be monitored for at least 4 to 6 hours, with repeated naloxone boluses or a continuous intravenous infusion administered as needed.

Additional pain-management principles:

• Use the WHO analgesic ladder for cancer pain.
• Choose multimodal analgesia (paracetamol plus an NSAID plus regional techniques) after surgery.
• Treat neuropathic pain with gabapentin or pregabalin, duloxetine or amitriptyline, not NSAIDs.
• Opioid prescribing: start low, prescribe a laxative, watch for sedation and respiratory depression (especially with benzodiazepines), and follow dangerous-drug prescribing rules.
• Tramadol (a weak mu agonist with SNRI activity) lowers the seizure threshold and causes serotonin syndrome with SSRIs.
• Meperidine is avoided because its metabolite normeperidine causes seizures, especially in renal failure.
• NSAID cautions: avoid in late pregnancy (premature ductus closure), CKD, heart failure, peptic ulcer and with anticoagulants. Add a PPI for patients at high GI risk.

Osteoporosis, arthritis and gout

• Osteoporosis:
  • calcium and vitamin D for all;
  • bisphosphonates (alendronate weekly, risedronate, zoledronic acid yearly IV) inhibit osteoclasts;
  • oral bisphosphonates must be taken fasting, upright, with a full glass of water and nothing else for 30 minutes, because of esophagitis;
  • rare adverse effects are osteonecrosis of the jaw and atypical femoral fractures, and a drug holiday is considered after 3 to 5 years;
  • denosumab (anti-RANKL every 6 months) causes rebound fractures if stopped without follow-on therapy;
  • teriparatide (intermittent PTH analog, anabolic) for severe osteoporosis;
  • raloxifene (a SERM) lowers vertebral fractures and breast cancer but increases VTE and hot flushes.
• Osteoarthritis:
  • exercise and weight loss;
  • paracetamol or topical NSAIDs first;
  • oral NSAIDs for short periods;
  • intra-articular corticosteroids for flares;
  • duloxetine;
  • joint replacement for severe disease.
• Rheumatoid arthritis:
  • start DMARDs early;
  • methotrexate (weekly, with folic acid) is the anchor. It is hepatotoxic, causes cytopenias, mucositis and pneumonitis, and is teratogenic. Avoid alcohol and trimethoprim, and monitor CBC and liver function;
  • hydroxychloroquine causes retinopathy, so regular eye screening is needed;
  • sulfasalazine is safe in pregnancy and causes hemolysis in G6PD deficiency;
  • leflunomide is teratogenic;
  • biologics (TNF inhibitors such as infliximab and adalimumab, and tocilizumab, rituximab and abatacept) and JAK inhibitors are used if response is inadequate;
  • screen for latent TB and hepatitis B before biologics, because TNF inhibitors reactivate TB;
  • low-dose steroids as a bridge.
• Septic arthritis: joint drainage plus IV antibiotics: cefazolin or an anti-staphylococcal penicillin, vancomycin if MRSA is a risk, and ceftriaxone for gonococcal arthritis.
• TB arthritis and spondylitis: standard anti-TB drugs for a longer course, often 9 to 12 months.
• Gout:
  • acute flare: NSAIDs (not aspirin), colchicine (low dose; causes diarrhea, and toxicity with CYP3A4 or P-gp inhibitors such as clarithromycin and in renal impairment), or corticosteroids (oral or intra-articular);
  • urate-lowering therapy for recurrent flares, tophi, chronic kidney disease or stones:
    • allopurinol, a xanthine oxidase inhibitor started low (100 mg, less in CKD) and titrated to serum urate below 6 mg/dL. Watch for severe hypersensitivity (HLA-B*58:01) and azathioprine and mercaptopurine toxicity, whose doses must be reduced;
    • febuxostat;
    • probenecid, a uricosuric that is avoided with stones or CKD;
  • do not stop urate-lowering therapy during a flare, and give colchicine or NSAID prophylaxis for 3 to 6 months when starting it;
  • drugs that raise urate include thiazides, loop diuretics, low-dose aspirin, pyrazinamide, ethambutol and cyclosporine.

SLE and psoriasis

• Systemic lupus erythematosus:
  • hydroxychloroquine for all patients unless contraindicated, because it reduces flares and improves survival;
  • corticosteroids for flares;
  • mycophenolate or cyclophosphamide for lupus nephritis;
  • azathioprine for maintenance (check TPMT activity);
  • belimumab;
  • sun protection;
  • drug-induced lupus: procainamide, hydralazine, isoniazid, minocycline and anti-TNF agents (anti-histone antibodies).
• Psoriasis:
  • topical corticosteroids;
  • vitamin D analogs (calcipotriol);
  • coal tar;
  • phototherapy;
  • methotrexate, cyclosporine or acitretin (teratogenic) for extensive disease;
  • biologics (anti-TNF, anti-IL-17, anti-IL-23);
  • avoid systemic corticosteroids, which can trigger a pustular or erythrodermic flare when withdrawn;
  • lithium, beta-blockers and antimalarials can worsen psoriasis.