Adverse Drug Reactions: Neurologic, Musculoskeletal & Skin

Peripheral neuropathy and seizures

Isoniazid and vitamin B6. Isoniazid combines with pyridoxine to form inactive hydrazones and inhibits pyridoxal kinase, lowering pyridoxal 5'-phosphate (PLP). PLP is the cofactor for glutamate decarboxylase (GABA synthesis) and for ALA synthase in heme synthesis, so B6 depletion explains three effects: a dose-related sensory neuropathy, seizures in overdose and, occasionally, sideroblastic anemia. Neuropathy is most likely in slow acetylators and in patients with alcohol use, diabetes, malnutrition, pregnancy, HIV or CKD, and prophylactic pyridoxine prevents it.

Chemotherapy. Vincristine blocks microtubule assembly and causes a dose-limiting sensorimotor and autonomic neuropathy with paresthesias, loss of ankle reflexes, foot drop and constipation. Vinblastine works the same way, but its dose-limiting toxicity is marrow suppression, which vincristine largely spares. Paclitaxel, a microtubule stabilizer, and cisplatin, which injures dorsal root ganglia, cause a mainly sensory stocking-glove neuropathy.

Metronidazole. Prolonged or high-dose courses cause a sensory neuropathy and, rarely, an encephalopathy.

Seizure threshold. Several drugs provoke seizures:

• Bupropion: dose related; contraindicated in bulimia, anorexia nervosa and seizure disorders.
• Imipenem: especially with renal impairment; meropenem carries less risk.
• Tramadol, at therapeutic doses as well as in overdose.
• Meperidine: its metabolite normeperidine accumulates in renal failure.
• Isoniazid overdose: B6-dependent GABA synthesis fails; seizures often resist benzodiazepines and require IV pyridoxine.

Intracranial pressure, cinchonism, vision and hearing

Idiopathic intracranial hypertension. Excess vitamin A and retinoids such as isotretinoin, tetracyclines (minocycline, doxycycline) and growth hormone can cause pseudotumor cerebri: headache, papilledema, transient visual obscurations and pulsatile tinnitus, with normal brain imaging and a raised CSF opening pressure. Stopping the drug and giving acetazolamide protect vision. Isotretinoin and a tetracycline should never be combined for acne because their risks add up.

Cinchonism. The cinchona alkaloids quinine and quinidine cause tinnitus, reversible high-frequency hearing loss, vertigo, headache, blurred vision, nausea and diarrhea. Quinidine also prolongs the QT interval, and quinine can cause severe immune thrombocytopenia.

Carriers of the mitochondrial 12S rRNA variant m.1555A>G (MT-RNR1) can become profoundly deaf after a single aminoglycoside dose, because the mutant ribosome resembles a bacterial one. Rifampin turns tears orange but does not damage the optic nerve.

Drug-induced lupus, myopathy and tendons

Drug-induced lupus. Hydralazine and procainamide, both acetylated by NAT2 and therefore riskier in slow acetylators, are the classic causes; isoniazid, minocycline and TNF-α inhibitors are others. Patients develop arthralgia, fever, serositis and rash with a positive ANA. The syndrome resolves over weeks to months after the drug is stopped.

Statin myopathy. Statins cause myalgia and, rarely, myositis or rhabdomyolysis with CK above 10× the upper limit of normal and myoglobinuria. Risk rises with gemfibrozil, which blocks statin glucuronidation and OATP1B1 hepatic uptake; with CYP3A4 inhibitors for simvastatin, lovastatin and atorvastatin; and with hypothyroidism, older age and SLCO1B1 variants. Fenofibrate interacts far less and is the preferred fibrate to pair with a statin.

Other myopathies. Colchicine causes a neuromyopathy, especially with renal failure or CYP3A4 or P-glycoprotein inhibitors. Daptomycin raises CK, so CK is checked weekly and statins are often held. Glucocorticoids cause proximal weakness with a normal CK.

Fluoroquinolone tendinopathy. Tendinitis and rupture, classically of the Achilles tendon, can occur within days of starting or months after stopping. Risk is highest over age 60, with systemic glucocorticoids and after kidney, heart or lung transplant. Because of cartilage damage in young animals, fluoroquinolones are avoided in children and pregnancy. Other class risks are QT prolongation, peripheral neuropathy, CNS effects, dysglycemia and aortic aneurysm or dissection.

Bone, joints and the mouth

Osteoporosis. Glucocorticoids are the commonest drug cause: they inhibit osteoblasts, raise RANKL and reduce intestinal Ca²⁺ absorption, so trabecular bone and vertebrae suffer first, and loss is fastest in the first months. Prolonged courses warrant calcium, vitamin D and often a bisphosphonate. Long-term heparin, PPIs (reduced Ca²⁺ absorption, more fractures) and enzyme-inducing anticonvulsants (phenytoin, carbamazepine, phenobarbital) add risk; the anticonvulsants speed vitamin D catabolism and can cause osteomalacia. Excess levothyroxine, aromatase inhibitors and depot medroxyprogesterone also reduce bone density.

Hyperuricemia and gout. Thiazide and loop diuretics raise urate because volume contraction increases proximal reabsorption and the drugs compete for tubular secretion. Pyrazinamide's metabolite pyrazinoate stimulates URAT1 reabsorption, making it the classic antituberculous cause; ethambutol raises urate less often. Niacin, cyclosporine, tacrolimus and low-dose aspirin complete the list.

Gingival hyperplasia. Phenytoin, cyclosporine and calcium channel blockers (nifedipine, amlodipine, verapamil) stimulate gingival fibroblasts to overproduce matrix within months, worse with plaque and poor hygiene. Management is meticulous oral hygiene, switching drugs (tacrolimus in place of cyclosporine) or gingivectomy.

Osteonecrosis of the jaw. Bisphosphonates and denosumab, an anti-RANKL antibody, can leave exposed jawbone that persists beyond 8 weeks, usually after a dental extraction. Risk is far higher with the monthly IV doses used for bone metastases than with osteoporosis dosing, so dental work is finished before therapy starts. Atypical femoral fractures are the related long-term risk.

Tetracyclines chelate calcium in developing teeth and bone, causing permanent yellow-gray-brown staining, enamel hypoplasia and reversible depression of bone growth. They are avoided in pregnancy and under age 8, although short doxycycline courses are acceptable when needed, as in Rocky Mountain spotted fever.

Skin reactions

Photosensitivity. Phototoxic reactions are direct, dose-dependent, UVA-driven injury that looks like exaggerated sunburn on exposed skin and can affect anyone. Photoallergic reactions are type IV hypersensitivity, eczematous, and occur only in sensitized patients. Common photosensitizers are sulfonamides, thiazides, tetracyclines (doxycycline, demeclocycline), amiodarone, fluoroquinolones and NSAIDs. Amiodarone also deposits in skin as slate-gray to blue pigmentation. Patients need sun avoidance and broad-spectrum sunscreen.

Stevens-Johnson syndrome and toxic epidermal necrolysis. These form one T-cell-mediated spectrum of keratinocyte death, usually 4–28 days after a new drug. Fever and painful dusky targetoid macules progress to blistering with erosions at two or more mucosal sites and a positive Nikolsky sign. Triggers include lamotrigine, carbamazepine, phenytoin, allopurinol and sulfonamides, plus nevirapine and oxicam NSAIDs. The drug is stopped at once and patients receive burn-unit care.

HLA screening. HLA-B*15:02, common in Han Chinese and Southeast Asian populations, predicts SJS/TEN from carbamazepine and also from phenytoin and oxcarbazepine, so it is tested before carbamazepine is started in these patients. HLA-B*58:01 predicts allopurinol SJS/TEN and DRESS. (HLA-B*57:01 predicts abacavir hypersensitivity, a different reaction.) Lamotrigine risk tracks rapid titration: start low, increase slowly, and halve doses with valproate, which roughly doubles lamotrigine levels by inhibiting its glucuronidation.