Why does hydralazine (antihypertensive medication) cause neuropathy?

Why Hydralazine Causes Neuropathy

Hydralazine produces peripheral neuropathy through its antipyridoxine (vitamin B6) effect, which depletes pyridoxine levels and leads to preferential damage of sensory neurons, particularly affecting distal motor function. 1

Mechanism of Neuropathy

Pyridoxine Depletion

• Hydralazine is a hydrazine compound that interferes with vitamin B6 metabolism, creating a functional pyridoxine deficiency 1, 2
• The FDA label explicitly states: "Peripheral neuritis, evidenced by paresthesia, numbness, and tingling, has been observed. Published evidence suggests an antipyridoxine effect, and that pyridoxine should be added to the regimen if symptoms develop" 1
• This mechanism is similar to other hydrazine medications like isoniazid and phenelzine, which also cause pyridoxine-responsive peripheral neuropathy 2

Neurological Pathophysiology

• The neuropathy preferentially affects the peripheral nervous system with loss of motor function, including numbness/paresthesia in extremities, loss of distal sensation, motor ataxia, weakness, and loss of deep tendon reflexes 3
• Motor neurons feeding more distal muscles are most affected, leading to progressive denervation of muscle fibers 3
• Pathological changes include axonal degeneration similar to Wallerian degeneration, with swelling of axonal mitochondria, disruption of axoplasmic ground substance, and accumulation of dense bodies within neurons 3

Clinical Presentation

Symptom Pattern

• The neuropathy manifests as paresthesia, numbness, and tingling, typically in a length-dependent distribution affecting the longest nerve axons first (toes progressing proximally) 1, 4
• Sensory axons are affected more than motor axons, though motor symptoms can develop 3, 4

Important Caveat

• Morphological nerve changes may be present even before clinical signs of neuromuscular dysfunction appear, meaning subclinical neuropathy can exist 3

Prevention and Management

Pyridoxine Supplementation

• The FDA explicitly recommends adding pyridoxine to the treatment regimen if symptoms of peripheral neuritis develop 1
• This intervention addresses the root cause of the antipyridoxine effect 1, 2

Monitoring Strategy

• Patients on long-term hydralazine therapy should be monitored for signs of peripheral neuropathy, particularly paresthesia, numbness, and tingling 1
• The risk increases with higher cumulative doses, particularly above 200 mg/day 3, 5

Clinical Context

Drug Positioning

• Hydralazine should be reserved as a fourth-line or fifth-line agent for resistant hypertension, which inherently limits prolonged exposure and neuropathy risk 5
• The medication is typically dosed at 100-200 mg/day in divided doses, with a maximum of 200 mg/day to minimize adverse effects including neuropathy 3, 5

Additional Risk Factors

• The neuropathy risk is distinct from hydralazine's other major adverse effects, including drug-induced lupus-like syndrome (which occurs at higher doses), reflex tachycardia, and sodium/water retention 3, 1