How does isoniazid (Isonicotinic Hydrazide) cause peripheral neuropathy?

Mechanism of Isoniazid-Induced Peripheral Neuropathy

Isoniazid causes peripheral neuropathy primarily by inducing pyridoxine (vitamin B6) deficiency, leading to axonal degeneration and disruption of nerve fibers, particularly affecting motor neurons that supply distal muscles. 1

Pathophysiological Mechanism

• Isoniazid acts as a vitamin B6 antagonist, interfering with the function of pyridoxal phosphate (PLP), the active form of vitamin B6, which is essential for numerous biosynthetic processes including amino acid metabolism 2
• This deficiency leads to ultrastructural changes in peripheral nerves, including:
  • Swelling of axonal mitochondria 2
  • Disruption of axoplasmic ground substance 2
  • Accumulation of dense bodies within neurons 2
  • Pathological disturbances in and around Schwann cells 2
• Motor neurons, particularly those supplying distal muscles, are most affected, leading to progressive denervation of muscle fibers 2

Progression of Nerve Damage

• Animal studies show that isoniazid administration can cause rapid nerve damage:
  • Significant loss of neural tissue and reduction in conduction velocity within 3 days 2
  • Extensive myelin disruption and fragmentation of intramuscular nerve fibers by day 10 2
  • Even after discontinuation, significant damage to peripheral nerve fibers may persist 2

Risk Factors

• Slow isoniazid inactivator status significantly increases risk 3
• Other risk factors include:
  • Malnutrition 2, 4
  • Diabetes 2
  • Uremia 2
  • Alcoholism 2
  • HIV infection 2, 5
  • Higher doses of isoniazid 4, 6

Clinical Manifestations

• Initial symptoms typically include numbness and paresthesia in the extremities 2, 1
• May progress to:
  • Loss of distal sensation 2
  • Motor ataxia 2
  • Weakness 2
  • Loss of deep tendon reflexes 2
  • In severe cases, can affect gait and daily functioning 1

Prevention and Management

• Prophylactic pyridoxine (vitamin B6) supplementation is recommended for all patients at high risk 2, 1
• Standard preventive dose is 10-25 mg daily, with higher doses (50 mg daily) for high-risk patients 2, 1
• For established neuropathy, pyridoxine doses of 50-100 mg daily are recommended until symptoms resolve 1
• Caution: Excessive pyridoxine doses (>200 mg daily) can itself cause peripheral neuropathy 1, 7

Monitoring

• Regular clinical assessment for symptoms of peripheral neuropathy should be performed in all patients on isoniazid therapy 2, 1
• Biochemical monitoring shows that peripheral neuropathy is associated with substantial reduction in glutamic-oxaloacetic transaminase (GOT) activity 3
• Patients should be instructed to report symptoms immediately 2

This mechanism highlights the importance of preventive pyridoxine supplementation in patients receiving isoniazid, particularly those with risk factors for developing peripheral neuropathy.