What are the side effects of sodium valproate, phenytoin, and other antiepileptic medications?

Side Effects of Sodium Valproate, Phenytoin, and Other Antiepileptic Drugs

Sodium Valproate Side Effects

Sodium valproate carries significant risks including hepatotoxicity, teratogenicity, weight gain with metabolic complications, and reproductive endocrine disorders, making it particularly problematic for women of childbearing potential. 1

Gastrointestinal Effects

• Nausea (48%), vomiting (27%), and abdominal pain (23%) are the most common initial side effects, though these are usually transient 1
• Diarrhea (13%), constipation (5%), anorexia (12%), and dyspepsia (8%) occur less frequently 1
• Pancreatitis, including fatal cases, has been reported and requires immediate discontinuation 1

Central Nervous System Effects

• Somnolence (27%), tremor (25%), and dizziness (25%) are the most frequent neurological side effects 1
• Diplopia (16%), ataxia (8%), and nystagmus (8%) occur with moderate frequency 1
• Cognitive effects include amnesia (5%), thinking abnormalities (6%), and emotional lability (6%) 1
• Rare but serious: encephalopathy with or without fever, particularly dangerous in patients with underlying urea cycle disorders, with reported fatalities 1
• Reversible cerebral atrophy and dementia have been reported in association with valproate therapy 1

Hematologic Effects

• Thrombocytopenia (24%) is the most significant hematologic complication, affecting platelet aggregation and increasing bleeding risk 1
• Ecchymosis (5%), petechiae, bruising, and frank hemorrhage may occur 1
• Rare but serious: pancytopenia, aplastic anemia, agranulocytosis, and bone marrow suppression 1

Metabolic and Endocrine Effects

• Weight gain (9%) is common and clinically significant, reducing insulin sensitivity and promoting polycystic ovary syndrome (PCOS) development 2, 3, 1
• Hyperammonemia can occur and may lead to encephalopathy, especially in patients with urea cycle disorders 1
• In women taking valproate monotherapy, 45% developed menstrual irregularities, 60% had polycystic ovaries, and 30% had elevated testosterone 2
• Valproate alters steroidogenesis, increasing testosterone to estradiol ratios in ovarian tissue 2, 3
• Hyperinsulinism and low insulin-like growth factor binding protein-1 contribute to hyperandrogenism 2

Hepatotoxicity

• Minor transaminase elevations (SGOT, SGPT, LDH) are frequent and dose-related 1
• Serious hepatotoxicity with potential fatality can occur, requiring monitoring of liver function 1
• Toxic hepatitis and liver damage have been reported 1

Dermatologic Effects

• Alopecia (24%) is common and reversible 1
• Transient hair loss, skin rash, photosensitivity, and pruritus occur 1
• Rare but serious: Stevens-Johnson syndrome, toxic epidermal necrolysis (including fatal cases) 1

Other Notable Effects

• Asthenia/weakness (21-27%) 1
• Headache (31%) 1
• Peripheral edema (8%) 1
• Respiratory infections (12-20%) 1

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Phenytoin Side Effects

Phenytoin causes significant dose-related neurological side effects, serious dermatologic reactions, and long-term complications including gingival hyperplasia and bone metabolism disorders. 4

Central Nervous System Effects (Most Common and Dose-Related)

• Nystagmus, ataxia, slurred speech, decreased coordination, and mental confusion are the most common manifestations 4
• Dizziness, insomnia, transient nervousness, motor twitchings, and paresthesias occur frequently 4
• Somnolence and headaches are common 4
• Rare movement disorders: phenytoin-induced dyskinesias including chorea, dystonia, tremor, and asterixis (similar to phenothiazine effects) 4
• Predominantly sensory peripheral polyneuropathy develops with long-term therapy 4

Dermatologic Effects (Potentially Life-Threatening)

• Morbilliform rash (measles-like) is the most common dermatological manifestation 4
• Scarlatiniform rashes sometimes accompanied by fever 4
• Serious and potentially fatal reactions: bullous dermatitis, exfoliative dermatitis, purpuric dermatitis, lupus erythematosus, Stevens-Johnson syndrome, and toxic epidermal necrolysis 4

Hematologic Effects (Some Fatal)

• Thrombocytopenia, leukopenia, granulocytopenia, and agranulocytosis 4
• Pancytopenia with or without bone marrow suppression 4
• Macrocytosis and megaloblastic anemia (usually respond to folic acid therapy) 4
• Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease 4

Gastrointestinal Effects

• Nausea, vomiting, and constipation 4
• Toxic hepatitis and liver damage 4

Connective Tissue and Cosmetic Effects

• Coarsening of facial features and enlargement of lips 4
• Gingival hyperplasia (a characteristic side effect) 4
• Hypertrichosis (excessive hair growth) 4
• Peyronie's disease 4

Musculoskeletal Effects (Long-Term Use)

• Bone fractures and osteomalacia associated with long-term use (>10 years) in patients with chronic epilepsy 4
• Osteoporosis and other bone metabolism disorders 4
• Hypocalcemia, hypophosphatemia, and decreased Vitamin D metabolite levels 4

Immunologic Effects

• Anticonvulsant Hypersensitivity Syndrome (AHS): arthralgias, eosinophilia, fever, liver dysfunction, lymphadenopathy, or rash 4
• Systemic lupus erythematosus and periarteritis nodosa 4
• Immunoglobulin abnormalities 4

Other Effects

• Anaphylactoid reaction and anaphylaxis 4
• Taste perversion 4

Comparative Side Effect Profile

• Phenytoin causes significantly more hypotension (12%) compared to valproate (0%) when used as second-line treatment for status epilepticus 5
• Studies show increased side effects and worsening neurological outcomes with phenytoin compared to levetiracetam in traumatic brain injury patients 2
• In pediatric studies, phenytoin showed more side effects than valproate: hyperactivity was a major side effect in 22% of children on phenobarbital, while side effects were minimal with valproate 6

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Other Antiepileptic Drugs - Comparative Side Effect Profiles

Levetiracetam

Levetiracetam has the most favorable side effect profile among second-line antiepileptics, with minimal cardiovascular effects and no significant drug interactions. 5

• Minimal adverse effects with 68-73% efficacy in status epilepticus 5
• No hypotension risk compared to 12% with phenytoin and 0% with valproate 5
• No significant drug interactions or enzyme-inducing properties 2, 7
• Better tolerability profile than older generation antiepileptics 7

Phenobarbital

• 58.2% efficacy as second-line agent for status epilepticus 5
• Higher risk of respiratory depression compared to other agents 5
• Hyperactivity is a major side effect, observed in 22% of children 6
• Sedation is common, especially in combination therapy 1

Carbamazepine

• Enzyme-inducing properties causing significant drug interactions 2
• Should be avoided when possible due to effects on cytochrome P450 system 2
• Weight loss, nausea, decreased appetite, increased sleep, drowsiness, and tremors reported 8

Newer Generation Antiepileptics (General Profile)

Newer antiepileptics including gabapentin, lamotrigine, topiramate, and oxcarbazepine have better tolerability profiles and fewer drug interactions than older agents. 7

• Better tolerability profiles with low interaction potential 7
• Significantly less enzyme-inducing or inhibiting properties 7
• Common side effects across class: dizziness, drowsiness, and mental slowing 7
• Specific newer side effects: weight gain, metabolic acidosis, nephrolithiasis, angle closure glaucoma, skin rash, hepatotoxicity, colitis, and movement/behavioral disorders 7

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Critical Clinical Considerations

Drug Interactions

• Enzyme-inducing AEDs (phenytoin, phenobarbital, carbamazepine) should be avoided due to effects on chemotherapeutic agent metabolism including irinotecan, gefitinib, erlotinib, and temsirolimus 2
• Valproate depresses phenytoin protein binding, invalidating plasma phenytoin monitoring—saliva monitoring should be used instead 9
• The degree of phenytoin binding depression is directly related to valproate plasma concentration but cannot be predicted even when valproate levels are known 9

Special Population Warnings

• Valproate should be avoided in women of childbearing potential due to significantly increased risks of fetal malformations and neurodevelopmental delay 2, 5
• Discontinuation of valproate led to reversal of hyperinsulinemia, hyperandrogenism, dyslipidemia, and polycystic ovaries in women followed for one year 2
• Levetiracetam is preferred over phenytoin in traumatic brain injury due to better tolerability and lack of worsening neurological outcomes 2

Monitoring Requirements

• Patients should be closely monitored for adverse effects of AEDs, particularly when used with chemotherapeutic agents 2
• Liver function monitoring is essential with valproate due to hepatotoxicity risk 2
• Hematologic monitoring for thrombocytopenia and other blood dyscrasias with both valproate and phenytoin 1, 4
• Long-term phenytoin users require monitoring for bone metabolism disorders and vitamin D levels 4

Common Pitfalls

• Do not use prophylactic antiepileptics in asymptomatic patients with brain tumors or after neurosurgical procedures—studies show this is ineffective 2
• Avoid high-dose glucocorticoids after severe traumatic brain injury due to association with higher mortality 2
• When serious skin reactions occur with valproate and lamotrigine combination, recognize this as a known dangerous interaction 2