1° MOA: ↑'s inhibitory effect of GABA, possibly by activation of glutamic acid decarboxylase or inhibition of GABA-transaminase; blockade of high-frequency repetitive firing by slowing the rate of Na+ recovery from inactivation, blocks the low-threshold T-type Ca2+ channel.
t½: 14 (9-18)° TMAX: 2-3°
Substrate of: UGT1A3, UGT2B7, mitochondrial β-oxidation; 2C9, 2A6, 2B6
Inhibits: 2C9 (major), 2C19 & 3A4 (minor), UGT1A4 & UGT2B7; Induces: ∅
Active Metabolites: ∅
- - inhibits metabolism of lamotrigine; so when coadministered lamotrigine dose should be halved
aspirin increases levels by ↓ its protein binding
highly (≥90%) bound to plasma proteins & ∴ subject to displacement interactions, e.g. phenytoin, carbamazepine, warfarin, tolbutamide, diazepam (unbound levels ↑ twofold)
- - first-line treatment for mania and mixed states; may not be as effective for treating bipolar depression
extended release is ~80% as bioavailable as IR, so plasma levels will ↓ ~20% when converting from immediate to extended-release
- - selenium & zinc supplementation may help prevent hair loss
more effective in preventing mania than treating depressive episodes, "a better ceiling than a floor"
Category D—*AVOID* High rate of neural tube defects; the absolute risk of producing a child with neural tube defects when used between the 17th and 30th days after fertilization is 1%–2%! Also associated with ↓ IQ scores and autism.
Though RID's up to as high as 15% have been measured, the American Academy of Pediatrics classified valproic acid as compatible with breastfeeding
Elderly are especially prone to somnolence
No dosage adjustment necessary
Contraindicated in patients with hepatic impairment