Anticonvulsants | The Massachusetts General Hospital Handbook of Neurology

Authors: Flaherty, Alice W.; Rost, Natalia S.

Title: Massachusetts General Hospital Handbook of Neurology, The, 2nd Edition

> Table of Contents > Drugs > Anticonvulsants

Anticonvulsants

A. See also

Seizure classification, p. 109.

B. Slow release forms

Better compliance, fewer SEs.

C. Drug rash

Stop likely med immediately. Beware progression to Stevens-Johnson syndrome (mucous membranes blister) or toxic epidermal necrolysis (epidermis peels off too).

D. Pregnancy and ACDs

see p. 97.

E. Carbamazepine

(Tegretol):

Load: First check CBC, LFTs, iron. Do not start if iron >15 g%. Carbamazepine autoinduces its metabolism.
- Input load: 200 mg qhs 2 d, 200 bid 2 d, then 200 tid; check levels after 3 d.
- Output load: Consider starting SR (Carbatrol or Tegretol XR) 200 mg qhs 1 wk, then 200 bid, then dose per level or effect.
Side effects: Rash, leukopenia, hepatitis, low Na, HA, nausea, ataxia. Need to increase oral contraceptive dose. Check Na, CBC, LFTs, level q mo at first.
To taper carbamazepine: Taper 200 mg qd q2wk.
Carbamazepine lowers levels of: Ethosuximide, tiagabine, topiramate, valproic acid, contraceptives (need to increase estrogen from 35-50 g), steroids, warfarin, antipsychotics, cyclosporine.
Carbamazepine raises levels of: Phenobarbital.

P.162

Carbamazepine levels raised by: (sometimes to toxic levels) cimetidine, erythromycin, Ca channel blockers, propoxyphene, isoniazid, lamotrigine.
Lithium and carbamazepine interact without raising level of either drug but can cause confusion, ataxia, tremor, hyperreflexia.
Mechanism: Stops high-frequency firing via Na channel.

F. Ethosuximide

(Zarontin): Starting dose is 20 mg/kg qd divided tid. For absence seizures. Acts on Ca channels in thalamus; also potentiates dopamine. Lowers carbamazepine levels.

G. Fosphenytoin (Cerebyx)

Dosed in mg phenytoin equivalents (PE). Status epilepticus load 1000 mg PE IV/IM, at <150 mg/min. Maintenance 4-6 mg PE/kg/min IV/IM.

H. Gabapentin (Neurontin)

Load 300 mg PO qhs &times 2 d, then 300 mg bid 2 d, then 300 mg tid; max. 3,600 mg qd. Enhances GABA synthesis; may inhibit Ca channels.

I. Lamotrigine (Lamictal)

Levels raised significantly by valproic acid. Beware rash. Load slowly at most 50 mg PO qhs 2 wk, then 50 mg bid 2 wk, then 150-250 mg bid. Slower if treating with valproic acid.

J. Levetiracetam (Keppra)

Not approved for monotherapy but effective and broad spectrum. Beware rash. Can load quickly (500 mg bid for 1 wk, then 1,000 mg bid). Renally cleared, has few interactions. Well tolerated, can cause drowsiness and behavior disturbances.

K. Oxcarbazepine (Trileptal)

Closely related to oxcarbazepine but fewer side effects and less rash. Approved for monotherapy; start at 600 mg/d bid, increase to 300 mg/d every 3 d to dose of 1,200 mg/d. Causes drowsiness.

L. Phenobarbital

A barbiturate.

Contraindications: Myasthenia, myxedema, porphyria, attention-deficit/hyperactivity disorder, depression.
Side effects: Very sedating, nystagmus, ataxia.
Dose: Typically 60 mg bid-tid qd, children 3-6 mg/kg qd.
Drug interactions: Decreases levels of carbamazepine, lamotrigine, DPH (variable), tiagabine, valproic acid.
Overdose: Similar to alcohol overdose. See ataxia, nystagmus, small reactive pupils, eventually respiratory depression and fixed and dilated pupils.
Withdrawal after heavy use: Similar to delirium tremens. Timing varies with the half-life of the barbiturate used, but generally seizures, hallucinations, and fever begin on the second day of withdrawal.

M. Phenytoin (Dilantin, DPH)

Overused. Often started because it can be loaded IV, but so can valproate.

Contraindications: Secondary or complete AV block, bradycardia, hypotension, low ejection fraction, pregnancy. All pts. on DPH should take folate.
Side effects:
- Short term: Sedation, nystagmus, ataxia, transient dystonias, ophthalmoplegia, rash.
- Chronic: Coarse features, gingival hyperplasia, ataxia, cerebellar atrophy.
Dose: Start 300 mg PO qd; adjust per symptoms. Because of zero-order kinetics, at near-therapeutic doses, a small dose change can cause large level changes. See Table 45.

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Table 45. Phenytoin dose adjustments for goal level of 10-20 mg/dl.

Present Level Change to Make

<6 mg/dL 100 mg/d

6-8 50

>8 25
To discontinue DPH: Taper 100 mg qd every 2 wk.
DPH lowers levels of: Carbamazepine, ethosuximide, primidone, topiramate, valproic acid, warfarin, steroids, cyclosporine, doxycycline, estrogen, furosemide, quinidine, rifampin, theophylline, vitamin D.
DPH raises levels of: Phenobarbital.
DPH levels raised by: Acute alcohol, Depakote, cimetidine and other H₂ blockers, allopurinol, amiodarone, diazepam, estrogens, ethosuximide, imipramine, isoniazid, phenothiazines, sulfonamides, salicylates, trazodone .
DPH levels lowered by: Chronic alcohol, carbamazepine, sucralfate, osmolyte, calcium antacids.
Mechanism: Lowers posttetanic potentiation in Na channel.
Low albumin or renal failure: Lowers DPH plasma level. The adjusted level should be 10-20 g/mL (or free level 1-2 g/mL).
- Low alb: Adj. level = measured level / [(0.2 albumin) + 0.1].
- Renal failure: Adj. = measured level / [(0.1 albumin) + 0.1].
To raise subtherapeutic level: Kinetics change from first-order to saturation near-therapeutic dose, so can increase level by 100 mg qd if level <8, but by no more than 50 mg if >8.
- IV dose (mg/kg) = 0.7 (desired observed plasma conc.).
- Oral dose (mg/kg) = IV dose + 10%.

N. Topiramate (Topamax)

Approved for monotherapy. Start at 25 mg bid, increased by 50 mg qd every week up to 400 mg qd maintenance. Effective in migraine prophylaxis (not effective after 100 mg qd), causes weight loss but also cognitive dulling.

O. Valproate (Depakote)

Strictly, Depakote is divalproex. Valproate is Depakene; less well tolerated. They act on chloride channel, GABA receptor.

Side effects: Check LFTs. Nausea, weight gain, thin hair, teratogenicity, polycystic ovarian syndrome. Small increased risk of bleeding; pancreatitis, hepatitis.
Dose: PO takes several weeks for effect. 1 wk on each dose: 250 mg qd, 250 bid, 250 tid, 250-250-500. IV: 10-15 mg/kg qd divided tid.
To discontinue valproate: Taper 250 mg qd q2wk.
Valproate lowers levels of: Carbamazepine, DPH (total, but free DPH levels increase), phenobarbital.
Valproate raises levels of: Ethosuximide, lamotrigine (lower the dose from tid to bid), phenobarbital, primidone.
Valproate levels raised by: Aspirin.