Antiepileptic
Levetiracetam (Keppra)
Also called Keppra
Indications
- Established status epilepticus after a benzodiazepine (off-label; ESETT 2019: 47% response, similar to fosphenytoin and valproate)
- IV replacement for oral therapy in focal-onset, myoclonic and generalized tonic-clonic seizures when oral dosing is temporarily not feasible
- Seizure prophylaxis after TBI, subarachnoid or intracerebral hemorrhage, or brain surgery (off-label; Brain Trauma Foundation guidance names phenytoin for early post-traumatic seizures)
- Nonconvulsive seizures found on ICU EEG (off-label)
Dosing
| Where | Dose |
|---|---|
| Seizures and neuro | Levetiracetam: 60 mg/kg (max 4,500 mg) over 10 min |
| Other ICU drugs | Levetiracetam: Reduce; supplement after hemodialysis |
On the quick cards
Mechanism of action
Levetiracetam binds synaptic vesicle protein 2A (SV2A), a transmembrane glycoprotein of presynaptic vesicles that regulates their readiness for calcium-triggered exocytosis. Binding reduces vesicle release, apparently most during the high-frequency bursts of a seizure, which limits seizure spread while sparing normal transmission. Related compounds protect against seizures in proportion to their SV2A affinity (Lynch 2004). It also partly inhibits N-type calcium channels but has no direct action on GABA receptors or sodium channels.
Pharmacology
- CNS: somnolence (15% vs 8% on placebo), asthenia, dizziness and poor coordination, mostly in the first 4 weeks
- Psychiatric: irritability, aggression, depression and rarely psychosis; behavioral symptoms in 13% of adults vs 6% on placebo, and more often in children
- Cardiovascular and respiratory: no meaningful hypotension, arrhythmia, QTc prolongation or respiratory depression at loading doses
- Hematologic: small falls in red and white cell counts; rare agranulocytosis or pancytopenia
- Other: neither induces nor inhibits liver enzymes, so drug interactions are minimal
Pharmacokinetics
| Onset | Peak level at the end of a 15-min infusion; oral peak about 1 h |
|---|---|
| Half-life | 7 ± 1 h in adults; about 2.5 h longer in older adults and longer still as creatinine clearance falls |
| Distribution | Close to total body water (about 0.5–0.7 L/kg); crosses the blood-brain barrier and placenta and enters breast milk |
| Protein binding | Under 10% |
| Metabolism | No CYP involvement: 24% is hydrolyzed at the acetamide group, largely in blood, to the inactive acid ucb L057 |
| Clearance | 0.96 mL/min/kg, about two-thirds renal by filtration with partial tubular reabsorption; tracks creatinine clearance |
| Elimination | Urine: 66% unchanged, the rest mainly as the metabolite |
| Bioavailability | Nearly 100% orally; IV and oral doses are interchangeable |
| Kidney dosing | Clearance falls 40%, 50% and 60% in mild, moderate and severe impairment and 70% in anuria; reduce doses and add a supplemental dose after hemodialysis, which removes about 50% in 4 h |
| Critical illness | Augmented renal clearance (young trauma, TBI, sepsis) and CRRT can leave standard doses too low; liver disease needs no change |
Chemistry
- (S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, a pyrrolidone (racetam) chemically unrelated to other antiepileptics
- The single S-enantiomer of etiracetam: the SV2A site is stereoselective, the R-enantiomer is far weaker, and neither converts to the other in the body
- Small (molecular weight 170), neutral and very water soluble (104 g/100 mL), with no group that ionizes at body pH
- 500 mg/5 mL vials with sodium chloride and acetate buffer, pH about 5.5; dilute to no more than 15 mg/mL in saline, lactated Ringer's or D5W and use within 4 h at room temperature; premixed bags also exist
- Physically compatible with lorazepam, diazepam and valproate
Adverse effects and cautions
In the one-pagers
- Pediatric Assessment and EmergenciesDKA, cerebral edema and status epilepticus: 20–40 min: Levetiracetam IV: 60 mg/kg (max 4,500 mg)
- Neuro: ICP and StrokeStatus epilepticus: Check glucose and protect the airway without delaying the benzodiazepine. Still seizing: levetiracetam, fosphenytoin or valproate.
- CRRT (Continuous Renal Replacement)Complications: drugs, nutrition, electrolytes, heat: CRRT at 25 mL/kg/h behaves like a glomerular filtration rate of 25–35 mL/min that never pauses, so renally cleared drugs are dosed as for a creatinine clearance of 25–50 mL/min, and loading doses are not reduced. A drug is removed when it is small (nearly all are), mostly unbound and has a small volume of distribution. Removed: beta-lactams, van
- Subarachnoid HemorrhageHeart, lungs, seizures and other systems: Seizure-like events are reported in up to 26%, seizures in 7.8–15.2% in recent studies (AHA/ASA 2023). Prophylaxis may be reasonable with MCA aneurysm, poor grade, ICH, hydrocephalus or cortical infarction (2b) and is not beneficial without them. After a seizure at onset, treat for 7 days or less (2a), since longer courses do not prevent later seizures; se
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Sources
- FDA label: Keppra injection (2023)
- Kapur 2019, ESETT (NEJM)
- Lynch 2004 (SV2A)
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