18 Using Parenteral Antiepileptic Medications

Jane G. Boggs

Neurology, Wake Forest University School of Medicine, Comprehensive Epilepsy Center, Winston Salem, NC, USA

Introduction

Parenteral antiepileptic drugs (AEDs) are used for treatment of status epilepticus (SE) and acute repetitive seizures (ARS), as well as when enteral administration is not possible. Complexities inherent to use of parenteral AEDs include choosing how and when to use a loading dose, what maintenance doses to give, and whether and for how long to administer a continuous infusion. This chapter reviews these issues for those AED preparations clinically available for parenteral use. Approaches to treating SE are reviewed in Chapters 31 and 32.

Agents

Benzodiazepines

Although tachyphylaxis limits the role of most benzodiazepines (BZDs) in the long-term treatment of chronic epilepsy, these agents are typically the first treatment for SE and ARS. Pharmacokinetics of diazepam (DZP) and lorazepam (LZP) are given in Chapter 19. Pharmacodynamic drug interactions of BZDs with barbiturates may result in synergistic effects on respiration. Respiratory status must be carefully monitored and intubation considered before combining sedatives. Use of BZDs as out-of-hospital rescue medications is discussed in Chapter 16.

SCIENCE REVISITED

While gastrointestinal absorption delays the action of oral medication, the effects of parenteral drugs depend on lipophilicity, which affects the efficiency with which they traverse the blood–brain barrier. The BZDs vary in lipid solubility as well as redistribution rates from the site of action (neurons) to the remainder of the compartments of the cranium and, subsequently, the body. Drugs with the fastest egress from the brain may control seizures only briefly, with seizure recurrence resulting from the rapid loss of the pharmacological effect on GABA-mediated inhibition.

Diazepam

Intravenous (IV) DZP has the fastest onset of CNS effect (less than 1 min) of current BZDs. Its 1–2 h distribution half-life (t_1/2) results in rapidly resolving sedation but mandates prompt introduction of longer-lasting AEDs in patients with repeated seizures. Initial DZP (5 mg/mL) adult IV dosing is 5–10 mg repeated every 10–15 min to reach a maximum of 30 mg. Dosing for neonates is 0.1–0.3 mg/kg/dose to a maximum of 2 mg, and for children, 0.04–0.3 mg/kg/dose to a maximum of 0.6 mg/kg/8 h. Injection rate should not exceed 5 mg/min and should be slower with cardiac, hepatic, or renal disease. Intramuscular (IM) injection may have erratic absorption. Tachyphylaxis may develop in less than 48 h. Other BZDs are preferred to DZP in kidney dysfunction, as renally eliminated active metabolites (e.g., desmethyldiazepam) may prolong sedation. DZP has modest cytochrome P450 induction (2B) and can accelerate clearance of other medications.

Lorazepam

Intravenous LZP has high lipophilicity and affects the EEG within 2 min, with peak effect at 30 min. The effect is more sustained than that of DZP, with a distribution half-life of 2–3 h. The recommended dose is a 4 mg bolus (0.1 mg/kg), given no faster than 2 mg/min, with a repeat 4 mg after 10–15 min. Maximum recommended total adult dose is 8 mg. LZP may cause hypotension, somnolence, or respiratory depression. Continuous infusions for SE are at doses of 0.5–10 mg/h. While an IV 4 mg bolus gives a peak level of 70 ng/mL, IM administration has unpredictable absorption, with an average peak level of 48 ng/mL.

Midazolam

Unlike DZP and LZP, midazolam (MDZ) does not contain propylene glycol. It is water soluble, making it suitable for IM injection. Because of conversion to the lipophilic form at physiological pH, its CNS effect is delayed up to 2 min, but it has rapid distribution t_1/2 (3.3–8.1 min). The initial recommended dose is 0.2 mg/kg over 2–3 min with a continuous infusion beginning at 2–4 mg/h, titrated to burst–suppression on the EEG. Tachyphylaxis often limits utility to <48 h. It can cause respiratory suppression.

Phenytoin

Phenytoin (PHT) has been shown to stop 80% of acute seizures, and it is commonly used after BZD to treat SE. The usual initial PHT loading dose in adults and pediatrics is 15–20 mg/kg. An additional 10 mg/kg can be given, to a maximum total load of 30 mg/kg. Maintenance therapy (Chapter 19) should be promptly started.

Phenytoin has striking local toxicity due to poor water solubility, alkaline pH, and suspension in propylene glycol. Administration should be in large veins and not faster than 50 mg/min. Infusion is often associated with pain, phlebitis, and loss of IV access. Rates in children should be less than 1–3 mg/kg/min. “Purple glove syndrome” is a rare, devastating complication of PHT infusions that may lead to amputation. Systemic side effects of PHT infusion include hypotension, cardiac conduction abnormalities, and arrhythmias. Cardiac telemetry and blood pressure monitoring are required during infusion. Slowing the infusion rate may reduce these side effects. Adults with significant renal, hepatic, or cardiac disease should not receive PHT faster than 25 mg/min. IM injection is caustic and not recommended due to risk of abscesses and crystallization within muscle.

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