Barbiturates	Haloperidol
Carbamazepine	Chlorpropamide
Oxcarbazepine	Thioridazine
Thiazides	Imipramine
Vincristine	MAO inhibitors
Cyclophosphamide	Bromocriptine
General anesthetics	Oxytocin
Nicotine	Acetamides
Clofibrate	Tolbutamide
Nonsteroidal antiinflammatory drugs

Adapted from Asconape J. Some common issues in the use of antiepileptic drugs. Semin Neurol 2002;22:27.

Drug Fever

Development of a fever coincident with initiation of an anticonvulsant in the ICU setting complicates patient management and is a serious potential concern. Drug fever is a particularly common occurrence with the two agents, phenytoin and fosphenytoin, but can occur with other anticonvulsants as well.¹ Peripheral eosinophilia supports the diagnosis. However, it is frequently the case that the diagnosis of drug-induced fever is firmly established only when hyperthermia resolves after an alternative anticonvulsant is substituted for the original agent.

Alteration In Neurologic Examination

The toxic side effects of phenytoin or carbamazepine can promote development of ataxia. Valproic acid can induce tremors. Carbamazepine toxicity can present in a biphasic fashion (i.e., acutely and subacutely) as a consequence of increasing levels of a toxic metabolite.¹

Renal Disease

Clearance of anticonvulsants can be significantly reduced when the glomerular filtration rate (GFR) falls below 10 mL/min. The clearance of phenobarbital and carbamazepine are not greatly affected by low GFR, but the clearance of phenytoin and valproic acid can be affected by changes in renal function. The higher protein binding exhibited by these latter agents makes measurement of the free levels of these drugs a better guide for dosage adjustments.¹ Hemodialysis does not affect circulating phenytoin levels to a large extent, but renal replacement therapy can markedly affect serum levels of phenobarbital.

Many anticonvulsants can affect metabolism and or protein binding of other agents. Phenytoin, carbamazepine, and phenobarbital are all potent inducers of the hepatic P450 enzyme systems (Tables 172-2 and 172-3), and treatment with these anticonvulsants can affect the circulating concentrations of other medications (Tables 172-4 and 172-5) including concomitantly administered anticonvulsant drugs (see Table 172-5). Phenytoin can reduce the plasma concentrations of carbamazepine and valproic acid, whereas interaction with phenobarbital is variable. Phenytoin decreases the effectiveness of warfarin and theophylline. Valproic acid inhibits the metabolism of phenobarbital and carbamazepine (including its 10,11-epoxide metabolite), which can result in increased serum levels. Carbamazepine increases the hepatic metabolism of diazepam and valproic acid. Phenobarbital results in decreased circulating levels of warfarin, theophylline, and cimetidine.³ Cimetidine, amiodarone, isoniazid (INH), and chlorpromazine all decrease hepatic metabolism of many drugs including phenytoin (Table 172-6). Drugs that commonly decrease circulating phenytoin levels include digoxin, cyclosporine, corticosteroids, warfarin, and theophylline. Aluminum hydroxide, magnesium hydroxide, and calcium-containing antacids decrease the absorption of enterally administered phenytoin. Some of the newer anticonvulsants such as levetiracetam and lacosamide are excreted via the kidneys for the most part, and their circulating levels are unaffected by hepatic metabolism. In addition, drug-drug interactions are not a major concern with these newer agents, and they do not affect the levels of other anticonvulsants.

TABLE 172-2 Metabolic Pathways of Anticonvulsant Drugs

TABLE 172-3 Anticonvulsant Induction of Hepatic Metabolic Enzymes

Inducers	Inhibitors	No or Minimal Effect
Carbamazepine	Valproate	Gabapentin
Phenytoin	Felbamate	Lamotrigine
Phenobarbital		Topiramate
Primidone		Tiagabine
		Oxcarbazepine
		Levetiracetam
		Zonisamide

Adapted from Asconape J. Some common issues in the use of antiepileptic drugs: Semin Neurol 2002;22:27.

TABLE 172-4 Alterations in Drug Plasma Levels with Combination Anticonvulsant Use

TABLE 172-5 Effects of Anticonvulsant Drugs on Commonly Used Medications

TABLE 172-6 Common Drug Interactions of Anticonvulsants

Phenytoin and Carbamazepine
Added Drug	Phenytoin	Carbamazepine
Salicylates	↑
Erythromycin		↑↑
Chloramphenicol	↑
Trimethoprim	↑
Isoniazid	↑	↑
Propoxyphene	↑	↑
Amiodarone	↑
Diltiazem, verapamil		↑
Cimetidine	↑	↑
Ethanol	↓
Rifampin	↓
Digitoxin	↓
Cyclosporine	↓
Warfarin	↓
Theophylline	↓
Glucocorticoids	↓

↓, decrease in plasma levels; ↑, increase in plasma levels.

Idiosyncratic Reactions

Hypersensitivity reactions are common with phenytoin and carbamazepine and can be manifested by fever, rash, and/or eosinophilia.¹ Drugs associated with a high risk for the development of rash include phenytoin, phenobarbital, primidone, lamotrigine, carbamazepine, oxcarbazepine, and zonisamide⁴ (Table 172-7). Transient leukopenia and thrombocytopenia are commonly seen with carbamazepine and valproate. Other less common drug-related effects include hepatic failure, pancreatitis (valproic acid), agranulocytosis, aplastic anemia, megaloblastic anemia (phenytoin), Stevens-Johnson syndrome, and lupus-like syndromes. Although rare, severe hepatic dysfunction secondary to formation of a toxic metabolite can occur with valproic acid therapy. This potentially fatal reaction most often occurs in children younger than 2 years of age who are also receiving aspirin and other drugs for control of seizures.

TABLE 172-7 Antiepileptic Drugs and Risk of Skin Rash

High Risk	Low Risk
Phenytoin	Valproate
Phenobarbital	Topiramate
Primidone	Gabapentin
Carbamazepine	Tiagabine
Oxcarbazepine	Levetiracetam
Lamotrigine	Lacosamide
Zonisamide

Data from Asconape J. Some common issues in the use of antiepileptic drugs: Semin Neurol 2002;22:27.

Management Of Anticonvulsant Toxicity

Management of patients suffering from severe toxicity requires comprehensive supportive therapy including airway management, hemodynamic support, and oral administration of activated charcoal. Charcoal has been especially useful for managing cases of acute valproate acid intoxication.⁵ In cases of valproic acid or carbamazepine poisoning, concurrent hemoperfusion and hemodialysis to enhance elimination of the anticonvulsant can be useful when patients are hemodynamically unstable and the clinical condition is worsening despite aggressive supportive care.⁶

Specific Anticonvulsant Properties by Class

Benzodiazepines

For immediate therapy, benzodiazepines are still considered first-line treatment for most seizures. These drugs are highly lipophilic, are potent γ-aminobutyric acid (GABA)-activated agonists, and serve to improve local inhibition of signal transmission. The most commonly used benzodiazepines in the ICU are diazepam, lorazepam, and midazolam. In the case of hepatic failure, oxazepam may be preferred because it is the only benzodiazepine not metabolized by the liver.⁷

There are instances where short-acting benzodiazepines (e.g., midazolam or diazepam) may be preferable; anticonvulsants that offer prolonged sedation may interfere with reliable neurologic assessment and management. When such concerns exist, it may be preferable to initiate treatment of seizures using a short-acting benzodiazepine, followed immediately by a loading dose of a less-sedating medication such as phenytoin or other maintenance anticonvulsant.

If the seizure(s) have not been controlled following therapeutic doses of benzodiazepines, treatment with additional medications is warranted. Tachyphylaxis rapidly develops with the use of benzodiazepines, and these agents are not indicated for prophylaxis or maintenance therapy. Common secondary agents which are efficacious in the acute setting and are available for IV administration include phenytoin, fosphenytoin, carbamazepine, and valproic acid. Levetiracetam and lacosamide are newly developed agents that can be administered IV and are often used as second-line agents in the setting of uncontrolled seizures in the ICU.

Diazepam

Diazepam (Valium) has been available for many years, and most clinicians have considerable experience with this drug. Its use has been declining in recent years due to the availability of more effective agents such as midazolam and lorazepam. Following administration, the highly lipophilic drug, diazepam, rapidly redistributes from plasma into tissue. Because of this, the anticonvulsant duration is just a few minutes. Diazepam is not water soluble and requires emulsification with a vehicle (propylene glycol) for IV administration. Diazepam can induce phlebitis and should be administered slowly and preferably into a large vein.

Pharmacokinetics

Oral absorption: 85-100%.

Distribution: 98% protein bound.

Elimination: half-life parent drug 20 to 50 hours; active major metabolite (desmethyldiazepam) 50 to 100 hours.

Metabolism: hepatic.

Drug interactions: theophylline can antagonize the effects of benzodiazepines. Oral contraceptives can decrease the clearance of benzodiazepines. Benzodiazepines can interfere with the therapeutic effects of levodopa. Additive sedative effects and/or respiratory depression can occur with ethanol, barbiturates, and narcotic analgesics. Potential hepatic P450 enzyme induction exists with phenobarbital, phenytoin, carbamazepine, rifampin, and rifabutin.^1,^3,¹⁰

Adverse reactions/toxicities: hypotension, drowsiness, ataxia, paradoxical excitement or rage, memory impairment, rash, decrease in respiratory rate, and frank apnea all can occur following administration of diazepam. All benzodiazepines are associated with dependence and/or withdrawal symptoms on discontinuation or reduction in dose following prolonged dosing.¹¹ Acute withdrawal symptoms including seizures can be precipitated when the drug is discontinued or the dosage is reduced. Withdrawal reactions including seizures can occur following administration of the GABA antagonist, flumazenil.¹²

Contraindications: narrow angle glaucoma, pregnancy.

Midazolam

When a short-acting benzodiazepine is needed, most clinicians now employ midazolam instead of diazepam. Midazolam is highly lipophilic, and the onset of its effects occur very rapidly following IV administration.¹³ Midazolam is marketed as a water-soluble prodrug. Following IV administration, the drug is transformed into a lipophilic compound by virtue of rapid closure of the diazepine ring. Thus the drug is less irritating to veins than diazepam.

Dosing

Adults: IV initial dose is 0.5 to 2 mg; no more than 2.5 mg should be administered over a period of 2 minutes. A total dose of more than 5 mg is generally not required. Maintenance is approximately 25% of the dose needed to reach the sedative effect. Consider a decrease in dosage by 30% if narcotics or other CNS depressants are administered concurrently.

Elderly: consider a dosage reduction based on altered kinetics ¹⁴ and sensitivity.

Hepatic impairment: reduce dose by 50% in patients with cirrhosis and avoid in severe/acute liver disease.

Renal impairment: midazolam is not dialyzable; supplemental dosing is not necessary.

Forms available: injection solution, 1 mg/mL (2 mL, 5 mL, 10 mL) and 5 mg/mL (1 mL, 2 mL, 5 mL, 10 mL); syrup, 2 mg/mL (118 mL); tablet (2 mg, 5 mg, 10 mg).

Mechanism(s) of action: midazolam binds to GABA_A receptors, resulting in the opening of the chloride channel, with resultant hyperpolarization and inhibition of neuronal firing.

Lorazepam

Lorazepam is the least lipid-soluble agent among the three commonly used benzodiazepines. As a consequence, the pharmacologic effects of lorazepam are delayed in onset and prolonged in duration.¹⁵ Lorazepam is ideally suited for acute therapy, together with longer prophylaxis against recurrence of seizures. In a 5-year randomized double-blind multicenter trial of four IV regimens for the treatment of generalized status epilepticus, Treiman et al. found that treatment with lorazepam (0.1 mg/kg) was successful in 64.9% of patients and significantly superior to phenytoin (P = 0.002) in a pairwise comparison.¹⁶ It is important to note that lorazepam’s longer duration of action can adversely impact the neurologic examination for several hours, potentially complicating medical management.

Dosing

Adults: oral, 1 to 2 mg every 30 to 60 minutes for tranquilization of agitated patient; IV, 2 to 4 mg, may repeat in 3 to 4 hours if needed.

In status epilepticus: IV, 4 to 8 mg given over 2 to 5 minutes; also can dose 0.1 mg/kg. May be given intramuscularly (IM) with little discomfort.

Elderly: consider a dosage reduction.

Hepatic impairment: reduce dose by 50% in patients with cirrhosis, and avoid in severe/acute liver disease.

Renal impairment: lorazepam is not dialyzable; supplemental dosing is not necessary. Large doses of the polyethylene glycol emulsion may induce nephrotoxicity.¹⁷

Forms available: injection solution, 2 mg/mL (30 mL); tablet (0.5 mg, 1 mg, 2 mg).

Mechanism(s) of action: binds to GABA_A receptors, resulting in opening of the GABA chloride channel, with resultant hyperpolarization and inhibition of neuronal firing.

Phenytoin

Phenytoin has been and remains the drug most commonly used in the ICU for prophylaxis against seizures. Several reasons for the continued popularity of phenytoin include its ease of administration, its availability in formulations suitable for either IV or enteral administration, its relative safety (severe toxic reactions are uncommon), and its efficacy against many seizure syndromes that occur in the ICU setting, including status epilepticus. Temkin et al. reported that prophylactic administration of phenytoin decreased the incidence of seizures during the first week following traumatic head injury by 73% compared to placebo.¹⁸ In light of its non-GABA-agonist action, phenytoin is not particularly effective against most drug-induced convulsions, especially those triggered by β-lactam antibiotics. Phenytoin is indicated for use against generalized tonic/clonic seizures and focal and complex-partial seizures. Phenytoin also is indicated for prevention of seizures following head trauma or elective neurosurgical procedures.

Dosing

Adults: for seizure prophylaxis or initial therapy to combat seizures, the loading dose is 15 to 20 mg/kg IV; oral (PO) loading doses should be administered as 3 divided doses every 2 hours. For IV administration, the drug should be given at a rate of less than 50 mg/min, because the glycol-based vehicle can induce hypotension and/or heart block. The maintenance dose of 5 to 6 mg/kg/d PO can be given all at once or in divided doses.

Elderly: administration rate should be decreased owing to increased likelihood of hypotension and/or heart block (e.g., rate of administration = 20 mg/min).

Hepatic impairment: phenytoin should be used with caution, as there is decreased clearance of the drug in patients with cirrhosis. Monitoring of liver function tests and free phenytoin levels is advocated.

Renal impairment: in patients with renal insufficiency, interpretation of total levels is difficult, since the free fraction is altered (increased) due to the reduction of plasma protein concentration. Monitoring of free serum levels is recommended.

Forms available: capsule (30 mg, 100 mg, 200 mg, 300 mg); injection (50 mg/mL; 2 mL, 5 mL); oral suspension (125 mg/5 mL; 240 mL); chewable tablet (50 mg).

Mechanism of action: its mechanism is not entirely clear, although it blocks sodium channels, which reduces neuronal excitation.

Pharmacokinetics

Absorption: phenytoin is slowly absorbed orally, and uptake from the gastrointestinal tract is even less reliable when the drug is given concurrently with enteric tube feedings. Thus, tube feedings should be discontinued for 2 hours prior to and 2 hours after each enteral dose. The bioavailability of phenytoin is form dependent; reference range 10 to 20 µg/mL total; free levels 0.1 to 0.2 µg/mL. Free drug levels should be monitored in physiologic states associated with decreased circulating albumin concentrations (e.g., burns, head injury,¹⁹ hepatic cirrhosis, nephrotic syndrome, pregnancy, cystic fibrosis), and in patients with hepatic and/or renal failure.

Distribution: V_d is 0.6 to 0.7 L/kg; 90% to 95% protein bound.

Elimination: hepatically metabolized; phenytoin is excreted in the urine as glucuronides, with a half-life of approximately 22 hours.

Metabolism: hepatic metabolism; phenytoin follows dose-dependent capacity-limited (Michaelis-Menten) pharmacokinetics. Thus, serum and free levels may abruptly increase once capacity for metabolism is exceeded (zero-order kinetics).

Drug interactions: as isolated phenomena, phenytoin can enhance the hepatotoxic potential of acetaminophen, blunt the diuretic effect of furosemide, increase the metabolism of HMG-CoA reductase inhibitors, decrease the duration of effect of neuromuscular blocking agents, and reduce the metabolism of thyroid hormones.^3,¹⁰ Antacids can decrease absorption of phenytoin, whereas amiodarone can increase circulating concentrations. The sedative effects of phenytoin can be additive with other CNS depressants.

As a known inducing agent for hepatic metabolism, phenytoin increases the clearance of corticosteroids and many anticonvulsants (barbiturates, carbamazepine, ethosuximide, felbamate, lamotrigine, tiagabine, topiramate, and zonisamide).³ Thus, anticonvulsant polypharmacy can be frustrated by the addition of phenytoin. However, phenytoin does not affect gabapentin or levetiracetam levels. As would be expected, circulating levels of phenytoin can be decreased by concomitant use of other “hepatic enzyme inducers” (e.g., barbiturates, carbamazepine, chronic ethanol, dexamethasone, rifampin). Because it can precipitate acute attacks, use of phenytoin should be avoided if possible in patients with hepatic forms of porphyria.

In contrast, inhibitors of the hepatic enzymes, CYP28/C9 (e.g., amiodarone, cimetidine, fluvoxamine, some nonsteroidal antiinflammatory drugs, metronidazole, ritonavir, sulfonamides, troglitazone, valproic acid) and CYP2C19 (e.g., felbamate, fluconazole, fluoxetine, fluvoxamine, omeprazole) can increase circulating phenytoin levels.⁴

Adverse reactions/toxicities: phenytoin is associated with thrombophlebitis and toxic epidermal necrolysis.^20,²¹ Administration of the drug can induce hypotension, bradycardia, and bundle branch block, especially if the drug is administered rapidly (>50 mg/min). A phenytoin-induced rash is quite common (20%).⁴ Hyperglycemia, leukopenia, and thrombocytopenia are reported complications of therapy with phenytoin. Skin necrosis related to extravasation of phenytoin can occur at the site for IV infusion of the drug. For this reason, fosphenytoin is a preferable agent, particularly when completely reliable venous access is unavailable. Small veins can develop phlebitis and cause transient discomfort during infusion even if no extravasation occurs.

Side effects: with long-term use of phenytoin include gingival hypertrophy, cerebellar atrophy, coarsening of facial features, osteoporosis, vitamin D deficiency, and peripheral neuropathy.^1,^4,¹⁰ In high doses or concentrations, administration of phenytoin can be associated with nystagmus, diplopia, ataxia, slurred speech, drowsiness, and coma.

Fosphenytoin

Fosphenytoin (Cerebyx) is a phosphate ester prodrug of phenytoin. It is highly water soluble. When administered parenterally (IV or IM), fosphenytoin is rapidly metabolized into phenytoin. It can be infused up to three times faster than phenytoin (i.e., maximal rate of infusion, 150 mg/min).²² The times to peak effect are similar for phenytoin and fosphenytoin, because enzymatic conversion of the prodrug occurs rapidly. Kugler et al. suggested that fosphenytoin and phenytoin are likely to control status epilepticus with similar rapidity.²³ The benefits of fosphenytoin compared to phenytoin are faster safe rate of administration and lower likelihood for certain adverse effects (e.g., hypotension, phlebitis, and soft-tissue injury from extravasation). Although fosphenytoin is more expensive than phenytoin, the costs associated with treating complications from the use of IV phenytoin can be substantially greater; accordingly, fosphenytoin may be advantageous on a pharmaco-economic basis.²⁰

Dosing

Although a different drug from phenytoin when initially administered, the dosage of fosphenytoin is always described in phenytoin equivalents (PE). Because fosphenytoin is water soluble, it can be administered safely IM, whereas phenytoin cannot.²⁴

Adults: for acute management and in prophylaxis, 15 to 20 mg/kg IV administered at 100 to 150 mg/min.²² Maintenance dose is 4 to 6 mg/kg/d IV or IM; oral phenytoin is 90% bioavailable, as compared to 100% bioavailability using IV and IM preparations, so a higher dosage may be necessary when converting from IV or IM to PO. Therapeutic range is the same as the therapeutic range for phenytoin: 10 to 20 µg/mL.

Elderly: the geriatric population may be more sensitive to hypotension and sedation associated with higher infusion rates.

Hepatic impairment: phenytoin clearance can be markedly reduced in cirrhosis; free phenytoin levels should be monitored.

Renal impairment: free phenytoin levels should be monitored closely. Phenytoin is not significantly dialyzed.

Forms available: injection solution 75 mg/mL (equivalent to phenytoin sodium 50 mg/mL).

Mechanism of action: fosphenytoin is the diphosphate ester salt of phenytoin, which acts as a water soluble prodrug of phenytoin. Following administration, plasma esterases convert fosphenytoin to phosphate, formaldehyde, and phenytoin as the active moiety. Phenytoin acts as a sodium channel blocker to reduce neuronal excitability.

Pharmacokinetics

Absorption: the rise in serum concentration of fosphenytoin may be faster compared to phenytoin when administered IV, because of the higher maximal recommended infusion rate for the prodrug (150 mg/min versus 50 mg/min, respectively). However, owing to the necessary biotransformation (conversion to phenytoin after IV administration is approximately 15 minutes), the resulting time-to-peak serum levels of phenytoin are similar for the two agents.²² Bioavailability of each approaches 100%.

Distribution: 95% to 99% of fosphenytoin is bound to albumin. During IV administration, fosphenytoin can displace phenytoin and increase free fraction (up to 30% unbound) during the period required for conversion of fosphenytoin to phenytoin. The half-life of fosphenytoin is 12 to 29 hours.

Elimination: fosphenytoin is excreted in the urine as an inactive metabolite.

Metabolism: fosphenytoin is converted via hydrolysis to phenytoin. See Phenytoin for further metabolism.

Drug interactions: see Phenytoin monograph.

Adverse reactions/toxicities: most important with IV use of fosphenytoin (or phenytoin) are cardiovascular collapse and/or CNS depression. Paresthesias and pruritus are more common with fosphenytoin than phenytoin and occur more often with IV than IM adminisitration.^4,¹⁰ The drug is contraindicated for patients with sinus bradycardia, sinoatrial block, second- or third-degree atrioventricular (AV) block, or Stokes-Adams syndrome. As with phenytoin, it is important to monitor hematologic and liver function tests. Other side effects include gingival hyperplasia, gynecomastia, bone marrow suppression, and vermian cerebellar atrophy.^4,¹⁰ Venous irritation is less common with fosphenytoin compared to phenytoin.²⁵

Contraindications: pregnancy category D.

Carbamazepine

Carbamazepine (Tegretol) is indicated for partial seizures with complex symptomatology (psychomotor, temporal lobe), generalized tonic/clonic (grand mal) seizures, and mixed seizure patterns. The drug is not available for IV administration and is rarely used for acute termination of seizures or as standard prophylaxis in the ICU. When using carbamazepine, it is recommended (see later) to monitor complete blood count, reticulocyte count, serum iron concentration, liver function tests, urinalysis, serum electrolytes, serum drug levels, and thyroid function tests.

Dosing

Adults: typically carbamazepine is dosed as 200 mg twice or thrice daily, then increased by 200 mg/d at weekly intervals until therapeutic levels are achieved. The usual therapeutic dose is 800 to 1200 mg/d in 3 to 4 divided doses. Dosage must be adjusted according to the patient’s response and serum concentrations (therapeutic range is 4-12 µg/mL).²⁶

Elderly: lower doses are typically used in the elderly: 100 mg 1 to 2 times per day. The typical dose is 400 to 1000 mg/d.

Hepatic impairment: carbamazepine is hepatically metabolized to an epoxide intermediate, which itself has an appreciable anticonvulsant action.

Renal impairment: in renal impairment, if GFR is less than 10 mL/min, administer 75% of typical dose.

Forms available: capsule, extended release (200 mg, 300 mg); oral suspension, 100 mg/5 mL; tablet, 200 mg; chewable tablet, 100 mg; extended-release tablet, 100 mg, 200 mg, 400 mg.

Mechanism of action: like phenytoin, carbamazepine acts as a sodium channel blocker. It also stimulates release of antidiuretic hormone (ADH) and is chemically related to the tricyclic antidepressants.

Pharmacokinetics

Absorption: orally administered doses of carbamazepine are slowly absorbed, and the time to peak circulating concentration is 4 to 8 hours. Bioavailability approximates 85%.

Distribution: V_d of carbamazepine is 1 to 2 L/kg in adults; 75% to 90% of the drug is protein bound.²⁶

Elimination: carbamazepine is excreted in the urine.

Metabolism: carbamazepine is hepatically metabolized to an active epoxide metabolite; half-life is 8 to 60 hours.²⁷

Drug interactions: oral carbamazepine suspension should not be administered at the same time as other liquid medicinal agents, as it can form a precipitate when combined with chlorpromazine or thioridazine. Barbiturates, benzodiazepines, and phenytoin can decrease plasma carbamazepine levels, owing to induction of hepatic metabolism.^3,¹⁰ Conversely, isoniazid, felbamate, danazol, diltiazem, and verapamil can increase plasma carbamazepine levels. Carbamazepine itself can increase the metabolism of warfarin, valproic acid, tricyclic antidepressants (particularly selective serotonin reuptake inhibitors [SSRIs]), thyroxine, theophylline, oral contraceptives, methadone, doxycycline, corticosteroids, calcium channel blockers (except diltiazem and verapamil), cyclosporine, tacrolimus, and ethosuximide.¹⁰

Adverse reactions/toxicities: like phenytoin, carbamazepine can induce AV block and other dysrhythmias.²⁸ Carbamazepine can promote sedation, dizziness, ataxia, and rash, although less commonly than phenytoin. Severe hyponatremia secondary to SIADH is a relatively common adverse effect of carbamazepine.² Nausea, aplastic anemia, agranulocytosis, thrombocytopenia, bone marrow suppression, and hepatic failure all have been reported. Pregnancy category D.

Contraindications: carbamazepine should not be used concurrently with monoamine oxidase (MAO) inhibitors and should be administered with caution to patients with hepatic, renal, or hematologic disease. Caution should be exercised in patients with increased intraocular pressure, as carbamazepine has mild anticholinergic activity.

Valproic Acid

Valproic acid is indicated as monotherapy and as adjunctive therapy in the treatment of almost all seizures types, including complex partial seizures, absence seizures, generalized tonic/clonic seizures, myoclonic seizures, and other partial seizures. In two European studies, IV valproate was shown to be effective for the treatment of refractory status epilepticus.^29,³⁰ Because of the recent availability of an IV formulation, valproic acid is now used relatively commonly in the ICU setting and as a treatment for acute seizures including status epilepticus.

Dosing

Adults: usual oral adult dose of valproic acid is 10 to 15 mg/kg/d in 3 divided doses, increased by 5 to 10 mg/kg/d at weekly intervals until therapeutic levels are achieved. Maintenance dose is 30 to 60 mg/kg/d. Sustained-release valproic acid (Depakote ER) is usually given once daily. Conversion to ER may require an increase in the dose by 20%. The IV dose is 15 to 20 mg/kg, with an IV infusion rate limit of 20 mg/min.

Elderly: dosing of valproic acid is approximately the same as the adult dosing recommendation.

Hepatic impairment: dosage reduction is necessary with hepatic failure, as the clearance of valproic acid is decreased in patients with impaired liver funciton.^1,³¹ Decreased plasma albumin concentration in hepatic disease is associated with a 2- to 2.6-fold increase in the unbound fraction of the drug. Therefore, free concentrations of valproate can be elevated even when the total concentration of drug is within the therapeutic range.

Renal impairment: when GFR is less than 10 mL/min, clearance of unbound in valproic acid is reduced by 27%. Hemodialysis reduces circulating valproic acid concentrations by 20%. Because valproic acid is highly protein bound, dialysis is not very effective for clearing the drug.

Forms available: capsule, 250 mg; capsule/sprinkles, 125 mg; injection, 100 mg/mL (5 mL), syrup, 250 mg/5 mL (5 mL, 480 mL); tablet, delayed release (125 mg, 250 mg, 500 mg); tablet, extended release (250 mg, 500 mg).

Mechanism of action: current data suggest that valproic acid increases the availability of GABA. Alternatively, the drug may enhance the action of GABA. Valproic acid also is thought to act on thalamic (T-type) calcium channels as an inhibitor, and it also may cause sodium channel blockade and enhanced potassium channel conductance.

Pharmacokinetics

Absorption: enteric forms of valproic acid are rapidly and nearly completely absorbed from the GI tract. Peak plasma concentrations are observed 1 to 4 hours following ingestion. Therapeutic serum concentrations are 50 to 125 µg/mL.

Distribution: valproic acid is 80% to 90% protein bound. Hence, at usual concentrations or dosing, the V_d is only slightly greater than plasma volume.

Elimination: valproic acid is excreted in urine following hepatic metabolism. Less than 3% of the anticonvulsant is excreted unchanged in the urine, and it is eliminated by first-order kinetics. The half-life of valproic acid is 9 to 16 hours.

Metabolism: valproic acid is metabolized extensively by the liver via glucuronic acid conjugation and mitochondrial β and ω oxidation to produce multiple metabolites, some of which are biologically active.

Drug interactions: serum levels of valproic acid can be reduced by acyclovir, whereas lamotrigine and phenytoin can induce metabolism of the drug.^3,¹⁰ Valproic acid can increase circulating diazepam, lamotrigine, and carbamazepine concentrations.³² Macrolide antibiotics and nimodipine can decrease metabolism of valproic acid. Metabolism of phenobarbital is inhibited by valproic acid.

Adverse reactions/toxicities: potential side effects of valproic acid include somnolence, dizziness, insomnia, alopecia, pancreatitis,³³ thrombocytopenia, tremor, weight gain, rash, bone marrow suppression,³⁴ decreased carnitine, hyperammonemia, and SIADH. Additionally, the anticonvulsant has been reported to cause frank hepatic failure. Developmentally, neural tube defects are a recognized toxicity. Valproic acid can stimulate the replication of human immunodeficiency virus (HIV) and cytomegalovirus (CMV) in infected patients.

Acute valproic acid intoxication induces mild to moderate lethargy at lower doses and coma or fatal cerebral edema at higher, more toxic doses.³⁵ In contrast to either phenytoin or carbamazepine, nystagmus, dysarthria, and ataxia are rarely noted following valproic acid overdose. Valproic acid can increase serum ammonia levels through interaction with carnitine. In the management of valproic acid intoxication, naloxone occasionally is effective for reversing symptoms.

Contraindications: pregnancy, urea cycle disorders, hepatic dysfunction.

Propofol

Typically used for induction and/or maintenance of anesthesia, propofol occasionally is used for the acute termination of seizures and for treatment of status epilepticus. Propofol is not a true “anticonvulsant,” as seizures are terminated only by virtue of the induction of general anesthesia. The drug must be used in association with continuous cardiac and blood pressure monitoring, and the patient prepared for mechanical ventilation.

Dosing

Adults: dosage of propofol must be individualized based on total body weight and titrated to desired effect. When given as a continuous infusion, the initial sedation dose is usually 1.2 mg/kg/h (20 µg/kg/min). However, for cessation of seizures, a dose yielding a general anesthetic state (or a flat or “burst-suppression” electroencephalogram [EEG]) is required, and this dose is in the range of 7.2 to 14 mg/kg/h (120-240 µg/kg/min).³⁶ The infusion rate can be increased by 1 to 2 mg/kg/h every 5 to 10 minutes until the desired sedation level or EEG correlate is achieved.

Elderly: doses of propofol should be reduced for elderly patients, as less drug is required to promote EEG silence or burst suppression.

Hepatic impairment: propofol is hepatically metabolized, and metabolic intermediates may be toxic. Such intermediates may accumulate during low-flow states (e.g., due to low cardiac output).

Renal impairment: propofol is hepatically metabolized, and the conjugated drug is excreted in urine.

Forms available: propofol comes as an emulsion (10 or 20 mg/mL); contains sodium metabisulfite, egg lecithin, soybean oil, and EDTA.

Mechanism of action: the mechanism of this drug appears to be similar to that for ultra short-acting barbiturates. Propofol is a GABA receptor agonist. It is a phenolic compound with general anesthetic properties. It is, however, structurally unrelated to the barbiturates, opioids, or benzodiazepines.

Pharmacokinetics

Absorption: onset of action of propofol is extremely rapid; one “arm-brain circulation time,” 10 to 15 seconds.³⁷

Distribution: the drug is highly lipophilic and has a large V_d of 2 to 10 L/kg. Propofol is 97% to 99% protein bound while in plasma.

Elimination: duration of action is approximately 3 to 5 minutes after a single bolus. It is excreted in the urine (88% as metabolites, 40% as the glucuronide metabolite). Clearance of propofol is 20 to 30 mL/kg/min, which exceeds liver blood flow.³⁷ There is some evidence to suggest extrahepatic sites of propofol metabolism to account for the rapid clearance of the drug.

Metabolism: propofol is metabolized in the liver (and possibly additional sites) to water-soluble sulfate and glucuronide conjugates.

Drug interactions: propofol can potentiate the neuromuscular blockade of vecuronium.³⁶

Adverse reactions/toxicities: common side effects include burning discomfort at the injection site, hypotension, and apnea. Propofol can promote respiratory acidosis as patients are weaned from mechanical ventilation. The use of propofol may have more severe cardiovascular consequences in patients with severe cardiac disease (ejection fraction < 50%). The emulsion promoted development of hypozincemia due to the chelating action of the additive, ethylenediaminetetraacetate (EDTA). Because the drug is insoluble in aqueous solvents, it is formulated as an emulsion that is a potential growth medium for bacteria.³⁸ Thus, EDTA is added as a bacteriostatic agent, but the risk of contamination with bacteria remains a concern. Strict aseptic technique must be observed with its use, and IV delivery lines should be changed routinely.

A “propofol infusion syndrome” has been described, and common clinical features can include hyperkalemia, hepatomegaly, lipemia, metabolic acidosis, myocardial failure, and rhabdomyolysis.³⁹ This syndrome was initially described in children who were cared for in an ICU for prolonged periods, using high doses of propofol for sedation.⁴⁰^–⁴² Propofol-induced lactic acidosis and myocardial dysfunction also can occur in adults.³⁹ Administration of propofol in the ICU should be restricted to doses ≤ 5 mg/kg/h, and infusion of propofol for the purpose of sedating critically ill adults should be limited to 48 hours, especially if high (general anesthesia level) doses are being used.

Contraindications: propofol is relatively contraindicated in patients with increased intracranial pressure (ICP) or in patients with hyperlipidemia or sepsis. Due to the emulsion base, patients who are allergic to egg whites also should not be given this drug. Pregnancy category is B. For seizure control, propofol is absolutely contraindicated in nonintubated patients, because induction of general anesthesia is required to terminate seizure activity.

Phenobarbital

Phenobarbital remains a mainstay of anticonvulsant therapy. As a potent GABA agonist, phenobarbital is an effective anticonvulsant against a broad range of seizure types, The drug is used most commonly to treat or prevent generalized motor seizures. A favorable feature is its relative lack of serious toxic effects. Additional desirable characteristics of the drug which recommend it for use in the ICU include its broad efficacy, its availability for IV administration, ability to titrate the dose of the drug to burst suppression on the EEG,⁴³^–⁴⁵ and ease of transition to PO dosing if desired. Its chief negative attributes include its long half-life and its tendency to induce hepatic enzyme expression.

Dosing

Adults: oral, 30 to 120 mg/d in 2 to 3 divided doses; in status epilepticus, loading dose is 15 to 18 mg/kg IV.⁴⁵ Anticonvulsant maintenance dose ranges between 1 and 3 mg/kg/d in divided doses.

Elderly: phenobarbital is not recommended for use in the elderly, although in the outpatient setting, the drug is often used in this population of patients.

Hepatic impairment: metabolism of phenobarbital is primarily hepatic, so increased side effects can occur in patients with severe liver disease. One should monitor plasma levels and liver function tests to estimate clearance of this already long-acting agent.

Renal impairment: when GFR is less than 10 mL/min, phenobarbital should be administered every 12 to 16 hours. Phenobarbital, unlike phenytoin, is substantively (20%-50%) cleared during hemodialysis.

Forms available: elixir, 20 mg/5 mL; injection, 60 mg/mL, 130 mg/mL; tablet, 15 mg, 30 mg, 32 mg, 60 mg, 65 mg, 100 mg.

Mechanism of action: classic and potent GABA agonist at the barbiturate locus of the GABA receptor site of the chloride channel.

Pharmacokinetics

Absorption: oral absorption is rapid and almost complete (70%-90%). Time to peak plasma concentration is 1 to 6 hours following an oral dose and approximately 30 minutes after IV administration. Serum reference range is 20 to 40 µg/mL.

Distribution: phenobarbital is 20% to 45% protein bound, which is less than the case for many other anticonvulsants.

Elimination: half-life in adults is 37 to 73 hours. Hepatic metabolites are excreted in urine, and 20% to 50% of the drug is excreted unchanged in urine.

Metabolism: phenobarbital is chemically modified by the liver via hydroxylation and glucuronide conjugation.

Drug interactions: barbiturates are enzyme inducers and thus can reduce the half-life of many agents, as well as increase toxicity of those drugs having toxic intermediates as a result of hepatic metabolism.^1,¹⁰ Thus, barbiturates can enhance the hepatotoxicity of acetaminophen. Phenobarbital increases the metabolism of antiarrhythmics (disopyramide, propafenone, and quinidine), anticonvulsants (ethosuximide, lamotrigine, phenytoin, tiagabine, topiramate, and zonisamide, but not levetiracetam or gabapentin), beta-blockers, calcium channel blockers, chloramphenicol, cimetidine, corticosteroids, cyclosporine, doxycycline, estrogens, furosemide, methadone, oral contraceptives, tricyclic antidepressants, and warfarin.^3,¹⁰ Conversely, the metabolism of barbiturates is inhibited by MAO inhibitors and valproic acid. Barbiturates can decrease vitamin D levels.

Adverse reactions/toxicities: phenobarbital, like all barbiturates, retards cerebral excitation and can lead to cognitive dysfunction, sedation, lethargy, ataxia, nystagmus, and (in large doses) coma and respiratory depression.⁴³^–⁴⁵ Although uncommon, hematologic disturbances can occur and include agranulocytosis, thrombocytopenia, and megaloblastic anemia.¹ Administration of activated charcoal and hemoperfusion are therapeutic interventions which have been implemented in cases of acute massive phenobarbital poisoning.⁴⁶^–⁴⁸

Contraindications: since barbiturates have a significant impact on hepatic function, these drugs should be used with caution or not at all in patients with hepatic impairment. Phenobarbital should not be given to patients with porphyria. When phenobarbital is given in large doses, such as to arrest active seizures, respiratory depression is a major concern, and airway protection is commonly required. Phenobarbital is not suggested for use during pregnancy, but considering that all anticonvulsants fall into this category, it appears no worse than other agents. Indeed, concerns related to promotion of neural tube defects and other malformations, which are associated with other agents, may be less of a concern with phenobarbital.