Anticonvulsants

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172 Anticonvulsants

The treatment of seizures in the intensive care unit (ICU) involves two distinct elements: (1) acute termination of all clinical and electrographic seizure activity and (2) prevention of further seizures. Many seizures manifest as a single, self-limiting episode that alerts the ICU team to a metabolic or structural abnormality. Correcting the underlying pathology and initiating prophylaxis may prevent recurrence of the seizure(s). Thus, there are instances in the ICU when acute treatment of the seizure is not necessary. Prophylaxis against recurrence may not be warranted if the precipitating factors have been eliminated. However, owing to the potential for refractory seizures, it is common to place a patient in the ICU on seizure prophylaxis once a seizure has been documented. To optimally treat patients in the ICU who have seizures or are at risk for seizures, the risks and benefits of the anticonvulsant must be assessed prior to initiation of therapy.

image Anticonvulsants: General ICU Concerns

An ideal anticonvulsant for use in the ICU would have the following properties: the drug can be administered intravenously (IV); the drug does not irritate veins; the drug is lipophilic, enabling excellent penetration into the central nervous system (CNS); the drug does not cause sedation; the drug provides prolonged protection against seizures; the drug does not cause side effects and is not toxic; the metabolites of the drug are biologically inactive; and the drug (and its metabolites) are cleared via mechanisms that are not dependent upon normal hepatic or renal function. From a review of our drug armamentarium, it is obvious that none of the currently available anticonvulsants meet all of these criteria.

Specific anticonvulsant medications are selected based on several considerations such as the type of seizure activity being treated, the periodicity of the seizure activity, and the need for acute or emergency therapy versus chronic seizure prophylaxis. In the ICU, additional concerns arise secondary to the common observance of drug-induced side effects. Both idiosyncratic and dose-dependent complications can occur. Various factors are implicated in the development of anticonvulsant toxicity. The following are common metabolic and pharmacodynamic features of anticonvulsants that are important concerns in ICU practice.

Protein Binding

Drugs such as phenytoin, carbamazepine, and valproic acid are extensively protein bound, but only the unbound drug in the plasma is biologically active. Critically ill patients are often catabolic and have abnormally low circulating protein levels; thus, the concentration of unbound drug can be greater than anticipated despite a total serum (or plasma) drug level that is within the normal target range for the medication.1 Patients with hepatic and/or renal dysfunction are prone to discordance between total and unbound (free) serum levels. Routine monitoring of free drug levels is expensive but warranted in these patients. Unfortunately, most hospital laboratories routinely offer unbound serum levels for only one commonly used anticonvulsant, phenytoin.

Metabolic Derangements

Hyponatremia has been reported in patients who have been treated with carbamazepine, oxcarbazepine, and (rarely) other anticonvulsants. Anticonvulsant-induced hyponatremia has been attributed to the syndrome of inappropriate antidiuretic hormone (SIADH) (Table 172-1). Selected subgroups of patients are more at risk for anticonvulsant-induced hyponatremia, including elderly persons, menstruating women, patients who require administration of large fluid volumes, patients with renal failure, postoperative patients, and patients who are concurrently receiving other medications associated with hyponatremia.2

TABLE 172-1 Medications Associated with SIADH

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.

Drug Interactions

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 172-3 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 172-6 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

image 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.

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.

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.