Benzodiazepines in epilepsy: pharmacology and pharmacokinetics

Transcription

1 Acta Neurol Scand 2008: 118: DOI: /j x Copyright Ó 2008 The Authors Journal compilation Ó 2008 Blackwell Munksgaard ACTA NEUROLOGICA SCANDINAVICA Review Article Benzodiazepines in epilepsy: pharmacology and pharmacokinetics Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand 2008: 118: Ó 2008 The Authors Journal compilation Ó 2008 Blackwell Munksgaard. Benzodiazepines (BZDs) remain important agents in the management of epilepsy. They are drugs of first choice for status epilepticus and seizures associated with post-anoxic insult and are also frequently used in the treatment of febrile, acute repetitive and alcohol withdrawal seizures. Clinical advantages of these drugs include rapid onset of action, high efficacy rates and minimal toxicity. Benzodiazepines are used in a variety of clinical situations because they have a broad spectrum of clinical activity and can be administered via several routes. Potential shortcomings of BZDs include tolerance, withdrawal symptoms, adverse events, such as cognitive impairment and sedation, and drug interactions. Benzodiazepines differ in their pharmacologic effects and pharmacokinetic profiles, which dictate how the drugs are used. Among the approximately 35 BZDs available, a select few are used for the management of seizures and epilepsy: clobazam, clonazepam, clorazepate, diazepam, lorazepam and midazolam. Among these BZDs, clorazepate has a unique profile that includes a long half-life of its active metabolite and slow onset of tolerance. Additionally, the pharmacokinetic characteristics of clorazepate (particularly the sustained-release formulation) could theoretically help minimize adverse events. However, larger, controlled studies of clorazepate are needed to further examine its role in the treatment of patients with epilepsy. J. Riss 1, J. Cloyd 1, J. Gates 2, S. Collins 3 1 Center for Orphan Drug Research, Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA; 2 Minnesota Epilepsy Group â, St Paul, MN, USA; 3 Ovation Pharmaceuticals, Inc., Deerfield, IL, USA Key words: benzodiazepines; epilepsy; pharmacokinetics; pharmacology; clorazepate James Cloyd, PharmD, McGuire Translational Research Facility, th Street SE, Minneapolis, MN 55455, USA Tel.: Fax: cloyd001@umn.edu Accepted for publication January 28, 2008 Introduction Much attention has been focused on the introduction of new antiepileptic drugs (AEDs) into the US market during the past 15 years. Nonetheless, benzodiazepines (BZDs), which have been used since the 1960s, remain important in epilepsy management and are the drugs of first choice for status epilepticus and seizures associated with postanoxic insult. Benzodiazepines also continue to play major roles in treating other conditions such as febrile seizures, acute repetitive seizures and alcohol withdrawal seizures. The major clinical advantages of BZDs are high efficacy rates, rapid onset of action and minimal toxicity. Few other drugs possess comparable attributes. All BZDs share similar neuropharmacologic properties including anxiety reduction, sedation, sleep induction, anticonvulsant effects and muscle relaxation (1). There are, however, differences among BZDs in affinity for receptor subtypes, which may produce different pharmacologic effects. Thus, some BZDs are more effective than others as anticonvulsants; few of the approximately 35 BZDs available worldwide (2) are used for managing epilepsy. Diazepam and lorazepam are primarily used for management of seizure emergencies, whereas clobazam, clonazepam and clorazepate are commonly used in chronic epilepsy management. Midazolam often is used as an alternative to diazepam and lorazepam in seizure emergencies and for treating refractory status 69

2 Riss et al. epilepticus. The BZDs also have widely varying pharmacokinetic profiles, with differences in absorption, onset and duration of action and formation of active metabolites. Thus, pharmacokinetic differences often dictate the use of specific BZDs, route(s) of administration and formulation(s). Additionally, the nature and importance of side effects and drug interactions have been identified and clarified in recent years. The purpose of this review was to provide clinicians with information for selecting BZDs and for managing BZD therapy in their patients. The article considers BZD pharmacology, pharmacokinetics, use in epilepsy management, tolerance and withdrawal. Also included in this review is an analysis and discussion of the effects of missed daily doses of immediate- and extended-release clorazepate formulations on plasma N-desmethyldiazepam (DMD) concentrations. Benzodiazepine pharmacology There are three principal c-aminobutyric acid (GABA) receptor subtypes. Ligand-activated ion channels that are selectively blocked by bicuculline and modulated by steroids, BZDs, and barbiturates are known as GABA A receptors (3). The second receptor subtype, GABA B, consists of G-protein-coupled, seven-transmembrane receptors, which are selectively activated by (R)-())- baclofen and 3-aminopropylphosphinic acid and are blocked by phaclofen (3). Transmitter-gated chloride channels, GABA C receptors, are selectively activated by certain conformationally restricted GABA analogs and are not modulated by steroids, BZDs or barbiturates (3). Benzodiazepines bind to GABA A receptors, ionotropic transmembrane proteins located in the neuronal membranes of the central nervous system (CNS) (3). The GABA A receptor consists of a pentameric structure with multiple subunits that are necessary for normal physiologic function. The receptor subunits are assembled from combinations of 19 polypeptides (i.e. a1 6, b1 3, c1 3, d, e, p, h and q1 3) (4); different subunit combinations determine the pharmacologic properties of the receptor (5, 6). The number and types of subunits vary depending on the location of the receptor in the CNS (7). The inhibitory neurotransmitter GABA binds to the receptor to open the chloride ion gates and produce an inhibitory current (6, 8). Binding of BZDs to the c subunit of the receptor is important in the potentiation of GABAergic inhibition (9). Differentiation between BZDs and GABA is important. Benzodiazepines do not substitute for GABA, but instead enhance the inhibitory effects of GABA. Benzodiazepines allosterically bind to the receptor at a different location than GABA does and enhance the chloride channelõs conductance by increasing the frequency of gated channel opening (6, 7, 10 12). In the search for BZD site ligands with higher therapeutic selectivity and a more favorable safety profile, GABA A receptor subtypes have long been considered promising targets (13). The pharmacologic relevance of GABA A receptor subtypes has been identified using a gene knock-in strategy in rodents. Based on in vivo point mutations, a-1-gaba A receptors have been found to mediate sedation and anterograde amnesia and to partially mediate anticonvulsant activity, whereas a-2-gaba A receptors mediate anxiolysis (14, 15). The basic chemical structure of BZDs is formed from the fusion of a benzene ring and a sevenmembered diazepine ring (16) (Fig. 1). Clobazam is an exception with its 1-5-BZD structure (17). The common chemical structure of the BZDs accounts for their similar mechanisms of action. In pharmacologic terms, BZD potency refers to the in vivo affinity of the drug (or its active metabolites) for its receptor (18). Benzodiazepines are classified as low, medium (e.g. clorazepate and diazepam) or high (e.g. clonazepam and lorazepam) potency (18, 19). Benzodiazepine pharmacokinetics Benzodiazepines have differences in their physiochemical properties, most notably lipid solubility, which influence their rate of absorption and diffusion into tissue compartments and their pharmacokinetics. Each BZD has a unique pharmacokinetic profile that must be considered when the optimal agent is selected for a particular patient and condition. Key factors to consider include R 7 R 1 N R 2 N O ortho Figure 1. General chemical structure of 1,4- benzodiazepines. R 3 70

3 Benzodiazepines in the treatment of epilepsy route of administration, rate and extent of absorption, metabolism, formation of active metabolites, elimination and drug interactions (20). Absorption and distribution When orally administered, most BZDs are extensively and rapidly absorbed, with bioavailabilities varying from 80% to 100% and times to peak concentration ranging from minutes to several hours (Table 1). Midazolam is an exception, with low oral bioavailability due to metabolism by cytochrome P-450 (CYP) enzyme 3A5 in intestinal epithelial tissue, which can reduce by up to 50% the fraction of the dose reaching the bloodstream (24). Benzodiazepines cross the blood brain barrier rapidly, although the diffusion rate into the brain varies by drug and is largely determined by lipophilicity (21). The faster the diffusion rate, the earlier is the onset of pharmacodynamic effects. Rapid entry of BZDs into the CNS and highly perfused tissues is consistent with their short distribution half-lives (21, 25). Following rapid uptake, BZDs redistribute into less well-perfused tissues; the rate of redistribution is the fastest for the most lipid-soluble drugs (25). After an intravenous (i.v.) BZD administration, BZD pharmacokinetics can be characterized by a multicompartmental mathematical model, with the first phase being distribution, followed by a longer elimination phase. Benzodiazepines also have large volumes of distribution, are highly bound to plasma proteins (Table 1) and readily cross into the placenta and breast milk (25). Table 1 Summary of absorption and distribution pharmacokinetics of selected BZDs Drug F (%) T max Protein binding (% bound) Distribution half-life a (min) V d (l kg) Clobazam h NA Clonazepam > h min (21) Clorazepate b PO: 100 PO: h min (22) IM: 91 IM: h Diazepam PO: 100 R: 90 (23) PO: min IM: min R: min min (21) Lorazepam PO: 99 IM: 96 SL: 94 Midazolam PO: 40 IM: 100 PO: 2.4 h IM: 1.2 h SL: 2.3 h PO: h IM: h 93.2 <11 min (21) min (21) Values refer to adults receiving monotherapy and are from Anderson and Miller (24) unless otherwise specified. BZD, benzodiazepine; F, bioavailability; T max, time to maximum concentration; V d, volume of distribution; NA, not applicable; PO, oral; IM, intramuscular; R, rectal; SL, sublingual. a After intravenous administration. b Pharmacokinetics for N-desmethyldiazepam after administration of clorazepate. Metabolism and elimination Benzodiazepines differ in their rates of elimination and the formation of pharmacologically active metabolites (Table 2). The elimination half-life (t 1 2 ) of a BZD or of its active metabolite is used to categorize BZD duration of effect: short acting (<10 h; lorazepam, midazolam), intermediate acting (10 24 h; clonazepam) or long acting (>24 h; clobazam, clorazepate and diazepam) (43). Benzodiazepine metabolism is primarily catalyzed by CYP-dependent hydroxylation, demethylation and nitroreduction (26, 44, 45). The CYP isoenzymes catalyzing these reactions include 3A4, 3A5, 2B6, 2C9 and 2C19 (Tables 2 and 3). Uridine diphosphate glucuronosyltransferase is also involved in the conjugation of some BZDs (Table 3). Several BZDs have active metabolites. Diazepam and clorazepate are metabolized into the long-acting metabolite DMD (56). With multiple doses, the pharmacologic and toxic effects of diazepam are attributable to the parent drug, DMD, and other minor active metabolites (i.e. temazepam and oxazepam) (24). By contrast, clorazepate undergoes rapid and complete chemical conversion to DMD in the gastrointestinal tract; its pharmacologic effects are largely due to DMD (24, 56). N-Desmethyldiazepam undergoes glucuronidation to form a glucuronide conjugate (25%) and is hydroxylated (50%) by CYP 2C19 and CYP 3A4 to form oxazepam (24, 37). Approximately 5 9% of DMD is excreted unchanged in the urine (24). The t 1 2 of DMD ranges widely from 20 to 179 h (24, 33, 34, 38). Other BZDs also have pharmacologically active metabolites. Clobazam is demethylated into an active metabolite (N-desmethylclobazam) (27). Midazolam is rapidly converted by CYP 3A4 and CYP 3A5 to 1-hydroxymidazolam, which contributes approximately 10% to the biologic activity of its parent drug (24, 41). Clonazepam and lorazepam undergo extensive metabolism, but no active metabolites are formed (18, 24). Effects of pharmacokinetics and pharmacodynamics on BZD use The differences in BZD pharmacokinetics and pharmacodynamics must be considered in order to use these drugs safely and effectively. Equivalent doses of BZDs differ as much as 20-fold because of differences in potency (57). The intensity of single-dose effects may vary, even if equipotent doses are used, because of varying oral absorption rates (58). Duration of action should be considered when choosing a BZD. When maintenance therapy is required (e.g. epilepsy and anxiety), long-acting BZDs are preferred because of their prolonged t 1 2, as effective drug concentrations can be maintained 71

4 Riss et al. Table 2 Summary of metabolism and elimination pharmacokinetics of selected BZDs Drug Primary metabolic pathway Active metabolites Elimination half-life of parent drug a (h) Elimination half-life of active metabolites (h) Clobazam Demethylation (26) N-desmethylclobazam (27) (28) (28) Clonazepam Nitroreduction (CYP 3A4), NA (32) NA acetylation (NAT), hydroxylation (29 31) Clorazepate Decarboxylation, glucuronidation, hydroxylation (CYP 2C19 and 3A4) (24) DMD (major), oxazepam (minor) (24) NA (24, 33, 34) Oxazepam: 6 24 (18) Diazepam Demethylation (CYP 2C9, 2C19, 2B6, 3A4, and 3A5), hydroxylation (CYP 3A4 and 2C19), glucuronidation (24, 35, 36) DMD (major), oxazepam (minor), temazepam (minor) (24, 35, 37) (23, 38) DMD: (33, 38) Oxazepam: 6 24 (18) Temazepam: 8 24 (18) Lorazepam Glucuronidation (24) NA 7 26 (39, 40) NA Midazolam Hydroxylation (CYP 3A4 and 3A5) (25, 41, 42) 1-hydroxymidazolam (minor) (24) 1 4 (24) 1 (24) BZD, benzodiazepine; CYP, cytochrome P-450; NAT, N-acetyltransferase; NA, not applicable; DMD, N- desmethyldiazepam. a Healthy subjects. Table 3 Enzyme-mediated BZD metabolism and drug interactions Enzyme associated with metabolism without the need for frequent dosing (56). Shortacting BZDs are preferred for intermittent hypnotic therapy, when the duration of action of the drug should be restricted to night-time, allowing patients to awaken feeling refreshed, without hangover effects (56). Drug drug interactions BZD substrates Inhibitors Inducers CYP 2C19 Diazepam (46) Fluvoxamine (46) Dexamethasone (48) MHD (weak) (47) Phenobarbital (48) Omeprazole (46) Phenytoin (49) Oxcarbazepine (46) Rifampin (46) Ticlopidine (46) St JohnÕs wort (50) Topiramate (46) CYP 3A4 Clonazepam (29) Azole antifungals Carbamazepine (46) (e.g. ketoconazole) (46) Diazepam (46) Cimetidine (46) Phenobarbital (48) Midazolam (46) Clarithromycin (46) Phenytoin (46) Diltiazem (46) Rifabutin (46) Erythromycin (46) Rifampin (52) Fluoxetine (51) Rifapentine (51) Grapefruit juice (46) St JohnÕs wort (50) HIV protease inhibitor (46) Nefazodone (46) Sertraline (51) UGT Lorazepam (53) Valproate (55) Carbamazepine (55) Oxazepam (54) Lamotrigine (weak) (55) Phenobarbital (55) Phenytoin (55) Rifampin (52) BZD, benzodiazepine; CYP, cytochrome P-450; MHD, monohydroxy derivative; HIV, human immunodeficiency virus; UGT, uridine diphosphate glucuronosyltransferase. Benzodiazepines interact with other drugs such as certain antidepressants, AEDs (e.g. phenobarbital, phenytoin and carbamazepine), sedative antihistamines, opiates, antipsychotics and alcohol (44, 57, 59), which may result in additive sedative effects. As discussed earlier, BZD metabolism is complex and largely catalyzed by CYP isoenzymes. Consequently, there is potential for interactions between BZDs and drugs that induce or inhibit CYP isoenzymes. The clinical importance of these interactions depends on the net effect of inhibition or induction on the metabolic pathway of a particular BZD. For example, inhibition of a minor pathway may have little impact on drug concentration, whereas inhibition of a major pathway may result in enhanced clinical effect or toxicity. By contrast, addition of an enzymeinducing drug that affects even a relatively minor pathway may lead to a clinically important reduction in plasma BZD concentration. For BZDs with active metabolites, the addition of an inhibitor or inducer may affect only the parent drug, only the metabolite, or both. Clinicians should exercise particular caution when using BZDs with selective serotonin reuptake inhibitors, cimetidine, macrolide antibiotics and antimycotics; these drugs may inhibit reactions catalyzed by certain CYP isoenzymes and, therefore, inhibit the metabolism of many BZDs, which results in increased plasma BZD concentrations (44). Conversely, potent enzyme inducers (e.g. phenytoin, phenobarbital and carbamazepine) substantially increase clearance and reduce the t 1 2 of certain BZDs (44). For a detailed review of pharmacokinetic drug interactions involving BZDs, see Tanaka (44). Oral contraceptive steroids may inhibit the metabolism of some BZDs that undergo oxidative metabolism or nitroreduction and accelerate the metabolism of some BZDs that are conjugated. Interactions between BZDs and oral contraceptives are described in detail by Back and Orme (60). 72

5 Benzodiazepines in the treatment of epilepsy Special populations Elderly patients Pharmacokinetics in older individuals differ from those in younger individuals because of age-related changes in physiology and the likelihood of concurrent diseases. Elderly individuals often have variable drug absorption, decreased plasma protein drug binding due to lower albumin concentrations, and reduced hepatic and renal clearance (61). Additionally, many elderly individuals take multiple medications, which increase their risk of drug drug interactions. Therefore, treatment of the elderly can be challenging. Increased sensitivity of older patients to BZDs is partly due to reduced drug metabolism (when compared with younger adults), which can result in drug accumulation (62). Furthermore, BZD pharmacologic effects appear to be greater in elderly patients than in younger patients even at similar plasma BZD concentrations (63, 64), possibly because of age-related changes in drug receptor interactions, post-receptor mechanisms and organ function. When a BZD is prescribed for an elderly patient, the initial maintenance dose should be half that recommended for younger adults (57), and BZD use should be only short term (limited to 2 weeks) (65). A short-acting BZD may be preferable for treating an elderly patient because such a drug is better tolerated than is a BZD or BZD active metabolite with a long t 1 2 (64). Pediatric patients Limited information is available regarding BZD absorption in children. Often, before children are administered medications, the tablet is crushed or the capsule is opened, and the contents are mixed with food or drink. Food and beverages may affect BZD bioavailability, but studies investigating this issue in children are lacking. Drug metabolism is variable in children and depends on the biotransformation pathway. Cytochrome P-450-catalyzed metabolism tends to be low at birth, but exceeds adult values by age 2 3 years; thereafter, CYP-catalyzed metabolism decreases, reaching adult levels around puberty (66). Metabolism via glucuronidation tends to be low in neonates, reaching adult levels by age 3 4 years (66). In neonates, the t 1 2 of clorazepate is prolonged and clearance is decreased (67). Infants have reduced hydroxylation metabolism, which results in a decreased clearance of diazepam (68). The t 1 2 of midazolam is shorter in children than in adults: h in children (69) vs h in adults (24). Clinicians should consider how patient age may affect BZD clearance, because clearance will affect BZD dosing. Special formulations of BZDs Extended-release drug formulations can help patients with epilepsy achieve their primary treatment goals of controlling seizures while reducing side effects by minimizing fluctuations in drug concentration and by improving compliance. Extended-release formulations may also improve quality of life and patient satisfaction with treatment, in part by simplifying dosage regimens (70). Currently, clorazepate is the only BZD available in both a sustained-release, single-dose (Tranxene Ò -SD, Ovation Pharmaceuticals, Deerfield, IL, USA) formulation ( and 22.5-mg tablets) and an immediate-release formulation that requires multiple doses per day (Tranxene Ò T-Tab; 3.75-, 7.5- and 15-mg tablets) that is approved in the USA for the treatment of seizures. Some BZDs are also available as oral liquids [diazepam (Diazepam Intensol; 5 mg ml), lorazepam (Lorazepam Intensol; 2 mg ml) and midazolam (generic only; 2mg ml)], disintegrating tablets [clonazepam (Klonopin Ò Wafer; Roche Pharmaceuticals, Nutley, NJ, USA; , 0.25-, 0.5-, 1- and 2-mg tablets)] or a rectal gel [diazepam (Diastat Ò AcuDial; Valeant Pharmaceuticals International, Costa Mesa, CA, USA; 2.5-, 10- and 20-mg delivery systems)]. Effect of extended-release formulations on plasma BZD concentrations: pharmacokinetic simulations with clorazepate Our group has performed simulation studies of plasma DMD concentrations over time to investigate differences between clorazepate formulations and to characterize the effect of missed doses with or without replacement doses under steady-state conditions when using the sustained-release and immediate-release formulations (71). These simulations were briefly described by Kaplan and DuPont (72), but detailed results are reported herein. The following simulations were performed for both formulations using WinNonlin Ò (Pharsight Corporation, version 4.1: Mountain View, CA, USA) software and a twocompartment, first-order, oral-absorption pharmacokinetic model: (1) steady-state conditions, (2) missed dose(s) without replacement and (3) missed dose(s) with replacement at the next scheduled dose. The following dosing schedules for the sustained-release and immediate-release formulations were entered to attain steady-state conditions (>7 days): clorazepate sustained-release 22.5 mg one tablet orally every 24 h for 20 days; and clorazepate immediate-release 7.5 mg one tablet orally three times daily (given 6 h apart) for 20 days. The resulting simulated plasma DMD 73

6 Riss et al. Predicted DMD concentration (µg/ml) Predicted DMD concentration (µg/ml) Time (h) Figure 2. Simulated plasma N-desmethyldiazepam (DMD) concentration over time for immediate-release clorazepate (solid line, 7.5 mg given every 6 h for three daily doses) and sustained-release clorazepate (dashed line, 22.5 mg once daily) with no missed doses Missed dose Missed doses Time (h) Figure 3. Simulated plasma N-desmethyldiazepam (DMD) concentration over time for immediate-release clorazepate (solid line, 7.5 mg given every 6 h for three daily doses) and sustained-release clorazepate (dashed line, 22.5 mg once daily), missed daily dose(s) without replacement. Predicted DMD concentration (µg/ml) Missed dose Missed doses Replaced dose Replaced doses Time (h) Figure 4. Simulated plasma N-desmethyldiazepam (DMD) concentration over time for immediate-release clorazepate (solid line, 7.5 mg given every 6 h for three daily doses) and sustained-release clorazepate (dashed line, 22.5 mg once daily), missed daily dose(s) replaced at next dayõs dose. concentrations over time are depicted in Figs 2 4. The mean steady-state plasma DMD concentration was approximately 0.71 lg ml for the immediaterelease formulation and 0.73 lg ml for the sustained-release formulation. The time to maximum concentration was 2.43 and 9.20 h for the immediate-release and sustained-release formulations respectively. Table 4 shows the effects of missed doses on plasma DMD concentrations. When a missed dayõs dose of the immediate-release formulation was simulated, peak-to-trough differences (compared with steady state) increased by 0.05 lg ml (38.5%) with no dose replacement and increased by 0.29 lg ml (223.1%) with replacement of the missed doses (Table 4). However, when a missed dayõs dose of the sustainedrelease formulation was simulated, peak-to-trough differences increased by 0.01 lg ml (5.9%) with no dose replacement and increased by 0.24 lg ml (141.2%) with replacement of the missed dose (Table 4). Despite the long half-life of DMD, a missed dayõs dosing can result in altered peak-to-trough concentration ratios. Overall, the differences between peak and trough plasma DMD concentrations after a missed daily dose of clorazepate increased more with the immediate-release formulation than with the sustained-release formulation (Table 4). There was little difference between the two formulations in peak and trough concentrations following a missed dayõs dose. Although the effect was modest, the sustained-release tablet maintained higher trough concentrations after a missed daily dose and replacement of the missed dose. This effect may prevent breakthrough seizures in some patients. Additionally, when a missed daily dose was replaced, the sustainedrelease formulation resulted in a smaller change in peak concentrations, which may reduce the risk of drug toxicity. Use of benzodiazepines in epilepsy Efficacy Benzodiazepines are among the most useful AEDs available for treating status epilepticus and acute repetitive seizures and for febrile seizure prophylaxis. Benzodiazepines were used in epilepsy management as early as 1965, when Gastaut et al. (73, 74) administered i.v. diazepam to treat status epilepticus. Since then, several other BZDs have been used for a variety of seizure disorders (Table 5). Several randomized controlled trials support the use of BZDs (particularly diazepam and loraze- 74

7 Benzodiazepines in the treatment of epilepsy Table 4 Effects of missed doses on simulated plasma DMD concentrations (71) Formulation Clorazepate sustained-release Clorazepate immediate-release Simulation scheme a Peak trough difference b at steady state (lg ml) 0.17 NA NA 0.13 NA NA Peak trough difference b after missed dose(s) (lg ml) NA NA Change in peak plasma DMD concentrations (%) NA ) NA ) Change in trough plasma DMD concentrations (%) NA )44.1 )41.9 NA )48.8 )48.8 DMD, N-desmethyldiazepam; NA, not applicable. a Simulation scheme: 1 = no missed doses; 2 = missed daily dose(s) without replacement; 3 = missed daily dose(s) with replacement. b Difference between maximum plasma DMD concentration and minimum plasma DMD concentration. Table 5 Recommended clinical uses of benzodiazepines Drug Trade Name Generic availability Product-labeled uses (75) Common uses in epilepsy (76) Clobazam Frisium NA Not FDA approved First-line adjunctive treatment for treatment-resistant partial and generalized seizures, intermittent therapy and non-convulsive status epilepticus Clonazepam Klonopin Yes Panic disorder, epileptic seizures (alone or adjunct) Clorazepate Tranxene T-Tab Tranxene-SD Yes Anxiety, alcohol withdrawal, adjunctive treatment of partial seizures Diazepam Valium Yes Anxiety, alcohol withdrawal, muscle relaxant, epileptic seizures Lorazepam Ativan Yes Anxiety, pre-anesthetic to induce amnesia, antiemetic adjunct, status epilepticus Midazolam Versed Yes Anesthesia, preoperative and procedural sedation NA, not applicable; FDA, US Food and Drug Administration; ARS, acute repetitive seizures. Second-line adjunctive treatment for partial and generalized (particularly absence and myoclonic) seizures, early status epilepticus and Lennox Gastaut syndrome; second-line treatment of status epilepticus Adjunctive treatment of partial seizures (75) First-line treatment for early status epilepticus; second-line therapy for established status epilepticus; treatment of non-convulsive status epilepticus; intermittent prophylactic therapy for febrile seizures; and at-home treatment of ARS First-line treatment for early status epilepticus and out-of-hospital status epilepticus Second-line therapy for early status epilepticus pam) as initial drug therapy in patients with status epilepticus (77 80). Intermittent use of BZDs is especially suitable for patients with clusters of repetitive seizures (81). Fewer studies have evaluated the clinical efficacy of BZDs in chronic epilepsy. Nevertheless, BZDs are useful as adjunctive agents in treating certain patients with both partial and primary generalized seizures (81). Benzodiazepines are versatile drugs that can be employed in a variety of clinical settings because of their broad spectrum of activity and multiple formulations and because they can be administered by several routes (81). Diazepam Diazepam is a drug of first choice for treatment of early status epilepticus and acute repetitive seizures and for febrile seizure prophylaxis. It can be administered as an i.v. bolus, as a continuous infusion, or rectally, which enhances its utility in managing seizure emergencies. Four randomized controlled trials support diazepam as a drug of first choice for managing status epilepticus (77 80). Success rates of i.v. diazepam for treating status epilepticus vary. In a randomized double-blind study comparing diazepam and lorazepam, Leppik et al. (80) found that 76% of status epilepticus episodes (25 of 33) were terminated by one or two diazepam doses (5 mg min). In a randomized, non-blinded trial of patients >15 years of age with status epilepticus, Shaner et al. (78) reported that seizures were aborted in <10 min in 55.6% of patients (10 of 18) treated with diazepam (2 mg min) and phenytoin (40 mg min). A randomized, double-blind, multicenter Veterans Affairs cooperative study was designed to compare the effectiveness of four treatments for overt or subtle status epilepticus (79). Three hundred eighty-four patients with overt 75

8 Riss et al. status epilepticus and 134 patients with subtle status epilepticus were randomly assigned to receive either diazepam (0.15 mg kg) followed by phenytoin (18 mg kg), lorazepam (0.1 mg kg) alone, phenobarbital (15 mg kg) alone or phenytoin (18 mg kg) alone. Treatment with diazepam plus phenytoin was successful in 55.8% of patients (53 of 95) with overt status epilepticus and 8.3% of patients (three of 36) with subtle status epilepticus (79). Alldredge et al. (77) conducted a randomized double-blind trial to determine the effectiveness of i.v. diazepam, lorazepam and placebo on status epilepticus when the drugs were administered by paramedics before patients arrived at the hospital. They found that status epilepticus was terminated by the time of arrival in the emergency department in 42.6% of the 68 patients treated with one or two 5-mg doses of i.v. diazepam (infused over 1 2 min). Limited published data indicate that continuous i.v. infusions of diazepam are safe and effective (82 84). Use of i.v. diazepam can result in seizure relapse within 2 h of a single injection in approximately 50% of patients (76). Therefore, multiple injections or continuous infusion may be required, which can lead to drug accumulation and possibly to acute respiratory depression, sedation and hypotension (76). The development of tolerance has also been reported for infusions lasting >24 h (85). Recommended dosing guidelines for i.v. diazepam for convulsive status epilepticus are mg kg in adults and mg kg in children (86). In placebo-controlled trials, rectal diazepam gel (doses of mg kg) reduced seizure recurrence in children, adolescents and adults who had clusters of repetitive seizures in a non-medical or home setting (87 90). Rectally administered diazepam may also be effective for short-term prophylaxis (at doses of 5 10 mg or mg kg in patients weighing <10 kg) in children prone to febrile seizures (91 93), and higher doses of rectal diazepam (20 30 mg) have been used in adult patients with drug-resistant epilepsy who are prone to serial seizures (94, 95). Use of oral diazepam is not recommended for long-term epilepsy treatment (76). Lorazepam Lorazepam is generally given as an i.v. bolus at doses of mg kg over 2 min, and the dose may be repeated in 10 min. The i.v. formulation is approved by the US Food and Drug Administration (FDA) for the treatment of status epilepticus. Results from four comparative studies (three of blinded design) have suggested that lorazepam is superior to phenytoin and as effective as clonazepam, diazepam or the combination of diazepam and phenytoin in the initial treatment of status epilepticus (77, 79, 80, 96). In the previously mentioned study by Alldredge et al. (77), i.v. lorazepam (2 mg, one to two doses) administered to 66 adults with repetitive or ongoing generalized seizures lasting >5 min terminated convulsions by the time of arrival at the emergency department in 59.1% of patients. Similarly, Leppik et al. (80) found that one or two lorazepam doses (4 mg each) terminated seizures in 89% of status epilepticus episodes. In the Veterans Affairs cooperative study of status epilepticus, lorazepam terminated seizures in 64.9% of patients and was significantly more effective than phenytoin (P = 0.002) (79). A nonblinded trial by Sorel et al. (96) compared i.v. lorazepam (4 10 mg, one to two doses) and clonazepam (1 mg, one to two doses) in 61 patients. In lorazepam-treated patients, 53.0% had 75% improvement, as did 39.6% of clonazepam-treated patients, as measured by electroencephalograms. Clinical results were comparable between groups, with 67.9% of lorazepam-treated patients and 69.0% of clonazepam-treated patients having 75% improvement. Large lorazepam doses (0.3 9mg h) have been used as an alternative to pentobarbital for treating refractory status epilepticus; for all nine cases in an open-label study, lorazepam terminated status epilepticus (97). Clinical studies in children have been mostly unblinded and have included retrospective and prospective designs. In a prospective open-label study, Appleton et al. (98) compared i.v. or rectal lorazepam and diazepam treatments in 86 children. A single dose terminated seizures in 76% of patients treated with lorazepam and in 51% of patients treated with diazepam; the difference between treatments was not statistically significant. Qureshi et al. (99) performed a comparative audit of i.v. lorazepam and diazepam. The authors suggested that lorazepam is probably as effective as diazepam is for stopping acute seizures in children. Seizures were controlled within 15 min in 65% of diazepam-treated patients (11 of 17) (median time, 3 min) and in 65% of lorazepamtreated patients (20 of 31) (median time, 5 min). The effectiveness of lorazepam in the treatment of patients with chronic epilepsy has been evaluated in relatively few studies (100). In a short-term, placebo-controlled trial, adjunctive oral lorazepam therapy was effective (i.e. reduced seizure frequency significantly more than placebo did, P < 0.01) for treating partial seizures that were unresponsive to standard AEDs (101). Clonazepam As reviewed by Browne (102), clonazepam has been shown to be efficacious in treating patients with both partial and generalized 76

9 Benzodiazepines in the treatment of epilepsy seizures. Clonazepam is used primarily as an adjunctive therapy to treat patients with a wide range of treatment-resistant primary and secondarily generalized seizures (103). During the 1970s and 1980s, the use of adjunctive clonazepam was evaluated in a few, mostly small, controlled clinical trials in patients with partial and generalized seizures that were refractory to standard treatments (76, 104). Uncontrolled studies of clonazepam in patients with partial and generalized epilepsy have generally shown modest effects (76). In generalized epilepsies, clonazepam is effective for treating patients with absence seizures (105, 106). In one study, 70% of children with absence seizures treated with clonazepam (seven of 10) had a 75% reduction in seizure frequency after 8 weeks of treatment, and an additional 10% of children (one of 10) had a 30% reduction in seizure frequency (105). Clonazepam also can be useful in treating patients with myoclonic seizures (107). It is considered the drug of choice in certain rare childhood epilepsy syndromes (108). It is also effective in controlling status epilepticus; a review of several studies ( ) of i.v. clonazepam use in status epilepticus found the drug to be effective in approximately 80 90% of patients (107). Clonazepam has been shown to be effective as adjunctive therapy for complex partial seizures, absence seizures, tonic clonic seizures and myoclonic seizures (121, 122). Midazolam Midazolam is the only available water-soluble BZD; solubility is achieved when the injectable solution is buffered to a ph of (123). In the treatment of status epilepticus, midazolam can be administered by i.v. bolus, continuous i.v. infusion or i.m. injection. It can also be administered buccally or nasally (124, 125). Rectal administration is not recommended because of poor bioavailability (126). Although it is used for many seizure types, midazolam does not have an FDA-approved indication for seizures. Clinical experience with midazolam for treating status epilepticus (as initial treatment or for refractory status epilepticus) is limited (76). In three controlled clinical trials, the efficacy of intranasal midazolam was similar to or better than that of i.v. or rectal diazepam (124, 127, 128). Midazolam has also been found to be safe and effective when administered as a continuous infusion to treat refractory generalized convulsive status epilepticus ( ). In a randomized trial comparing buccal midazolam with rectal diazepam in children, the drugs showed similar efficacy and onset of action (125). In that study, seizure cessation was achieved in 75% of cases (30 of 40) with midazolam and in 59% of cases (23 of 39) with diazepam treatment (P = 0.16). Results from another randomized controlled trial that compared buccal midazolam with rectal diazepam for emergency treatment of seizures in children suggested that midazolam was more effective than diazepam (134). Therapeutic success (defined as cessation of visible signs of seizure activity within 10 min of drug administration, lack of respiratory depression and no further seizures within 1 h) was noted in 56% of midazolam-treated patients (61 of 109) and 27% of diazepam-treated patients (30 of 110), a 29% difference between groups; (95% confidence interval, 16 41%). Open-label studies have suggested that intranasal midazolam is safe and effective for acute seizure management in children (124, 127, 128, 135, 136). In a prospective, randomized, open-label study, intranasal midazolam was as safe and effective as i.v. diazepam was for managing febrile seizures, with 88% of seizures (23 of 26) responding to initial treatment with midazolam and 92% (24 of 26) responding to diazepam (124). Intranasal midazolam takes less time to administer than i.v. diazepam does but has disadvantages. Often, the parenteral formulation has been used for intranasal administration. A large volume is required to deliver a therapeutic dose, making administration difficult because much of the solution may leak out of the nose or be swallowed (137). Additionally, pain is common with intranasal midazolam administration, which may indicate irritation of the nasal mucosa due to the low ph (3 4.3) of the formulation ( ). Finally, the short t 1 2 of midazolam (24) may put patients at risk of seizure recurrence as plasma concentrations rapidly decline. Clobazam Although not currently approved in the USA, clobazam is commonly used elsewhere as adjunctive therapy for patients with refractory epilepsy (103). It is highly effective as adjunctive therapy for partial and generalized seizures, for intermittent therapy and for controlling nonconvulsive status epilepticus, and it produces less sedation than other BZDs do (140). Its use is limited by the potential for the development of tolerance. However, a portion of patients (up to 25%) may remain seizure free while taking adjunctive clobazam for long periods ( ). The Canadian Clobazam Cooperative Group reported that, on the basis of results from a retrospective study, 40 50% of patients could be maintained on clobazam for 4 years or longer (141). In several double-blind, placebo-controlled, add-on trials in patients with refractory epilepsy, adjunctive clobazam was shown to be effective 77

10 Riss et al. (17, ). In a crossover study of 21 patients, a >50% reduction in seizure frequency was seen in 52% of patients receiving clobazam (145). In another crossover study, Schmidt et al. (146) reported a seizure frequency reduction of 75% in 40% of patients receiving adjunctive clobazam. These findings compare favorably with adjunctive therapy results for many AEDs currently available in the USA. Clobazam was studied in a large double-blind trial as first-line monotherapy in children with partial, partial with secondary generalization or primary generalized tonic clonic seizures and was reported to have efficacy and tolerability similar to that of monotherapy with phenytoin or carbamazepine (153, 154). Seizure freedom was maintained for the entire 12 months of the study for 23%, 25% and 11% of patients randomly assigned to receive clobazam, carbamazepine and phenytoin respectively. Clorazepate The effectiveness of adjunctive clorazepate for various treatment-resistant seizures has been demonstrated; however, the clinical experience and data available are less extensive for clorazepate than for other BZDs (103). An openlabel clinical study of clorazepate therapy suggested that the drug might be useful as an add-on treatment for generalized major and minor seizures (e.g. absence, akinetic and myoclonic) (155). In that study, an excellent response (defined as complete seizure control or seizure control that produced a notable improvement in social, educational or vocational assessment) was observed for 19% of patients with major generalized seizures (three of 16), 39% of patients with absence seizures (seven of 18), 33% of patients with akinetic seizures (three of nine) and 57% of patients with myoclonic seizures (four of seven). Other doubleblind (156) and open-label ( ) studies have demonstrated the efficacy of adjunctive clorazepate for both partial (simple and complex) and generalized seizures. Clorazepate also appears to be useful in childhood epilepsy. In an open-label, add-on study, 22% of patients with Lennox Gastaut syndrome (two of nine) had a partial response (<75% reduction in seizure frequency) to clorazepate (158). In an uncontrolled, open-label study of 18 children with Lennox Gastaut syndrome or other conditions with atypical absence seizures, the authors stated that five patients (28%) had an excellent response and eight patients (44%) had a good response to adjunctive clorazepate therapy, although the terms ÔexcellentÕ and ÔgoodÕ were not clearly defined (160). Other studies have found good results with clorazepate in the treatment of refractory childhood epilepsies. In an open-label study by Naidu et al. (161), 11 children with generalized seizures (absence and atonic) who received clorazepate as monotherapy (n =4) or as adjunctive therapy with valproate (n = 7) had a reduction in the number of clinically observed seizures. In another open-label study, clorazepate was added to standard AEDs in 29 children with various seizure disorders; 72% of patients experienced improved seizure control (162). Adverse effects Although BZDs as a class are well tolerated, clinicians should be aware of potential safety issues associated with BZD use. Drowsiness and confusion may be indicative of over-sedation, a doserelated extension of the sedative hypnotic effects of BZDs (62, 163, 164). Over-sedation is more problematic in the elderly than in younger patients, and it may occur at lower doses in the elderly (165, 166). Elderly patients treated with BZDs can experience confusion, amnesia, ataxia and hangover effects (62). Benzodiazepine use is also associated with falls, a possible result of over-sedation in elderly patients (167). Benzodiazepines may cause amnesia, particularly anterograde amnesia (168). This effect is sometimes deliberately utilized in presurgical medication (169). However, memory impairment may also be associated with clinical doses of orally administered BZDs (168). For individuals who use BZDs long term, the possible degree of recovery and the extent of residual impairment that may remain after the drugs are withdrawn are unclear (170). In a metaanalysis, Barker et al. (170) concluded that longterm BZD users show recovery of function in visuospatial skills, attention concentration, general intelligence, psychomotor speed and nonverbal memory assessments after withdrawal. The authors found, however, that significant cognitive impairment was more persistent in long-term users than in control groups or in normative data. The authors reported that the study data did not demonstrate complete restoration of function within the first 6 months following discontinuation of BZD use; they suggested that longer than 6 months may be needed for recovery from some deficits. Paradoxical excitement is sometimes associated with BZD use and may include exacerbation of seizures in patients with epilepsy (171). Children and elderly patients, patients with a history of alcohol abuse and individuals with a history of aggressive behavior anger may be more likely to 78

11 Benzodiazepines in the treatment of epilepsy experience paradoxical excitement effects than are other patients (172). Additionally, BZDs can cause or aggravate depression (57). Dependence refers to the compulsion to take a drug to produce a desired effect or to prevent unpleasant effects that occur when the drug is withheld. Dependence develops in almost onethird of patients who are treated with BZDs for 4 weeks (173). A withdrawal syndrome upon BZD discontinuation (see Tolerance and withdrawal section) is a common manifestation of BZD dependence (173). High BZD dosage and potency, short duration of BZD action, long duration of therapy and premorbid dependent personality traits are risk factors for the development of BZD dependence (173). Potent BZDs with relatively short t 1 2 (e.g. triazolam, alprazolam and lorazepam) appear to carry the highest risk of dependence (173). Substantial differences in adverse event occurrences associated with the BZDs profiled here have not been reported in large randomized, controlled trials comparing BZDs. Some study results have suggested that diazepam may have greater effects on respiratory depression than are observed with other BZDs such as lorazepam and midazolam (174, 175). Additionally, although BZDs are generally known to affect memory, some studies have shown that effects differ depending on the BZD used. Lorazepam appears to impair both explicit memory and implicit memory, and although diazepam impairs explicit memory, results regarding impairment of implicit memory by diazepam are mixed ( ). The adverse event profiles of BZDs should be considered when decisions are made regarding therapy. Clinicians should weigh the possible benefits of therapy with BZDs against the potential adverse effects. Tolerance and withdrawal Tolerance Tolerance to AEDs is associated with a progressive increase in the number and severity of seizures and an increased risk of withdrawal seizures in the presence of a constant maintenance dose. Tolerance to several BZDs has been demonstrated in experimental epilepsy models ( ). Because of the development of anticonvulsant tolerance, BZDs are generally considered unsuitable for longterm control of epilepsy (57, 186). Increasing the BZD dose may overcome anticonvulsant tolerance. However, tolerance may recur at the higher dose, and adverse effects may persist or worsen. Cross-tolerance between BZDs occurs and appears to be drug specific. Ramsey-Williams et al. (187) demonstrated that after 3 weeks of diazepam treatment, rats developed cross-tolerance to the anticonvulsant effects of clobazam, clonazepam and midazolam. Rats treated with midazolam for 3 weeks developed cross-tolerance to diazepam but not to clobazam or clonazepam. The authors suggested that differences in tolerance and crosstolerance could result from differential regulation of receptor subunit expression by each drug and from differences between the drugs in their interactions with receptors at the time of testing. When BZDs are used as anticonvulsants, the time to onset of tolerance varies, and the potential of a BZD to induce anticonvulsant tolerance does not appear to have any relationship with its chemical or pharmacokinetic properties (188). Differences in the development of anticonvulsant tolerance have been reported for various BZDs in an amygdala-kindling rat model. Young et al. (185) found that tolerance to clobazam developed within 3 days of initial drug exposure, whereas tolerance to clonazepam developed gradually over the course of a 19-day study. Rosenberg et al. (189) compared the anticonvulsant activity of clonazepam, clobazam and diazepam in rats and found that tolerance developed most rapidly to clobazam and most slowly to clonazepam. In studies investigating anticonvulsant tolerance, animals treated with clorazepate exhibited a later onset or a lesser degree of tolerance than did those treated with either diazepam ( ) or clonazepam (184, 192). Nonetheless, clinicians must be aware of the possibility of tolerance with long-term clorazepate administration. In a study comparing clorazepate and clobazam, tolerance was defined as initial seizure freedom, marked efficacy ( 80% seizure frequency reduction) or efficacy ( 50% seizure frequency reduction) followed by an increase in seizure frequency to a level greater than that seen with initial treatment. Tolerance occurred in 48% of patients treated with clorazepate for 4 weeks, but in only 24% of patients treated with clobazam for 3 months (193). However, when the dosage was maintained or increased, clorazepate once again became effective in 50% of patients who had previously developed tolerance. Likewise, in 70% of patients who had developed tolerance to clobazam, the drug once again became effective with an increased dosage or at the same dosage. The mechanism responsible for such reversal of tolerance is unclear. Tolerance to some side effects of BZDs can also develop. The onset of tolerance to the sedative effects of BZDs usually occurs within 1 2 weeks (194, 195). Memory and cognition, however, often 79