Benzodiazepines in epilepsy: pharmacology and pharmacokinetics

In the paper

“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).”

In the paper

“The time to maximum concentration was 2.43 and 9.20 h for the immediate-release and sustained-release formulations respectively.”

In the paper

“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).”

In the paper

“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”

In the paper

“Change in trough plasma DMD concentrations (%) | NA | )44.1 | )41.9 | NA | )48.8 | )48.8”

What the sources say

• Not checked yetcites [71] Riss

In the paper

“Peak ⁄ trough difference b at steady state (lg ⁄ ml) | 0.17 | NA | NA | 0.13 | NA | NA”

What the sources say

• Not checked yetcites [71] Riss

In the paper

“Change in peak plasma DMD concentrations (%) | NA | )29.6 | 6.0 | NA | )27.1 | 9.6”

What the sources say

• Not checked yetcites [71] Riss

In the paper

“Peak ⁄ trough difference b after missed dose(s) (lg ⁄ ml) | NA | 0.18 | 0.41 | NA | 0.18 | 0.42”

What the sources say

• Not checked yetcites [71] Riss

In the paper

“Change in peak plasma DMD concentrations (%) | NA | )29.6 | 6.0 | NA | )27.1 | 9.6”

What the sources say

• Not checked yetcites [71] Riss

In the paper

“Change in trough plasma DMD concentrations (%) | NA | )44.1 | )41.9 | NA | )48.8 | )48.8”

What the sources say

• Not checked yetcites [71] Riss

In the paper

“are also frequently used in the treatment of febrile, acute repetitive and alcohol withdrawal seizures”

• Also stated in: § Introduction · plain

  “Benzodiazepines also continue to play major roles in treating other conditions such as febrile seizures, acute repetitive seizures and alcohol withdrawal seizures.”

What the sources say

• Not checked yetcites [81] Ko, 1997

In the paper

“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.”

• Also stated in: § Efficacy · plain

  “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”

What the sources say

• Not checked yetcites [81] Ko, 1997

In the paper

“Clinical advantages of these drugs include rapid onset of action, high efficacy rates and minimal toxicity.”

• Also stated in: § Introduction · plain

  “The major clinical advantages of BZDs are high efficacy rates, rapid onset of action and minimal toxicity.”

In the paper

“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”

• Also stated in: § Introduction · plain

  “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.”

What the sources say

• Not checked yetcites [77] Alldredge, 2001, A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus, N Engl J Med source
• Not checked yetcites [78] Shaner, 1988, Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin, Neurology source
• Not checked yetcites [79] Treiman, 1998, A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group, N Engl J Med source

In the paper

“Benzodiazepines differ in their pharmacologic effects and pharmacokinetic profiles, which dictate how the drugs are used.”

• Also stated in: § Introduction · hedged

  “Thus, pharmacokinetic differences often dictate the use of specific BZDs, route(s) of administration and formulation(s).”

In the paper

“Potential shortcomings of BZDs include tolerance, withdrawal symptoms, adverse events, such as cognitive impairment and sedation, and drug interactions.”

In the paper

“Clobazam is an exception with its 1-5-BZD structure (17).”

What the sources say

• Not checked yetcites [17] Shorvon, 1995

In the paper

“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).”

What the sources say

• Not checked yetcites [24] Anderson, 2002

In the paper

“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).”

What the sources say

• Not checked yetcites [3] Chebib, 1999, The ABC of GABA receptors: a brief review, Clin Exp Pharmacol Physiol source

In the paper

“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).”

What the sources say

• Not checked yetcites [25] Hobbs, 1996

In the paper

“Additionally, the pharmacokinetic characteristics of clorazepate (particularly the sustained-release formulation) could theoretically help minimize adverse events.”

In the paper

“Diazepam and lorazepam are primarily used for management of seizure emergencies, whereas clobazam, clonazepam and clorazepate are commonly used in chronic epilepsy management.”

In the paper

“The inhibitory neurotransmitter GABA binds to the receptor to open the chloride ion gates and produce an inhibitory current (6,8).”

What the sources say

• Not checked yetcites [6] Macdonald, 1994, GABAA receptor channels, Annu Rev Neurosci source
• Not checked yetcites [8] Barker, 1978, Amino acid pharmacology of mammalian central neurones grown in tissue culture, J Physiol source

In the paper

“Ligand-activated ion channels that are selectively blocked by bicuculline and modulated by steroids, BZDs, and barbiturates are known as GABA A receptors (3).”

What the sources say

• Not checked yetcites [3] Chebib, 1999, The ABC of GABA receptors: a brief review, Clin Exp Pharmacol Physiol source

In the paper

“Among these BZDs, clorazepate has a unique profile that includes a long half-life of its active metabolite and slow onset of tolerance.”

In the paper

“Benzodiazepines differ in their rates of elimination and the formation of pharmacologically active metabolites (Table 2).”

In the paper

“The basic chemical structure of BZDs is formed from the fusion of a benzene ring and a sevenmembered diazepine ring (16) (Fig. 1).”

What the sources say

• Not checked yetcites [16] Feldman, 1997

In the paper

“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)(11)(12).”

What the sources say

• Not checked yetcites [6] Macdonald, 1994, GABAA receptor channels, Annu Rev Neurosci source
• Not checked yetcites [7] McKernan, 1996, Which GABAA-receptor subtypes really occur in the brain?, Trends Neurosci source
• Not checked yetcites [10] Atack, 2006, Rat pharmacokinetics and pharmacodynamics of a sustained release formulation of the GABAA5-selective compound L-655,708, Drug Metab Dispos source

In the paper

“There are three principal c-aminobutyric acid (GABA) receptor subtypes.”

What the sources say

• Not checked yetcites [3] Chebib, 1999, The ABC of GABA receptors: a brief review, Clin Exp Pharmacol Physiol source

In the paper

“The GABA A receptor consists of a pentameric structure with multiple subunits that are necessary for normal physiologic function.”

In the paper

“Midazolam often is used as an alternative to diazepam and lorazepam in seizure emergencies and for treating refractory status epilepticus.”

In the paper

“Following rapid uptake, BZDs redistribute into less well-perfused tissues; the rate of redistribution is the fastest for the most lipid-soluble drugs (25).”

What the sources say

• Not checked yetcites [25] Hobbs, 1996

In the paper

“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).”

What the sources say

• Not checked yetcites [14] Lw, 2000, Molecular and neuronal substrate for the selective attenuation of anxiety, Science source
• Not checked yetcites [15] Rudolph, 1999, Benzodiazepine actions mediated by specific -aminobutyric acidA receptor subtypes, Nature source

In the paper

“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).”

What the sources say

• Not checked yetcites [3] Chebib, 1999, The ABC of GABA receptors: a brief review, Clin Exp Pharmacol Physiol source

In the paper

“There are, however, differences among BZDs in affinity for receptor subtypes, which may produce different pharmacologic effects.”

In the paper

“Benzodiazepines are classified as low, medium (e.g.clorazepate and diazepam) or high (e.g.clonazepam and lorazepam) potency (18,19).”

What the sources say

• Not checked yetcites [18] Nelson, 1999, Guidelines for the clinical use of benzodiazepines: pharmacokinetics, dependency, rebound and withdrawal, Can J Clin Pharmacol
• Not checked yetcites [19] Chouinard, 2004, Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound, J Clin Psychiatry

In the paper

“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).”

What the sources say

• Not checked yetcites [4] Simon, 2004, Analysis of the set of GABAA receptor genes in the human genome, J Biol Chem source
• Not checked yetcites [5] Sieghart, 1999, Structure and subunit composition of GABAA receptors, Neurochem Int source
• Not checked yetcites [6] Macdonald, 1994, GABAA receptor channels, Annu Rev Neurosci source

In the paper

“Benzodiazepines cross the blood-brain barrier rapidly, although the diffusion rate into the brain varies by drug and is largely determined by lipophilicity (21).”

What the sources say

• Not checked yetcites [21] Rey, 1999, Pharmacokinetic optimization of benzodiazepine therapy for acute seizures. Focus on delivery routes, Clin Pharmacokinet source

In the paper

“In neonates, the t 1 ⁄ 2 of clorazepate is prolonged and clearance is decreased (67).”

What the sources say

• Not checked yetcites [67] Rey, 1979, Pharmacokinetics of the placental transfer and distribution of clorazepate and its metabolite nordiazepam in the feto-placental unit and in the neonate, Eur J Clin Pharmacol source

In the paper

“Additionally, many elderly individuals take multiple medications, which increase their risk of drug-drug interactions.”

In the paper

“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).”

What the sources say

• Not checked yetcites [62] Demaagd, 1995, High-risk drugs in the elderly population, Geriatr Nurs source

In the paper

“Clonazepam and lorazepam undergo extensive metabolism, but no active metabolites are formed (18,24).”

What the sources say

• Not checked yetcites [18] Nelson, 1999, Guidelines for the clinical use of benzodiazepines: pharmacokinetics, dependency, rebound and withdrawal, Can J Clin Pharmacol
• Not checked yetcites [24] Anderson, 2002

In the paper

“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).”

What the sources say

• Not checked yetcites [24] Anderson, 2002
• Not checked yetcites [56] Breimer, 1980, Pharmacokinetics of benzodiazepines. Short-acting versus long-acting, Arzneimittelforschung

In the paper

“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.”

What the sources say

• Not checked yetcites [63] Castleden, 1977, Increased sensitivity to nitrazepam in old age, Br Med J source
• Not checked yetcites [64] Kraemer, 1999, Managing alcohol withdrawal in the elderly, Drugs Aging source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [60] Back, 1990, Pharmacokinetic drug interactions with oral contraceptives, Clin Pharmacokinet source

In the paper

“Some BZDs are also available as oral liquids [diazepam (Diazepam Intensol; 5 mg ⁄ ml), lorazepam (Lorazepam Intensol; 2 mg ⁄ ml) and midazolam (generic only; 2 mg ⁄ ml)], disintegrating tablets [clonazepam (Klonopin Ò Wafer; Roche Pharmaceuticals, Nutley, NJ, USA; 0.125-, 0.25-, 0.5-, 1-and 2-mg tablets)] or a rectal gel [diazepam (Diastat Ò AcuDial; Valeant Pharmaceuticals International, Costa M”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [66] Anderson, 2002, Children versus adults: pharmacokinetic and adverse-effect differences, Epilepsia source

In the paper

“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).”

What the sources say

• Not checked yetcites [24] Anderson, 2002
• Not checked yetcites [41] Gorski, 1994, Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily, Biochem Pharmacol source

In the paper

“Elderly individuals often have variable drug absorption, decreased plasma protein-drug binding due to lower albumin concentrations, and reduced hepatic and renal clearance (61).”

What the sources say

• Not checked yetcites [61] Patsalos, 2002, The importance of drug interactions in epilepsy therapy, Epilepsia source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [79] Treiman, 1998, A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group, N Engl J Med source

In the paper

“Fewer studies have evaluated the clinical efficacy of BZDs in chronic epilepsy.”

In the paper

“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).”

What the sources say

• Not checked yetcites [77] Alldredge, 2001, A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus, N Engl J Med source
• Not checked yetcites [79] Treiman, 1998, A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group, N Engl J Med source
• Not checked yetcites [80] Leppik, 1983, Double-blind study of lorazepam and diazepam in status epilepticus, JAMA source

In the paper

“Benzodiazepines were used in epilepsy management as early as 1965, when Gastaut et al. (73,74) administered i.v.diazepam to treat status epilepticus.”

What the sources say

• Not checked yetcites [73] Gastaut, 1965, Treatment of status epilepticus with diazepam (Valium), Epilepsia source
• Not checked yetcites [74] Gastaut, 1965, Laction du diazepam (Valium) dans le traitement des formes non-convulsive de lepilepsie generalisee [in French], Rev Neurol (Paris)

In the paper

“Benzodiazepines are among the most useful AEDs available for treating status epilepticus and acute repetitive seizures and for febrile seizure prophylaxis.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [76] Schmidt, 2002

In the paper

“Diazepam is a drug of first choice for treatment of early status epilepticus and acute repetitive seizures and for febrile seizure prophylaxis.”

In the paper

“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).”

What the sources say

• Not checked yetcites [105] Dreifuss, 1975, Serum clonazepam concentrations in children with absence seizures, Neurology source

In the paper

“In a randomized trial comparing buccal midazolam with rectal diazepam in children, the drugs showed similar efficacy and onset of action (125).”

What the sources say

• Not checked yetcites [125] Scott, 1999, Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial, Lancet source

In the paper

“Although it is used for many seizure types, midazolam does not have an FDA-approved indication for seizures.”

In the paper

“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%).”

What the sources say

• Not checked yetcites [134] McIntyre, 2005, Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial, Lancet source

In the paper

“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).”

What the sources say

• Not checked yetcites [125] Scott, 1999, Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial, Lancet source

In the paper

“Although not currently approved in the USA, clobazam is commonly used elsewhere as adjunctive therapy for patients with refractory epilepsy (103).”

What the sources say

• Not checked yetcites [103] Trimble, 2002, On the use of tranquillisers in epilepsy, Epilepsia source

In the paper

“Midazolam is the only available water-soluble BZD; solubility is achieved when the injectable solution is buffered to a pH of 2.9-3.7 (123).”

What the sources say

• Not checked yetcites [123] 123.Midazolam HCl injection [package insert]. Weston, FL: Apotex Corp, 2000.

In the paper

“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).”

What the sources say

• Not checked yetcites [153] Canadian Study Group for Childhood Epilepsy, 1998, Clobazam has equivalent efficacy to carbamazepine and phenytoin as monotherapy for childhood epilepsy, Epilepsia source
• Not checked yetcites [154] Bawden, 1999, The cognitive and behavioural effects of clobazam and standard monotherapy are comparable, Epilepsy Res source

In the paper

“Open-label studies have suggested that intranasal midazolam is safe and effective for acute seizure management in children (124, 127, 128, 135, 136).”

What the sources say

• Not checked yetcites [124] Lahat, 2000, Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study, BMJ source
• Not checked yetcites [127] Fisgin, 2002, Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study, J Child Neurol source
• Not checked yetcites [128] Mahmoudian, 2004, Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children, Epilepsy Behav source

In the paper

“with 88% of seizures (23 of 26) responding to initial treatment with midazolam and 92% (24 of 26) responding to diazepam (124).”

What the sources say

• Not checked yetcites [124] Lahat, 2000, Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study, BMJ source

In the paper

“It is highly effective as adjunctive therapy for partial and generalized seizures, for intermittent therapy and for controlling nonconvulsive status epilepticus”

What the sources say

• Not checked yetcites [140] Shorvon, 1998, The use of clobazam, midazolam, and nitrazepam in epilepsy, Epilepsia source

In the paper

“studies have suggested that intranasal midazolam is safe and effective for acute seizure management in children (124, 127, 128, 135, 136).”

What the sources say

• Not checked yetcites [124] Lahat, 2000, Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study, BMJ source
• Not checked yetcites [127] Fisgin, 2002, Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study, J Child Neurol source
• Not checked yetcites [128] Mahmoudian, 2004, Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children, Epilepsy Behav source

In the paper

“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 (137-139).”

What the sources say

• Not checked yetcites [137] Scott, 2001, Intranasal midazolam for treating febrile seizures in children. Buccal midazolam should be preferred to nasal midazolam [letter], BMJ source
• Not checked yetcites [138] Loftsson, 2001, Cyclodextrin solubilization of benzodiazepines: formulation of midazolam nasal spray, Int J Pharm source
• Not checked yetcites [139] Gudmundsdttir, 2001, Intranasal administration of midazolam in a cyclodextrin based formulation: bioavailability and clinical evaluation in humans, Pharmazie

In the paper

“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).”

What the sources say

• Not checked yetcites [137] Scott, 2001, Intranasal midazolam for treating febrile seizures in children. Buccal midazolam should be preferred to nasal midazolam [letter], BMJ source

In the paper

“Paradoxical excitement is sometimes associated with BZD use and may include exacerbation of seizures in patients with epilepsy (171).”

What the sources say

• Not checked yetcites [171] Gayatri, 2006, Aggravation of epilepsy by anti-epileptic drugs, Dev Med Child Neurol source

In the paper

“and although diazepam impairs explicit memory, results regarding impairment of implicit memory by diazepam are mixed (176-179).”

What the sources say

• Not checked yetcites [176] Legrand, 1995, Time course of the effects of diazepam and lorazepam on perceptual priming and explicit memory, Psychopharmacology source
• Not checked yetcites [177] Wagemans, 1998, Lorazepam but not diazepam impairs identification of pictures on the basis of specific contour fragments, Psychopharmacology source
• Not checked yetcites [178] Vidailhet, 1994, Lorazepam and diazepam effects on memory acquisition in priming tasks, Psychopharmacology source

In the paper

“Benzodiazepine use is also associated with falls, a possible result of over-sedation in elderly patients (167).”

What the sources say

• Not checked yetcites [167] Souchet, 2005, Drug related falls: a study in the French pharmacovigilance database, Pharmacoepidemiol Drug Saf source

In the paper

“Over-sedation is more problematic in the elderly than in younger patients, and it may occur at lower doses in the elderly (165, 166).”

What the sources say

• Not checked yetcites [165] Greenblatt, 1982, Drug therapy: drug disposition in old age, N Engl J Med source
• Not checked yetcites [166] Montamat, 1989, Management of drug therapy in the elderly, N Engl J Med source

In the paper

“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).”

What the sources say

• Not checked yetcites [173] Marriott, 1993, Benzodiazepine dependence. Avoidance and withdrawal, Drug Saf source

In the paper

“Lorazepam appears to impair both explicit memory and implicit memory”

What the sources say

• Not checked yetcites [176] Legrand, 1995, Time course of the effects of diazepam and lorazepam on perceptual priming and explicit memory, Psychopharmacology source
• Not checked yetcites [177] Wagemans, 1998, Lorazepam but not diazepam impairs identification of pictures on the basis of specific contour fragments, Psychopharmacology source
• Not checked yetcites [178] Vidailhet, 1994, Lorazepam and diazepam effects on memory acquisition in priming tasks, Psychopharmacology source

In the paper

“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).”

What the sources say

• Not checked yetcites [170] Barker, 2004, Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis, Arch Clin Neuropsychol source

In the paper

“This effect is sometimes deliberately utilized in presurgical medication (169).”

What the sources say

• Not checked yetcites [169] Ranta, 2002, Patients conscious recollections from cardiac anesthesia, J Cardiothorac Vasc Anesth source

In the paper

“Additionally, although BZDs are generally known to affect memory, some studies have shown that effects differ depending on the BZD used.”

What the sources say

• Not checked yetcites [176] Legrand, 1995, Time course of the effects of diazepam and lorazepam on perceptual priming and explicit memory, Psychopharmacology source
• Not checked yetcites [177] Wagemans, 1998, Lorazepam but not diazepam impairs identification of pictures on the basis of specific contour fragments, Psychopharmacology source
• Not checked yetcites [178] Vidailhet, 1994, Lorazepam and diazepam effects on memory acquisition in priming tasks, Psychopharmacology source

In the paper

“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”

What the sources say

• Not checked yetcites [155] Booker, 1974, Clorazepate dipotassium in the treatment of intractable epilepsy, JAMA source

In the paper

“Elderly patients treated with BZDs can experience confusion, amnesia, ataxia and hangover effects (62).”

What the sources say

• Not checked yetcites [62] Demaagd, 1995, High-risk drugs in the elderly population, Geriatr Nurs source

In the paper

“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.”

What the sources say

• Not checked yetcites [185] Young, 1988, Differences in the development of tolerance to two anticonvulsant benzodiazepines in the amygdaloid kindled rat, J Pharm Pharmacol source

In the paper

“Other shortcomings include adverse events, such as cognitive impairment and sedation, and drug interactions.”

In the paper

“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.”

What the sources say

• Not checked yetcites [187] Ramsey-Williams, 1994, Comparison of anticonvulsant tolerance, crosstolerance, and benzodiazepine receptor binding following chronic treatment with diazepam or midazolam, Pharmacol Biochem Behav source

In the paper

“They have the clinical advantages of being highly effective, with a rapid onset of action and relatively low toxicity.”

In the paper

“Rats treated with midazolam for 3 weeks developed cross-tolerance to diazepam but not to clobazam or clonazepam.”

What the sources say

• Not checked yetcites [187] Ramsey-Williams, 1994, Comparison of anticonvulsant tolerance, crosstolerance, and benzodiazepine receptor binding following chronic treatment with diazepam or midazolam, Pharmacol Biochem Behav source

In the paper

“Benzodiazepines can be used in a variety of clinical situations because they can be administered by several routes and in different formulations.”

In the paper

“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).”

What the sources say

• Not checked yetcites [188] Garratt, 1988, Can benzodiazepines be classified by characterising their anticonvulsant tolerance-inducing potential?, Eur J Pharmacol source

In the paper

“Cross-tolerance between BZDs occurs and appears to be drug specific.”

What the sources say

• Not checked yetcites [187] Ramsey-Williams, 1994, Comparison of anticonvulsant tolerance, crosstolerance, and benzodiazepine receptor binding following chronic treatment with diazepam or midazolam, Pharmacol Biochem Behav source

In the paper

“Clobazam | Demethylation (26) | N-desmethylclobazam (27) | 10-30 (28) | 36-46 (28)”

What the sources say

• Not checked yetcites [28] Rupp, 1979, Pharmacokinetics of single and multiple doses of clobazam in humans, Br J Clin Pharmacol source

In the paper

“Clonazepam | Nitroreduction (CYP 3A4), | NA | 19-60 (32) | NA”

What the sources say

• Not checked yetcites [29] Seree, 1993, Fundam Clin Pharmacol source
• Not checked yetcites [30] Miller, 1981, Clonazepam acetylation in fast and slow acetylators, Clin Pharmacol Ther source
• Not checked yetcites [31] Peng, 1984, Polymorphic acetylation of 7-amino-clonazepam in human liver cytosol, Pediatr Pharmacol (New York)

In the paper

“Clorazepate is unique among BZDs in that it is associated with slow onset of tolerance, its active metabolite has a long t 1 ⁄ 2 , and it is available as a sustained-release formulation”

In the paper

“Benzodiazepines are indicated for the treatment of seizure emergencies and epilepsy.”

In the paper

“Studies of clorazepate in patients with epilepsy have mainly been small, open-label investigations.”

In the paper

“Gobbi et al. (199) demonstrated that diazepam and DMD have the same affinity for the central type of BZD receptors, but when the intrinsic activity of DMD was calculated, it proved to be a partial agonist, with intrinsic activity approximately 43% that of diazepam.”

What the sources say

• Not checked yetcites [199] Gobbi, 1987, Diazepam and desmethyldiazepam differ in their affinities and efficacies at central and peripheral benzodiazepine receptors, J Pharm Pharmacol source

In the paper

“One putative mechanism for the development of tolerance is simple down-regulation of GABA receptors in response to prolonged BZD exposure; however, studies testing this hypothesis have reported mixed results (197).”

What the sources say

• Not checked yetcites [197] Bateson, 2002, Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal, Curr Pharm Des source

In the paper

“Several other mechanisms for BZD tolerance have been proposed on the basis of animal and cell culture models.These processes include uncoupling of allosteric linkage between GABA and BZD sites, changes in the turnover of receptor subunits and changes in receptor gene expression (197).”

What the sources say

• Not checked yetcites [197] Bateson, 2002, Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal, Curr Pharm Des source

In the paper

“all of which may, theoretically, help minimize adverse effects and withdrawal symptoms.”

In the paper

“Li et al. (198) suggested that down-regulation of BZD receptor binding sites could not fully explain the development of tolerance because tolerance to some BZDs has been observed even when no changes in BZDreceptor binding were noted (187).”

What the sources say

• Not checked yetcites [198] Li, 2000, Down-regulation of benzodiazepine binding to alpha-5 subunit-containing gamma-aminobutyric acidA receptors in tolerant rat brain indicates particular involvement of the hippocampal CA1 region, J Pharmacol Exp Ther
• Not checked yetcites [187] Ramsey-Williams, 1994, Comparison of anticonvulsant tolerance, crosstolerance, and benzodiazepine receptor binding following chronic treatment with diazepam or midazolam, Pharmacol Biochem Behav source

In the paper

“However, results from other studies have suggested that, compared with long-t 1 ⁄ 2 BZDs, BZDs with short t 1 ⁄ 2 are associated with faster onset of withdrawal symptoms or more severe withdrawal symptoms when BZD therapy is stopped abruptly (211, 212).”

What the sources say

• Not checked yetcites [211] Rickels, 1990, Long-term therapeutic use of benzodiazepines. I. Effects of abrupt discontinuation [erratum in Arch Gen Psychiatry 1991;48:51], Arch Gen Psychiatry source
• Not checked yetcites [212] Busto, 1986, Withdrawal reaction after long-term therapeutic use of benzodiazepines, N Engl J Med source

In the paper

“Clobazam | Demethylation (26) | N-desmethylclobazam (27) | 10-30 (28) | 36-46 (28)”

What the sources say

• Not checked yetcites [26] Volz, 1979, Kinetics and metabolism of clobazam in animals and man, Br J Clin Pharmacol source
• Not checked yetcites [27] Hanks, 1979, Clobazam: pharmacological and therapeutic profile, Br J Clin Pharmacol source

In the paper

“Clorazepate | Decarboxylation, glucuronidation, | DMD (major), oxazepam (minor) (24) | NA | 20-160 (24, 33, 34)”

What the sources say

• Not checked yetcites [24] Anderson, 2002
• Not checked yetcites [33] Greenblatt, 1988, Desmethyldiazepam pharmacokinetics: studies following intravenous and oral desmethyldiazepam, oral clorazepate, and intravenous diazepam, J Clin Pharmacol source
• Not checked yetcites [34] Bertler, 1980, Pharmacokinetics of dipotassium chlorazepate in patients after repeated 50mg oral doses, Psychopharmacology (Berl) source

In the paper

“However, tolerance may recur at the higher dose, and adverse effects may persist or worsen.”

In the paper

“Tolerance may develop over time, making BZDs unsuitable for use in long-term epilepsy management.”

In the paper

“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.”

What the sources say

• Not checked yetcites [189] Rosenberg, 1989, Tolerance to anticonvulsant effects of diazepam, clonazepam, and clobazam in amygdala-kindled rats, Epilepsia source

In the paper

“Additionally, withdrawal symptoms, some severe, may develop after cessation of BZD therapy.”

In the paper

“Considering the evidence that tolerance to the various behavioral effects of BZDs develops at different rates and that behavioral effects of BZDs are mediated by different GABA A receptor subtypes, Bateson (197) proposed that multiple mechanisms mediate tolerance and dependence.He described a unified model of molecular mechanisms underlying tolerance that incorporates the molecular processes”

What the sources say

• Not checked yetcites [197] Bateson, 2002, Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal, Curr Pharm Des source

In the paper

“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).”

What the sources say

• Not checked yetcites [193] Sugai, 2004, Clobazam as a new antiepileptic drug and clorazepate dipotassium as an alternative antiepileptic drug in Japan, Epilepsia source

In the paper

“Some reports have suggested that BZD t 1 ⁄ 2 does not influence withdrawal symptoms (208, 210).”

What the sources say

• Not checked yetcites [208] Schweizer, 1990, Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper, Arch Gen Psychiatry source
• Not checked yetcites [210] Murphy, 1991, A double-blind comparison of the effects of gradual withdrawal of lorazepam, diazepam and bromazepam in benzodiazepine dependence, Br J Psychiatry source

In the paper

“Numerous reports have identified certain predictors of the occurrence or increased severity of withdrawal symptoms: higher BZD dose (200-204), longer duration of BZD use (202, 203, 205, 206), immediate cessation or rapid tapering of the BZD dose (200, 203, 204, 207-209), history of drug abuse (202, 203), dependence on other drugs (209), personality pathology (e.g.neuroticism and dependency) (203)”

What the sources say

• Not checked yetcites [200] Martnez-Cano, 1995, Benzodiazepine withdrawal syndrome seizures, Pharmacopsychiatry source
• Not checked yetcites [202] Uhlenhuth, 1999, International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications. IV. Therapeutic dose dependence and abuse liability of benzodiazepines in the long-term treatment of anxiety disorders, J Clin Psychopharmacol source
• Not checked yetcites [203] Schweizer, 1998, Benzodiazepine dependence and withdrawal: a review of the syndrome and its clinical management, Acta Psychiatr Scand Suppl source

In the paper

“Clorazepate | Tranxene T-Tab | Yes | Anxiety, alcohol withdrawal, | Adjunctive treatment of partial seizures (75)”

What the sources say

• Not checked yetcites [75] Lacy, 2004
• Not checked yetcites [76] Schmidt, 2002

In the paper

“Clobazam | Frisium | NA | Not FDA approved | First-line adjunctive treatment for treatment-resistant”

What the sources say

• Not checked yetcites [75] Lacy, 2004
• Not checked yetcites [76] Schmidt, 2002

In the paper

“Lorazepam | Glucuronidation (24) | NA | 7-26 (39, 40) | NA”

What the sources say

• Not checked yetcites [24] Anderson, 2002
• Not checked yetcites [39] Greenblatt, 1979, Pharmacokinetics and bioavailability of intravenous, intramuscular, and oral lorazepam in humans, J Pharm Sci source
• Not checked yetcites [40] Greenblatt, 1982, Pharmacokinetic comparison of sublingual lorazepam with intravenous, intramuscular, and oral lorazepam, J Pharm Sci source

In the paper

“Diazepam | Demethylation (CYP 2C9, 2C19, 2B6, 3A4, | DMD (major), oxazepam (minor), | 21-70 (23, 38) | DMD: 49-179 (33, 38)”

What the sources say

• Not checked yetcites [23] Cloyd, 1998, A single-blind, crossover comparison of the pharmacokinetics and cognitive effects of a new diazepam rectal gel with intravenous diazepam, Epilepsia source
• Not checked yetcites [38] Kaplan, 1973, Pharmacokinetic profile of diazepam in man following single intravenous and oral and chronic oral administrations, J Pharm Sci source
• Not checked yetcites [24] Anderson, 2002

In the paper

“Midazolam | Versed | Yes | Anesthesia, preoperative and procedural | Second-line therapy for early status epilepticus”

What the sources say

• Not checked yetcites [75] Lacy, 2004
• Not checked yetcites [76] Schmidt, 2002

In the paper

“Clonazepam | Klonopin | Yes | Panic disorder, epileptic | Second-line adjunctive treatment for partial and”

What the sources say

• Not checked yetcites [75] Lacy, 2004
• Not checked yetcites [76] Schmidt, 2002

In the paper

“Midazolam | Hydroxylation (CYP 3A4 and 3A5) (25, 41, 42) | 1-hydroxymidazolam (minor) (24) | 1-4 (24) | 1 (24)”

What the sources say

• Not checked yetcites [25] Hobbs, 1996
• Not checked yetcites [41] Gorski, 1994, Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily, Biochem Pharmacol source
• Not checked yetcites [42] Kronbach, 1989, Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4, Mol Pharmacol

In the paper

“Diazepam | Valium | Yes | Anxiety, alcohol withdrawal, | First-line treatment for early status epilepticus;”

What the sources say

• Not checked yetcites [75] Lacy, 2004
• Not checked yetcites [76] Schmidt, 2002

In the paper

“Lorazepam | Ativan | Yes | Anxiety, pre-anesthetic to induce amnesia, | First-line treatment for early status epilepticus”

What the sources say

• Not checked yetcites [75] Lacy, 2004
• Not checked yetcites [76] Schmidt, 2002