Benzodiazepines

Benzodiazepines 

Classification 

Slow elimination of the parent drug or active metabolite Flurazepam: 

• Long t ½
• Residual effects are likely next morning
• Cumulation occurs on daily ingestion peaking after 3-4 days
• Suitable for patients who have frequent nocturnal awakening and in whom day sedation is acceptable
• Relatively slow elimination but marked redistribution
• Flurazepam is an effective hypnotic drug with the optimum dose for use in general practice being 15 mg at night. ⁽¹⁾
• Grouped male mice fed a diet containing 0.005% nitrazepam or 0.02% flurazepam were more aggressive than untreated controls. Combat related mortality during a two week rouping period was significantly higher among treated males. ⁽²⁾
• Flurazepam is effective in the treatment of sleep disorders in childhood like sleep talking, bruxism, sleep terror and excessive movement during sleep. The side effects include excessive drowsiness, nausea and vomiting. ⁽³⁾
• When ventilatory response to CO2 was measured, flurazepam produces a significant decrease in CO2 sensitivity although there was no significant change in FEV1 or mixed venous PCO2. ⁽⁴⁾
• Flurazepam substantially suppresses both REM and stage 4 sleep. The distortion in sleep EEG produced by flurazepam qualitatively resembe, but are quantitatively greater than those produced by barbiturates in equivalent hypnotic dose. ⁽⁵⁾
• There is rapid and essentially complete absorption followed by rapid elimination of plasma flurazepam in humans. The biotrnasformation of the drug is rapid and virtually complete. The major metabolite in man is the analogous alcohol (the N₁-ethanol analog). ⁽⁶⁾
• Chronic benzodiazepine treatment leads to a reduced number of functional synaptic GABA_A receptors in a region specific manner that may stem from differences in the subunit composition of synaptic GABA_A receptors. ⁽⁷⁾
• Flurazepam intake during the second half of pregnancy can lead to irreversible anomalies. It is better to avoid benzodiazepine therapy in pregnant woman. ⁽⁸⁾
• The sleep induced respiratory abnormalities are not systematically worsened by flurazepam. Flurazepam (15 mg) has no effect on the sleep disturbances in patients with COPD after 7 nights of administration. ⁽⁹⁾
• There is a significant increase in spindle rate over drug nights with flurazepam administration. The rate per minute of K-complexes is significantly decreased during the drug administration. ⁽¹⁰⁾
• Cholestatic jaundice is associated with the use of flurazepam hydrochloride. ⁽¹¹⁾

Diazepam

• Used as anxiolytic, hypnotic, muscle relaxant, premedicant, anesthetic and for emergency control of seizures
• It generates active metabolite (desmethyl-diazepam, oxazepam)
• On occasional use, it is free of side effects
• With regular use, accumulation occurs and prolonged anxiolytic effects may be obtained
• Cause rebound insomnia on discontinuation of chronic use
• Withdrawal phenomenon are mild
• Rectal diazepam is the most commonly used treatment for continuous or serial seizures before admission. Buccal midazolam is safe, effective and popular home treatment for prolonged or serial epileptic seizures. ⁽¹²⁾
• Pretreatment with diazepam exhibits anti-inflammatory property in cerulein-induced acute pancreatitis possibly through peripheral benzodiazepine receptors. ⁽¹³⁾
• DIazepam 10 mg is equivalent to lorazepam 2-2.5 mg. Diazepam is better absorbed after oral than after im administration, clinical effect and amnesia begins more rapidly. Lorazepam is more effective than diazepam in blocking the emergence sequelae from ketamine. Lorazepam iv is followed by a lesser frequency of venous thrombosis. ⁽¹⁴⁾
• Among pediatric patients with convulsive status epilepticus, treatment with lorazepam does not result in improved efficacy or safety compared to diazepam. ⁽¹⁵⁾
• Acute administration of diazepam with daily methadone doses may enhance methadone effects. ⁽¹⁶⁾
• diazepam causes a lower stress reaction, which is beneficial in diminishing the incidence of malignant arrhythmias and preventing the existing myocardial injury from spreading. ⁽¹⁷⁾
• In addition to its central sedative effects, diazepam also has a nitroglycerin- like action on the coronary and systemic circulation. ⁽¹⁸⁾
• Tolerance to diazepam’s sedative actions needs concomitant activation of GABA_A-α₁/GABA_A-α₅ receptors. ⁽¹⁹⁾
• Buccal midazolam is more effective than rectal diazepam for children presenting to hospital with acute seizures and was not associated with an increased incidence of respiratory depression. ⁽²⁰⁾
• Diazepam use is associated with side effects and adverse reactions like tachycardia, blisters all over the body, gross swelling of the right upper limb where the drug was administered, fever, diplopia, headache, as well as sudden hypotension preceded by hypertension. ⁽²¹⁾
• Diazepam is used in suppressing gammahydroxybutyrate (GHB) dependence and related withdrawal symptoms. ⁽²²⁾
• Intravenous sodium valproate is an effective alternative to diazepam infusion in controlling refractory status epilepticus in children and is free of repiratory depression and hypotension. ⁽²³⁾
• Diazepam and lorazepam can be stored on ambulances. When ambient storage temperatures are 30 deg C or less, ambulances carrying lorazepam and diazepam should be restocked every 30 to 60 days. ⁽²⁴⁾

Nitrazepam

• Dose to dose equipotent as diazepam
• Good for patients with frequent nocturnal awakenings and some day sedation is acceptable
• Nitrazepam causes depression of central respiratory drive in patients. ⁽²⁵⁾
• Respiratory depression caused by nitrazepam in patients with respiratory failure. Restlessness may be a sign of worsening respiratory failure where sedatives are contraindicated. ⁽²⁶⁾
• Oxygenation during sleep in non obese patients with stable hypoxemic nonhypercapnic COPD, all on maintenance theophylline therapy, is affected very little by single therapeutic doses of nitrazepam or flunitrazepam. ⁽²⁷⁾
• Cimetidine impairs nitrazepam clearance. It impir drug oxidation in man extending to the capacity for clearance of nitrazepam. ⁽²⁸⁾
• Nitrazepam is metabolized in part by nitro-reduction to an amine followed by acetylation. This acetylation step has been shown to be under the control of the same genetic polymorphism as sulphamethazine. ⁽²⁹⁾
• Nitrazepam is effective in the treatement of myoclonic epilepsy. ⁽³⁰⁾
• Both nitrazepam and corticotropin results in significant reduction in infantile spasms. Patients treated with corticotropin are qualitatively more severe. ⁽³¹⁾
• Nitrazepam is effective in acute epilepsy. It is moderate in a wide range of seizure typpes. It is predominantly used in children with severe epilepsy intractable to conventional medications. ⁽³²⁾
• Nitrazeoam is an effective intermittent treatemnt of febrile convulsions. ⁽³³⁾
• The use of nitrazepam is associated with road traffic accident risk. ⁽³⁴⁾

 Relatively rapid elimination and marked redistribution Alprazolam

• Potent and intermediate acting BZD used in anxiety disorder
• Night time hypnotic with few residual effects next day
• Discontinuation after regular use produce marked withdrawal phenomena
• Alprazolam use is associated with dependence and subsequent withdrawal. Most patients with diagnosed alpazolam dependence uses doses in the range recommended by the package information. ⁽³⁵⁾
• Alprazolam is not effective in reliebing exercise dyspnea in patients with obstructive lung disease. ⁽³⁶⁾
• Alprazolam causes side effects during treatment like depression, enuresis, disinhibition and aggression, sedation, irritability, impaired memory, weight loss and ataxia but many patients of agarophobia with panic disorders are willing to accept it. ⁽³⁷⁾
• Alprazolam users must be warned not to drive an automobile or operate potentially dangerous machinery. ⁽³⁸⁾
• Alprazolam is generally considered a safe and effective drug for the treatment of anxiety disorder and panic attacks. A case has been reported of fatality due to alprazolam intoxication and the distribution of alprazolam and an active metabolite, α-hydroxyalprazolam in tissues obtained at autopsy. ⁽³⁹⁾
• Alprazolam may provide therapeutic benefits in patients with essential tremors especially who require only intermittent therapy. ⁽⁴⁰⁾
• Women with premenstrualdysphoric disorder (PMS) have negative mood premenstrually and increased food cravings and food intake. Although, alprazolam is used to treat PMS, alprazolam has been shown to increase food intake. Restrained eaters are more sensitive to the food intake increasing effects of alprazolam premenstrually. ⁽⁴¹⁾
• Alprazolam is a fairly innocent drug when used as monotherapy, but toxicity problems arise when co-ingested with illicit drugs and/or psychoactive medication. ⁽⁴²⁾
• Alprazolam use is associated with hepatotoxicity. ⁽⁴³⁾
• Acute dystonic reaction can occur after ingestion of alprazolam which can cause torticollis, oculogyric crisis and opisthotonus. ⁽⁴⁴⁾
• Sub-acute administration of propanolol with alprazolam decreases but does not abolish the significant antidepressant activity which is seen after administration of alprazolam alone. ⁽⁴⁵⁾
• Alprazolam is effective in the treatment of chronic drug resistant urticaria. ⁽⁴⁶⁾
• Alprazolam is not as effective as amitriptylline in major depressions with a shortened rapid eye movement latency. ⁽⁴⁷⁾
• A Sustained release (SR) formulation for alprazolam may be useful in tailoring high dose alprazolam therapy. ⁽⁴⁸⁾
• Bispectral Index (BIS) monitoring is quite useful in the management of the patients poisoned with benzodiazepines like alprazolam. ⁽⁴⁹⁾

 Temazepam

• Intermediate acting BZD
• Absortion is slow
• Good for sleep onset difficulty, free of residual effects
• When used in patients with sleep diorders, there is no change in sleep onset latencies. The number of awakening and the duration of awakening was reduced by 30 mg temazepam. Awake activity was also reduced by 20 and 30 mg tmeazepam. ⁽⁵⁰⁾
• Temazepam is used in combination with heroin to enhance the experience of intoxication. Intense intoxication are desired for pleasurable bodily sensations and emotional feelings it produced. ⁽⁵¹⁾
• Temazepam 20 mg significantly reduces pre-operative anxiety and increase the recovery time following alfentanil-propofol anaesthesia. There is significant deficits in attention and memory following anaesthesia, which are increased in range and magnitude by temazepam, which are apparent 30 min after surgery and had largely, but not completely recovered at 4 h. ⁽⁵²⁾
• Cognitive behaviour therapy or temazepam or both improved short term outcomes in older adults with persistent insomnia. ⁽⁵³⁾
• Temazepam is effective for maintaining sleep with short term use, there os rapid development of tolerance for this effect with intermediate term use. Temazepam does not produce any behavioural side effects. It is associated with some sleep and mood disturbance on the first withdrawal night. ⁽⁵⁴⁾
• One week usage of temazepam 10 mg does not influence circadian respiratory function, dyspnea and sleepiness in patients with stable, severe, normocapnic COPD and insomnia and it improves total sleep time and subjective sleep latency. ⁽⁵⁵⁾
• The withdrawal of temazepam can be minimized by using an alternative benzodiazepine. The use of antihistamines as a substitute hypnotics is not advocated. ⁽⁵⁶⁾
• A newborn developed an apparent life-threatening event shortly after birth caused by maternal temazepam use during labour. A single dose of 20 mg temazepam results in a supratherapeutic plasma level in the newborn. 20 mg temazepam is reserved in prescribing to use any dose of any kind of benzodiazepine during labour. ⁽⁵⁷⁾
• There is a highly significant improvement in sleep latency, number of times waking during the night and quality and duration of sleep with the use of temazepam and zopiclone. ⁽⁵⁸⁾
• Benzodiazepines attenuate the ability of SSRIs to elevate hippocampal 5-HT levels. Thus co-administration of benzodiazepines might affect the therapeutic efficacy of SSRI treatment. ⁽⁵⁹⁾
• The 7.5 and 15 mg doses of temazepam are equally effective for the treatment of transient insomnia. The initiation of treatemnt with temazepam for transient insomnia should begin with the lowest effective dose, ie 7.5 mg. ⁽⁶⁰⁾

 Ultra rapid elimination Triazolam

• Very potent, peak effect in < 1 hour
• Good for sleep induction but poor in maintaining it
• Rebound insomnia occur after discontinuation
• Higher dose can alter sleep architecture, produce anterograde amnesia and anxiety the following day
• Next day memory impairment/ amnesia after a bedtime dose of triazolam tends to increase with continued or intermittent drug use. Cognitive impairments associated with traizolam represent a spectrum of organic brain dysfunction with memory impairment/ amnesia and confusion being the commonest, milder anifestations and hallucinations and delusions the more severe and less common features. ⁽⁶¹⁾
• Triazolam is safe and highly effective in reducing both anxious cognitions and disruptive movement during oral injections of local anesthetic and drilling in anxious dental patients. ⁽⁶²⁾
• Brotizolam has an hypnotic efficacy comparable to that of triazolam. ⁽⁶³⁾
• Diltiazem inhibit the metabolism of triazolam during the first-pass and elimination phases. Prescription of triazolam should be avoided if a patient is using diltiazem or other potent inhibitors of CYP3A. ⁽⁶⁴⁾
• Triazolamearlier was considered as a promising sedative agent for use in pediatric dentisrty. There is no improvement seen in child behaviour when triazolam is used a a sedative, also it does not shorten the length of dental treatment. ⁽⁶⁵⁾
• There is a higher occurence of adverse behavioural reactions with triazolam, particularly when used at higher doses. Physician should prescribe lowest recommended doses for the shortest clinically necessary durations and discontinue medication use when adverse reactions occur. ⁽⁶⁶⁾
• Prenanolone selectively enhances the anti conflict effects of triazolam, which raises the possibility that neuroactive steroids potentiate the anxiolytic effects of benzodiazepines. ⁽⁶⁷⁾
• Triazolam, zolpidem and temazepam are effective in the treatment of insomnia in elderly patients. Triazolam produces a significantly higher incidence of nervousness than zolpidem. ⁽⁶⁸⁾
• Triazolam is associated with non cardiac pulmonary edema, which can be more severe in obese patients. ⁽⁶⁹⁾
• Triazolam increases the arousal threshold to airway occlusion. This results in modest prolongation of event duration and increased desaturation at a dose of 0.25 mg in large sleep apnea patients. ⁽⁷⁰⁾
• Triazolam is a useful premedication since it provides comparable level of anxiolysis and sedation as well as greater amnesia of events during immediate perioperativ eperiod. ⁽⁷¹⁾
• Triazolam reduces blood pressure gradually and increases PaCo2 during stage 2 sleep while keeping absolute CBF constant in the occipital cortex and cerebral white matter. During triazolam induced stage 2 sleep, the cerebral white matter has a strong positive correlation of MAP to the absolute CBF and may compensatorily receive a modulated CBF regulation with the strengthened positive correlation of PaCo2 to absoulte CBF in the region except for the frontal white matter. ⁽⁷²⁾

 Midazolam

• Extremely rapid absorption- peak in 20 min
• Cause problem in anxiety (ataxia, blackouts)
• It is mainly used as im premedicant or an iv anesthetic
• There is a high bioavailability and reliable plasma concentrations following buccal midazolam. The clinical benefit of buccal midazolam may be in particular patient controlled premedication or sedation in adults. ⁽⁷³⁾
• Midazolam is a short acting, water soluble benzodiazepine. It has anxiolytic, sedative, hypnotic, anticonvulsant, muscle relaxant and anterograde amnesic effect. It is used as a pre-anesthetic agent in adults and most recently in children. Intranasal administration of midazolam is safe, easy to administer and has a rapid onset of sedation. ⁽⁷⁴⁾
• Propofol is proved to be a satisfactory agent for sedation in critically ill patients and is compared favourably with midazolam. Weaning from mechanical ventilation is achieved significantly faster after discontinuation of propofol than of midazolam. ⁽⁷⁵⁾
• When a survey was done to evaluate the effectiveness and convenience of nasal/buccal midazolam in terminating prolonged seizure in the community, 83% families have found it to be effective and easy to use. 83% preferred using midazolam to rectal diazepam. ⁽⁷⁶⁾
• Midazolam is safe and effective drug which may be used as a sedative or an antiepileptic for treatment of infants refractory to standard antiepileptic therapy. It is particularly useful in the treatment of status epilepticus in infants. It is extensively hydroxylated by two cytochrome P-450 forms, CYP3A4 and CYP3A5. Neonates have  alower expression of these enzymes than older infants and adults. Consequently, the metabolic rate of midazolam is lower in neonates. ⁽⁷⁷⁾
• Midazolam sedation produces complete amnesia for bronchoscopy. ⁽⁷⁸⁾
• Midazolam is considered as a safe and effective antiepileptic drug in refractory neonatal seizures of diverse etiologies. ⁽⁷⁹⁾
• Nasal midazolam spray offers relief to children anxious about procedures such as insertion of a needle in a subcutaneously implanted intravenous port, venous blood sampling, venous cannulation etc. ⁽⁸⁰⁾
• Diazepam and midazolam are both effective for conscious sedation in ED patients. Midazolam causes less pain on injection, a significantly greater degree of early sedation and a more rapid return to baseline function. ⁽⁸¹⁾
• Intravenous midazolam appears to be an effective treatment for refractory generalized status epilepticus, and may represent a substantial improvement over current therapeutic approaches such as pentobarbital anesthesia. ⁽⁸²⁾
• The atomized intranasal ketamine and Midazolam makes gastric aspirates more acceptable and easy to perform in children. ⁽⁸³⁾
• Nurse-administered propofol results in several advantages for outpatient colonoscopy compared with midazolam plus fentanyl, but does not improve patient satisfaction. ⁽⁸⁴⁾
• The addition of midazolam 50 mcg/kg to 30 ml of bupivacaine 0.5% for supraclavicular brachial plexus block prolonged sensory blockade and post-operative analgesia without increasing the risk of adverse effects. ⁽⁸⁵⁾
• Sedation provided by continuous infusion of midazolam and morphine appears to be comparable to morphine alone in newborn babies on mechanical ventilation, with no significant adverse effects. The course of mechanical ventilation is not influenced by use of midazolam. ⁽⁸⁶⁾
• Intranasal midazolam which delivers antiepileptic medication directly to the blood and CSF via nasal mucosa is safe, inexpensive, easy to learn by parents and paramedics and provides better seizure control than rectal diazepam in pediatric status epilepticus. ⁽⁸⁷⁾
• Hiccups can be induced by midazolam during sedation in flexible bronchoscopy which may be easily reverted with flumazenil. ⁽⁸⁸⁾
• Midazolam is a safe, effective and promptly acting sedative for upper gastroinetstinal endoscopy. Compared to diazepam, it is significantly more potent, faster acting and is associated with greater amnesia. ⁽⁸⁹⁾

Phamacokinetics and clinical features of BZDs  

 Pharmacological action 

1. BZDs produce a lower degree of neuronal depression than barbiturates. They have high therapeutic index.
2. Hypnotic dose do not affect respiration or cardiovascular functions. High dose produce mild respiratory depression and hypotension
3. BZDs have practically no action on other body systems. On iv injection, BP fall and cardiac contractility decreases. Fall in BP in case of diazepam and lorazepam is due to reduction in cardiac output while that due to midazolam is due to decrease in peripheral resistance
4. BZDs cause less distortion of sleep architecture; rebound phenomena after discontinuation of regular use is less marked
5. BZDs do not alter disposition of other drugs by microsomal enzyme induction
6. They have lower abuse liability; tolerance is mild; psychological and physical dependence, drug seeking and withdrawal syndrome are less marked

CNS actions

• They are not general depressnats
• Exert relatively selective anxiolytic, hypnotic muscle relaxant and anti convulsant effects in different measures
• Antianxiety
• Sleep:
• They hasten onset of sleep, reduce intermittent awakening and increase total sleep time
• Time spent in stage 2 is increased while that in stage 3 and 4 is decreased
• They tend to shorten the REM phase but more REM cycles may occur
• Night terrors and body movements during sleep are reduced and stage shifts to stage 1 and 0 are lessened
• Muscle relaxant: centrally mediated skeletal muscle relaxation without impairing voluntary activity. Very high doses depress neuromuscular transmission
• Anti convulsant: diazepam and lorazepam are highly effective for short term use in status epilepticus.
• Other action:
• Diazepam decreases nocturnal gastric secretion and prevents stress ulcers
• BZD do not significantly affect bowel movement
• Short lasting coronary dilatation is produced by iv diazepamSite and mechanism of action
• BZDs act preferentially on midbrain ascending reticular formation and on the limbic system
• Muscle relaxation is produced by a primary medullary site of action and ataxia is due to action on cerebellum
• BZDs act by enhancing presynaptic/ postsynaptic inhibition through a specific BZD receptor-Cl- channel complex
• Only the α and β subunits are required for GABA action, and most likely the binding site for GABA is located on the β subunit
• The modulatory BZD receptor increases the frequency of Cl- channel opening induced by submaximal concentration of GABA
• The BZDs also enhance the GABA binging to GABAA receptor
• The BZDs do not themselves increase Cl- conductance; have only GABA facilitatory but no GABA mimetic action

 Drugs affecting GABAA receptor gated chloride channel ​ 

  Pharmacokinetics

• Oral absorption of some is rapid while that of others is slow
• Absorption from im site is irregular except for lorazepam
• Plasma protein binding also varies markedly. (flurazepam 10% to diazepam 99%)
• BZDs are widely distributed in the body
• The more lipid soluble members  enter brain rapidly and have a two phase plasma concentration decay curve; first due to distribution to other tissues and later due to elimination
• A relatively short duration of action is obtained with a single dose of a drug that is rapidly distributed, even though ot may have a long t ½.
• BZDs are metabolized in liver by CYP3A4 and CYP2C19 to dealkylated and hydroxylated metabolites, some of which may be active
• The biological effect half life of these drugs may be much longer than the plasma t ½ of the administered compound.
• The phase I metabolites and certain BZDs themselves are conjugated with glucuronic acid
• Some BZDs (eg. diazepam) undergo enterohepatic circulation
• BZD and their phase I metabolites are excreted in urine as glucuronide conjugates.
• BZDs cross placenta and are excreted in milk

 Drug interaction

• BZD synergise with alcohol and other CNS depressants leading to excessive impairment
• Use of BZD with sod. Valproate has provoked psychotic symptom
• BZD action can be prolonged by CYP3A4 inhibitors like ketoconazole, erythromycin and others
• Cimetidine, isoniazid and oral contraceptives retard BZD metabolism

 Uses

1. As hypnotic
2. As anxiolytic and for day time sedation
3. As anticonvulsant, emergency control of status epilepticus, febrile convulsions, tetanus etc
4. For preanesthetic medication, iv anesthesia and conscious sedation
5. Before ECT, electric cardioversion of arrhythmias, cardiac catheterization, endoscopies, in obstetrics and many minor procedures.
6. Alcohol withdrawal in dependent patients
7. Along with analgesics, NSAIDs, spasmolytics, antiulcer and as adjuvants to treat gas or nonspecific dyspeptic symptoms

 Flumazenil

• The administration of flumazenil shouldbe considered in patients presenting with an overdose of BZDs. It should not be used if the patient is benzodiazepine dependent. Co-ingestion of pro-convulsant including tricyclic antidepressants, or a history of epilepsy are contraindiactions of flumazenil. ⁽⁹⁰⁾
• Flumazenil can reverse tolerance to benzodiazepines but without precipitating withdrawal seizures. ⁽⁹¹⁾
• Flumazenil is effective in the management of BZD overdose and is associated with a low incidence of seizures. ⁽⁹²⁾
• Low dose flumazenil infusion appears to be safe and effective treatement resulting in withdrawal symptoms of lesser severity than any other cessation method currently available. ⁽⁹³⁾
• Flumazenil rapidly and effectively reverses the clinical signs and symptoms of BZD overdose. Most patients responds to 3 mg or less, but a small number may require a higher dose for reversal of clinical symptoms. Patients with concomitant tricyclic antidepressant overdose may be at risk of developing seizures. ⁽⁹⁴⁾
• Flumazenil can cause provocation of panic attacks due to differential production of an anxiolytic endogenous ligand or an altered benzodiazepine receptor set-point. ⁽⁹⁵⁾
• Flumazenil apears to up-regulate GABA-BZD receptors and exert a weak agonist action that suppresses BZD withdrawal symptoms. ⁽⁹⁶⁾
• The elimination of flumazenil is impaired in patients who have stable alcoholic cirrhosis. ⁽⁹⁷⁾
• Flumazenil has no effect on the midazolam induced decrease in left ventricle pressure and heart rate. Thus, the cardiac depressant effect of midazolam is not mediated through peripheral benzodiazepine receptors. ⁽⁹⁸⁾
• Single administration of flumazenil is effective in reversal of alcohol dependence and tolerance. ⁽⁹⁹⁾
• Flumazenil binding asymmetry is a sensitive method to detect regions of epileptic foci in patients with intractable temporal lobe epilepsy. ⁽¹⁰⁰⁾
• The permanently and irreversibly damaged cortex can be detected by reduced flumazenil binding early after stroke. Permanent cortical damage can be detected by flumazenil positron emission tomography in acute stroke. ⁽¹⁰¹⁾
• 11C Flumazenil PET provides a useful tool for investigating the hippocampal damage in vivo even in patients with no remarkable hippocampal abnormalities on quantitative MRI. ⁽¹⁰²⁾
• 11C Flumazenil brain uptake is influenced by the blood-brain barrier efflux transporter P-glycoprotein. ⁽¹⁰³⁾
• Flumazenil is not effective in the treatment of obstructive sleep apnea syndrome. (104)
• Flumazenil induces clinical and EEG improvement of hepatic encephalopathy in patients with cirrhosis. ⁽¹⁰⁵⁾

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