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Benzodiazepines

Sumari Davis, BPharm

Amayeza Information Services

Correspondence to: Sumari Davis, e-mail: [email protected]

The first to be discovered in the mid-1950’s was the long-acting .1,2 The initial All benzodiazepines are completely absorbed, with the had low to medium potency and were used as first-line options exception of clorazepate, which is rapidly decarboxylated in for treating and due to their relatively low the gastrointestinal tract and then completely absorbed as potential for toxicity.1 These were followed by the high-potency nordiazepam.6,8 benzodiazepines such as , and that were used for treatment of panic disorders and as adjuncts for Benzodiazepines and their metabolites are highly plasma-bound treatment of acute mania or agitation and obsessive-compulsive and preferentially accumulate in lipid-rich areas such as the CNS disorder.1 The high-potency benzodiazepines have a faster onset and adipose tissue.1 They cross the blood brain barrier and the of action, but also an increased risk for adverse effects. placenta and are distributed into breast milk.4 The more lipophilic agents generally have higher rates of absorption and a faster Gamma-aminobutyric acid (GABA) is the most common onset of action.1 The route of administration also affects the onset neurotransmitter in the central nervous system (CNS) and is present of action.1 in high concentrations in the cortex and limbic system. GABA inhibits the excitability of neurons, thereby producing a calming Benzodiazepines are divided into four groups based on their 7,8,9,10,11 effect on the brain.1 Benzodiazepines are synthetic compounds elimination half-lives (Table I). 3,4,5 that enhance the effects of GABA. Benzodiazepines are equally Elimination half-lives exhibit wide inter-patient variation and are effective at therapeutic doses and the choice of benzodiazepine affected by pre-existing comorbidities and patient age.1 Patients will depend on pharmacokinetic differences between these with disease and the elderly may show prolonged elimination medications.6 half-lives of all benzodiazepines and their metabolites.5 Most of the benzodiazepines are metabolised extensively in the liver by Indications enzymes of the cytochrome P450 family, particularly CYP3A4 Benzodiazepines are used in4,5,7: and CYP2C19.8 Strong inhibitors or inducers of CYP3A4 may lead to increased or decreased plasma concentrations of these • Anxiety and panic-related disorders benzodiazepines, respectively.6 and lorazepam are • Severe disabling insomnia (short-term use only) conjugated directly and are not metabolised by these CYP450 • Myoclonic , status epilepticus and as adjunct to enzymes.1 After conjugation, metabolites are excreted mainly anticonvulsive treatment in the urine. Benzodiazepines in general are not appreciably • Muscle spasm following musculoskeletal trauma or removed by haemodialysis.6 inflammation and spasticity due to disorders such as cerebral Dosing palsy, tetanus and dystonias • Acute sedation in emergency room and psychiatric settings Treatment of anxiety and insomnia should be started at the lowest possible dose for the shortest possible period of time. Often, • Anaesthetic induction and maintenance patients may receive short interrupted courses of treatment • Pre-operative medication to provide sedation, muscle relaxation rather than the prolonged continuous treatment.5 Doses should and be reduced in patients with liver disease, except possibly for • Management of withdrawal oxazepam and lorazepam.6

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7,8,9,10,11 Table I. Classification of benzodiazepines based on half-life (t1/2)*

Onset of action Duration of action Elimination t1/2 Ultra-short acting

(t1/2 < 6 hours) Midazolam IV 1 – 5 min 30 – 80 min 1.8 – 6.4 hours IM 5 – 15 min Oral 30 – 90 min Rectal 16.3 min (paed) Buccal 1,5 – 8 min () 15 – 30 min 6 – 7 hours 1.6 – 5.4 hours Short-acting

(t1/2 = 6 – 12 hours) 15 – 30 min 7 hours 5 hours 30 min 6 – 8 hours 3.3 – 19.8 hours Oxazepam 120 – 180 min - 2.8 – 21.2 hours 30 – 60 min Amnestic 4 hours 3.5 – 18.4 hours Intermediate-acting

(t1/2 = 12 – 24 hours) Alprazolam 60 – 90 min 5 hours (immediate release) 10.6 – 12.5 hours 60 – 240 min - 20.6 hours 15 – 30 min 10 – 30 hours 2.3 hours Metabolites: 16 – 100 hours Lorazepam 20 – 30 min 5 hours 6 – 8 hours Status epilepticus 3 – 6 hours Long-acting

(t1/2 > 24 hours) Chlordiazepoxide 2 – 4 hours - 10 – 48 hours Metabolites: 14 – 95 hours - Single dose 5 days 36 – 42 hours Multiple doses 2 weeks Metabolites: 71 – 82 hours Clonazepam 20 – 40 min 6 – 12 hours 30 – 40 hours Clorazepate 60 – 150 min < 6 hours 2,29 hours Metabolites: 46 – 48 hours Oral 30 min IV 15 – 30 min Up to 48 hours Metabolites: 100 – 194 hours 20 – 50 min 4 – 8 hours 24 – 29 hours 90 – 120 min (sublingual) 7 hours sublingual 78 hours 3 hours oral Metabolites: 36 – 120 hours

For treatment of muscle spasticity, epilepsy and anxiety, but diazepam and lorazepam have also been used. Efficacy of benzodiazepines are often started with three or four daily doses treatment after six to eight months has not been evaluated, but until patients are stabilised. Some clinicians prefer to then give benzodiazepines have been used for longer periods (e.g. eight all or most of the dose at night to prevent or reduce daytime to twelve months or longer), without apparent loss of efficacy.6 sedation.6 Benzodiazepines can reduce the number of spontaneous and situational panic attacks. They also reduce the associated anxiety, Dosing should be carefully individualised6 and benefits and risks phobic , avoidance behaviour and somatic manifestations and should be re-assessed at regular intervals to determine the need interference with normal work and social activities.6 Lorazepam, and benefit of continuing treatment with benzodiazepines.2 oxazepam or triazolam are often preferred when treating the Efficacy elderly and patients with liver disease as they do not have active metabolites and have a relatively short elimination half-life.6 Anxiety Insomnia Benzodiazepines are more effective than and in the treatment of anxiety disorders.6 Alprazolam Patients with insomnia subjectively describe problems with falling and clonazepam are mainly used for treatment of panic disorder, asleep, remaining asleep or awakening too early.2 Benzodiazepines

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Table II. Comparative oral doses for benzodiazepines5,8 sedation and anxiolysis and is preferred for short surgical 6 Ultra-short acting procedures. Oral benzodiazepines are also effective to relieve anxiety and to provide sedation and light anaesthesia with 7.5 mg anterograde amnesia in the pre-operative setting.5 Triazolam 0.25 mg Short acting Benzodiazepines are effective in relieving agitation and Loprazolam 0.5 – 1 mg and to prevent or provide relief of tremens and hallucinations during alcohol withdrawal.5 Benzodiazepines such Oxazepam 15 mg as diazepam, lorazepam and midazolam are also effective in Temazepam 10 mg sedation of intubated and mechanically-ventilated patients in a Intermediate-acting critical care setting.6 Alprazolam 0.5 mg Diazepam is effective in short- and long-term management of Bromazepam 1.5 mg skeletal muscle spasticity in cerebral palsy, paraplegia, stiff-man Flurazepam 30 mg syndrome, strychnine poisoning or tetanus.6 Lorazepam 1 mg Long-acting Safety Chlordiazepoxide 10 mg Warnings and special precautions Clonazepam 0.25 mg Benzodiazepines may affect the ability of the patient to drive or Diazepam 5 mg operate machinery and the risk is higher with agents that have a Nitrazepam 5 mg longer elimination half-life. Patients should be warned that there is a risk of complex sleep-related behaviours such as sleep-driving improve insomnia by shortening sleep onset latency, reducing or making and eating food while sleeping.6 Benzodiazepines can time to rapid eye-movement (REM) sleep, and decreasing also cause amnesia that increases the risk of abuse (e.g. drug- nocturnal awakenings.1 Although most experience to date has facilitated sexual abuse).1 been with the use of triazolam, flurazepam and temazepam, other benzodiazepines have also been used in the treatment Benzodiazepines should be used with caution in patients of insomnia.6 Triazolam is indicated for treatment of sleep onset with chronic pulmonary insufficiency or sleep apnoea, seizure 2,6 insomnia due to its quick onset and short half-life. However, the disorders, hepatic or renal disease. Oxazepam and lorazepam risk of rebound insomnia, anterograde amnesia, psychological are preferred treatment options in patients with hepatic disease 3 dependence and anxiety prevents it from being used as first- as they are not directly metabolised in the liver. 2 line therapy. Benzodiazepines with short to intermediate half- Tolerance to benzodiazepines can develop, and benzodiazepines lives such as temazepam and flurazepam are indicated for sleep can also cause psychological and physical dependence. Treatment 1,6 maintenance insomnia. Diazepam has been used effectively in should not be stopped abruptly.6 The lowest possible dose should 6 preventing night terrors in adults as it suppresses stage 4 sleep. be used for the shortest possible period, especially in the elderly.2 Seizure disorders The elderly are more sensitive to the effects of benzodiazepines due to age-related changes in drug pharmacokinetics that may Although both IV diazepam and IV lorazepam are effective in lead to accumulation of the medicine.2 the treatment of status epilepticus, some clinicians prefer to use lorazepam since it has a prolonged duration of effect.6 It is Adverse effects imperative to treat as soon as possible since the clinical response Common adverse effects with all benzodiazepines include to benzodiazepines is lost with prolonged status epilepticus.12 drowsiness, lethargy and fatigue and at higher doses dizziness, Clonazepam and clobazam are effective when used as adjunct vertigo, slurred speech, impaired motor coordination, blurry therapy in seizure prophylaxis when patients are refractory to vision, euphoria, hostile or erratic behaviour and mood swings. multiple anti-epileptic medicines.11 Clonazepam has been studied Because benzodiazepines are lipophilic and accumulate in fatty more than other benzodiazepines and is used as monotherapy or tissues, some of the symptoms can develop over time.2 in combination with other anti-epileptic medicines.6 Clobazam Drug interactions is preferred due to its affinity for the α2 subunit of the GABAA receptor which is associated with a lower potential for causing Benzodiazepines are metabolised via the cytochrome P450 system, sedation.11 and although they do not induce or inhibit these enzymes, their is affected by other inducers and inhibitors. Enzyme Other uses inhibitors such as the azole , some oral contraceptives, Benzodiazepines can cause anterograde amnesia, which is useful HIV protease inhibitors, non-nucleoside reverse transcriptase in the pre-operative setting. Midazolam IV is used for conscious inhibitors (NNRTIs), some antibiotics and grapefruit

S Afr Pharm J 59 2017 Vol 84 No 4 FOCUS ON.... juice may increase the levels of benzodiazepines while hepatic • is a benzodiazepine antagonist that may be used to enzyme inducers such as , , , reverse the central effects of benzodiazepines.5 nevirapine, and St John’s wort can decrease the plasma levels of benzodiazepines.1,13 References 1. Griffin CE, Kaye Am, Bueno FR, et al. Benzodiazepine pharmacology and central nervous Concomitant use with other CNS suppressants such as opioids and system-mediated effects. Ochsner J. 2013 Summer; 13(2): 214–223. Available from https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC3684331/pdf/i1524-5012-13-2-214.pdf alcohol should be avoided to prevent additive CNS depressant 2. Schroeck JL, Ford J, Conway EL, et al. Review of safety and efficacy of sleep medicines in effects.1,5,6 older adults. Clinical Therapeutics 2016; 38(11):2340-2364. 3. Dale MM, Haylett DG. Pharmacology Condensed. Churchill Livingstone; 2004. Important prescribing points 4. Ogbru O. Benzodiazepines (Benzodiazepine drug class) MedicineNet.com [homepage on the internet] c1996-2017 Updated 13 March 2017; Accessed 3 July 2017. Available from: • Treatment with benzodiazepines should always be with the http://www.medicinenet.com/benzodiazepines_sleep-inducing-oral/article.htm th lowest effective dose for the shortest possible period.5 5. Rossiter D. (Ed) South African Medicines Formulary. 12 Edition. 2016. 6. McEvoy GK, editor. American hospital formulary service drug information. Pharmaceutical • Some patients may experience paradoxical disinhibition, Press; 2012. aggression and agitation following benzodiazepine 7. Snyman J. (Ed) Drug class overview tables: Benzodiazepines. Mims Desk Reference Vol 51 April 2016. 5 administration. 8. Hardman JG, Limbird LE. Goodman and Gilman’s The Pharmacological Basis of Therapeu- • Patients should be warned that benzodiazepines can affect tics. and 2002 May 1;94(5):399. 9. Micromedex® 2.0, (electronic version). Truven Health Analytics, Greenwood Village, Colo- their psycho-motor skills and they should not drive or operate rado, USA. Available at: http://www.micromedexsolutions.com/ Accessed 13 July 2017. machinery until the extent of individual response has been 10. Vancouver Acute Pharmaceutical Sciences Comparison of benzodiazepines. Vancouver 5 Coastal Health [homepage on the internet] c2016. No date. Accessed 3 July 2017. Available determined. from: http://www.vhpharmsci.com/vhformulary/Tools/Benzodiazepines-comparison.htm • Intravenous administration may cause respiratory arrest.5 11. Farinde, A. Benzodiazepine equivalency table [homepage on the internet] c1994-2017 Updated 28 April 2017; Accessed 3 July 2017. Available from: http://emedicine.medscape. • The elderly are more susceptible to the effects and adverse com/article/2172250-overview effects (including daytime sedation, dementia, falls with 12. Ochoa JG, Kilgo WA. The role of benzodiazepines in the treatment of epilepsy. Curr Treat Options Neurol 2016;18:18 or without resulting fractures and vehicle accidents) of 13. Stockley IH, editor. Stockley's drug interactions: a source book of interactions, their mecha- benzodiazepines.1 nisms, clinical importance and management. Pharmaceutical Press; 2010.

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