Dr Sharon Rees @reesprescribe
In 1957 the first #benzodiazepine (BZD) chlordiazepoxide was discovered by accident (chance modification of tricyclic-like compounds) as having sedative and anti-convulsant properties. It was marketed as Librium in 1960. #Diazepam (Valium) followed in 1963 #prescribing
Dr Sharon Rees @reesprescribe
Viewed as an improvement on barbiturates, by the 1970s, the BZDs became the most prescribed drugs in the world, mainly for neuroses #prescribing
Dr Sharon Rees @reesprescribe
BZDs are effective and relatively safe for appropriate short-term use (great care is needed in the elderly). But long-term use can lead to major issues, including toxicity, dependency and addiction. There are currently 13 BZDs on the UK formulary: 4 for anxiety, 4 for epilepsy and 5 for insomnia #prescribing
Dr Sharon Rees @reesprescribe
Another indication for chlordiazepoxide and #diazepam includes alcohol withdrawal, as long-acting and active metabolites allow smoother withdrawal with lower seizure risk. #Diazepam is useful for muscle spasm/dystonia; diazepam, temazepam, midazolam are used for conscious sedation and for premed; lorazepam is used for panic attack #prescribing
Dr Sharon Rees @reesprescribe
GABA is a powerful inhibitory neurotransmitter acting in brain. #Diazepam/BZDs bind in the GABA ‘A’ receptor pocket, increasing chloride influx. This causes hyperpolarisation, which enhances the effects of GABA. Hence there is greater inhibition of nerve signaling, reducing spasm and causing sedation. Alcohol is also an indirect GABA agonist #prescribing
Dr Sharon Rees @reesprescribe
The GABA receptor has multiple sub-units, with differing concentrations depending on location; eg high alpha 1 subunit in the cortex cerebellum and thalamus produces sedation, amnesia and anti-spasm effects #prescribing
Dr Sharon Rees @reesprescribe
#Diazepam kinetics are important to clinical use. It has good oral absorption and is very lipid soluble. This allows entry into the central nervous system (increased in elderly). Liver metabolism releases two active metabolites (oxazepam, temazepam, nordiazepam), with biphasic t½ of 2–5 days (increased for neonates, elderly, in renal/hepatic impaired). Note: CYP metabolism subject to genetic variation #prescribing
Dr Sharon Rees @reesprescribe
BZDs further classified as short-acting: 3–8 hours (eg midazolam), intermediate: 11–20 hours (eg temazepam) and long acting 1–3+ days (eg #diazepam and chlordiazepoxide). There are many different formulations including tablets, solutions for injection, enema, oromucosa #prescribing
Dr Sharon Rees @reesprescribe
Common adverse drug reactions for #diazepam include ataxia, confusion, tremor and withdrawal reactions (anxiety, gastrointestinal disorders, psychosis, muscle spasm, delirium). The majority of drug–drug interactions are ‘dynamic’, ie enhance central nervous system suppression eg alcohol or morphine. Unusual drug–drug interaction with phenytoin, where levels can increase or decrease #prescribing
Dr Sharon Rees @reesprescribe
Overdose can be fatal, especially if taken with alcohol and/or other central nervous system depressants. Ventilation and/or activated charcoal is needed. Flumazenil may help reversal e.g if COPD. Symptoms of #diazepam overdose include ataxia, drowsiness, dysarthria and profound sleep. Extreme overdose leads to coma, areflexia and cardio-respiratory depression #prescribing
Dr Sharon Rees @reesprescribe
High prescribing stats for #diazepam: In December 2018 in England: 403 374 items were prescribed, with minimal change in the last 4 years. The UK is one of the biggest global markets for online/illegal access BZDs. Medical advice is to ‘avoid long-term use’, but Davies et al (2017) reported over a quarter million UK prescription users take for longer than 4 weeks #prescribing