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Outline: Benzodiazepines
Benzodiazepines: Pharmacology
Binds to benzodiazepine receptors on postsynaptic GABA (-butyric acid) neuron at several sites in CNS. Binding opens the channel allowing more Clinflux GABA activity enhancement Net effect: Neurons more resistant to excitation
B
A: Benzene ring B: 7-membered diazepine ring
5 major effects:
Anxiolytic/Sedative Hypnotic Myorelaxant Anticonvulsant Amnesic Alcohol detoxification Acute psychosis with hyperexcitability & aggression
Types of Benzodiazepines
DRUG Midazolam
HALF-LIFE (hrs) 25
Short acting
Lorazepam 10 20
Alprazolam
12 15
Intermediate acting
Clonazepam 18 50
20 80
Diazepam
Long acting
Benzodiazepines: Pharmacokinetics
Comparison Table
Drug Equivalent Oral Dose (mg)
0.5 0.5 10
Lorazepam
Midazolam
1
-
30 60
1 5 (IV)
6 8 hrs
Onset determined by rate of absorption from GIT. Relatively lipophilic (e.g. diazepam) has faster onset than 8 relatively water soluble(e.g. lorazepam) Conversely, lorazepam has longer CNS duration of action than diazepam.
Flunitrazepam
30
Relatively safe drugs cf. barbiturates Fatalities rare after overdose unless concomitant drugs/ethanol are taken Next day sedation Cognitive impairment Psychomotor impairment
Paradoxical effects
Chronic use associated with for development of dependence & abuse Withdrawal phenomena
Typically seen with short-acting benzodiazepines. Tolerance may develop with regular use. Risk factors for development of dependence:
high dosage regular continuous use use of benzodiazepines with a short t1/2 use in patients with dependent personality history of drug/alcohol dependence development of tolerance
Benzodiazepines: Withdrawal
Symptoms:
Anxiety, tremor, confusion, insomnia, perceptual disorders, fits, depression, gastrointestinal & other somatic sx.
Appear shortly after stopping benzodiazepine with a short t1/2 & up to several days after stopping one with long t1/2. CSM recommends that benzodiazepines limited for use in following ways:
Dosage tapered to avoid severe withdrawal symptoms Withdraw in steps of 1/8 of the daily dose every fortnight (range 1/10 to 1/4)
Benzodiazepines: Intoxication
Clinical features:
Slurred speech Incoordination Unsteady gait Impaired attention or memory Stupor/Coma 0.2mg IV 0.3mg IV 0.5mg IV
Max: 3mg
Cautions in:
Seizure disorder Respiratory depression Severe hepatic disease Renal impairment Elderly
Contraindicated (pregnancy risk factor D) Crosses placenta Withdrawal symptoms may occur in neonate following in utero exposure Congenital malformations
Cleft palate
Benzodiazepines: Misuse
Most commonly used to facilitate as date rape: flunitrazepam (Rohypnol) Produces anterograde amnesia Tasteless & odourless Fast onset Readily soluble in ethanol
Conclusion
Benzodiazepines is a group of drugs that are predominantly used for hypnotic-sedative effect. Characteristics differences such as lipophilicity, t1/2, duration of action affects the therapeutic uses of each compound. Relatively safe class of drugs, unless used in concomitant with other drugs. Duration of use should be limited to minimize development of addiction or tolerance.
References
1. 2. 3. 4. 5. 6. 7. 8.
Goodman & Gilmans. The Pharmacologic Basis of Therapeutics. 11th edn, 2006. Ashton CH. Benzodiazepines: how they work and how to withdraw (The Ashton Manual). Last revised Aug 2002. Retrieved on 27th Jul 2009 from http://www.benzo.org.uk/manual/index.htm Weaver MF. Sedative and stimulant abuse in adults. UptoDate 15.1 Micromedex Healthcare Series. Vol 141, 3rd Quarter 2009. Scottish Intercollegiate Guidelines Network. Guideline 74: The management of harmful
9. 10. 11.
http://www.nida.nih.gov/PDF/Infofacts/Rohypnol06.pdf
Committee on Safety of Medicines. Benzodiazepine dependence and withdrawal symptoms. Curr. Prob; 1988,21. NICE (2007). Antenatal and postnatal mental health
MORNING
Lorazepam 1 mg Lorazepam 0.5mg, Diazepam 5mg Lorazepam 0.5mg, Diazepam 5mg Lorazepam 0.5mg, Diazepam 4mg STOP LORAZEPAM, Diazepam 8mg Diazepam 8mg Diazepam 6mg Diazepam 6mg
MIDDAY
Lorazepam 1 mg Lorazepam 1 mg Lorazepam 0.5mg, Diazepam 5mg Lorazepam 0.5mg, Diazepam 5mg Lorazepam 0.5mg, Diazepam 4mg STOP LORAZEPAM, Diazepam 8mg Diazepam 8mg Diazepam 6mg
EVENING
Lorazepam 0.5mg, Diazepam 5mg Lorazepam 0.5mg, Diazepam 5mg Lorazepam 0.5mg, Diazepam 5mg STOP LORAZEPAM, Diazepam 10mg Diazepam 10mg Diazepam 10mg Diazepam 10mg Diazepam 10mg
Reduce diazepam by 2mg every 2 wks until a total dosage of 10-15mg/day daily achieved Reduce in steps of 1mg every 2 weeks or according to progress Switch to BD dosing once dose diazepam 20mg/day achieved Further dose reduction involves reductions in OM dose first, ON dose last