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Benzodiazepines
By Daphne Gima
29th July 2009
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Outline: Benzodiazepines
Pharmacology
Therapeutic Uses
Types
Adverse Effects Tolerance & Dependence
Withdrawal Phenomena
Intoxication Management
Contraindications
Drug Misuse
Conclusion
References
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Benzodiazepines:
Pharmacology
Binds to benzodiazepine receptors on
postsynaptic GABA (-butyric acid) neuron at
several sites in CNS.
Binding opens the channel allowing more Cl-
influx GABA activity enhancement
Net effect: Neurons more resistant to
excitation
A
BA: Benzene ring
B: 7-membered diazepine ring
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Benzodiazepines:
Pharmacology (2)
FIG 1. Binding of benzodiazepine at the GABA A receptor subunit.
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Benzodiazepines: Therapeutic
Uses
5 major effects:
Anxiolytic/Sedative
Hypnotic
Myorelaxant Anticonvulsant
Amnesic
Other clinical effects:
Alcohol detoxification
Acute psychosis with hyperexcitability & aggression
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Types of Benzodiazepines
Can be divided into 3
groups based on
duration of action.
DRUG HALF-LIFE (hrs)
Midazolam 2 5
Lorazepam 10 20
Alprazolam 12 15
Clonazepam 18 50
Diazepam 20 80
Short acting
Intermediate acting
Long acting
MidazolamInjection: 5mg/ml, 5mg/5ml
Oral: 7.5mg
Lorazepam
Oral: 1mg
Alprazolam
Oral: 0.25mg, 0.5mg
Clonazepam
Oral: 0.5mg, 2mg
Diazepam
Injection: 10mg/2ml
Oral: 5mg
Rectal: 5mg/2.5ml
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Benzodiazepines: PharmacokineticsComparison Table
Drug Equivalent
Oral Dose
(mg)
Onset of
Action
(mins)
Duration of
Action (hrs)
Alprazolam 0.5 60 5
Clonazepam 0.5 20 60 12 (adults)
Diazepam 10 Almost
immediate
0.3 0.5
Lorazepam 1 30 60 6 8 hrs
Midazolam - 1 5 (IV) -
Flunitrazepam 1 30 8
Onset determined by rate of absorption
from GIT. Relatively lipophilic
(e.g. diazepam) has faster onset than
relatively water soluble(e.g. lorazepam)
Conversely, lorazepam has longer CNS
duration of action than diazepam.
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Benzodiazepines: Adverse
Effects
Relatively safe drugs cf. barbiturates
Fatalities rare after overdose unless
concomitant drugs/ethanol are taken
Next day sedation
Cognitive impairment
Psychomotor impairment increased reaction time
motor incoordination
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Benzodiazepines: Adverse
Effects (2)
Paradoxical effects
release agression in certain patients
Chronic use associated with for developmentof dependence & abuse
Withdrawal phenomena
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Benzodiazepines: Tolerance &
Dependence
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
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Benzodiazepines: Withdrawal
Symptoms:
Anxiety, tremor, confusion, insomnia, perceptual disorders,
fits, depression, gastrointestinal & other somatic sx.
Appear shortly after stopping benzodiazepine with ashort t1/2 & up to several days after stopping one
with long t1/2.
CSM recommends that benzodiazepines limited for
use in following ways: Anxiolytic (2-4 wks only)
Hypnotic (< 4 wks)
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Benzodiazepines: Withdrawal
(2)
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)
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Benzodiazepines: Intoxication
Clinical features:
Slurred speech
Incoordination
Unsteady gait Impaired attention or memory
Stupor/Coma
Treatment includes flumazenil.
0.2mg IV 0.3mg IV 0.5mg IV
Max: 3mg
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Benzodiazepine: Cautions &
Contraindications
Cautions in:
Seizure disorder
Respiratory depression
Severe hepatic disease
Renal impairment
Elderly
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Benzodiazepines: Pregnancy
& Lactation
Contraindicated (pregnancy risk factor D)
Crosses placenta
Withdrawal symptoms may occur in neonatefollowing in utero exposure
Congenital malformations
Cleft palate
Other nonteratogenic effects
Enters breast milk
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Benzodiazepines: Misuse
Most commonly used to facilitate as date
rape: flunitrazepam (Rohypnol)
Produces anterograde amnesia
Tasteless & odourless
Fast onset
Readily soluble in ethanol
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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 inconcomitant with other drugs.
Duration of use should be limited to minimize
development of addiction or tolerance.
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References
1. Goodman & Gilmans. The Pharmacologic Basis of Therapeutics. 11th edn, 2006.
2. Ashton CH. Benzodiazepines: how they work and how to withdraw (The Ashton Manual). Lastrevised Aug 2002. Retrieved on 27th Jul 2009 from http://www.benzo.org.uk/manual/index.htm
3. Weaver MF. Sedative and stimulant abuse in adults. UptoDate 15.1
4. Micromedex Healthcare Series. Vol 141, 3rd Quarter 2009.
5. Scottish Intercollegiate Guidelines Network. Guideline 74: The management of harmfuldrinking and alcohol dependence in primary care. Last revised 3/12/04.
6. British National Formulary 557. Committee on Safety of Medicines. Benzodiazepines, dependence and withdrawal symptoms.
Current Problems 1988;21:1-2.
8. National Institute of Clinical Excellence. Anxiety: management of anxiety (panic disorder, withor without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary andcommunity care. April 2007.
9. National Institute on Drug Abuse. Rohypnol and GHB. Retrieved on 27th Jul 2009 fromhttp://www.nida.nih.gov/PDF/Infofacts/Rohypnol06.pdf
10. Committee on Safety of Medicines. Benzodiazepine dependence and withdrawal symptoms.Curr. Prob; 1988,21.
11. NICE (2007). Antenatal and postnatal mental health
http://www.benzo.org.uk/manual/index.htmhttp://www.benzo.org.uk/manual/index.htmhttp://www.nida.nih.gov/PDF/Infofacts/Rohypnol06.pdfhttp://www.nida.nih.gov/PDF/Infofacts/Rohypnol06.pdfhttp://www.nice.org.uk/http://www.nice.org.uk/http://www.nida.nih.gov/PDF/Infofacts/Rohypnol06.pdfhttp://www.benzo.org.uk/manual/index.htm -
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Benzodiazepine Withdrawal:
Example
WEEK MORNING MIDDAY EVENING
1 Lorazepam 1 mg Lorazepam 1 mg Lorazepam 0.5mg,
Diazepam 5mg
2 Lorazepam 0.5mg,Diazepam 5mg
Lorazepam 1 mg Lorazepam 0.5mg,Diazepam 5mg
3 Lorazepam 0.5mg,
Diazepam 5mg
Lorazepam 0.5mg,
Diazepam 5mg
Lorazepam 0.5mg,
Diazepam 5mg
4 Lorazepam 0.5mg,
Diazepam 4mg
Lorazepam 0.5mg,
Diazepam 5mg
STOP LORAZEPAM,
Diazepam 10mg
5 STOP LORAZEPAM,
Diazepam 8mg
Lorazepam 0.5mg,
Diazepam 4mg
Diazepam 10mg
6 Diazepam 8mg STOP LORAZEPAM,
Diazepam 8mg
Diazepam 10mg
8 Diazepam 6mg Diazepam 8mg Diazepam 10mg
10 Diazepam 6mg Diazepam 6mg Diazepam 10mg
Tapering down of 1mg Lorazepam TDS (1mg lorazepam 10mg diazepam)
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Benzodiazepine Withdrawal:
Example (2)
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