benzodiazepines
TRANSCRIPT
Benzodiazepines
By Daphne Gima
29th July 2009
Outline: Benzodiazepines Pharmacology Therapeutic Uses Types Adverse Effects
Tolerance & Dependence Withdrawal Phenomena
Intoxication Management Contraindications Drug Misuse Conclusion References
Benzodiazepines: Pharmacology
Binds to benzodiazepine receptors on postsynaptic GABA (γ-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
AB
A: Benzene ring
B: 7-membered diazepine ring
Benzodiazepines: Pharmacology (2)
FIG 1. Binding of benzodiazepine at the GABA A receptor subunit.
Benzodiazepines: Therapeutic Uses
5 major effects: Anxiolytic/Sedative Hypnotic Myorelaxant Anticonvulsant Amnesic
Other clinical effects: Alcohol detoxification Acute psychosis with hyperexcitability & aggression
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/5mlOral: 7.5mg
LorazepamOral: 1mg
AlprazolamOral: 0.25mg, 0.5mg
ClonazepamOral: 0.5mg, 2mg
DiazepamInjection: 10mg/2mlOral: 5mgRectal: 5mg/2.5ml
Benzodiazepines: Pharmacokinetics Comparison 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.
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
Benzodiazepines: Adverse Effects (2)
Paradoxical effects release agression in certain patients
Chronic use associated with for development of dependence & abuse
Withdrawal phenomena
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
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: Anxiolytic (2-4 wks only) Hypnotic (< 4 wks)
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)
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
Benzodiazepine: Cautions & Contraindications
Cautions in: Seizure disorder Respiratory depression Severe hepatic disease Renal impairment Elderly
Benzodiazepines: Pregnancy & Lactation
Contraindicated (pregnancy risk factor D) Crosses placenta Withdrawal symptoms may occur in neonate
following in utero exposure Congenital malformations
Cleft palate Other nonteratogenic effects Enters breast milk
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.
References1. Goodman & Gilman’s. The Pharmacologic Basis of Therapeutics. 11th edn, 2006.2. 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 3. Weaver MF. Sedative and stimulant abuse in adults. UptoDate 15.14. Micromedex Healthcare Series. Vol 141, 3rd Quarter 2009.5. Scottish Intercollegiate Guidelines Network. Guideline 74: The management of harmful
drinking 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, with
or without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary and community care. April 2007.
9. National Institute on Drug Abuse. Rohypnol and GHB. Retrieved on 27 th Jul 2009 from http://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
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)
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