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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 Clinflux GABA activity enhancement  Net effect: Neurons more resistant to excitation
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 Alcohol detoxification Acute psychosis with hyperexcitability & aggression

Other clinical effects:
 

Types of Benzodiazepines

Can be divided into 3 groups based on duration of action.
Midazolam Injection: 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

DRUG Midazolam Lorazepam

HALF-LIFE (hrs) 2–5

Short acting
10 – 20


12 – 15

Intermediate acting
Clonazepam Diazepam 18 – 50 20 – 80

Long acting

Benzodiazepines: Pharmacokinetics
Comparison Table
Drug Equivalent Oral Dose (mg)
0.5 0.5 10 1 1

Onset of Duration of Action (mins) Action (hrs)
60 20 – 60 Almost immediate 30 – 60 1 – 5 (IV) 30 5 ≤ 12 (adults) 0.3 – 0.5 6 – 8 hrs
Onset determined by rate of absorption from GIT. Relatively lipophilic 8 (e.g. diazepam) has faster onset than relatively water soluble(e.g. lorazepam) Conversely, lorazepam has longer CNS duration of action than diazepam.

Alprazolam Clonazepam Diazepam Lorazepam Midazolam Flunitrazepam


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


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


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 0.2mg IV Max: 3mg 0.3mg IV 0.5mg IV

Treatment includes flumazenil.

Benzodiazepine: Cautions & Contraindications
 Cautions
    


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

 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.

1. 2. 3. 4. 5. 6. 7. 8.

Goodman & Gilman’s. 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

drinking and alcohol dependence in primary care. Last revised 3/12/04.

9. 10. 11.

British National Formulary 55 Committee on Safety of Medicines. Benzodiazepines, dependence and withdrawal symptoms. Current Problems 1988;21:1-2. 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. National Institute on Drug Abuse. Rohypnol and GHB. Retrieved on 27th Jul 2009 from


Committee on Safety of Medicines. Benzodiazepine dependence and withdrawal symptoms. Curr. Prob; 1988,21. NICE (2007). Antenatal and postnatal mental health

Benzodiazepine Withdrawal: Example
Tapering down of 1mg Lorazepam TDS (1mg lorazepam ≈ 10mg diazepam)
1 2 3 4 5 6 8 10

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

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

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

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

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