benzodiazepines

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