21998125 Benzodiazepines

7/30/2019 21998125 Benzodiazepines

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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

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21998125 Benzodiazepines