1. Anxiolytics & Hypnotics by Sue Henderson

2. Therapeutic actions
Hypnotic
Anxiolytic
Anticonvulsant
Amnestic
Myorelaxant
In what medical circumstances might the amnestic properties of benzodiazepines be useful?
Insomnia – induce sleep
Anxiety: panic disorders, phobias, agitated psychosis
Convulsions, seizures
Muscle relaxant, relieve spasms
Pre surgical operations, sedation for minor surgical procedures (twilight - amnestic)
Sedation/anticonvulsant for alcohol withdrawal
Answer: Unpleasant surgical or test procedures e.g. colonoscopy

3. Indications
Why are benzodiazepines useful in the treatment of alcohol detoxification?
Can they be used in the long term to prevent further alcohol abuse?
Alcohol and benzodiazepines are both CNS depressants.
Benzo’s can be gradually tapered off preventing rebound CNS over excitability.
They cannot be used in the long term because they are addictive.
People addicted to alcohol have cross addiction with benzodiazepines.

4. Anti-Anxiety & Hypnotics
Benzodiazepine e.g. Diazepam
Non Benzodiazepine e.g. Buspirone
Hypnotics: Sedatives
Benzodiazepine e.g. Temazepam
Non Benzodiazepine e.g. Zopiclone

5. Differentiate
What is the difference between an anti-anxiety medication and a hypnotic?
Hypnotics induce sleep.
Hypnotics at lower doses cause sedation (anti-anxiety effect)
Anti-anxiety drugs result in a reduction in anxiety but can induce sleep in higher doses

6. Antidepressants for anxiety
Clomipramine (TCA)
OCD
Fluvoxamine (SSRI)
Paroxetine (SSRI)
OCD, panic disorder, social phobia
Sertraline (SSRI)
OCD, panic dis, PTSD
Venlafaxine (SNRI)
GAD
Fluoxetine (SSRI)
Clomipramine (TCA) Anafranil, Clopram, Placil
Fluvoxamine (SSRI) Faverin, Luvox
Paroxetine (SSRI) Aropax, Oxetine, Paxtine
Sertraline (SSRI) Zoloft
Venlafaxine (SNRI) Efexor
Fluoxetine (SSRI) Auscap, Fluohexal, Lovan, Prozac, Zactin

7. Benzodiazepines Used mostly in primary care rather than psychiatry.
Often prescribed for problems that are more effectively managed with non-drug therapies.
Temazepam in 10 most frequently prescribed up until 2001.

8. Benzodiazepines
Should not be 1st line therapy in mental health & sleep management.
Limit use to less than 2 weeks.
Only benefit of continued use is avoiding withdrawal effects (NPS, 1999).
All equally effective but differ in metabolism, speed of onset & half life

9. 2004-05 National Health Survey
5% of Australians had used a benzodiazepine for anxiety management in the 2 weeks prior to the survey.
Benzodiazepine use was higher in women and in older age groups (mostly due to sleeping tablets).
Overall use has fallen since 80’s but total use remains high (ABS, 2006).

10. Anxiolytic/hypnotics
Temazepam 9.8
Diazepam 5.6
Other benzodiazepines
Oxazepam 2.6

11. MCQ Benzodiazepines can safely be prescribed during pregnancy. A. True
A. True
B. False
Benzodiazepines may cause hypotonia, respiratory depression and hypothermia in the newborn infant if used in high doses during labour. Withdrawal symptoms in newborn infants have been reported with prolonged use of this class of drugs.
Category C (TGA)
Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.

12. Diazepam, Alprazolam, Bromazepam, Lorazepam, Oxazepam, Buspirone*
Indications
Drug
Anxiolytic
Diazepam, Alprazolam, Bromazepam, Lorazepam, Oxazepam, Buspirone*
Muscle relaxant
Diazepam
Pre-med
Diazepam, Lorazepam
Alcohol withdrawal
Diazepam, Oxazepam,
Panic disorder
Alprazolam, Clonazepam.
Anti-convulsant
Clobazam, Clonazepam, Diazepam, Lorazepam
Hypnotic
Flunitrazepam, Nitrazepam
Temazepam, Zolpidem, Zopiclone*
* = Non benzodiazepine

13. Dose Equivalents Drug Daily range mg Equiv 5mg diazepam.
Duration (½ life)
alprazolam
1 – 4
Short/Intermediate
bromazepam
6 – 9
3 – 6
clobazam
30 – 80 10
Intermediate
clonazepam
4 – 8
0.5
diazepam
5 – 20 5
Long
flunitrazepam
0.5 – 2
1 – 2
lorazepam
2 – 4 1
nitrazepam
5 – 10
oxazepam
45 – 90
15 – 30
Short
temazepam
10 – 30
triazolam
0.25
buspirone* -
zopiclone*
* Non benzodiazepine

14. Short Acting: 3 - 8 hrs Oxazepam Temazepam Triazolam Buspirone*
Zopiclone*
Non benzodiazepine

15. Intermediate Acting: 10 - 20 hours
Alprazolam
Bromazepam
Clobazam
Clonazepam
Flunitrazepam
Lorazepam
Nitrazepam

16. Hypnotics
Explain the benefit of using Temazepam over Nitrazepam for assisting with sleep.
Why should hypnotics be used for a limited time to assist with sleep?
Temazepam is short acting and will induce sleep but not cause a hangover effect.
Prolonged use of benzodiazepines can result in tolerance (more drug needed to induce same effect)

17. Long Acting 1- 3 days: DiazepamX X X

18. Addiction
Why are short acting benzodiazepines more of a problem with addiction than the long acting ones?
Drugs with short half lives are cleared from the bloodstream fairly quickly and may induce withdrawal effects such as rebound excitement and insomnia.
Those with longer half lives are cleared less quickly resulting in a decrease in withdrawal effects.
The resulting slow drop in blood levels allows the body to adjust to the lack of drug more effectively

19. Dependency cycle of benzodiazepines
Use of benzodiazepine
Reduced anxiety
Effect wears off
Even more anxious
Green, 1996, p. 88

20. Benzodiazepines: Action
CNS depressant
Enhance the effect of GABA.
GABA is a neurotransmitter that inhibits neuronal activity i.e. reduces the firing rate of neurones.
Potentiate other CNS depressants: Alcohol, anti-histamines, analgesics, anti-convulsants, anti-psychotics, hypnotics, barbiturates, anaesthetics.
Combination will lead to sedation and may lead to unconsciousness and death.

21. Agonist = Facilitate
Benzodiazepines bind to a site near the GABA binding site thus facilitating the action of GABA
Drug binds to a site near the binding site for the endogenous transmitter facilitating binding. Also an agonist action.
Benzodiazepines bind to a site near the GABA binding site thus facilitating the action of GABA

22. Death Increasing Coma dose General Anaesthesia of Sleep drug Sedation
Disinhibition
Relief from anxiety
No effect
Death if mixed with other CNS depressants.
Rare if taken on own.
(Julien, 2001)

23. Combination CNS depressants

24. Contra-indications Myasthenia gravis.
Severe respiratory impairment e.g sleep apnoea, COAD.

25. Avoid (if possible)
Pregnancy
Lactation

26. Adverse Effects Physical dependence occurs in about 1 in 3 patients.
History substance abuse > risk dependence
Increased accident risk.
Tolerance & rebound insomnia.
Alcohol & CNS depressants potentiate adverse effects.

27. Adverse effects
60y+ > vulnerability to confusion, memory impairment, over sedation (most common S/E) & falls.
Adverse mood effects: depression, emotional anaesthesia, aggression, increased suicide risk in elderly.

28. Withdrawal from Benzodiazepines
Abrupt cessation: > seizures
Withdrawal symptoms may occur between doses during continuous use (inter-dose withdrawal). Patients may think these symptoms are due to the original problem.
Withdrawal symptoms: increased anxiety, sleep disorder, aching limbs, nervousness & nausea.

29. Withdrawal from Benzodiazepines
Withdrawal experienced by 45% of patients discontinuing low dose benzodiazepines & 100% patients on high doses.
Short half life benzodiazepines are associated with more acute & intense withdrawal symptoms.
Long half life benzodiazepines - milder, more delayed withdrawal (NPS, 1999).

30. Withdrawal from benzodiazepines
Benzodiazepines should not be ceased abruptly.
Dose reduced by 10-20% per week.
Patient allowed to stabilise between each reduction.
Admission for high dose users, history of seizures or psychosis, or for more rapid withdrawal.

31. Withdrawal from benzodiazepines
Implement relaxation/cognitive techniques.
If necessary referral:
Drug & Alcohol Services
Self Help group TRANX
Psychologist (for CBT)

32. Overdose Benzodiazepines
Generally safe in overdose unless mixed with alcohol/CNS depressants.
Symptoms overdose: hypotension, respiratory depression & coma.
Treatment: Supportive
Flumazenil rarely indicated

33. IV Flumazenil
Dangerous to use if mixed overdose (e.g benzodiazepine + tricyclics, amphetamines, other pro-convulsants) - Result in uncontrolled seizure
In dependent individuals severe withdrawal
Flumazenil has a shorter half life ( one hour) than all benzodiazepines Therefore, repeat doses of flumazenil may be required to prevent recurrent symptoms of overdosage once the initial dose of flumazenil wears off.

34. Flumazenil is a benzodiazepine Antagonist = Blocker
Attaches to the benzodiazepine binding site but does not facilitate action of GABA. Competes with any benzodiazepine that is present, displacing the benzodiazepine from the receptor and reversing the action of the benzodiazepine
Flumazenil binds to GABA receptor displacing benzodizepine

35. Non benzodiazepines Anxiolytic: Buspirone (Buspar)
Different action to bzd.
Not a CNS depressant.
Partial agonist (stimulant) of dopaminergic & serotoninergic receptors.
No sedation, anti-convulsant or muscle relaxant properties - just anxiolytic.
Delayed action (1-2 weeks)
Effect reduced if benzodiazepine used in last 3/12

36. Comparison of benzodiazepine & buspirone
Delayed onset (cannot be used PRN)
Does not cause sedation
Does not impair performance
No additive effect with alcohol
Non addictive
No pharmacokinetic change with age
Does not cause falls in elderly
Expensive (Not on PBS)
Benzodiazepine
Rapid onset
Can cause sedation
May impair performance
Additive effects with alcohol
May cause dependence & withdrawal
Pharmacokinetic change with age
Associated with falls in elderly (Keltner & Folks, 2001)
Gradual improvement in 1 to 2 weeks, maximum effect in 4 to 6 weeks

37. Presentation: Buspar
White scored
5 mg & 10 mg tabs

38. Buspirone: Agonist = Mimic
Buspirone attaches to Serotonin 1A receptor and activates it mimicking serotonin action on the receptor, which results in an anti-anxiety action.
Drug mimics action of the transmitter = Agonist
Green symbolises “Go”
Buspirone attaches to serotonin receptor mimicking serotonin.

39. Non benzo Hypnotic: Zopiclone (Imovane)
Similar action, side effects & contraindications to benzo’s.

40. Benzodiazepines key points
Should not be used in patients with liver disease, history of substance abuse, severe respiratory distress, performing hazardous tasks
Avoid during pregnancy/lactation if possible
Assess for over sedation
Cease slowly
Monitor elderly (cognition, falls)
Be aware they raise seizure threshold, and
Potentiate CNS depressants (alcohol)

41. Hypnotic key points Advise re rebound insomnia when medications ceased
Should not be used in sleep apnoea
Avoid alcohol
Hangover effect (impairing performance)
Monitor in elderly (falls, double dosing)

42. References
Australian Bureau of Statistics. (2006). National health survey : Summary of results. Canberra: Australian Bureau of Statistics.
Fortinash, K. M., & Holoday-Worret, P. A. (2000). Psychiatric mental health nursing ( 2nd ed.). St. Louis: Mosby.
Galbraith, A., Bullock, S. & Manias, E. (2001). Fundamentals of pharmacology (3rd ed.). Melbourne: Prentice Hall.

43. References
Julien, R. M. (2001). A primer of drug action: A concise, non-technical guide to the actions, uses, and side effects of psychoactive drugs. New York: W. H. Freeman and Co.
Keltner, N. L., & Folks, D. G. (2001). Psychotropic drugs (3rd ed.). St. Louis: Mosby.
National Prescribing Service. (1999). Helping patients withdraw. National Prescribing Service Newsletter, No. 4 June.
National Prescribing Service. (1999). Benzodiazepines reviewing long term use: A suggested approach. Prescribing Practice Review, No. 4 July.