Anxiolytics & Hypnotics by Sue Henderson

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

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.

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

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

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

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.

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

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).

Anxiolytic/hypnotics Temazepam 9.8 Diazepam 5.6 Other benzodiazepines 4.9 Oxazepam 2.6

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.

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

Dose Equivalents Drug Daily range mg Equiv 5mg diazepam. Duration (½ life) alprazolam 1 – 4 0.5 - 1 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 10 - 20 triazolam 0.125 - 0.25 0.25 buspirone* - zopiclone* 3.75 - 7.5 * Non benzodiazepine

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

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

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)

Long Acting 1- 3 days: Diazepam X X X

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

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

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.

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

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)

Combination CNS depressants

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

Avoid (if possible) Pregnancy Lactation

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.

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.

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.

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).

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.

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

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

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.

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

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

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

Presentation: Buspar White scored 5 mg & 10 mg tabs

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.

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

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)

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)

References Australian Bureau of Statistics. (2006). National health survey 2004-05: 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.

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.