Anxiolytics, sedative/hypnotics NURS526 Pharmacology Dr. Nolan

Anxiety Nervousness, tension, worry, feelings of dread, apprehension Palpitations, chest pressure, dizziness May be chronic, related to chronic illness, home, school, work

Anxiety May be episodic, related to acute illness, death, loss of employment, taking a test “Situational anxiety” is a natural, adaptive response – can motivate to problem solving and coping activities, prepare a person to meet a challenge Remember, “anxiety” is a normal, human response “anxiety disorder” is where we see drug therapy employed

Anxiety When does anxiety become “disorder” and require treatment? no clear line generally, when anxiety becomes long term (months) and impairs person’s ability to successfully function in school, work, home, it’s termed “anxiety disorder” ~18% incidence in US

Anxiety Types of anxiety disorder GAD – generalized anxiety disorder DSM-IV – excessive worry over two or more circumstances with multiple sx for ≥ 6 mos symptoms include motor tension, restlessness, fatigue, over-activity of ANS (dyspnea, palpitations, diaphoresis, tachycardia, xerostomia, nausea, diarrhea) can be triggered by/exacerbated by SNS stimulating drugs: decongestants, beta-2 agonists, nicotine, caffeine

Anxiety Types of anxiety disorder SAD – social anxiety disorder excessive concern in social situations regarding rejection, “saying the wrong thing”, etc. often irrational concern they will be humiliated or embarrassed Panic disorder sudden, acute attacks of anxiety intense fear, terror, impending doom symptoms include SOB, palpitations, tachycardia, nausea usually last 1-10 minutes dx requires ≥ 1 month of worry about another attack

Neurotransmitters NE – excitatory GABA – inhibitory gamma aminobutyric acid major inhibitory neurotransmitter in CNS when GABA receptors are stimulated, the nerve terminal is less likely to “fire” Serotonin – role in anxiety response? Anxiety = “imbalance” of these neurotransmitters? over-simplistic, but does relate to the way we treat the disorder

Sleep Sleep latency Sleep (75% deep, 25% REM) the period of drowsiness before sleep, ~ 30 min Sleep (75% deep, 25% REM) stages I, II – early sleep stages III-IV – deep sleep physically restorative REM – post stage 4 mentally and emotionally restorative deprivation can lead to serious psychological problems Insomnia – altered sleep pattern increased sleep latency, decreased deep sleep

Drugs used to treat anxiety & insomnia Benzodiazepines Modulate GABA non-benzodiazepines Modulate NE, serotonin, dopamine SSRI’s (selective serotonin reuptake inhibitors) Modulate synaptic serotonin levels TCA’s (tri-cyclic antidepressants) Modulate serotonin, NE barbiturates

Benzodiazepines (“benzo’s”) Uses acute anxiety generalized anxiety (second line) insomnia (short term!) pre-operative sedation/anxiety alcohol withdrawal seizures critical care sedation

Benzodiazepines (“benzo’s”) Bind to GABA receptors and intensify the effect of GABA resulting in neuronal inhibition Main difference between BZD’s is onset and duration of effect

Benzodiazepines (“benzo’s”) Some SHORT acting BZD’s triazolam (Halcion) – 30m onset, 2h duration oxazepam (Serax) – 3h onset, 4+ h duration midazolam (Versed) – 30m onset, 3h duration Some INTERMEDIATE actings BZD’s alprazolam (Xanax) – 6-12h duration lorazepam (Ativan) – 6-12h duration temazepam (Restoril) – 8-20h duration

Benzodiazepines (“benzo’s”) Some LONG acting BZD’s clorazepate (Tranzene) chlordiazepoxide (Librium) diazepam (Valium) flurazepam (Dalmane) clonazepam (Klonopin)

Benzodiazepines (“benzo’s”) BZD’s typically used for anxiety alprazolam chlordiazepoxide clonazepam clorazepate diazepam lorazepam oxazepam

Benzodiazepines (“benzo’s”) BZD’s typically used for sleep 3-4x per week for a few weeks only! estazolam (Prosom) flurazepam (Dalmane) temazepam (Restoril) triazolam (Halcion) BZD’s typically used for muscle relaxing effects Diazepam (the only FDA approved benzo for skeletal muscle spasms ) BZD’s typically used for procedure related sedation Midazolam Diazepam Lorazepam

Benzodiazepines (“benzo’s”) BZD’s indicated for seizure disorder Onfi (clobazam) Diazepam Clonazepam Clorazepate Lorazepam (for status epilepticus)

Benzodiazepines Adverse effects tolerance considerably less risk of tolerance/dependence than barbiturates can develop after weeks of therapy, usually much more prominent re: sedative effects than anxiolytic effects WEAN dose slowly when D/C’ing to avoid rebound insomnia Withdrawal symptoms seen if D/C’d too quickly

Benzodiazepines Adverse effects sedation often cause daytime sleepiness, but effects diminish after a week or two of therapy can cause sleep related behaviors that pt does not remember sleepwalking, eating, driving no respiratory depression at therapeutic doses overdose: unlikely to cause death except at extreme doses symptoms: respiratory depression, coma

Benzodiazepines Adverse effects withdrawal pregnancy/lactation usually occurs 1-2 days after the last dose of short acting, 5-10 days after last dose of long acting resembles withdrawal of other CNS depressants severe withdrawal can occur after abrupt D/C of high doses after 4 months of therapy prevention: taper by 10% per week pregnancy/lactation contraindicated! geriatrics caution! (BEERS list drug) risk of sedation and falls

Benzodiazepines Reversal flumazenil (Romazicon) given rapid IV injection (usually into IV line in large vein) compete with BZD’s for GABA receptor reverses sedation within minutes but NOT respiratory depression very short duration, repeat doses may be needed every 45 seconds Caution! pt may awaken suddenly with agitation and even seizures

Non-benzodiazepines buspirone (Buspar) Not chemically or pharmacologically related to BZD or barbiturates No anticonvulsant or muscle relaxant effect No prominent sedative effect 5-HT1a agonist (serotonin agonist) Moderate affinity for D2 receptors (antagonizes) Increases adrenergic neuron firing No affinity for BZD receptor and no effect on GABA Indicated for short term tx of anxiety only

Non-benzodiazepines buspirone (Buspar) takes weeks for optimal effect does not potentiate the effects of opioids/EtOH does not cause dependence not a controlled substance usually USELESS if follows BZD therapy

Other agents used in anxiety SSRI’s / SNRI’s Most have been shown to be effective in GAD and/or SAD TCA’s Effective as other antidepressants, but more adverse effects Anticholinergic adverse effects

Non BZD drugs used to treat insomnia zolpidem (Ambien® & Ambien CR) zaleplon (Sonata®) eszopiclone (Lunesta®) ramelteon (Rozerem®) trazodone “PM” OTC drugs contain…. ?

Non BZD drugs used to treat insomnia zolpidem (Ambien® & Ambien CR) interacts with BZD/GABA receptor complex approved only for the short term treatment of insomnia 7-10 days very often used beyond that time frame decreases sleep latency (how long it takes to fall asleep) decreases nighttime awakenings some dependence risk (CIV) UPDATE: the FDA has just announced it is requiring zolpidem manufacturers to recommend half the currently used dose studies show many patients (especially women) have serum concentrations of zolpidem in the AM high enough to impair driving 39 million Rx’s for zolpidem in 2011

Non BZD drugs used to treat insomnia zaleplon (Sonata®) similar to zolpidem, shorter onset and duration eszopiclone (Lunesta®) similar to zolpidem, FDA approved for longer term treatment of insomnia T1/2 longer than zolpidem ramelteon (Rozerem) metatonin receptor agonist does not work as well as zolpidem etc. especially re: sleep maintenance appears safe for long term use, no dependence risk

Non BZD drugs used to treat insomnia trazodone this and other antidepressants with anticholinergic side effects are used for insomnia, but most cause next day sleepiness and xerotomia no dependence risk