1. Anxiolytics, sedative/hypnotics
NURS526
Pharmacology
Dr. Nolan

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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

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

11. 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

12. 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

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

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

15. 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

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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

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

25. 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

26. 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

27. 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