3 Sedative-Hypnotics and Anxiolytics Flashcards
Symptoms of anxiety
Palpitations, tremor, perspiration, GI effects, dizziness, and headache
_______ anxiety is an appropriate reaction to danger (fear, arousal)
Adaptive
Leads to increased sympathetic activity
______ anxiety is the result of chronic, psychological stress
Maladaptive
Leads to organ dysfunction (GI, cardiac), physical symptoms
Anxiety that becomes chronic and interferes with normal functioning should be treated
The “ideal” anti-anxiety drug should…
Relieve anxiety without sedation or drowsiness, no physical or psychological dependence
What are the different classifications of anxiety disorders?
Acute Anxiety
Generalized Anxiety Disorder
Panic Disorder
Phobias
Obsessive Compulsive
Post Traumatic Stress Disorder
Classify the anxiety disorder:
Short term, self limiting
Acute anxiety
Treat with benzos
Classify the anxiety disorder:
Chronic anxiety
Generalized Anxiety Disorders
Treat with benzos or buspirone
Classify the anxiety disorder:
Episodic, severe attacks of anxiety
Panic disorder
Classify the anxiety disorder:
Fear of specific things or circumstances
Phobias
Classify the anxiety disorder:
Recurrent, obsessive behaviors
Obsessive Compulsive
Classify the anxiety disorder:
Anxiety after a stressful event
Post Traumatic Stress Disorder
What are the different classifications of sleep disorders?
Insomnia - short term tx with sedative hypnotic
Hypersonic, Narcolepsy - tx with stimulants
Kleine-Levin Syndrome (“Sleeping beauty”)
Enuresis (bed wetting) - tx with TCA
Sleep apnea - tx with CPAP
DOC for enuresis
Tricyclic antidepressants
Difficulty falling asleep, early or frequent awakening, and unrefreshing sleep
Insomnia
__________ insomnia occurs with situational stress (bereavement, conflict at work or in the family, hospitalization)
Transient or Short-term
Sedative-hypnotics are most useful
_______ insomnia may be related to underlying psychiatric disease or chronic alcohol/drug use
Long-term
Best treated with behavioral therapy and lifestyle changes
Describe the “ideal” sedative-hypnotic
Causes one to fall asleep quickly, stay asleep as long as wanted, and wears off early in the morning with no hangover effect
How does GABA work to relieve anxiety and promote sedation?
Gamma-amino-butyric-acid
It’s the primary CNS inhibitory neurotransmitter - acts as a depressant and is widely distributed in the CNS
GABA receptors are ______ channels, and activation causes the membrane to _________
Cl-
Hyperpolarize
What are the major subtypes of GABA?
GABA-a
GABA-b
GABA-c
Activation of ________ receptor causes depression of electrical activity which decreases anxiety and promotes sleep
GABA-a
Hydroxyzine (Vistaril) is an antihistamine but is also used as …
Anti-anxiety medication
It’s a 1st gen antihistamine so SEDATION is big
No abuse potential so good for use in recovering addicts
Inhibits smooth muscle response and vasodilation
CNS depression or stimulation
Prevents nausea and emesis caused by motion sickness
Has some anti-Parkinson effects
Barbiturates bind to ______ and stimulate _______ to produce _______.
GABA receptor
Cl- influx
Inhibition INDEPENDENT of GABA
Barbiturates cause marked _______ and _______
CNS depression (hypnosis) and euphoria
Considered a drug of abuse (schedule II or III controlled substances)
Uses for barbiturates
Thiopental (Pentothal) - short acting barbiturate used for induction of anesthesia
Long-acting barbiturates such as phenobarbital (Luminal) are used as anticonvulsants
If you see phenobarbital on the exam, think…
DRUG INTERACTIONS
They induce CYP450s with chronic use, so alters metabolism of alcohol, many hormones, and other barbiturates
Side effects of barbiturates
CNS depression** - drowsiness, distortion of mood, impaired judgement and motor skills, can last 10-22 hours
Paradoxical excitement (esp in elderly patients)**
Vertigo, nausea, vomiting, diarrhea, and allergic reactions
May depress the vasomotor and respiratory centers of the medulla
Severe physiological and psychological dependence**
Contraindications for the use of barbiturates
Porphyria - b/c they enhance porphyrin synthesis
Pulmonary insufficiency - may cause resp depression
Supra-additive effects when combined with other CNS depressants (ie alcohol, benzos)
What does barbiturate withdrawal look like?
Can be severe
Restlessness, anxiety, weakness, orthostatic hypotension, hyperactive reflexes and seizures
What makes barbiturates so dangerous?
Low margin of safety (no “ceiling effect”) b/c not dependent on GABA
Benzos are safer b/c their dose/effect curve plateaus
When combined with alcohol, barbiturates can be Supra-additive
Overdose of barbiturates is marked by…
Coma, respiratory depression, and decreased BP
Treatment is supportive
Stimulants increase mortality rate
What is the best way to manage a barbiturate overdose?
Supportive care
Cleared with diuresis and alkalization of the urine (ion trapping)
The most commonly used group of anxiolytics and sedative-hypnotics
Benzodiazepines
Overprescribed in the 60s-80s (whomp whomp)
Main drawbacks of benzos
CNS depression - decrease in anxiety often accompanied by drowsiness
Hypnosis can occur with high doses
The elderly do not metabolize benzos as quickly so avoid as much as possible
Benzos are metabolized by ________ and converted to _________
CYP3A4 in the liver
Active metabolites
Duration of action for different benzos depends upon…
The metabolites
Active metabolites = long duration of action
Short-acting metabolites = intermediate duration
Inactive metabolites = intermediate duration
Benzos with long duration of action
(Long duration b/c active metabolites
Diazepam is converted to desmthyldiazepam, then to oxazepam, for a total 1/2 life of ~75 hours
Flurazepam also converted to long-acting metabolites (t1/2 = 74 hours)
Benzos with intermediate duration of action
Alprazolam
Oxazepam/lorazepam
Benzo with very short duration of action
Midazolam
MOA for benzos
Bind to specific sites on the GABA-a receptor for an effect that is DEPENDENT on GABA
Increases affinity of the receptor to GABA, prolonging its action
B/c it’s dependent on GABA —> CEILING EFFECT (vs barbs that are GABA independent)
DOC for benzos is based largely on…
Duration of action
Anxiety disorders in which benzos are NOT used
Obsessive-compulsive disorder (treat with SSRI)
Agoraphobia and panic disorders (treat with SSRI)
PTSD (treat with antidepressants)
Anxiety in children and adolescents (treat with antidepressants)
Benzos used in insomnia
Flurazepam and temazepam
Minor depression of REM sleep so may cause hangover effect
These two are shorter acting drugs so helpful for the person who has difficulty falling asleep but not staying asleep
Benzos used in epilepsy and seizures
Diazepam and lorazepam for Status Epilepticus (ongoing seizures >3 min)
Benzo used for sedation, amnesia, and anesthesia
Midazolam - used in prep for anesthesia for short surgical procedures
Anterograde amnesia possible
Benzo used for muscle relaxation
Diazepam sometimes used for acute muscle spasm and pain as a result of injury
Use of benzos during withdrawal from alcohol/barbiturates
Long-term use of alcohol/barbiturates can produce physical dependence and result in withdrawal that is very severe and can be life threatening
Benzos (chlordiazepoxide, diazepam, and lorazepam) are used to provide a more tapered withdrawal
Side effects of benzos
CNS depression: dizziness, drowsiness, excessive sedation, impaired motor coordination, confusion, memory loss
Effects are most common in the first few weeks - will decrease as tolerance develops
Less common are blurred vision and hallucinations
Paradoxical excitement** - due to disinhibition of suppressed behavior (more likely in the elderly*)
Supra-additive CNS depression when combined with alcohol
Sleep-related behaviors (sleep driving, eating, walking)
Contraindications for the use of benzos
Should not be given during pregnancy unless absolutely necessary (Cat D)
Sleep apnea - may decrease tone of upper airway)
Elderly
Abrupt discontinuation of benzos can cause…
Rebound increases in insomnia and anxiety
Muscle weakness, tremor, hyperalgesia, N/V, weight loss, and convulsions
Benzos should be tapered very slowly following chronic use
Overdose on benzos generally results in…
A long deep sleep (24-48 hours)
Although Schedule IV, do have some abuse potential
Fatalities may occur in people with respiratory difficulties in children, and when combined with alcohol
Benzodiazepine antagonist that competes with benzos for GABA receptor to reverse their effects
Flumazenil (Mazicon)
Reverses the effect of midazolam (Versed), which sometimes causes resp depression
Also reverses the effects of other drugs (“z-drugs”) that act on the benzo binding site
Evidence showing effective treatment for hypersomnia conditions
Major adverse effect of Flumazenil
Triggers withdrawal and seizures in patients who are physically dependent on benzos
DO NOT USE in patients addicted to benzos or with Hx of SEIZURES
What are the “z-drugs”?
Zolpidem (Ambien), Zaleplon (Sonata), Eszopiclone (Lunesta)
Bind to the BZ1 subtype of the GABA receptor to increase GABA-mediated inhibition
Very strong and rapid sedative effects
NO anxiolytic, anticonvulsant, or muscle relaxant properties
Pharmacokinetics of the Z drugs
Well-absorbed orally, peak levels at 30-60 min
Metabolized in liver (CYP3A4), excreted by kidney
Short duration of action, so morning drowsiness unlikely (exception = eszopiclone - used for long-term treatment)
Half-life may be prolonged in severe hepatic disease
Side effects of z drugs
VERY HIGH margin of safety
GI - diarrhea and nausea
CNS - drowsiness and dizziness
Sleep-related behaviors
Amnesia occurs with higher than recommended doses
Confusion, memory loss, and psychosis in the elderly
May increase the depressant effects of other sedative drugs
REBOUND INSOMNIA may occur after rapid d/c
WITHDRAWAL Sx with abrupt cessation
MOA for Suvorexant (Belsomra)
Antagonist at orexin receptors
Orexins are involved in regulating the sleep-wake cycle and promote wakefulness
Metabolized by CYP3A4 so drug interactions likely with inhibitors such as cimetidine
Side effects of suvorexant (belsomra)
HA and abnormal dreams
Can cause sleep paralysis***, hallucinations, and muscle weakness while falling asleep or waking up
Depression may worsen in patients with underlying depression
Effects will be magnified if combined with other CNS depressants
Suvorexant (Belsomra) is contraindicated in …
Patients with narcolepsy
MOA for Ramelteon (Rozerem)
Melatonin analogue - resets sleep-wake cycle
Promotes sleepiness w/o GABA effect
Side effects of Ramelteon (Rozerem)
Additive sedation with alcohol and other sedative hypnotics
Drowsiness, dizziness and nausea
Why are antihistamines in this lecture?
Not classical sedatives, but 1st gen antihistamines have sedative properties
They are the active ingredient in the majority of OTC preparations for insomnia
Useful for occasional insomnia and esp in someone who has been addicted to benzos/alcohol
MOA for Chloral Hydrate (Noctec)
Converted to trichloroethanol, which causes sedation
Acts similarly to barbiturates on GABA-a
LOW MARGIN OF SAFETY - high doses induce resp and vasomotor depression
Down sides of Chloral Hydrate (Noctec)
Causes gastric irritation, N/V, allergic responses, may produce cardiac arrhythmias
Long-term use may cause liver damage and fatal intoxication
Why does anyone use Chloral hydrate (Noctec)
CHEAP
• In children for sedation during pediatric dental procedures
• In nursing homes and chronic care institutions
Use as a sedative-hypnotic not recommended
MOA for Buspirone (BuSpar)
Relieves anxiety without producing sedation
Partial agonist at the POST-SYNAPTIC 5-HT receptor —> inhibition of cell signaling
FULL agonist for PRE-SYNAPTIC 5-HT receptors —> decreased release of 5-HT
Good option for anxiety in recovering addicts b/c it works outside of GABA system
Anxiolytic effect takes about 2 weeks to develop
No muscle relaxant or anticonvulsant properties
Uses for Busprione (BuSpar)
Generalized anxiety and anxiety with depression
ADHD and autistic patients with anxiety
Premenstrual syndrome
Very low addiction potential - GREAT CHOICE for recovering alcoholics/addicts with anxiety
Not good for severe anxiety and/or panic disorder
