Anxiolytics and Sedatives Flashcards
What drugs reduce anxiety?
Anxiolytics
What drugs induce sedation and reduce anxiety?
Sedatives
What drugs induce drowsiness and sleep from which one can be aroused?
Hypnotics
When does anxiety become a disorder?
When it begins to interfere with normal life. When it is no longer useful as a warning system.
What part of the brain is used in the limbic system when anxiety and fear is involved?
The amygdala
What is the ascending arousal system?
It is the state of CNS activity and reactivity leading from sleep to wakefulness to excitement to panic . This is opposed to to the GABA system which promotes sleep.
What pathway needs to be shut off in order to sleep?
The ascending arousal pathway
What small molecules are used in the regulation of sleep?
Glutamate NE ACh 5-HT DA
What aa is used in the regulation of sleep?
GABA
What neuropeptide is used in the regulation of sleep?
Orexin/hypocretin
What else is present in the ascending arousal pathway?
Histamine. Specifically H1 (H1 antagonist has strong sedating and anti-emetic effects. H2 doesn’t cross BBB and has low CNS effects)
What biological components are important in the arousal system?
Biological clocks
Pineal gland (releases melatonin)
Suprachiasmic Nucleus - master clock in hypothalamus
Retina - light (synchronizes the endogenous clock)
What are some subjective features that are linked with anxiety?
Apprehension Worry Anticipation Fear Jumpiness Restlessness Impaired concentration Comorbid depression
What are some physiological features that are linked with anxiety?
tension, fatigue, tremor
dry mouth, difficulty swallowing
hyperventilation
palpitations
GAD
generalized anxiety disorder - excessive anxiety and worry most of the time about life
Panic disorder
discrete periods of intense fear
phobic anxiety disorder
irrational fear that interferes with normal behavior
SAD
social anxiety disorder
OCD
obsessive compulsive disorder (persistent thoughts/ideas and impulses for intentional behaviors)
PTSD
normal reaction to abnormal event
acute stress disorder
reaction to recent stress, lasts less than 6 months
What is the goal for a good anxiolytic?
A non-sedating drug that works against anxiety
Benzodiazepines
- mechanism
- advantages
- disadvantages
- GABAa receptors in the limbic system that control emotional behavior
- rapid onset, high therapeutic index, effectiveness for acute and other form of anxiety (not GAD)
- tolerance, CNS depressant/sedative, impaired cognition, additive alcohol danger, dependency
What do BZD’s do to the GABA receptor?
They increase the frequency of channel opening = enhanced inhibition.
Is potency or efficacy of GABA increased by BZDs?
Potency because the binding affinity of GABA for its receptor is increased when BZD binds to its spot.
What are the short-acting BZDs?
Chlorazepate
Oxazepam
What are the intermediate-acting BZDs?
Oxazepam
alprazolam
lorazepam
What are the long-acting BZDs?
Chlordiazepoxide
diazepam
clonazepam
What other things treat anxiety, but not acutely?
CBT
SSRI’s
SNRI’s
buspirone (5HT1A selective agonist)
What non-BZD can treat performance anxiety acutely?
A beta-blocker such as propranolol
What was the first non-BZD approved for GAD?
buspirone
What drug cannot be used in those with panic attacks?
buspirone - it may exacerbate (possibly due to metabolite that is has an alpha2 antagonist effect that heightens NE response)
Does buspirone have a risk of dependency?
No
What is the mechanism of action for buspirone?
5HT1a receptor agonist. Over time may desensitize. Also dopamine receptor antagonist. Weakens serotonergic transmission, especially in the Raphe nuclei.
What type of medication works better in the first 4 weeks for anxiety?
BZD’s. Buspirone works moderately well until 4 weeks hit, and antidepressants work the least effectively until 4 weeks hit. Then they all work about the same.
What are sedative-hypnotic drugs used for?
Anxiety Insomnia Sedation and amnesia Component of balanced anesthesia Epilepsy/seizures muscle relaxant Withdrawal from addictive substances
What are the types of sedatives/hypnotics?
BZD’s (triazolam, estazolam, temazepam, flurazepam and quazepam used for insomnia)
Z-drugs: zaleplon, zolpidem, eszopiclone
Barbiturates
What is the length of action of this barbiturate? Methohexital.
ultrashort (5-15 minutes) - for induction of anesthesia
What is the length of action of these barbiturates? Amobarbital, pentobarbital, secobarbital.
short-acting (3-8 hours) for insomnia or pre-operative sedation
What is the length of action of this barbiturate? phenobarbital.
Long-Acting (days) for seizures
Can GABA receptor activators be used for anesthesia?
Yes
What is the main difference between barbiturates/non-BZD hypnotics and BZD/Z-drugs?
Death can result from too much drug alone in the barbiturates/non-BZD hypnotics.
What anxiolytics/sedatives/hypnotics bind to GABAa receptors? What do they do?
BZD barbiturates Z-drugs chloral hydrate meprobate They increase the receptor activity as positive allosteric modulators.
How many subunits does GABA have?
5
What are the two main combinations?
2 alpha, 2 beta, 1 gamma
2 alpha, 2 gamma, 1 beta
What is the BZD antagonist that can reverse overdose but has no clinical effect alone?
Flumazenil
When tolerance develops, how does the curve shift?
To the right; it decreases potency.
What subunits do BZD’s bind to?
alpha 1,2,3 or 5 (not 4 or 6)
What subunits do Z-drugs bind to?
alpha 1
What are the main components you have to have in order to have insomnia?
- daytime impairment
- difficulty initiating or maintaining sleep despite adequate opportunity
What classes of drugs aid in treating insomnia?
Z-drugs BZD melatonin receptor agonists orexin receptor antagonists OTC antihistamine and melatonin
What percentage of your sleep is REM?
20-25% of your sleep
How long are your sleep cycles?
90-110 minutes
How do BZD affect sleep stages?
They increase stage 2, and decrease REM and time spent in deep sleep. Tolerance will occur
How do Z-drugs affect sleep stages?
less suppression of REM, but cause complex behavior such as sleep driving and cooking.
Are sleeping pills and alcohol good for sleep cycles?
They don’t recreate normal sleep, although it may feel more refreshing.
Do all GABAa receptors bind BZDs?
No
What gives diazepam the sedative, amnesic, and anticonvulsant effects?
The GABA receptors that contain the alpha1 subunit mediate these effects.
What drug is used for sedation and analgesia for intensive care patients over BZDs and propofol?
Dexmedetomidine. It acts as an agonist at a negative feedback loop to stop the release of NE.
What receptors do melatonin, ramelteon, and tasimelteon work at to regulate sleep?
The M1/M2 receptors to drive rhythmic signaling in the 24 hour clock.
What drugs do you use to treat restless legs?
ropinirole
pramipexole
rotigotine
How does chloral hydrate work?
At the GABAa receptor causing a barbiturate-like effect
How does flunitrazepam work?
It is a fast-acting BZD causing amnesia… date-rape
How does propofol work?
A tepid-acting sedative for induction and maintenance anesthesia acting at the GABAa receptor. (not used as much as dexmedotomide).
What antidepressants are sedating?
trazodone
doxepin
mirtazipine
What is the target of the OTC benadryl?
H1 receptor
What did the narcoleptic dogs in the Stanford study lack?
Orexin receptors, which are in the ascending arousal pathway.
What do the orexin projection neurons cause?
Awakening, wakefulness
What does a deficit of orexin neurons cause?
narcolepsy
What is DORA?
dual orexin receptor antagonists (OX1R, OX2R). Orexin is a neuropeptide secreted by the hypothalamus. They block alertness in insomnia.
What is special about DORA?
It avoids GABA receptors
When should belsomra be taken?
within 30 minutes of sleep, with at least 7 hours remaining before planned awakening
What is the common dose of belsomra? Common warnings?
20mg once daily. Like other insomnia medications, the warning is drowsiness and possible daytime impairment.
Onset of BZDs: what are the fastest?
Chlorazepate and diazepam.
Onset of BZDs: intermediate onset?
clonazepam
lorazepam
alprazolam
chlordiazepoxide
Onset of BZDs: slow?
oxazepam
What kinds of disorders can have secondary anxiety?
Cardio-pulmonary disorders Endocrine disorders Autoimmune Neurological Medication (use or withdrawal): BZD, nicotine, alcohol, opioids, albuterol, caffeine
What drug classes can you use to treat anxiety disorders?
BZDs
Antidepressants (SSRIs, SNRIs, TCA, MAO-Is)
Z-drugs
Misc. GABA agonist, 5HT1a agonist
Which BZDs have the shortest half-life?
lorazepam and oxazepam
Which BZDs have the longest half-life?
Clonazepam, chlorazepate, and diazepam
What anxiety disorders are clomipramine indicated for?
Panic disorder, OCD (TCA)
What anxiety disorders are imipramine indicated for?
Panic disorder, MDD, enuresis (TCA)
What anxiety disorders are desimipramine indicated for?
MDD, panic disorder, IBD (TCA)
What anxiety disorders are nortriptyline indicated for?
MDD, panic disorder, IBD (TCA)
What anxiety disorders are phenelzine indicated for?
SAD, MDD, PTSD, panic disorder (MAOI)
What anxiety disorders are nefazodone indicated for?
GAD, SAD, MDD (TCA)
What anxiety disorders are hydroxyzine indicated for?
GAD, SAD, panic (antihistamine)
What anxiety disorders are meprobamate indicated for?
Just GAD, short-term (GABAa)
What anxiety disorders are buspirone indicated for?
GAD, SAD (5HT1a receptor agonist)
What criteria do you need to meet to have general anxiety disorder (GAD)?
- excessive worry and anxiety for at least 6 months
- at least 3 other qualifications
edginess
fatigue
impaired concentration
irritability
muscle tension
difficulty sleeping
What is the difference between psychic and somatic anxiety?
Psychic symptoms are more emotional, such as edginess, irritability, impaired concentration. Somatic anxiety is more physical, such as muscle soreness, difficulty sleeping, fatigue, GI issues, palpitations, etc.
What do most other people with GAD have?
Another psychiatric disorder, such as depression or dysthymia.
What kind of overlapping symptoms do GAD and MDD have?
worry, fatigue, irritability, sleep disturbances, psychomotor agitation, impaired concentration
Hamilton Anxiety Rating Scale (HAM-A)
Most used
scores greater than 18-20 indicate need for treatment
Generalized Anxiety Disorder Severity Scale (GADSS)
severity of scale indicates whether they need to be treated
Penn State Worry Questionnaire
Discriminates among anxiety disorders
What are the most educated mental health counselors?
Psychiatrists
What are some nonpharm ways to treat GAD?
Biofeedback
Relaxation techniques
CBT
cognitive therapy
How does CBT help a patient?
A lot of work has to be put in by the patient to change their way of thinking. It addresses distorted beliefs or misconceptions about self and others.
What medications are most effective for somatic symptoms of GAD?
BZDs
What medications are most effective for psychic symptoms of GAD?
Antidepressants, for longterm use
What are the 1st, 2nd, 3rd line treatments for GAD? How long do you use them?
1st: CBT w/ or w/o SSRI (citalopram, escitalopram, sertraline, paroxetine)
2nd: SNRI (duloxetine or venlafaxine)
3rd: SSRI/SNRI + second gen antipsychotic (risperidone, quetiapine, olanzapine)
Continue meds for at least 1 year
Bad things: SSRIs
If stopped abruptly, can cause dizziness, seizures, insomnia, flu-like symptoms
Bad things: SNRIs
If stopped abruptly, can cause “electrical zing”, flu-like symptoms, headache. Associated with increased blood pressure, need monitoring.
Bad things: TCAs
Anti-cholinergic, avoid in those with high risk of suicide, possibility of toxicity with overdose
Bad things: MAOIs
lots of dietary restrictions. SSRI and clomipramine interactions
Bad things: tetracyclics
Weight gain, drowsiness
Bad things: BZD
If stopped abruptly may cause seizures, withdrawal, psychosis, delirium, confusion
Bad things: pregabalin
abused, discontinuation symptoms
Bad things: second gen antipsychotics
weight gain, less tolerable. Quetiapine is used to augment SSRIs for OCD, can be abused in prison system.
What is SAD?
social anxiety disorder. Anxiety related to social or performance situations
What % of American adults have SAD?
6% or so
What is used to treat SAD?
CBT produces longer-lasting results
Meds work faster
1st line meds: SSRI (paroxetine, sertraline, citalopram, excitalopram)
2nd line meds: different SSRI or SNRI (venlafaxine, mirtazipine). Use BZD as needed (lorazepam).
3rd line meds: 2nd gen antipsychotic, MAOI, anticonvulsant
What can beta blocker be used for in SAD?
Only performance anxiety
How long should CBT and meds be used to treat SAD?
At least 6-12 months
What three characteristics would a person with PTSD be experiencing/exhibiting?
Exposure Intrusion Avoidance Cognition/mood Arousal and reactivity >1 month Exclusion
What two parts to disassociation are there in PTSD?
Depersonalization
De-realization
What types of comorbidities exist with PTSD?
Depression Suicide Head trauma Pain Substance abuse
What is the primary treatment for PTSD?
Psychotherapy, with or without medications
What are the first line meds for PTSD? What about second line?
1st line: SSRIs (sertraline, fluoxetine, paroxetine) or SNRIs (duloxetine, fluoxetine) or TCAs (amitriptyline, nortriptyline, desipramine)
2nd line, it depends on what else they have issues with. (sleep, nightmares, mood, psychosis)
Are BZDs usually used for PTSD?
No, because of abuse potential
Treatment resistant PTSD?
Atypical antipsychotics, divalproex, gabapentin augmentation
What anticonvulsants can you use for PTSD?
Gabapentin lamotrigine topiramate valproate divalproex tiagabine carbamazepine pregabalin
What are the typical antipsychotics used for PTSD?
risperidone
olanzapine
quetiapine
What are atypical antipsychotics good for in PTSD?
They work at the 5HT1a and 5HT2 receptors, and have high limbic activity. High SE profile. Have some effectiveness for intrusive thoughts, flashbacks, emotional regulation. Usually used in adjunct to SSRis or SNRIs.
What are clonidine and prazosin used for in PTSD?
Aha adrenergic activity associated with the fear and startle response.
Clonidine is an alpha 2 agonist - reduces severity and duration of nightmares
Prazosin is an alpha 1 antagonist
What is a personality characteristic that focuses on order, but still functions in society with minimal conflict?
Obsessive compulsive personality
What is OCPD?
Obsessive compulsive personality disorder A person needs to have 4 of the following patterns to be considered: - Control - Perfectionism - Dislike of teams - Prioritizing work over relationships - Miserly - Inflexible - Hoarder - Stubborn in morality
What is OCP and OCPD treatment?
CBT, no medication unless physical or mental illness accompanies
OCD is a what kind of disorder?
Anxiety disorder rather than a personality disorder
What are the qualifications for having OCD?
- obsessions
- compulsive activity takes up at least 1 hour/day
- rituals performed to reduce severe anxiety caused by obsessive thoughts
What are abnormal about obsessions?
They feel to the person like they are out of control, and are more distressing than everyday worries
What is the difference between the compulsions of a person with OCP and OCD?
A person with compulsive personality will think they are normal while being compulsive, while a person with OCD will realize that something is wrong.
What are some non-pharm options for OCD?
Relaxation techniques
Psychotherapy (CBT and Exposure and Response Prevention)
What are the four steps of medication use for OCD?
1st line - fluvoxamine and clomipramine, or SSRIs/SNRIs
2nd line - different SSRI or TCA
3rd line - SSRI/TCA + atypical antipsychotic/mirtazipine
4th line - different combos of SSRI/ TCA and clomipramine/buspirone/pindolol
If a person is resistant to treatment, what theory opens up a door to another type of medication?
Glutamate transporter imbalance theory: extra glutamate in OCD patients. N-acetylcycteine hits an NMDA receptor for glutamate, and could be used for this.
How is panic disorder defined?
- 4 or more attacks in a 4-week period
- 1 or more followed by a month of fear of another panic attack
- symptoms are of brief periods of intense fear and hit at least 4 out of 15 symptoms
What are some common panic triggers?
Cannabis, SSRI withdrawal in someone with a panic disorder, stimulants, illness, interpersonal stress, injury
During a panic attack, what is there an urge to do? And after?
Flee, and after, avoid situations where it might occur again. Intense worry.
What are some co-morbidities associated with panic disorder?
OCD, depression, agoraphobia, IBS, migraine headache
What neurotransmitters are targeted in panic disorder?
5HT2 - antagonist blocks reuptake, leaving more serotonin in synapse to reduce anxiety
alpha adrenergic antagonism - increases synaptic NE and serotonin
What is the treatment of choice for panic disorder?
CBT. It is more effective than medication, and it can be combined with medication.
What medications can be used to treat panic disorder?
SSRIs - 1st line SNRIs TCAs MAOIs BZDs - for use in acute situations. Not longterm
What drugs used in panic disorder have concerns for cardiac disorders?
Citalopram (QT prolongation and cimetidine interaction 2C19)
TCAs - risk of arrhythmias
What is the most common comorbid condition seen with insomnia?
depression (40-50% psychiatric illness)
What percent of the population will complain about insomnia in their lifetime?
50%. Over 70 years old, 80% will.
Chronic insomnia affects what percentage of the population and requires treatment?
5-16%. involves daytime impairment and often anxiety and depression later in life
What are the 3 insomnia diagnostic criteria?
- Difficulty in initiating sleep (30 minutes or more) 3 x/week
- Difficulty maintaining sleep. Waking 3 times a night or waking too early in the morning
- Feeling unrefreshed after 7 hours of sleep3x a week
Persist for at least 3 months
Not due to underlying medical causes
What neurotransmitters promote sleep?
GABA, melatonin, adenosine (may inhibit wake-promoting neurons)
When is melatonin expressed?
At night. It is suppressed in the daytime.
What neurotransmitters promote wakefulness?
NE 5HT ACH histamine Dopamine Orexin
What are the treatment guidelines for insomnia?
1st line - behavioral intervention, CBT
2nd line - antihistamine (3 days), short-acting BZD, z-drugs, sedating antidepressant (trazodone, doxepin)
3rd line - ramelteon, sedating antipsychotics
What is ramelteon indicated for?
Sleep onset, not maintenance
What is tasimelteon indicated for?
Non-24 hour sleep-wake disorder (blond people)
What are the sedating antidepressants used for insomnia?
Trazodone, doxepin, mirtazipine
At what dose is mirtazipine useful as a sleep aid?
At lower doses.
What are the barbiturates used for? Why are they not useful in insomnia?
They are mostly used in anesthesia because of their long half-lives. Phenobarbital is useful in treating seizures.
When do barbiturates lose their effectiveness as sleep aids?
Within 2 weeks. Also addictive, additive with alcohol, cause ‘hangovers” and can cause seizures if stopped abruptly.
What is chloral hydrate used as?
It is a GABAa receptor agonist used as a sedative and a hypnotic in sever treatment resistant insomnia, pre-operative sedation or post-op pain.
What should elderly insomniacs avoid in terms of BZDs?
Triazolam and flurazepam, because of their long half-lives and anterograde amnesia
Which BZD is used mosts often for sleep?
Temazepam, because of the intermediate half-life
Which BDZ is used in dental procedures?
Triazolam
Which GABA subunits are responsible for anxiolytic, amnesia, and muscle relaxant properties?
alpha 2, 3, and 5 subunits
Which BZD is like the Z drugs in terms of what subunit it binds to?
quazepam. But it has a long half-life.
What other BZDs should you avoid in the elderly?
Triazolam and alprazolam. They are short-acting and could increase the risk of falls.
What are the intermediate-acting BZDs?
Lorazepam, temazepam, oxazepam. They are more likely to be used longterm.
What are the long-acting BZDs?
Clonazepam, diazepam, flurazepam
What type of sleep are zolpidem and eszopiclone used for?
Sleep onset and maintenance. Need 7-8 hours of sleep.
What type of sleep is zaleplon used for?
Onset only. Administer immediately before bed. Only need 4 hours of sleep.
What sedating antipsychotic is used for insomnia?
Quetiapine. It has abuse potential and SEs though, so not used very much. Use at doses under 150mg for sleep to hit H1 receptors.
Which sedating antidepressant has anticholinergic SE’s?
Doxepin. Avoid in the elderly. Use for sleep maintenance, take on empty stomach.
Which sedating antidepressant acts as an antihistamine under 15mg?
Mirtazipine. Low Ach. SEs though of weight gain, limb movements in sleep.
Which sedating antidepressant is safe for the elderly?
Trazodone. Risk of priapism.
What is the Orexin receptor antagonist?
Suvorexant. It blocks Orexin neuropeptides A and B to receptor types 1 and 2. It assists in sleep onset and fewer awakenings. Can impair daytime wakefulness.
Which is the Z drug with the bitter taste?
Eszopiclone
Which has the longer half-life, eszopiclone or zolpidem?
Eszopiclone
Which antidepressant is FDA approved for sleep?
Doxepin (H1 blocker)
