Anxiolytics (Week 6)

Question 1

Anxiety Disorders Listed in DSM V

Answer 1

Generalized anxiety disorder, Panic Disorder, Social Anxiety Disorder, Social anxiety disorder, Specific Phobia, Separation anxiety Disorder, Selective Mutism, Agoraphobia.

Question 2

Neuroanatomy of anxiety

Answer 2

-Anxiety and fear are regulated by amygdala-center circuit
-Worry is regulated by cortico-striato-thalamo-cortical circuit (CSTC)
-Overactivation of orbitofrontal cortex and anterior cingulate cortex leads to fear
-Overactivation of dorsolateral prefrontal cortex (DLPCF) and CSTC may lead to worry and obsessions
These circuits may be involved in all anxiety disorders.

Question 3

Neurochemistry of Anxiety

Answer 3

Noradrenergic System
Corticotropin-Releasing Hormone
Cortisol
Dopamine
Serotonin
Glutamate
GABA and benzodiazepine receptors

Question 4

Neurobiology of Anxiety: GABA

Answer 4

Produced from the amino acid gluatamate
Neurotransmitter involved in anxiety disorders and effects of anxiolytic drugs
Regulatory role
Reduces activity of neurons in amygdala and CSTC
Three main types of GABA receptors, A, B, and C

Question 5

Benzodiazepines

Answer 5

Modulate excessive amygdala activity
Some theories explain mechanism of action:
Enhance phasic inhibitory actions at postsynaptic GABA A receptor (less anxiety and fear)
Binding of alpha 2 subunits blocking excessive release of glutamate (less anxiety)
Binds to benzodiazepine receptors to enhance GABA effects
Schedule IV drugs (Controlled substance)

Question 6

Uses for Benzodiazepines

Answer 6

Insomnia,anxiety, alcohol withdrawal states, muscle spasms due to a variety of causes, including tetanus and cerebral spasticity, epilepsy(clonazepam),anesthesiaandsedationforendoscopiesand cardioversion.

The choice of drug as hypnotic and anxiolyticis determined by pharmacokinetic properties.

Question 7

Diazepam

Answer 7

Formulation: tab 2mg, 5mg, 10mg

FDA approved: Anxiety, sedation, muscle spasms, alcohol withdrawal, seizure disorder, status epilepticus
Off label use: sleep walking, serotonin syndrome
Half-life: 30-100 hours
Anxiety dosing: 2 – 4 mg po 2 times daily to 4 times daily
Alcohol withdrawal dosing: 5mg po 3 times daily or 4 times daily prn

Question 8

Clonazepam

Answer 8

Formulation: tab 0.5mg, 1mg, 2mg

FDA approved: seizure disorder and panic disorder
Off label use: anxiety disorders restless leg syndrome, confusional arousals, sleep terrors
Half life:20-50 hours
Starting dose: 0.25mg po bid, Max dose 4mg/daily

Question 9

Black Box Warning for Benzodiazepines

Answer 9

Black box warning: Avoid concomitant use with opioids. Monitor patients for sedation. Avoid in pregnancy and lactation

Question 10

Beers Criteria for Benzodiazepines

Answer 10

Beers Criteria:Avoid benzodiazepines (any type) for treatment of insomnia, agitation, or delirium

Question 11

Chlordiazepoxide (Librium)

Answer 11

FDA approved: Anxiety, sedation, alcohol withdrawal
Half- life: 5-30 hours
Starting dose 10 mg TID, Therapeutic Dose 15 to 100 mg

Question 12

Lorazepam (intermediate acting)

Answer 12

Formulation: 0.5mg, 1mg, 2mg
FDA approved: Anxiety, insomnia, status epilepticus,
Off label use: chemo related nausea/vomiting, preop sedation, neuroleptic malignant syndrome
-Half-life: 5-30 hours
Starting dose 1 – 2 mg
Therapeutic dose 1 – 10 mg

Question 13

Alprazolam (Xanax)-Short-Acting

Answer 13

Formulation: tab 0.25mg, 0.5mg, 1mg, 2mg
FDA approved: Anxiety, panic disorder
Half- life: 6-12 hours
Startingdose 0.25 mg po bid,Therapeutic dose 0.25 to 10 mg

Question 14

Benzodiazepine side effects

Answer 14

MOST COMMON SIDE EFFECTS:
Sedation and drowsiness, ataxia and memory impairment
OTHER SIDE EFFECTS:
Headache, giddiness, GI upset, skin rashes,reduced libido
Extrapyramidal reactions are rare.Paradoxical behavior effects and
perceptual disorders,e.g.hallucinations can occur.
Benzodiazepines cross the placenta andcan cause fetal cardiac
Arrhythmiaand muscularhypotonia, suckling hypothermia, and
Respiratorydepression in the newborn.

Question 15

Flumazenil:

Answer 15

Flumazenilreverses the sedative effects of benzodiazepines.

Question 16

Long-term Benzodiazepine use may lead to:

Answer 16

Dependence
Increased tolerance
Rebound anxiety
Rebound insomnia
Seizures and tremors
Withdrawal

Question 17

Which SSRI is best for anger?

Answer 17

Fluoxetine

Question 18

Which receptor modulates the anti-anxiety effects of SSRI’s?

Answer 18

Serotonin 1A receptors

Question 19

Buspirone(Buspar)

Answer 19

Formulation: 5mg, 7.5mg, 10mg, 15mg, 30mg

Considered a generalized anxiolytic agent
Buspirone is believed to have partial agonist actions at pre and post synaptic 5HT 1A
-Doesn’t tend to work well alone.
FDA approved: Anxiety
Starting dose 5-10 mg TID
Therapeutic dose 30-60 mg

Question 20

Generalized Anxiety Disorder Treatment

Answer 20

First-line of treatment includes: SSRIs, SNRIs, Benzodiazepines, Buspar, Gabapentin, andPregabalin
Benzodiazepines may be used inconjunction with SSRIs or SNRIs
Longer time needed to achieve remission of symptoms with SSRIs and SNRIs
Second-line of treatment may include Mirtazapine, Trazodone, TCAs, and Vilazodone
Adjunctive medication approaches include hypnotics, and atypical antipsychotics

Question 21

PTSD treatment

Answer 21

First-line of treatment includes: SSRIs and SNRIs
Second-line treatments (with caution)include:TCAs,MAOIs ,Gabapentin,andBenzodiazepines
Adjunctivemedicationapproachesinclude:Naltrexone,Acamprosate,Mirtazapine and, beta blockers

Question 22

Social anxiety Disorder treatment

Answer 22

First-line of treatment includes: SSRIs, SNRIs, Gabapentin, and Pregabalin
Second-line treatment include:Beta blockers: Propranolol (Inderal) Starting dose 10-20 BID/TID, Therapeutic dose 20 to 320 mg,Benzodiazepines, and MAOIs
Limited evidence about the use of TCAs, Mirtazapine, Trazodone
Adjunctive medication approaches include Naltrexone, and Acamprosate

Question 23

Tricyclic antidepressants in anxiety

Answer 23

Imipramine
Formulation: cap 75mg, 100mg, 125mg, 150mg
Formulation: tab 10mg, 25mg, 50mg
Off label use: generalized anxiety disorder
Inhibits norepinephrine and serotonin reuptake

Anxiety dosing: 75mg-200mg daily, divided in 3 doses
Side effects: urinary retention, pruritis, insomnia, weight gain, impotence, gynecomastia,urinary frequency, impaired coordination Adverse effects: blood dyscrasias, hypotension, AV block, myocardial infarction, stroke, tardive dyskinesia,glaucoma, serotonin syndrome

Question 24

Alpha-1 Adrenergic Antagonist

Answer 24

Prazosin (Minipress)
Formulation: cap 1mg, 2mg 5mg

Used off label fornightmares in PTSD
Possibly reduces the corticotropin-releasing hormone
Reduces non-rapid eye movement in stage 1 of sleep

Start at 1mg qhs X 3 nights
Increased by 1mg q 3 nights until nightmares improve or patient develops postural hypotension
Some patients can gain benefit a 1mg and some need >10mg,Max dose 15 mg
Side effects: dizziness, drowsiness, headache,urinary frequency,impotence
Adverse effects: tachycardia, orthostatic hypotension, palpitations

Question 25

Alpha-2 Adrenergic Antagonist