Anxiolytics & Sedative- Hypotonic meds

anxiety disorders

- Panic disorder +/- agoraphobia

- GAD

-Agoraphobia w/o h/o Panic disorder

- SAD

-OCD

-PTSD

Psychic sxs of Anxiety disorders

- repetitive thoughts

- compulsions

- Depression

Somatic sxs of Anxiety disorders

-sweating

-palpitations

- restlessness

GAD (Generalized Anxiety Disorder)

A. Excessive anxiety and worry, occurring more days than not for at least 6 months, about a number of events or activities

B. Person finds it difficult to control the worry

C. Anxiety and worry are associated with 3 or more of the sxs (next card)

D. The disturbance is not better explained by another mental disorder

E. cause significant distress or impairment

F. Disturbance not attributable to the physiological effects of a substance or another medical condition

Describe the sxs associated in criteria C

C. Anxiety and worry are associated with 3 or more of the sxs

1. restlessness or feeling keyed up or on edge

2. easily fatigued

3. difficulty concentrating or mind "going blank"

4. Irritability

5. Muscle tension

6. sleep disturbance

Non-pharmacological tx

- cognitive behavioral therapy--> stress management--> exercise/Meditation + pharmacotherapy --> Exposure therapy ( exposing pt to their fear in a safe environment

Goals of therapy

-reduction of severity, duration and frequency of episodes

- improve functioning and quality of life

- prevent sxs

- sxs remission

Pharmacotherapy for anxiety

- Benzodiazepines

- Buspirone

-*Antidepressants ( go-to, first line)

-Beta blocker

-Alpha blocker ( to decrease HR and BP)

-Antipsychotics

Tx concepts

-SSRIs/SNRIs are considered first line for all anxiety disorders

- antidepressants work in the long-term to tx chronic anxiety

- Benzos may be used in short-term to manage acute anxiety sxs (along w/ SSRIs)

- When dosing, start low, go slow and aim high!

T/F anxious pts are more sensitive to adverse effects

TRUE--> higher dose is usually required for them

Tx for psychic sxs

- Buspirone (anxiolytic)

-SSRIs

-SNRIs

-TCAs

-MAOIs/ Antipsychotics

Tx for somatic sxs

- Benzos

- Buspirone

- Beta blockers

-Clonidine (a2 adrenergic agonist)

What tx approach should be taken if pt requires immediate treatment for anxiety disorder

-Benzodiazepine for 2-4 weeks

- non-pharm interventions after; problem solving, coping skills, relaxation and breathing techniques etc

- antidepressants

- reevaluate tx: 4-6 weeks

Non immediate treatment approach for anxiety disorder

- non-pharm interventions ; problem solving, coping skills, relaxation and breathing techniques etc

- antidepressants

- reevaluate tx: 4-6 weeks

What is goal of chronic treatment for anxiety disorder

Remission ( 70% reduction of sxs from baseline)

response to tx

50 % reduction of sxs from baseline

Non response to tx

< 25 % response to tx

How long do antidepressants take for anxiolytic effects?

2-4 weeks after initiation, if sxs don't improve after 4 weeks, the likelihood of response decreases

- in pts who respond, continue therapy for 1 year

- avoid abrupt discontinuation- gradually taper dose

- if relapse occurs, may continue tx indefinitely

First line Pharmacotherapy of GAD

- SSRIs or SNRIs

- Benzodiazepine ( short term as bridge)

Second line Pharmacotherapy of GAD

- Buspirone

- Bupropion ( Wellbutrin)

- TCA

- Quetiapine ( antipsychotic- more for anxiety secondary to mood disorders)

- Lyrica ( GABA analogue) ( anxiety, fibromyalgia etc)

third line Pharmacotherapy of GAD

pts w/ anxiety secondary to mood disorders

- MAOIs

- refer pt to psych

Benefits of SSRI/SNRI

- effective for cognitive sxs such as worry

- ideal or pts w/ comorbid depression

- long term tx maintains remission and prevents relapse

- lack of abuse

Drawback of SSRI/SNRI

- May take up to 6 weeks to take full effect

- can cause withdrawal sxs upon abrupt discontinuation- tapper off

- sexual dysfunction

How do SSRIs and SNRIs work?

- ↑ extracellular levels of NT serotonin and NE by limiting reabsorption into the presynaptic cell

- use caution in children and young adults ; ↑ risk of SI at beginning of therapy- MONITOR CLOSLY

- Can cause serotonin syndrome ( mild to deadly )

What is serotonin syndrome?

a condition caused by use of 2 or more serotonergic drugs

↑ Hr, fever, shivering, sweating, dilated pupils, myoclonus, hyperreflexia

tx is d/c meds, supportive care

Which SSRIs are FDA approved for GAD?

Paxil and Lexapro

- others have been used but off-label : Celexa ( SLE; OT prolongation) , Zoloft

Which SNRIs are FDA approved for GAD?

Effexor and Cymbalta

management of SSRIs and SNRIs

- periodic assessment is essential

- recommended to continue tx for 6-9 months to determine effectiveness

- safety monitoring

Benzodiazepines for GAD

- enhances GABA ( sedative , hypotonic-sleep- inducing, anxiolytic, anticonvulsant, muscle relaxant properties) ,

-decreases nerve cell excitability

- used for ACUTE sxs in all anxiety disorders

-* High abuse potential

- Indicated for short term use only ; overlap for 2-4 weeks w/ antidepressants

- short or intermediate acting preferred for insomnia

ADRs of benzodiazepines

Sedation

amnesia

loss of coordination

tolerance, dependence, withdrawal

Rebound anxiety upon discontinuation

List of benzodiazepines

-Alprazolam (Xanax)

-Lorazepam (Ativan)

-Clonazepam (Klonopin)

-Diazepam (Valium)

Xanax

- greater abuse potential rapid onset/short duration of action

- frequent daily dosing required

Ativan

Most commonly used

- preferred in pts w/ hepatic dysfunction/ elderly

- parenteral formulations ( IM/IV)

Klonopin

longer time to onset/duration of action

Valium

- Fast onset/long duration of action ( long 1/2 life)

- Parenteral formulations ( IM/IV) and rectal gel

BZD drug interactions : pharmacodynamics

CNS depressants ( ETOH, barbiturates, opioids)

BZD drug interations: pharmacokinetics

CYP 34A inducers: carbamazepine, phenobarbital, phenytoin

CYP34A Inhibitors: OCP, verapamil, protease inhibitors

Discontinuing BZD

TAPPER, DON'T abruptly stop

- risk of withdrawal syndrome ( rebound anxiety sleep disturbance, irritability, panic attacks, hand tremor, shaking, sweating, confusion, nausea, palpitations)

- type of BZD specific taper : Decrease total dose by 25% every few days, when reach 1/8 of original dose, continue 1 week then stop

Buspirone

- 2nd line tx

- Serotonin 5-HT1A receptor agonist & antagonist of Dopamine D2 receptor

- Delayed onset to therapeutic effect

- No abuse potential

- preferred to BZD w/ comorbid depression

- option for pts who cannot take BZD

ADRs of buspirone

dizziness, nausea, headache, nervousness, dysphoria

Pregabalin (Lyrica)

Anticonvulsant, anxiolytic, analgesis properties

- similar overall efficacy to lorazepam and venlafaxine (Effexor)

- controlled substance ( schedule V)

- approved in US and Europe for GAD

Hydroxyzine (Atarax)

not really used anymore

- antihistamine ( was used for itchiness, nausea due to motion sickness)

- 50 mg / day anxiolytic properties

- often used for acute sxs of anxiety prn b/c of sedating effects

- very anticholinergic

Propranolol for performance anxiety

- indicated as adjunct therapy to SSRIs and SNRIs for performance anxiety

- useful in pts w/ physical sxs of anxiety ( rapid HR, sweating etc)

- beta blocker of choice: 10-80 mg 1 hr prior to "performance"

- dose low and titrate as needed

- admin test dose prior to event to test tolerability

PTSD

SSRIs and SNRIs first line

- only Paxil, Zoloft and Effexor are FDA approved

-BZD contraindicated!!-> can interfere w/ extinction of fear conditioning ( when using talk therapy to face fears & benzo's may interfere w/ this process)

- Trauma focused psychotherapy superior to drugs

Which drug is used for PTSD related night terrors?

Prazosin ( Minipress)

- A1 blocker ( antihypertensive or BPH)

- controversy over effectiveness but may decrease nightmares and sleep disturbances

Dose: 1-15 mg/day--> monitor BP w/ dose escalation

Panic Attack DSM 5 Criteria

distinct period of intense fear of discomfort in which 4 or more of the following develop abruptly and reach a peak within 10 mins

1. palpitations or ↑ HR

2. sweating

3 trembling or shaking

4. sensation of SOB or smothering

5. feeling of choking

6. chest pain or discomfort

7. nausea or abd distress

8. feeling dizzy, unsteady, lightheaded or faint

9. feeling of unreality or being detached from oneself

10. fear of losing control or going crazy

11. fear of dying

12. numbness or tingling sensation

13. chills or hot flashes

Panic Disorder DSM 5 criteria

A) Recurrent, unexpected, Panic Attacks At least one of the attacks has been followed by ≥1 month of at least one of the following

1. Persistent concern or worry about additional panic attacks

2. being anxious about implications of the attack ( losing control, having a heart attack, "going crazy")

3. maladaptive change in behavior designed to avoid having panic attacks

B. not caused by direct effects of a substance or another psych illness or medical illness

Panic Disorder subtypes

w/ agoraphobia

w/o agoraphobia

Management of panic attack

- non-pharmacological modalities

- PRN benzos NOT recommended

Management of panic disorder

-CBT: 8-20 sessions

-SSRIs or SNRI + short term scheduled BDZ

- can use TCA if SSRI/SNRI not tolerated

- Zoloft & Lexapro had high rates of remission w/ low risk of ADRs.

Length of tx

SSRI/SNRI/TCA: 6 months then assess; should taper over several weeks

BZD: few weeks then taper slowly

OCD (Obsessive Compulsive Disorder)

Recurrent obsessions and compulsions of at least 1 hr/day and interfere w/ some aspect of functioning

Obsession

intrusive, repetitive thought that cannot be suppressed voluntarily and causes anxiety to the person

ex: germs & contamination, need for order and symmetry; aggressive thoughts, sexual thoughts

Compulsion

Ritualistic behavior that is repetitive as means to prevent or reduce the stress associated w/ obsession

Ex: checking, cleaning, arranging symmetrically , hoarding, counting, need to ask questions

Impact of OCD

Mild sxs seen for years before full OCD emerges

- onset can occur in childhood/ adolescence

- worsens during stressful periods in life

- can have serious effects on functional abilities and QOL

- Majority will have comorbid depression or another anxiety disorder

Screening for OCD

4 questions:

1. Do you have to wash your hand over and over?

2. do you have to check things repeatedly?

3. do you have recurrent distressing thoughts that you can't get rid of?

4. do you have to complete actions again and again in a certain way?

Y-BOCS: Yale-Brown Obsessive Compulsive Scale

Scoring:

mild:l 8 to 15

moderate: 16-23

Severe: 24-31

Extreme: 32-40

Tx of OCD

- CBT ( must be incorporated)

-SSRI

-Clomipramine- TCA

- Effexor ( SNRI), Cymbalta( 2nd line) ( SNRI)

Augmentation of tx for OCD

combo of any of the above or

- antipsychotic meds

Pharmacotherapy efficacy of OCD

- OCD generally takes longer to respond to meds than depression ; trials must be min 10 weeks!

- higher dose= greater response

- **40-60 % pt will respond

- response does NOT mean sxs are gone! only 40-60 % of sx reduced w/ drug alone

- relapse is common when meds are discontinued

classifications of sleep disorders

Insomnia

Narcolepsy

Obstructive sleep apnea

Circadian rhythm disorders

Insomnia

difficulty in different aspects of sleep cycle

- sleep latency: length of time it takes to fall asleep

- sleep maintenance: staying asleep

- duration: how long

-quality: superficial? deep?

Impairment of daytime functioning

classifications of insomnia

classified as

-Transient (< 1 week)

- short-term ( 1-4 weeks)

- chronic ( > 1 month)

Meds causing insomnia

- alcohol

- stimulants : Ritalin, amphetamine salts

- Provigil - txs narcolepsy, sleep apnea, shift work disorder

- appetite suppressants

- caffeine

- pseudoephedrine

- levothyroxine

- cigarettes

-SSRIs

- Buproprion

- Theophylline

- corticosteroids

Nonpharmacologic Therapy for insomnia

- Sleep hygiene ; avoid caffeine, large meals , establish a relaxing pre-sleep ritual

- create a comfortable sleep environment

- re-associate of bed for sleep , sex, or when ill only

- physical activity but not close to bedtime

- avoid napping, minimize to 30-60 mins before 3 PM

Leave bedroom if cannot sleep > 20 mins

- CBT

Tx approach for insomnia

- Asses duration of problem ( transient, short-term, chronic)

- Identify secondary causes ; counsel pts on appropriate use of meds and tx underlying cause

-make pharm and non pharm recommendations

What must you do before treating insomnia?

r/o sleep apnea

Medication targets for insomnia

Sleep onset: decrease sleep latency

Sleep maintenance : increase total sleep time

Middle of night awakening: wake after sleep onset

Quality of sleep: pt report

- select agents based on efficacy of specific target

Pharmacological options for insomnia

BZD

BZD receptor agonists " Z hypnotic"

Melatonin receptor agonist

sedating antidepressants

sedating antihistamines

Desirable characteristics of sleep aids

- rapid sleep induction

- immediate offset

- maintain sleep architecture

- sustained sleep throughout the night

Undesirable characteristics of sleep aids

- tolerance/ dependence

- residual daytime effect

- memory deficits

- rebound insomnia

BZD

- bind non-selectively to GABA receptors subunits to increase GABA

- Act as a sedative, anxiolytic, muscle relaxant and anticonvulsants

Z-hypnotics

non-benzo but "benzo like", known as Z drugs

- bind SELECTIVELY to BZD omega-1 receptor subtype

- schedule IV controlled substance

- caution on elderly and pts on other CNS depressants

- consider short 1/2 life agents for pts being initiated to minimize daytime sedation

What is the only indication for z hypnotics?

SLEEP

Select class warning of Z hypnotics

- CNS depressant effect

- eval for comorbid dx causing insomnia-> if persists > 10 days consider alternative causes of insomnia

- respiratory distress

- withdrawal effects

- severe injuries from drowsiness

- dependence

BZD and sleep

- best for short term use only!

- schedule IV controlled substance

- consider anxiety-related insomnia

- select agent based on the presence of t 1/2, metabolite, renal/hepatic dysfunction, concomitant meds, drug interactions

which BZD has a short 1/2 life and is for sleep-onset only?

Triazolam ( Halcion)

Which BZDs have intermediate 1/2 life and is for sleep onset and maintenance?

Ativan, Prosom, Restoril

Which BZDs has long 1/2 life and is for sleep onset and maintenance ( has been d/c) ?

Flurazepam --> metabolite

What are the Z-hypnotics

Zolpidem (Ambien) & Eszopiclone (Lunesta) for sleep onset and maintenance

Zalephlon ( Sonata) for sleep onset and middle of night awakenings

BZD and Z hypnotics ADRs

- dizziness / drowsiness

- lightheadedness

- cognitive impairment

- next day impairment

- anterograde amnesia ( forget things that happen after taking meds)

- rebound insomnia after discontinutation

complex sleep behaviors (CSB)

- specific to z hypnotics ( cause CBS)

- Black box warning

- contraindicated in pts w/ prior episode

- CBS followed by amnesia include:

sleep walking, driving, preparing food and making phone calls while sleeping

- labeling warns against serious injuries and death relating to CBS

Drug infractions w/ Z drugs

-CNS depressants

alcohol, other sedating agents/ CNS depressants

- Strong 3A4 inhibitors

increases conc. of Zolpidem

dose adjustment may be necessary to avoid excessive depression

- Strong 34A inducers

may decrease conc. of Zolpidem

Melatonin

- An endogenous hormone manufactured by the pineal gland - -modulates circadian rhythms

- OTC

-mostly effective for jet-lag

-other indications: shift-work disorder insomnia, circadian rhythm sleep disorders in blind pts

Ramelteon (Rozerem)

-selective agonist for melatonin MT1 and MT2 receptors

-no tolerance or dependence

- data for long term use

- less hangover effect

- no rebound insomnia

- Cost:

ADRs or Ramelteon (Rozerem)

Somnolence

dizziness

increases prolactin

orexin receptor antagonist

targets sleep-onset and maintenance ; NOT first line

- $

- schedule IV controlled substances

- Risk of dependence

- consideration after failing multiple other meds

Orexin-receptor antagonists

"xant"

Suvorexant (Belsomra)

Lemborexant (Dayvigo)

Daridorexant ( Quviviq)

miscellaneous antidepressants

Trazodone ( Desyrel)

- SARI- Serotonin antagonist and reuptake inhibitor

- reduces sleep latency/ increases total sleep time

- frequently prescribed

- use w/ caution in elderly pts

- low dose for sleep , higher for depression

Trazodone ( Desyrel) ADRS

Orthostasis, dry mouth "hungover effect"

constipation

priapism

QTc prolongation ( rare)

TCAs

- consider for pts w/ comorbid depression, pain, migraines, anxiety

-Doxepin

-Amitriptyline

-Nortriptyline

- ADRs: anticholinergic, toxic on OD, Orthostatic hypotension, weight gain

Advantages of antidepressants

- no abuse potential

-inexpensive

- tx of comorbid disorders; depression, fibromyalgia, migraines, anxiety

Disadvatages of antidepressants

- ADRs

- lethal in OD

- off label use

Antihistamines

- routine use is not recommended by guidelines b/c of ADRs but used in practice

- Benadryl

-doxylamine (Unisom)

- Hydroxyzine ( Atarax)

ADRs of antihistamines

Anticholinergic

- "hangover effect"

Other OTC agents of insomnia

Valerian

Kava Kava

Valerian

MOA: inhibits an enzyme that breaks down GABA

ADRs: HA, GI upset, Cardiac disturbances

-NOT FDA approved

Kava Kava

- Not recommended

- Hepatotoxicity associated w/ use

- NOT FDA approved