IDT Exam 3

Anxiolytic / Sedative / Hypnotic MOA/USE

Anxiolytics: reduce anxiety

Sedatives: induce “sedation”, decrease activity, with this they have a calming effect/reduce anxiety

Hypnotics: induce drowsiness, cognitive performance decreases, allows onset and maintenance of sleep (from which one can be aroused)

Ascending arousal system receptors in brain

Locus Ceruleus (NE)

Raphe (5-HT)

yPAG (DA)

LH (Orexin)

TMH (His)

BF (ACh, GABA)

Orexin

older name: Hypocretin

from hypothealamus

Sleep neurochemistry transxmitters

GLU, NE, ACh, 5-HT, DA, GABA, Orexin, His

Biological Clock components

•Pineal gland releases melatonin (derived from serotonin in pineal gland)

•Suprachiasmatic Nucleus (SCN) – the master clock in the hypothalamus

•Retina – light** (LIGAND) synchronizes the endogenous clock

Pineal gland

synthesizes + releases melatonin (derived from serotonin in pineal gland)

•Suprachiasmatic Nucleus (SCN)

– the master clock in the hypothalamus

Cycle of sleep

Anxiety Subjective + Physiological Features

Apprehension    Hypervigilance (‘jumpiness’)

Worry   Restlessness

Anticipation  Impaired concentration

Fear   Depression

Neuromuscular (e.g. tension, fatigue, tremor)

Gastrointestinal (e.g. dry mouth, difficulty in swallowing)

Respiratory (e.g. hyperventilation)

Cardiovascular (e.g. palpitations)

Generalized anxiety disorder (GAD)

excessive anxiety and worry most of the time about life

Phobic anxiety disorders

an irrational fear that interferes with normal behavior

Panic Disorder

discrete periods of intense fear

Social Anxiety Disorder (SAD)

Situational – specific circumstances

Obsessive-compulsive disorder (OCD)

Obsessions: persistent thoughts, ideas, or images that intrude into conscious awareness

Compulsions are urges or impulses for repetitive intentional behaviors

Post-traumatic stress disorder

recurrent anxiety precipitated by exposure to an exceptionally stressful/horrific or life-threatening event (really a normal reaction to an abnormal event) 

Acute stress disorder

a reaction to a recent identifiable stress; lasts less than six months

Comorbid depression and anxiety

depression and anxiety occurring together at the same time in the same patient (SSRI, SNRIs)

Anxiolytics and sedative/hypnotics act on

ascending arousal system provides rationale for:

(1)Targeting of GABA_A receptors (BDZs)

(2)other mechanisms of action / drug-receptor targets

(3)general clinical uses of "CNS depressants" 

Goal would be to separate responses: a non sedating anxiolytic

Benzodiazepenes

Mechanism:   Anxiolytic effect is likely in the limbic system high density of GABA_A a₂d of HVCC to reduce excitation ; Benzodiazepenes potentiate GABA binding enhance the affinity + Increase frequency of channel opening; NOT EFFICACY

Advantages:      Rapid onset of action

      Relatively High therapeutic index

      Very effective for acute anxiety and effective for other forms of anxiety

Benzodiazepine use should be “short term”

Disadvantages:    Tolerance

      CNS depressants/sedative

      Impair cognition/memory 

      Additive danger with opioids, alcohol etc.

      DEA Schedule IV habituation/dependence/abuse

Classification of Benzodiazepenes based on elimination

Midazolam (Versed) - v. short! ^<<*; Chlordiazepoxide * (Librium), Chlorazepate * (Tranxene)

Oxazepam */** (Serax), Alpralozam** (Xanax); ; ; Lorazepam** (Ativan); Temazepam**(Restoril)

Diazepam ***(Valium); Clonazepam*** (Klonapin)

*  Short-acting (3-8 hours)

**  Intermediate (6-24 hours)

***   Long-acting (1-3 days)

First line Anxiolytics

SSRIs

SNRIs

(slow onset)

Drugs WITH Anxiolytic Properties

ØSelective Serotonin Reuptake Inhibitors (SSRIs)

ØSerotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

ØTricyclic Antidepressants

  Disadvantage (all) - relatively slow onset of action

ØGABApentinoids: Pregabalin and Gabapentin (for GAD)

  inhibit neurotransmitter release through binding to

  a₂d (alpha 2 delta) subunit of presynaptic calcium channel.    “Atypical calcium channel blocker”

  Disadvantage safety – FDA warning of severe/ fatal breathing   problems especially in combination with opioids and in   patients at risk for decreased lung function; abuse liability

Acute and Novel Anxiolytic Drugs

Acute:

ØBeta-blockers e.g. Propranolol; Atenolol

Used for performance and social anxiety

  Only treats physiological symptoms (palpitations,   tremor and gastrointestinal upset, etc.); Acute action (Like benzodiazpenes)

Novel:

ØBuspirone (Buspar)  -  5-HT1A agonist
  Efficacy comparable to diazepam but a relatively selective   anxiolytic no sedative, hypnotic, anticonvulsant, muscle   relaxant properties, minimal abuse liability, unsuitable for   acute anxiety – slow onset of action

Comparable Anxiolytic action/efficacy of:

Bendoziazepenes, Buspirone, and Antidepressants

SSRIs / SNRIs

INDIRECT Action on Anxiety: Acts on 5-HT to decrease 5-HT at ascending arousal system

General uses of sedative-hypnotic drugs

•Relief of anxiety

•Insomnia

•Sedation and amnesia (e.g. pre-anesthesia allows less “hypnotic”; suitable for short uncomfortable procedures)

•As a component of balanced anesthesia

•Treatment of epilepsy, seizures, status epilepticus

•Muscle relaxants for neuromuscular disorders (including back pain)

•Treatment/control of ethanol or other sedative-hypnotic withdrawal states

Sedative/hypnotic drugs

Benzodiazepines (bold, good for insomnia)

Clonazepam ***(Klonopin); Diazepam ***(Valium); Lorazepam **(Ativan); Oxazepam (Serax); Triazolam (Halcion); Estazolam *(ProSom); Temazepam (Restoril); Flurazepam *(Dalmane); Quazepam ***(Doral); Midazolam ^<*(Versed)

Non-benzodiazepine agonists: Z drugs

Zaleplon (Sonata); Zolpidem (Ambien); Zopiclone (both isomers) marketed as Eszopiclone (Lunesta)

Barbiturates

Amobarbital **(Amytal); Aprobarbital (Alurate); Butabarbital (Butisol); Mephobarbital (Mebaral); Methohexital (Brevital); Pentobarbital* (Nembutal); Phenobarbital ***(Luminal); Secobarbital **(Seconal); Thiopental* (Pentothal)

Barbiturates

Amobarbital **(Amytal); Aprobarbital (Alurate); Butabarbital (Butisol); Mephobarbital (Mebaral); Methohexital (Brevital); Pentobarbital* (Nembutal); Phenobarbital ***(Luminal); Secobarbital **(Seconal); Thiopental* (Pentothal)

*Ultrashort (5-15 min)/induction of anesthesia

**Short acting (3-8 hrs)/insomnia/preoperative sedation

***Long acting (days) treatment of seizures

Newer GABA receptor activators are also used for anesthesia

-LOWER TI THAN BENZOS