L02 Anxiolytics Flashcards
Differentiate anxiety from fear.
Differences:
- Fear: response to imminent, clear & present danger or threat
- Anxiety: response to anticipated, vague & ill-defined threat; more foreboding
Similarities:
- For both fear & anxiety, threats may be real or perceived.
- Response may include defensive behaviors, autonomic reflexes, arousal, corticosteroid production & negative emotions
At what point is anxiety considered to be a psychiatric disorder to be treated?
Normal: arousal, efficient, “fight or flight” response
Psychiatric: interferes w/ activities of daily living, work & relationships
How is anxiety manifested in patients diagnosed with generalised anxiety disorder (GAD)?
Psychological:
- Negative emotions: worry, nervousness, unease
- Arousal: mind is always alert/vigilant
- Lack of concentration: result from a constant heightened state of brain activity (i.e. arousal)
- Insomnia (due to constant aroused state)
AND/OR
Physical (adrenergic activation of “fight-or-flight”):
- Tachycardia, SOB/tachypnea
- Nausea, gastric acid hypersecretion
- Trembling due to overactivation of skeletal muscles
Explain the biochemical basis behind the manifestation of anxiety states.
1) Central & peripheral adrenergic/noradrenergic activation i.e. “flight, fright, or fight response”
2) Hypothalamus-pituitary-adrenal (HPA) axis, leading to secretion of stress hormones i.e. cortisols
Explain how GAD is diagnosed in a patient.
Generalised Anxiety Disorder (GAD):
- Excessive, uncontrollable worry over everyday matters
- Interferes with daily functioning
- Has BOTH psychological & physical symptoms
- Diagnosed when present for at least 6 months
- Most common cause of disability in workplaces
What are some other anxiety and fear disorders that may be diagnosed?
Triggers are more specific:
1) Post-traumatic stress disorders (PTSD):
- Specific anxiety response to a traumatic event
- Common in soldiers
2) Phobias: specific, unreasonable kind of fear
3) Panic disorder:
- Dramatic breakdown into a panic
- More acute presentation of anxiety disorder
4) Obsessive-compulsive disorder (OCD):
- More complex in nature, yet classical
- A mental state of an intrusive, persistent thought leading to a physical need to act in response to obsession
What is the therapeutic rationale behind the use of anxiolytics in the Tx of GAD?
MOA: CNS depression to reduce overactivation of adrenergic receptors
- Effects of CNS depression is dose-dependent (i.e. closely-related)
- Low dose: Anxiolytic & sedating
- High dose: Hypnotic
- Even higher dose: Anaesthesia used for surgery
- Same drug CAN have more than one action depending on the dose (i.e. on a continuum & NOT mutually exclusive!!)
Differentiate the meaning of “sedative”, “hypnotic” & “anxiolytic” effects.
Sedative:
- Causes sedation, relaxation
- NOT necessarily losing consciousness
Hypnotic:
- Induces drowsiness & sleep
- May have amnestic effects
Anxiolytic:
- Reduces symptoms of anxiety
List the drug classes that may be used as sedative-hypnotics & anxiolytics for the Tx of GAD.
1) Benzodiazepines (BZD; -zepam / -zolam)
- Anxiolytics / Sedatives: Diazepam, lorazepam
- Hypnotics: Diazepam, triazolam, temazepam
- Pre-anaesthetics for surgery: Diazepam, midazolam
- Additional anticonvulsant/antiepileptic: Diazepam
2) Non-BZD:
- Barbiturates: Phenobarbital
- Buspirone
- Zolpidem
- Pregabalin
- Hydroxyzine
- Propranolol
- TCA: Clomipramine
- SSRI: Fluoxetine, citalopram, sertraline & paroxetine
- SNRI: Venlafaxine & duloxetine
- NaSSA: Mirtazapine
Explain the role of GABA-A receptors in the mediation of CNS depression when using anxiolytics.
- GABA (gamma-aminobutyric acid) works as inhibitory neurotransmitters w/in brain & binds to GABA-A receptors Cl- channels.
- Allows influx of Cl- ions from extracellular fluid to intracellular fluid upon GABA binding which reduces membrane potential
- Subsequently reduce propensity for depolarisation
- Results in slower / less active firing of action potential of neurons (i.e. inhibitory neurotransmission)
- Consequently mediate CNS depressive effect (i.e. reduces neural excitability)
What is the mechanism of action of benzodiazepines (BZDs)?
BZDs allosterically binds to GABA benzodiazepine (allosteric) site, separate from primary GABA site.
- Enhances GABA binding to GABA-A receptors
- Potentiates influx of Cl- ions
- Leads to hyperpolarisation by increasing frequency of GABA-induced channel opening
- Subsequently reduced neural excitability (i.e. CNS depressive effect)
Thus, this results in:
- Mood alteration via limbic system
- Drowsiness via reticular activating system
- Muscle relaxation via motor cortex
Name some examples of short-acting BZDs.
Complusory: Midazolam
Optional: Triazolam
Half-life = approx. 3-8 h
Name some examples of intermediate-acting BZDs.
Complusory: Lorazepam
Optional: Alprazolam, clonazepam, oxazepem, temazepam
Half-life = approx. 8-24 h
Name some examples of long-acting BZDs.
Complusory: Diazepam
Optional: Chlordiazepoxide, flurazepam
Half-life = approx. 1-3 days
Which BZDs can be used for the indication of status epilepticus (i.e. a form of epilepsy)?
Lorazepam & Diazepam
Which type of BZDs is indicated for induction of general anaesthesia or procedural sedation?
Short-acting BZDs: Midazolam, triazolam
Which BZDs are not indicated for Tx of anxiety disorders?
Triazolam, temazepam & flurazepam
Which drug is used for the reversal of acute toxicity / overdose of BZDs?
Flumazenil (BZD antagonist)
What are some of the side effects of BZDs?
1) CNS depressive effects:
- Drowsiness
- Confusion
- Amnesia
- Impaired muscle coordination
2) Acute toxicity / overdose:
- Severe respiratory depression (esp. w/ concomitant use of alcohol)
3) Tolerance & dependence:
- Tolerance is dependent on frequency of use (develop faster for epilepsy than insomnia)
- Dependence can result in withdrawal effects if abrupt
- Withdrawal effects: Disturbed sleep, rebound anxiety, tremors & convulsions
- Has abuse potential
Describe the clinical use of zolpidem in the Tx of anxiety disorders.
Zolpidem is primarily used to treat insomnia due to good hypnotic effect.
- NOT effective as anxiolytics
Which non-BZD drug CANNOT be used for the Tx of anxiety disorders?
Zolpidem
Describe the mechanism of action of zolpidem.
Potentiates GABA-A-mediated Cl- currents by binding allosterically at benzodiazepine site of GABA-A receptors.
Describe the mechanism of action of buspirone.
Serotonin 5-HT1A receptor partial agonist & also binds to dopamine receptors.
Which anxiety disorder is buspirone indicated for?
Is there a difference in therapeutic effect between buspirone and BZDs for this particular indication?
GAD, but onset of anxiolytic effect takes 1-2 weeks.
Lacks anticonvulsant & muscle relaxant properties.
- Due to different MOA (5-HT1A & dopamine agonism) unlike BZDs (via allosteric binding to GABA-A receptors Cl- channels)
Describe the mechanism of action of barbiturates.
Potentiates GABA-A-mediated Cl- currents by binding allosterically at the barbiturate site of GABA-A receptors.
- Note that difference in allosteric binding site from BZDs & zolpidem!!
Flumazenil is effective for treating barbiturate overdoses. True or false?
False! Flumazenil is an antagonist at BZD allosteric site of GABA-A receptors, NOT an antagonist at the barbiturate allosteric site!
Why have barbiturates been largely replaced by BZDs for the Tx of anxiety disorders?
- Higher tendency of barbituates to develop tolerance & dependence.
- More severe withdrawal symptoms when used as sedative-hypnotic
- At anaesthetic (i.e. very high) doses, barbiturates (e.g. phenobarbital) can directly open Cl- channels & block Na+ channels.
Classify the types of barbiturates & describe their respective indications.
1) Ultrashort-acting (20 min): Thiopental (Thiopentone)
- Used for IV induction of general anaesthesia
- Primary use for barbiturates
2) Short-acting (3-8 h): Pentobarbital & amobarbital
- Used as sedative-hypnotic
3) Long-acting (1-2 days): Phenobarbital
- Used as last-line anticonvulsant / antiepileptic
- High abuse potential & severe withdrawal effects
What are some side effects of barbiturates?
1) Greater tolerance & dependency than BZDs
2) More severe withdrawal effects than BZDs
- i.e. disturbed sleep, rebound anxiety, tremors & convulsions
3) Medullary depression & coma
- Impt. autonomic responses are heavily depressed at very high doses
- Absent in increasing dose of BZD due to plateau of dose-response curve, unlike positive correlation for barbiturates
Describe the mechanism of action of pregabalin.
GABA analogue that increases synaptic GABA concentration, resulting in hyperpolarisation.
- However, pregabalin does NOT act on GABA itself
- Also acts on voltage-gated Ca2+ channels
What indications can pregabalin be used in the Tx of anxiety disorders?
GAD & epilepsy
- Pregabalin has anticonvulsant effects.
What important severe side effect is pregabalin known to be associated with?
Emergence of worsening of suicidal thoughts
- CONTRAINDICATED for pt. w/ depression!!
Describe the mechanism of action of hydroxyzine.
First-generation antihistamine w/ 5-HT2 antagonism activity.
- Has additional alpha-adrenergic receptor activity
- Anxiolytic effects can be attributed to serotonergic antagonism of hydroxyzine
What are some advantages of using hydroxyzine over BZD & barbiturates?
Low addictive potential compared to BZDs & barbiturates
Additional anti-itch & antiemetic properties that helps w/ itching & nausea symptoms associated w/ anxiety.
What indications can propranolol be used in the Tx of anxiety disorders? How so?
Performance anxiety & social phobias.
Reduces physical symptoms associated with adrenergic activation due to beta-adrenergic receptor antagonism.
- CONTRAINDICATED in pt w/ asthma & heart conditions.
