Anxiolytics Flashcards
Fear
Fear is a response to imminent, clear and present danger or threat.
Anxiety
Anxiety is a response to anticipated threat, which may be vague and ill-defined.
what are fear and anxiety
For both fear and anxiety, the threat may be real or perceived.
For both fear and anxiety, the response include defensive behaviors, autonomic reflexes, arousal, corticosteroid production, and negative emotions.
Under normal emotion: aroused, efficient, “fight or flight”.
For a psychiatric state: interferes with activities of daily living, work and relationships
- psychiatric state = ill-defined and chronic
Manifestation of anxiety states
• Psychological components: – Negative emotions: Worry, nervousness, unease. – Arousal. (continuously alert) – Lack of concentration. – Insomnia.
• Physical symptoms: – Tachycardia. – Shortness of breath. – Nausea. – Gastric acid hypersecretion. (ulcer) – Trembling.
Biochemical basis of anxiety
- Central and peripheral noradrenergic / adrenergic activation —> the “Flight or Fight” response
- Stress response —> Hypothalamus-pituitary-adrenal (HPA) axis —> secretion of stress hormones (cortisol).
Types of Anxiety disorders
• Generalized anxiety disorder (GAD):
– Excessive,uncontrollable worry over everyday matters.
– Interferes with daily functioning.
– Has both psychological and physical symptoms.
– Diagnosed when present for at least 6 months.
– Most common cause of disability in the workplace.
• Other anxiety and fear disorders: – Post-traumatic stress disorders (PTSD). – Phobias. – Panic disorder. – Obsessive compulsive disorders (OCD).
Anxiety disorders: therapeutic rationale
• CNS depressant:
– Sedative –> causes sedation, relaxation.
– Hypnotic –> induces drowsiness and sleep, may have amnestic effects.
– Anxiolytic –> reduces anxiety.
Note: These actions are closely-related. The same drug can have more than one action depending on dose.
Eg:
– Low dose –> anxiolytic and sedative effects
– Higher doses –> hypnotic
– Even higher doses –> can cause anesthesia, used for surgery
Strength of CNS depression
1) Hypnotic
2) Sedative
3) Anxiolytic
Benzodiazepines
– Used as anxiolytics / sedatives: eg, diazepam, lorazepam, alprazolam.
– Used as hypnotics: eg, diazepam, triazolam, temazepam.
– Used as pre-anaesthetics: eg, diazepam, midazolam.
– May also have anti-convulsant effects: eg, diazepam, clonazepam
Benzodiazepines Used as anxiolytics / sedatives:
– Used as anxiolytics / sedatives: eg, diazepam, lorazepam, alprazolam.
Benzodiazepines – Used as hypnotics:
Used as hypnotics: eg, diazepam, triazolam, temazepam.
Benzodiazepines – Used as pre-anaesthetics:
– Used as pre-anaesthetics: eg, diazepam, midazolam
Benzodiazepines – May also have anti-convulsant effects:
– May also have anti-convulsant effects: eg, diazepam, clonazepam
Benzodiazepines MOA
Binds to +ve allosteric site of GABA receptor and potentiate the effect of GABA actions by increasing the frequency of GABA-induced channel opening.
GABA—inhibitory transmitter in brain regions: acts via GABAA receptors Cl-channels. It causes the CL ions channel to open, leading to hyperpolarization of the cell.
BZD potentiates influx of CL ions leading to hyperpolarization, making cell more difficult to depolarize and therefore reduces neural excitability.
therefore neurons not firing.
Eg:
- limbic system (alter mood)
- Reticular activating system (causes drowsiness)
- Motor cortex (relax muscles)
Short acting BZD
1) Midazolam (Anxiety. induction of general anesthesia, procedural sedation)
2) Triazolam (insomnia)
Midazolam
Short acting BZD
1) Midazolam (Anxiety. induction of general anesthesia, procedural sedation)
Triazolam
Short acting BZD
Triazolam (insomnia)
Intermediate acting BZD
Alprazolam (Anxiety, panic disorder)
Clonazepam (panic disorder, seizure)
Lorazepam (Anxiety, insomnia, status, epilepticus)
Oxazepam ( Anxiety, Alcohol withdrawal syndrome)
Temazepam (Insomnia)
Alprazolam
Intermediate acting BZD
Alprazolam (Anxiety, panic disorder)
Clonazepam
Intermediate acting BZD
Clonazepam (panic disorder, seizure)
Lorazepam
Intermediate acting BZD
Lorazepam (Anxiety, insomnia, status, epilepticus)
Oxazepam
Intermediate acting BZD
Oxazepam ( Anxiety, Alcohol withdrawal syndrome)
Temazepam (Insomnia)
Temazepam
Intermediate acting BZD
Temazepam (Insomnia)
Long acting BZD
Chlordiazepoxide (Anxiety, Alcohol withdrawal syndrome)
Diazepam (Anxiety, Alcohol withdrawal syndrome, sedation, status, epilepticus, seizure, refractory seizure, adjunct skeletal muscle spasm)
Flurazepam (insomnia)
Chlordiazepoxide
Long acting BZD
Chlordiazepoxide (Anxiety, Alcohol withdrawal syndrome)
Diazepam
Long acting BZD
Diazepam (Anxiety, Alcohol withdrawal syndrome, sedation, status, epilepticus, seizure, refractory seizure, adjunct skeletal muscle spasm)
Flurazepam
Long acting BZD
Flurazepam (insomnia)
BZD ADR (Acute toxicity / overdose) + tx
– Can cause severe respiratory depression, especially used concurrently with alcohol.
– Treatment is by flumazenil, a benzodiazepine antagonist
BZD ADR ( Side effects during use)
– Drowsiness, confusion, amnesia.
– Impaired muscle co-ordination (impairs manual skills).
• Tolerance and dependence:
– Depends on frequency of use. Therefore, tolerance develops faster for epilepsy than for use to induce sleep.
– Dependence can develop. Withdrawal symptoms include disturbed sleep, rebound anxiety, tremor and convulsions.
– Important to withdraw gradually.
– Has abuse potential.
Barbiturates
–E.g.: pentobarbital, amobarbital
–Also potentiate GABA(A) mediated Cl- currents, but at a site distinct from benzodiazepines.
–Use as a sedative-hypnotic has largely been replaced by benzodiazepines due to barbiturates’ tendency to develop tolerance and dependence
Long acting Barbiturates
Anticonvulsant: Eg, phenobarbital.
Anticonvulsant Barbiturates
Long acting (1-2days) - phenobarbital
Sedative & Hypnotic: Barbiturates
Short (3-8hrs) Sedative & Hypnotic:
Eg, pentobarbital and amobarbital.
I.V induction of anesthesia Barbiturates
Ultrashort (20 min) I.V induction of anesthesia: Eg, Thiopental
Barbiturates indication
Clinical indications based on duration of action
Barbiturates ADR
–Severe withdrawal symptoms (~BZDs).
–Overdose may be fatal due to respiratory collapse.
–Flumazenil not effective for treating barbiturate overdose => coz bind to different site
–At anesthetic doses, barbiturates such as phenobarbital can directly open Cl- channels as well as block Na+ channels. (therefore stronger action)
Buspirone
–A serotonin 5-HT1A receptor partial agonist. Also binds dopamine receptors.
–Indicated for GAD but anxiolytic effects takes 1-2 weeks.
–Lacks anticonvulsant and muscle relaxant properties.
Propanolol
–A beta-adrenergic receptor antagonist (“betablocker”).
–Used for treating performance anxiety and social phobias.
–Reduces physical symptoms associated with adrenergic activation.
–Contraindicated in patients with asthma and heart conditions.
Pregabalin
–GABA analogue, increases synaptic GABA —> GABA receptor mediated Cl- currents resulting in hyperpolarization.
–Also acts on voltage-gated Ca2+channels.
–Used to treat GAD, also has anticonvulsant effects.
–May be associated with emergence of worsening of suicidal thoughts. (DONT GIVE DEPRESSED PT)
Hydroxyzine
–A first generation antihistamine with activities on serotonergic and α-adrenergic receptors.
–Anxiolytic effects attributed to antagonism of serotonin 5-HT2 receptors.
–Has low addictive potential compared to BZDs and barbiturates.
–Because of antihistamine activities, also helps with itching.
