anxiolytics and sedative-hypnotic drugs Flashcards
3 types of anxiety disorders
generalised anxiety - persistent and excessive anxiety
panic disorder - attacks of overwhelmed fear with marked somatic symptoms (sweating, tachycardia, chest pains etc.)
social anxiety disorder (social phobia) - fearful and anxious about social interactions an situations that may be subject to scrutiny
GABAa receptor
19 subunits
native GABAa receptors - two a subunits, two b subunits and one subunit of a third type (usually gamma)
distinct pharmacological profiles and physiological roles
GABA
the primary inhibitory neurotransmitter in the brain
binds to the GABAa receptor at the interface of a/b subunits
BZD binds at
interface of alpha and gamma subunit in GABAa receptor
benzo diazepine side effects - a2 subunit mediated
anxiolytic effects -
short acting drugs may paradoxically increase aggression due to withdrawal syndromes
muscle relaxant effects - act through the GABAa receptor in the spinal cord, facilitates anxiolytic effects (increased muscle tone is common to anxiety)
BZD side effects - a1 subunit mediated
hypnotic and sedative side effects - decrease sleep latency and increase sleep duration, short acting preferred, long acting drugs lead to drowsiness
anticonvulsant effects
anterograde amnesia - prevent memory of events experienced under influence of drugs, can also be a5-mediated
BZD chemical structure
seven membered ring fused to an aromatic ring
positive allosteric modulator - binds to BZD site at interface of a/y, increasing affinity for GABA and the frequency of channel opening, producing greater inhibitory effect on the target neuron
four BZDs
midazolam, alprazolam, diazepam, oxazepam
why is BZD a PAM
positive allosteric modulator - binds to a different site than GABA but increases affinity for GABA
midazolam
ultra short acting
produces minor active metabolites
hypnotic, anaesthetic and anticonvulsant
short acting BZD
oxazepam
oxazepam
short acting
no active metabolites
anxiolytic, hypnotic
medium acting BZD
alprazolam
long acting BZD
diazepam
alprazolam
active metabolites
anxiolytic
medium acting
diazepam
long actiing
active metabolites
anxiolytic, muscle relaxant, anticonvulsant
drug administration of BZD
oral (common, IV or rectal
good oral absorbtion and bioavailability
fast onset (30-60 minutes) of therapeutic effects
BZD used for
acute anxiety
behavioural emergencies
premedication for surgery and procedures
undesribale effects of BZD
drowsiness, amnesia, and impaired coordination
short acting drugs are
hypnotics
long acting drugs are
anxiolytics
diazepam in older patients
drug metabolism by cytochrome P450
significant impact of aging on drug metabolism
has active metabolites
oxazepam in elderly patients
drug metabolism by glucuronidation, relatively minor effect of aging on drug emtabolism
does not form active metabolites
drug drug interactions with BZD
eg. coadministration of diazepam and fluvoxamine (an SSRI)
diazepam uses CYP2C19 and flluvoxamine is a CYP2C19 inhibitor
tolerance in BZD
develops due to continued use
decrease in therapeutic effects when given the same dose
use for <2 weeks
withdrawal symptoms in BXD
on cessation of use
rebound anxiety, tremor, sleep disturbance, loss of appetite
short acting drugs are more problematic
acute overdose of BZD
relatively safe
treated with IV flumazenil (compete with benzodiazepines for the binding site)
if combined with other CNS depressants (alcohol or opioids) - severe respiratory depression
flumazenil
used to treat BZD overdose
competed with BZD for binding site
short duration of action
for long acting BZD overuse - may require multiple flumazenil injections
buspirone
5-HT1a receptor partial agonist
delayed anxiolytic effect
less problematic than benozdiazepines (no sedation or impaired motor control, no tolerance or withdrawal)
effective for generalised anxiety
side effects of buspirone
nausea, dizziness, headache and restlessness
does not cause sedation or impared notor coordination
does not lead to tolerance or withdrawal effects
antidepressants
SSRIs are preferred due to better side effect profile
delayed anxiolytic effects
reduce depression associated with anxiety
does not produce hypnotic effect
effective for generalised and socialised anxiety disorder
transient insomnia
shift work, jet lag
short term insomnia
experience emotional or stressful events
chronic insomnia
underlying conditions (eg. anxiety, depression, drug abuse)
BZD for insomnia
a1 subunit-mediated hypnotic effects
- decrease sleep latency and increase sleep duration
- improved sleeping quality while on treatment but rebound worsening of sleep
- short term use ( <2 weeks)
Z-drugs
zolpidem, zaleplon, and eszopiclone
structurally distinct from benzodiazepines but share the same binding site
a1-selective - hypnotic effects, short acting
lacks appreciable anxiolytic activity
adverse effects of Z-drugs
similar to benzodiazepines
short-term use to avoid tolerance and dependance
reports of bizarre behaviours and falls - use with caution, particularly in elderly patients
overdose - treated with flumazenil
more dangerous when combined with other CNS depressants
3 Z-drugs examples
zolpidem, zaleplon, eszopiclone
