Anxiolytics Flashcards
Most commonly used agents for anxiety disorders?
Antidepressants–>5HT (SSRIs, SNRIs)
[BDZ–>GABA: declining use b/c abuse potential
Buspirone–>5HT: weaker than BDZ for anx but fewer SE
Barbiturates–>GABA: seldom used b/c low safety margin, drug interactions, abuse potential]
Sedative-Hypnotic Drugs
- graded dose-dep depressant effects on CNS
- augment GABA and or inhibit glutamate
- sedative drugs: as decreasing activity, moderating excitement, and calming the recipient
- hypnotic drugs: produce drowsiness and facilitate the onset and maintenance of sleep that resembles natural sleep and from which the recipient can be easily aroused
Therapeutic range effects of BDZs and barbiturates
-antianxiety, anticonvulsant, muscle relaxant, sedative, and hypnotic effects
Higher doses of BARBs: GA, can progress to depression of respiratory and vasomotor centers–>coma, death
BDZs: non-linear, much greater dosage increments are required to achieve CNS depression beyond hypnosis/sleep; so greater SAFETY
Do BDZs/non-BDZs binding to the gamma or alpha subunit of GABA channel initiate chloride current?
This does NOT directly initiate chloride current, it facilitates channel opening.
Do BDZs and barbiturates impact GABA-ergic effect?
@ separate binding sites, both indirectly increase the GABA-ergic effect to diminish neuronal excitability further.
BDZ: intensify effect of GABA
Barbs: prolong effect of GABA; but at high concentrations they interact directly with GABA receptor and here GABA isn’t required to be present
Barbs actions is less selective and also depresses excitatory NTs (glut)
Barbs can give greater CNS depression and surg anesthesia, so less safe
Z drugs
- zolpidem
- eszopiclone
- zaleplon
non-benzodiazepines that interact with the benzodiazepine binding site as agonists
Flumazenil
an antagonist @ BDZ binding site, reverses the CNS effects of BDZs
- use in overdose or after surgery to help recovery time
- NOT for barb or ethanol toxicity which have supportive tx only
GABA receptors w/ alpha1 subunits
highly expressed in cortex
-mediate sedative actions of BDZ
GABA recep w/ alpha2-5 subunits
- highly expressed in LIMBIC system and brainstem
- mediate anxiolytic effects of BDZs
Which GABA chloride channels (alpha1 vs a2-5) does BDZ bind?
- BOTH
- result: both sleep and anxiolysis
Which receptors do Z drugs bind?
- bind to GABA-chloride channels with alpha1 subunits resulting in SLEEP without anxiolysis.
- reduced potential for dependence
Which properties are shared by BDZs and barbs?
- augment GABA action at GABA-receptor chloride channel complex @ low doses
- efficacy in tx of sz disorders
alpha1 agonist, location actions vs alpha2-5
alpha 1
agonist: BDZs, Z drugs
location: cortex
Actions: sleep, anticonvulsant [amnesia, additive CNS depression]
alpha2-5
agonist: BDZ
location: limbic system, brainstem
actions: anxiolytic, myorelaxant [tolerance, dependence, addiction]
Pharm effects of BDZs (from lowest to highest doses)
- axiolysis (sedation)–can impair psychomotor function, behavioral disinhibition can occur
- anticonvulsant (most Barbs, some BDZs) (diazepam drug of choice for status epilepticus)
- muscle relaxation (action to inhibit spinal cord polysynaptic reflexes may aid in muscle spasms)(so muscle relaxation requires higher doses, usually accomp by CNS depression)
- hypnosis (sleep) @ high enough doses
- anesthesia: BDZs aren’t capable of induction, but used as adjuncts (anxiolytic, amnestic); Barbs are used to induce/maintain surgical anesthesia
- tolerance: continuous use at high doses. rapidly to sedative and anticonvulsant effects, less to anxiolytic action.
Psychologic dependence of BDZs
- schedule IV
- desirable effects (anxiety relief, euphoria, sleep) freq lead to compulsive misuse and psychologic dependence.
- all cause physical dependence if used on chronic basis (increased if high dosage, regular/continuous use, dependent personality, or prior abuse hx)
Withdrawal syndrome BDZs
nausea, fatigue, tachycardia, insomnia, depression, and weight loss
- potential for increased excitability (anxiety, tremors, hyperreflexia)
- more severe in BDZs w/ short half lives (and from barbs and ethanol)
Pharmacokinetics of BDZs
absorp, distrib, metab/ex
Absorp:
- oral (rapid)
- Diazepam (poor IM), alprazolam, and triazolam have rapid oral absorption
- Oxazepam and temazepam have slow oral absorp
IM
- used when need faster onset
- Lorazepam good IM absorp
Distribution
-most are lipid soluble and enter CNS rapidly
Metab/excretion:
- t1/2 depends on activity of drug metabolizing activities (CYP2c19, CYP3A4)
- accum of metabolites can result in daytime sedation (diazepam, chlordiazepoxide, flurazepam)
- most BDZ undergo CYP450 oxidations (phase I) and inactivation via conjugation by glucuronidation (phaseII)
- elim in urine
shorter t1/2, fewer problems w/ residual effectslorazepam, oxazepam (good choices for elderly w/ impaired phase I metab pathways and those w/ hepatic dysfunction)
Old Livers pneumonic
Oxazepam and lorazepam are metabolized into inactive glucuronides
- No P450 step
- shorter t1/2, fewer problems w/ residual effects
- good for ELDERLY, HEPATIC dysfunc
ADRs of BDZs
-most common ADRS are extension of CNS depression
-daytime sedation and performance impairment (high doses, longer half lives)
-very high SAFETY MARGIN when used alone
-but additive effects w/ other CNS depressants (like alcohol)
-No effect on resp/cardio function by oral doses of BDZs used alone.
(look out w/ sleep apnea, COPD)
anterograde amnesia:
common w/ drugs that enhance GABA neuronal function (indirectly depressing glut func)
psych/phys dependence
Barbiturates and DDIs
- inducers of CYP450 enzymes, and lead to DDIs
- contrib to declining use
When can porphyria be exacerbated?
thru use of barbiturates (not BDZs)
Black box warning for BDZs
-strange sleep-related behavior and severe allergic rxn
First line medical tx for GAD
SSRIs or SNRIs (pharmacotherapy or CBT use first line)
-duration 6-12 months if respond
Second line meds for GAD
TCADs: not preferred due to cardiotoxicity in OD and decreased tolerability
BDZs: efficacious within mins to hrs, concerns w/ abuse, adjunct to SSRI/SNRI for acute mgmt while SSRI takes effect
Buspirone: time to onset longer and weaker anxiolytic effect than BDZs, used as augmentation to SSRIs
