Week 11 - Anxiolytics & Sedatives Flashcards
anxiolytics & sedative-hynotics
used to reduce anxiety, sedate, aid sleep, act as anticonvulsants and as anaesthetics
the three classes of drugs to achieve these effects
- benzodiazepines
- barbiturates
- other
illicit use of BDZs
- misused by those with drug addictions and used in ways that are not consistent with optimal therapeutic goals
- combined with other drugs (opiates & alcohol)
- controlled substances according to WHO standards
modern BDZs without active metabolites
- ozazepam
- temazepam
- lorazepam
- clonazepam
modern BDZs with active metabolites
- diazepam
- chlordiazepoxide
- nitrazepam
- alprazolam
- flurazepam
- bromazepam
examples of BBTs
- secobarbital
- phenobarbital
- amobarbital
- mephobarbital
- secobarbital
- aprobarbital
administration
- orally, parenaterally (i.v., i.m.) absorption from digestive system better than i.m. absorption bc of biochemical properties
- BBTs & BDZs readily absorbed after oral and parenteral routes
- choice of route of admin depends on reason for use
Absorption - barbituates
- weak acid
- pKa near 8.0 - almost entirely nonionized at pH of digestive system - readily absorbed
- variability in lipid solubility
absorption - benzodiazepines
- weak acid
- pKa of 3.5 to 5.0 readily absorbed from digestive dystem
- range of lipid solubility
- absorption may be increased by alcohol
distribution
- determined by lipid solubility
- cross placental barrier and present in break milk
- highly lipid soluble will cross BBB, effects seen quickly but dissipate quickly
- drug released slowly from fat deposits - metabolised by liver
2-phase excretion: BDZs
phase 1: rapid drop in blood level due to redistribution in fat deposits (half life ~2-10 hours)
phase 2: metabolism liver, CYP450 enzyme (half-life ~27-48 hours)
excretion - BDZs
- older BDZs almost fully metabolized - active metabolites of these drugs = duration of effect not determind by half-life
- metabolism increased by repeated administration; slowed by alcohol
excretion - BBTs
- most fully metabolized by liver enzymes before excretion
- repeated admin = increase metabolism
- metab also increased by anti-psychotics, anesthetics, chronic alcohol use, antihistamines, nicotine
excretion - BBTs (other drugs)
- BBTs stimulate enzymes that metabolize other drugs (chlorpromazine, morphine, caffeine, general and local anesthetics)
- ODs can be treated by making urine more alkaline
how do they affect GABA receptors
- ionotropic, mainly postsynaptic, quick response, couple to Cl- channels
- own receptor sites on GABA-Chloride Ionophore Complex
- make GABA NT more effective at these sites: increases ability to open channel
BBT vs BDZ mode of action
BBTs: increase time channel is open creates larger increases of Cl-
BDZs: increases frequency of channel opening & increases affinity of GABA for receptor
neurophysiology
- some act as negative GABA modulators
- interact with their own receptor sites
- BDZs affect adenosine by blocking re-uptake
- increases dopamine in nacc via GABA
BDZ effects on the body
- relatively mild decrease in respiration
- mild decrease in blood pressure
- increase appetite/ weight gain
- increase muscle relaxation
- anticonvulsant - petit mal seizures & infantile spasms
BDZs effect on sleep
- widely used for sedative-hypnotic properties
- effective as short-term intervention
- decreases time to fall asleep; decreases awakening and REM & stage 3 & 4 sleep, increase total sleep time - withdrawal rebound effect
- tolerance to effects does not develop
- eliminate withdrawal rebound by re-administer drug
BDZs subjective effects
- sedation/fatigue/confusion
- euphoria & ‘liking’
- anxiolytics
BDZs effects on performance
- decreased visual & auditory acuity
- decreased simple RT (at high doses)
- explicit memory - anterograde amnesia, not implicit memory
- if clinicallty anxious, BDZs may improve performance
BDZs hangover effects
- disruption in mood and performance 12 hrs after admin
- amplifies effects of alcohol
BDZs effects of driving
- increases collisions
- increased by alcohol
- increased risk in first time users who report feeling fine
BBTs effects on the body
- significant decrease in respiration
- heart rate
- blood pressure
- anticonvulsants
BBTs effects on sleep
- sleeping pills - decreased sleep onset latency; increased total sleep time
- decrease REM sleep - tolerance after 1 week
- withdrawal rebound up to 40% of sleep time for several weeks
BBTs subjective effects
similar to benzodiazepines
BBTs effects on performance
- decreased visual acuity
- overestimate time
- decreased steadiness
- decreased visual tracking
- decreased divided attention
- decreased athletic performance
BBTs hangover effects
- simple RT deficits detcted the next day
- decreased pursuit tasks
- decreased body steadiness after 18 hours
BBTs effects on driving
equivalent to BAL of .15
unconditioned behaviour
- taming seen in lab animals first
- restricted to decreased defensive aggression
conditioned behaviour
- increased responding to punished stimuli
- decreased avoidance behaviour
discrimination - barbituates
- not able to discriminate different types of BBTs
- generalized to other BBTs, BDZs - not to amphetamines or LSD
- can discriminate alcohol
discrimination - benzodiazepines
- animals readily discriminate BDZs from saline
- generalize to other BDZs & BBTs but not antipsychotics
- discrim effects can be blocked by drugs that block BDZ receptor
Chronic tolerance- barbituates
develop at different rates for different effects
examples:
- antiepileptic effects = no tolerance
- RT/coordination ~ 1 week
- total sleep time ~ 70 days
acute tolerance - benzodiazepines
- can develop during single administration
- behaviour and motor-imparing effects
chronic tolerance - benzodiazepines
- depressant effects develop tolerance 1st
- locomotor, ataxic, muscle relaxant & anticonvulsant effects
- anti-anxiety: variable in humans
- drowsiness
- sleep: after ~ 4wks
- short-acting drugs avoid residual effects but progess to tolerance quicker
- REM suppression does not develop tolerance
cross-tolerance - barbituates
- cross tolerant with each other, alcohol & BDZs
- considerable cross-tolerance with other depressants
- cross-tolerance with metabolizing enzymes induce by BBTs
cross-tolerance - benzodiazepines
- other depressant drugs
- alcohol & BBTs
BBT withdrawal
low doses - REM rebound
high doses - can precipitate medical emergency
- symptoms commence 12-24 hrs (or 48-72 hrs for long acting) after final dose and may last up to 2 wks
symptoms of BBT withdrawal
- tremors
- anxiety
- insomnia
- nausea
- delirium
- seizures - death
- hallucinations
- disorientation
- confusion
- fear
- agitation
- REM rebound
most symptoms gone in 2 wks similar to high-dose BDZ withdrawal
2 types of BDZ withdrawal
- sedative-hypnotic withdrawal
- low-dose withdrawal
Sedative-hypnotic withdrawal
- occur with high doses > ~ 1month
- usually seen in benzodiazepines with short half-lives
- usually gone <10 days
- sensitive to resuming treatment
- notable symptoms: tremors, cramps, delirium, convulsions
low-dose withdrawal
- occur when low doses taken for extended periods (>6mnths)
- duration 2 weeks or up to a year
- usually come in waves
- sensitive to resuming treatment
- notable symptoms: anxiety, panic, irregular HB, decreased memory and concentration, increased BP, sensory sensitivity, distortion of reality
BBT self-administration in animals
- reinforcing properties using various reinforcement schedules
- reinforcement properties of short vs long-acting barbituates
- monkeys increase consumption until stable, then constant level of admin
BDZ self-administration in animals
- IV and oral
- short & long acting
- not as reinforcing as BBTs
- reinforcing properties can be enhanced by priming with the drug, BBTs or other BDZs
- longer acting BDZs, past use determines how reinforcing they are
BBT experimental self-administration in humans
- not chosen more often than placebo in lab studies
- reinforcing for those with a history of use
BBT non-experimental self-administration in humans
- street use
- usually in high-dose binges combined with other drugs
- injected with heroin or amphetamines - Iatrogenic use
- initially prescribed for variety of symptoms
- reinforcing properties lead to abuse & doctor shopping
BDZ experimental self-administration in humans
not chosen more often than placebo in lab studies even by those with high anxiety
BDZ non-experimental self-administration in humans
- street use
- usually combined with another drug (alcohol/methadone)
- rohypnol - Iatrogenic use
- prescribed for anxiety
BBTs effects on reproduction
- baby goes through withdrawal when born - onset 7 days
- birth defects
- cleft lip & palate
- abnormalities of heart, skeleton & CNS
- brain weight
- neurological development
- decreased later male sexual behaviour (decreased testosterone)
- learning disabilities, decreased IQ and psychosocial problems
BBTs overdose
- low TI
- additive effect with alcohol - BAL .1 + .5mg secobarbital = lethal
- poisoning causes unconsciousness, decrease HR & BP, blisters, decreased urine flow, decrease temperature regulation, respiratory depression
BDZs on reproduction
- suggestion that BDZ cause birth defects (fetal benzodiazepine syndrome similar to FAS)
- withdrawal in infants similar to opiate withdrawal, start <2.5-6hrs after delivery
- floppy baby syndrome after BDZ delivery process
BDZ overdose
- not as dangerous as BBT OD; seldom fatal on its own
- sleep/drowsiness, no coma or severe respiratory depression
- intensify depressant effects of alcohol and BBTs - combo of these in OD usually fatal
- can be treated with BDZ receptor antagonist
BDZ use as anxiolytic or s-h
- symptomatic
- underlying cause of anxiety/insomnia remains untreated
- rebound insomnia/ rebound anxiety
BDZ on sleep
disruption to sleep architecture may have harmful effects (re chronic REM sleep deprivation)
BDZ over sedation
2 mechanisms
1. risk increase with BDZ with active metabolite (when used for anxiolytic or s-h purposes)
2. when use is combined with additional CNS depressants
BDZ on memory
- appears to impair memory
- nature of impairment: intentional retrieval; explicit memory
- significant drug related impairtment on average 82% of the times tested
BDZ effects on older people
- older people sensitive to CNS depressant effects
- may cause confusion, amnesia, ataxia & pseudodementia
- recommendations to minimise harm ( 1/2 regular adult dose, short term use, use without active metabolites)
BDZ dependency
- dependency leads to chronic use
- withdrawal should be done under medical supervision to avoid convulsions, respiratory failure
- involves gradual reduction of dose over 8-12 weeks
- alternative coping strategies are essential
- longer term management may be needed to avoid relapse
