PBSI 336 chapter 7: sedative-hypnotics

sedative hypnotics

depress the CNS and behavior and have anxiolytic properties

additive effects, cross- dependence and tolerance

sedative hypnotics show

alcohol, barbiturates, benzodiazepines

sedative hypnotics include

nonbenzodiazepines, methaqualone, GHB, opiates/opioids

other structurally unrelated drugs with similar effects to sedative hypnotics

too toxic to consume

any alcohol other than ethanol are

fermentation

alcohol is produced by

15%

yeast fermentation can only produce alcohol concentrations up to

spirits or hard liquor >15%

distillation produces

spread of distillation

incidence of alcohol abuse increased with

non-ionized molecule

alcohol is a small

10%

percent of alcohol absorbed in stomach

90%

percent of alcohol absorbed in small intestine

gastric emptying and absorption, more alcohol is degraded before being absorbed

presence of food in stomach slows

alcohol dehydrogenase in stomach and liver

most alcohol is broken down by

sweat tears urine and breath

about 10% of alcohol is eliminated without being metabolized via

affects blood levels of alcohol

60% more gastric in men

ADH individual variation

affects blood levels of acetaldehyde

50% of certain asian groups have reduced function

ALDH individual variation

zero order kinetics

cleared from blood at a constant rate

BAC of 0.2 - 0.3

quite drunk

BAC of 0.45

coma; lethal for 50% of population

respiratory centers in brainstem shut down

cause of death from alcohol

impaired reaction time

impaired judgement

increased aggression

alcohol greatly increases probability of car accidents due to

dilates blood vessels

feeling of warmth

increased blood circulation due to alcohol

increases urination and dehydration

alcohol inhibition of ADH

impairs REM sleep

alcohol modifies sleep patterns

makes blood less dense, changes density of cupula as compared to surrounding fluid; sensation of movement triggers vestibular ocular reflex

how alcohol affects the vestibular system

mini withdrawal

hangovers are partly a

can be fatal

withdrawals from alcohol

delirium tremens

seizures, hallucinations, tremors, autonomic disruption

benzodiazepines bc of cross dependence

alcohol withdrawals are treated using another sedative hypnotic

increased expression of alcohol dehydrogenase

induction of liver enzymes of cytochrome P450 family

metabolic tolerance

overdose

drunk driving

acute alcohol (short term health risks)

withdrawal can be fatal

alcoholism/addiction

effects on body and brain

• liver diseases, cancer, brain damage, dementia

fetal alcohol syndrome

chronic alcohol (long term health risks)

11.3%

percent of adults in the US who have had AUD

lifetime anxiety, early life stress, or increased novelty seeking

increased alcoholism risk in individuals with

3-7x greater risk of alcoholism

greater cortisol response to stress

greater ability for alcohol to decrease stress effects

family history of alcoholism

liver damage

brain damage (korsakoff syndrome)

increased cancer risk

chronic heavy alcohol use negative effects

alcohol readily crosses placenta

lower birth body and brain weight, craniofacial malformations, variety of neurological problems

fetal alcohol syndrome FAS

little alcohol, not to intoxication

most animals will drink only a

more alcohol or abstain from alcohol

selective breeding yields rodents that prefer

barbital 1903

veronal

phenobarbital 1912

luminal

anxiolytics, hypnotics, and anticonvulsants

originally, barbs were used as

benzodiazepines for anxiety and insomnia

barbs have significant addiction potential and overdose risk, they were replaced by

lipid solubility and metabolism

many barbs differ in speed of onset and duration of action due to

truth serums

barbiturates have been used as

anesthesia, sedation, epilepsy

barbs still used for

sleep induction, anxiety, alcohol withdrawal

barbs no longer used for

schedules II, III, IV

DEA classification of barbs

reduced REM sleep

reduced cognitive function

dangerous with alcohol

tolerance leads to dose escalation

dependence and withdrawal

barbs side effects

relief of anxiety, loss of inhibitions

barbs used recreationally because of

respiratory centers in brainstem shut down

barbiturate overdose mechanisms

anxiolytics, sedatives, anticonvulsants, treatment for alcohol withdrawal, and surgical sedation/amnesia

benzos are widely used as

redistribution to other sites

metabolic pathways

duration of action varies for different benzos due to

nonbenzodiazepines or Z drugs

similar benefits, side effects, and risks but different chemical structure from benzos

sleep disorders

nonbenzodiazepines most commonly used for

benzodiazepine binding site of GABA-A receptor

nonbenzodiazepines act at

less metabolic tolerance, lower dependence and abuse, higher therapeutic index; do not affect respiratory centers in brain

compared to barbs, benzos are associated with

rare, however, contribute to overdose when taken with other CNS depressants

lethal overdose of a benzodiazepine alone is

reversal agent: flumazenil

benzodiazepines are also safer because there is a

mild form of alcohol/barbs symptoms

emotional disturbances

benzos withdrawal

date rape

benzos other forms of abuse

drowsy and cause sleep driving

benzos sleep medications can leave people

anxiolytic, similar to humans

in animals, barbs and benzos are

GABA-A receptors (ionotropic)

sedative hypnotics enhance chloride influx through

binding sites on GABA-A receptor

barbs and benzos have unique

unknown but similar to barbs and benzos

• similar spectrum of behavioral effects

• similar increase in chloride currents

• cross tolerance and cross dependence

alcohols mechanism at GABA-A receptor is

quaalude

originally used as hypnotic, sedative, muscle relaxant

GHB binds to

GABA-B receptor and GHB receptor

abuse potential

GHB has a decreased use due to

alcohol with some mild stimulant like effects too

subjective effects of GHB mostly resemble

Xyrem for narcolepsy/cataplexy

current medical use for GHB

club drug and date-rape drug

GHB abuse

GHB receptor and GABA-B receptor

GHB acts as an agonist at two types of GPCRs

2 subunits

GABA-B receptor is a unique GPCR requiring

behavioral effects of GHB

GABA-B receptor (not GHB receptor) is primarily involved in

GABA-B receptor knockout mice

what mice don’t display typical behavior or physical responses to GHB

GABA

most important inhibitory neurotransmitter in the adult, vertebrate brain

throughout brain in high concentrations ( many neurons and nuclei)

where is GABA found

regulating excitation

GABA plays an important role in

formed from glutamate via enzyme glutamic acid decarboxylase

GABA synthesis

vesicular GABA transporter VGAT

GABA is packaged into vesicles via

GABA transporters GAT-1 GAT-2 GAT-3

after release, GABA is transported out of synapse via

enzyme GABA amino-transferase

metabolism/degradation of GABA in neurons and glia via

ionotropic

ligand gated Cl- channels

pentameric

GABA-A receptors characteristics

metabotropic

unlike most GPCRs, GABA-B receptors need two different subunits

used as the autoreceptor on GABA terminals

GABA-B receptor characteristics

5, 2 alpha, 2 beta, and a gama

how many subunits does GABA-A have

hyperpolarization (inhibition) and IPSPs

GABA binds to GABA-A receptor and increases Cl- conductance leading to

chloride influx through GABA-A receptors

all sedative-hypnotics enhance

GABA-A receptors and a different site than GABA

barbs and benzos act at different sites on

more frequently

benzos cause GABA-A channels to open

for longer duration

barbs cause GABA-A channels to stay open

benzo

GABA + diazepam

barb

GABA + phenobarbital

benzos need GABA

barbs do not need GABA

Benzos ___ need GABA to have any sort of effect

Barbs ___ need GABA to have any sort of effect

anxiolytic effects

benzo binding correlates with

inverse agonists

beta-carbolines are

positively

negatively

benzos ____ modulate GABA-A

beta-carbolines ____ modulate

psychedelic drug ayahuasca

beta-carbolines are found in

GABA-A receptors with different subunits

differentially involved in various behavioral effects of benzos