alcohol pt 1

types of alcohol

methyl alcohol

ethyl alcohol

isopropyl alcohol

proof

twice the percentage of alcohol

alcohol can cross

BBB

amount of alcohol to produce a measurable effect

0.04%

Alcohol readily crosses

cell membranes

why is drinking alcohol on an empty stomach danger

on an empty stomach, ingestion of an intoxicating dose does not reach even suboptimal intoxicating levels for at least 20 mins. it takes time to be absorbed so it lasts longer.

LD50

lethal dose for 50% of the population

0.31 to 0.45%

significant risk of coma and/or death due to suppressio of vital functions

absorption occur

from the GI tract (passive diffusion)

• 10 % from stomach

• 90% from small intestine

food slows down

absorption

carbonated alcoholic beverages

absorbed more rapidly

first pass metabolism of alcohol by stomach ADH, which is greater in males, may also contribute to the higher blood alcohol levels found in women

alcohol metabolism

95% is metabolized by the liver

5% metabolized by the stomach

ADH and ALDH

liver enzymes not in CYP450 family

ADH higher in stomach

pathway for alcohol

ALDH genes and asians

about 10% of Asians are homozygous for the inactive form of the ALDH gene

40% are heterozygous for inactive form

a marker for low risk of alcoholism

2 enzyme in alcohol metabolism

CYP2E1; aka: MEOS

• only is active after a person has consumed large

amounts of alcohol

• Can be induced>>>with repeated exposure system’s

capacity can more than double within 2 weeks—> metabolic tolerance

• metabolizes many other drugs too—> cross tolerance

Catalase

▪metabolizes only a small fraction of alcohol in the body

acute tolerance

occurs within a single exposure to alcohol

• Drug effects are

greater while the

blood level of alcohol

is increasing and

smaller while the

blood level is falling

• With high BAC they have a sober response

metabolic tolerance

increase in CYP450 liver

microsomal enzymes that

metabolize alcohol

pharmodynamic tolerance

neurons adapt to the continued presence of alcohol by making compensatory changes in cell functions

behavior tolerance

practicing behaviors while under the influence of alcohol allows adjustment and compensation, the idea of the functional alcoholic

withdrawal of alcohol

2-4 days

tremor (the

“shakes”), anxiety, high blood

pressure, rapid heart rate, sweating,

rapid breathing, nausea and vomiting

DT

DT

rare:

convulsions, hallucinations,

disorientation, panic attacks,

unstable blood pressure, etc.

rebound phenomena

CNS causes hyperexcitability because the body adjusts to alcohol removing it, the body goes into overexcitation.

withdrawal

motivates the user

to take the drug again

relief from withdrawal

negative-

reinforcement

• Leads to a continuous

loop of repeated

abstinence followed by

relapse

way to treat addiction to alcohol

because alcohol shows cross dependence with other drugs that are sedative hypnotic (barbiturates and BDZs) you can ease the symptoms.

thiamine defiency

critical for brain glucose metabolism

▪ Low levels>>> cell death

• ethanol interferes with thiamine uptake

in the GI tract

wernicke korsakoff syndrome

confusion and disorientation, tremors,

poor coordination, ataxia

▪ First stage: confusion/disorientation

▪ later stages: patient remembers the

remote past, nothing else

▪ a result of permanent damage to

thalamic nuclei and brain regions

involved with memory due to lack of

thiamine

▪ Animals fed thiamine deficient diets

have similar brain lesions and

deficits in learning and memory

loss in medial thalamus and mammillary bodies

wernicke-korsakoff syndrome treatment

thiamine treatment can stop the degeneration, cannot reverse it

important to neurodegnerative processes and loss of it causes cell death

alcohol induced brain damage

ventricle enlargement

frontal lobe cell loss- personality changes

hippocampal and MTL cell loss- contributes to memory dysfunction

cerebellar cell loss- associated with ataxia

cerebellum- impacts motor loss

systemic effects of alcohol

dilation of peripheral blood vessels: flushing and warmth

• body is losing heat

vasodilation in the brain may improve cognitive function in older adults

Note: the hypothetical beneficial effects are counteracted when consumption is greater

fatty liver

alcohol is metabolized first in the liver leaving the fat on storage

alcoholic cirrhosis

death of liver cells stimulates scar formation

blood vessels carrying ozygen are cut off

very long time to develop and rare

cause of liver cell damage

abnormal ER function may be a major contributor to liver cell damage following heavy and prolonged alcohol consumption

CYP2E1 located on the smooth ER is induced by chronic alcohol use

• enhanced metabolism causes the release of free radicals producing oxidatie stress that induces cellular injury

FAS

fetal alcohol syndrome

• alcohol easily goes through the placental barrier and the fetus quickly reaches the same BAC as the mom

• amount and pattern of alcohol ingestion and the developmental stage of the fetus when it is exposed are critical in determining the specific effects

  • alcohol from 4 to 9 weeks produces most serve effects

fas symptoms

low iq and developmental delays

low birthweight

neurological problems

distinctive craniofacial malformations

glutamate and alcohol (acute)

alcohol acts as

• ndma antagonist

• ampa antagonist

• mGluR autoreceptor agonist in the hippocampus

• impaired LTP= a mechanism for alcohol induced amnesia

glutamate and alcohol (chronic)

upregulation of NDMA receptors in response to reduced glutamate activity

• number of nmda receptors in the cortex and hippocampus is increased in alcoholics

• rebound increase in glutamate release during withdrawal

rebound hyperexcitability

animals receives intragastric ETOH every 6 hrs for 6 days

• glutamate was correlated with withdrawal score

• rapid increase of glutamate in straitum

• correlation of high glutamate and a high withdrawal score which explains CNS hyperexcitability and seizures

GABA and alcohol (acute)

binds to the GABA a receptors and opens cannel

• allows Cl- to enter the cell to hyperpolarize the membrae

• GABA a receptors that are highly sensitive to alcohol contains delta subunit along with alpha 4 or alpha 6 subunits

  • rats that had fewer delta and a4 or a6 subunits showed a lower preference for alcohol

  • delta KO mice show reduced preference

GABA and alcohol chronic

repeated exposure to ethanol reduces GABAa mediated Cl- flux

• more animals more sensitive to seizure inducing doses of the GABA antagonist

• A decrease in GABA function without a change in receptor number

dopamine and alcohol acute

increase DA transmission in the mesolimbic pathway

rats in operant chambers self admin alcohol directly into the VTA (gives a reinforcement effects)

DA independent mechanisms of reinforcement

DA antagonist in the NAC and 6OHDA destruction of DA nerve terminals in NAC reduce self admin of ETOH

• even with stopping DA, the animals still self adminster at the same place so there has to be something else

dopamine and alcohol chronic

withdrawal of alcohol after chronic use reduces the firing rate of mesolimbic neurons

decrease da release in the na

animals also show behavioral signs of withdrawal which are slightly delayed

dopamine and alcohol icss paradiagm

elevation of threshold for intracranial self stimulation, reinforcement is less rewarding than it was during alcohol use, reward system is damaged in withdrawal. much more current to produce an effects