Alcohol Flashcards
(171 cards)
1
Q
Colloquially alcohol refers to
A
ethyl
alcohol or ethanol
(EtOH)
2
Q
alcohol and quantity
A
Relative to other drugs, very large quantities of alcohol are
required to elicit effects
3
Q
EtOH administered by
A
oral dose has high bioavailability
4
Q
Almost exclusively administered as
A
dilute aqueous
solutions
5
Q
Neutral grain spirits (vodka) are almost pure
A
EtOH in
water
6
Q
Alcohol has high
A
caloric content but little nutritive value
7
Q
Alcohol is amphipathic
A
(polar and non-polar
character) and can readily diffuse through cell
membranes
8
Q
Absorbed readily in the
A
GI
9
Q
10% is absorbed in the
A
stomach
10
Q
90% is absorbed in the
A
small intestine
11
Q
Transport by
A
passive diffusion
12
Q
Relative concentrations drive rate
A
of uptake
13
Q
Higher concentration of alcohol is
A
absorbed faster
14
Q
Rate of passage to the small intestine affects
A
s rate
of uptake
15
Q
Food in stomach
A
slows passage to intestine –
slower uptake
16
Q
Carbonation (e.g. champagne)
A
) accelerates passage
– faster uptake
17
Q
Alcohol dehydrogenase (ADH) is
A
secreted in
gastric fluids
18
Q
Alcohol dehydrogenase (ADH) is secreted in gastric fluids (3)
A
- Can break down EtOH in GI, preventing uptake
- Sex difference (60% more ADH activity in males)
- Gastric ADH is inhibited by aspirin
19
Q
- EtOH readily diffuses into all
A
aqueous fluids/tissues via passive diffusion
20
Q
Easy access through
A
BBB and placental barrier
21
Q
Excluded from
A
fat tissues
22
Q
Sex bias
A
– females tend to have higher %
body fat
23
Q
Age bias
A
as males age % body fat increases
24
Q
more fatty tissues means
A
higher blood
concentration
25
Metabolism - 2 key enzymes
Liver metabolism of alcohol depends
on the key enzymes alcohol
dehydrogenase and aldehyde
dehydrogenase
26
Metabolism occurs via
zero-order
kinetics (fixed rate of metabolism)
27
ethanol metabolism
Ethanol --Alcohol dehydrogenase--> Acetaldehyde --- aldehyde dehydrogenase--> acetic acid --acyl-CoA synthase--> Acetyl-CoA -> Krebs cycle
28
Acetaldehyde
Toxic intermediate
29
Acetaldehyde Toxic intermediate
* Flushing reaction
* Nausea
* Headache
* Tachycardia
30
Most liver metabolism occurs through
ADH & ALDH
31
Some metabolism through
cytochrome P450 family enzymes (leads to drug
interactions)
32
Drug interactions caused by
competition for P450 → elevated drug concentration
33
Induction of P450 with chronic use →
decreased drug concentration
34
95% of ingested EtOH is metabolized by the
liver to CO2 and H2O (excreted
through kidneys)
35
5% of EtOH is excreted through the
e lungs – provides the basis for the
Breathalyzer test
36
Specific effects –
result of interactions with receptors
37
Specific effects – result of interactions with receptors
Cause most of the acute and chronic effects of intoxication
Responsible for most subjective effects of intoxication
38
Non-specific effects
result of interaction with
phospholipid membranes or bodily fluids
39
Non-specific effects – result of interaction with
phospholipid membranes or bodily fluids
EtOH interacts with cell membranes causing changes in
membrane protein function and cellular dysfunction
40
Ethanol interacts with the _____ receptor at the
GABA
receptor at the transmembrane surface of the delta-subunit
41
EtOH acts as a
positive allosteric
modulator of GABAA
42
* CNS effects
depressant and sedative effects of
EtOH moderated through GABA
43
EtOH can be _____ & ____ with benzos & barbituates
cross-tolerant and crossdependent with benzodiazepines and
barbiturates
44
At low doses EtOH antagonizes
NMDA
receptors
45
At low doses EtOH antagonizes NMDA
receptors
Decreases LTP
* Impairs learning and memory
46
NMDAR responsible for
amnesiac
effects of ethanol
47
EtOH reduces
glutamate release
48
EtOH reduces glutamate release
Measured by microdialysis
Esp. hippocampal glutamate release
49
Chronic effects on NMDA
With prolonged EtOH use NMDA
receptors increase
50
With prolonged EtOH use NMDA
receptors increase
* Adaptive response
* Increased in cortex and hippocampus of
animal models and human alcoholics
51
Glutamate release increases as a result
of
EtOH withdrawal
52
Glutamate release increases as a result
of EtOH withdrawal
Rebound hyperactivity
Can result in seizures as a consequence of
withdrawal
53
* Glutamatergic excitotoxicity leads to
permanent brain damage in alcoholics
54
Dopamine
EtOH increases the firing rate of VTA
dopamine projections into the nucleus
accumbens
55
Dramatic decrease in VTA firing on
withdrawal – may cause dysphoria of
withdrawal
56
* Positive modulator of
5HT3
receptors
57
Positive modulator of 5HT3
receptors
Seratonergic input to VTA
58
Positive modulator of NACh receptors
Cholinergic inputs to VTA
59
Opioid receptors
Acute administration of ethanol increases
endogenous opioid activity
60
Increases release of endorphins from
pituitary
61
impact on opioid receptors Likely contributes to
reinforcing effects in VTA →
NAc
62
Opioid antagonists reduce
EtOH selfconsumption in animal models
63
Chronic administration of ethanol reduces
opioid
expression
64
Contributes to the dysphoric effects of
withdrawal from
chronic alcohol use
65
At low doses alcohol is
s anxiolytic, mildly
euphoric, and calming / sedating.
66
With increasing dose significant cognitive
impairment occurs – inhibitions and caution are
decreased, judgement is impaired, and
impulsivity increases.
67
At high doses emotions are
exaggerated and
plastic – prone to outbursts and aggression,
pronounced motor and vision impairment,
unconsciousness, coma, and death
68
Physiological effects At low doses
Diuretic
Sedative and hypnotic
REM sleep both decreased for the first part of the night subsequently increased (second part of the night)
At higher doses – complete REM disruption
69
Vasodilation
Dilation of blood vessels in skin (flushed face, warm skin)
* Feeling of warmth – though increases heat loss (risk of hypothermia)
* Increased cerebral blood flow may lead to decreased risk of dementia
70
Balance and coordination
Alcohol intoxication has pronounced motor
effects (coordination) and disturbs balance
71
Non-specific effects on vestibular system
Ethanol thins the fluid in the inner ear
* Fluid moves more rapidly leading to
overcompensation
72
Balance easily tested by
Romberg sway test
73
The effects of alcohol are greatly diminished with
repeated administration
74
Cross-tolerance also develops with other sedative-hypnotic
drugs, particularly
benzodiazepines and barbiturates
75
Tolerance develops by several
mechanisms
depending on the patterns of use
76
Acute tolerance
Tolerance to the subjective effects of
alcohol develop within a single
administration session.
77
Effects associated with intoxication –
euphoria, anxiolysis, and mild
stimulation occur when blood alcohol
levels are rising.
78
At plateau or falling doses effects
include
sedation, anger, depression
79
Metabolic tolerance
– induction of liver
enzymes (ADH and P450) increases the
rate of alcohol metabolism
80
* Metabolic tolerance can be demonstrated
in
short daily doses (e.g. 7 day dosing in
humans)
81
Pharmacodynamic tolerance
Adaptive changes in CNS function in response to chronic alcohol consumption
82
Pharmacodynamic tolerance Contributes to the effects of
alcohol withdrawal
83
Pharmacodynamic tolerance (increased)
Increased NMDA receptor function,
increased glutamate release
84
Pharmacodynamic tolerance (decreased)
* Decreased GABA receptor function
* Decreased synthesis and release of opioids
* Decreased firing of mesolimbic dopamine neurons
85
Behavioural tolerance
Environmental cues induce compensatory
physiological changes
Tolerance diminished in novel environment
86
Behavioural tolerance May play a strong role in
craving
87
Behavioural changes:
Practicing behaviours under the influence of
alcohol leads to improved performance
88
High-functioning alcoholic
Practicing behaviours under the influence of
alcohol leads to improved performance
89
Tolerance develops
rapidly in animals and humans
90
tolerance Reaches maximum
within a few weeks
91
tolerance is
Reversible
92
Reversible
– tolerance diminishes after 2-3 weeks of
abstinence
93
Repeated exposure leads to more
rapid development of
tolerance
94
Physical dependence
Prolonged intoxication can result in adaptive changes
95
Prolonged intoxication can result in adaptive changes
* Mechanisms of tolerance esp. pharmacodynamics
* Restoration of homeostasis in presence of drug
96
Physical dependence Can be readily demonstrated by the
development of
symptoms of abstinence syndrome (withdrawal)
97
Withdrawal symptoms begin as early as
a few hours after last
dose and severity depends on the duration and dose
98
Acute withdrawal
Symptoms of hangover
99
Symptoms of hangover
Nausea
* Headache
* Dehydration, dry mouth
* Fatigue
* General malaise
100
Hangover is often described as an
early
component of withdrawal
101
Hangover is often described as an early
component of withdrawal may result from
m acute tolerance rather than
dependence
102
hangover Alternately considered to be signs of
acute
toxicity from alcohol and metabolites
103
Contributors to hangover
Toxicity:
Dehydration:
Alcohol-induced gastric irritation
Rebound effects on blood sugar
Congeners
104
Toxicity and hangovers
Accumulation of acetaldehyde can have acutely
toxic effects
* Acute effects include nausea, vomiting, and
headache
105
disulfuram
toxicity induced demonstrated by use of ALDH inhibitor
106
Dehydration
Dry mouth and headache
107
Alcohol-induced gastric irritation
Dry-mouth, nausea, and diarrhea
108
* Rebound effects on blood sugar
Hypoglycemia, faintness, fatigue and malaise
109
Congeners
* Ingredients or fermentation byproducts that
exacerbate condition
Red wine – tannins, sulfates
* Distilled spirits – methanol
110
methanol metabolism
Methanol -- alcohol dehydrogenase -> formaldehyde --Aldehyde dehydrogenase ---> formic acid
111
formic acid
Toxic end-product of methanol metabolism
112
Formic acid inhibits
cytochrome C oxidase
113
formic acid causes
cellular hypoxia Blindness, coma, death
114
Withdrawal from chronic alcohol use has an
early and late
component
115
Early component alcohol withdrawal
Agitation, tremors, muscle cramps, vomiting, nausea, sweating, vivid
dreams (rebound effects on REM), irregular heartbeat
Less severe component of alcohol withdrawal
116
Fewer than 5% of patients hospitalized for alcohol withdrawal go on to
develop the late stage of withdrawal
117
Rebound effects
GABAA RECEPTOR
1. Alcohol enhances
2. GABAA function
receptor function decreases due to
pharmacodynamic tolerance
118
GABAA RECEPTOR Rebound effects lead to development of
hyperexcitability
119
hyperexcitability GABA
* Tremors
* Seizures
120
Rebound effects NMDA RECEPTOR
1. Alcohol inhibits NMDAR function
2. NMDA receptor function and glutamate release `increase with prolonged intoxication
121
NMDA RECEPTOR Rebound effects lead to
hyperexcitability
122
hyperexcitability NMDA receptor
* Seizures
* Glutamatergic excitotoxicity
* Hallucinations
123
Late withdrawal
Delirium tremens (DT)
124
Delirium tremens (DT)
Onset ~48 hours after last dose, may last
7-10 days
* Tremors and seizures
Vivid hallucinatory episodes
125
Delirium tremens (DT) - Vivid hallucinatory episodes
* Often terrifying
* Altered sensorium
* Paranoid and nihilistic delusions
126
Altered sensorium
lack of recognition of
real world
127
Paranoid and nihilistic delusions
sense of
doom
128
Management of DT involves
administration of
benzodiazepines –
effective due to cross tolerance at
GABAA
129
Severe risk with DTs - Excitotoxicity
Irreversible brain damage
Epileptogenesis
Seizures and coma
130
Epileptogenesis
kindling effect can
lead to prolonged risk of seizures
131
Severe risk with DTs Altered GABA homeostasis leads to
unopposed sympathetic activation
132
Altered GABA homeostasis leads to
unopposed sympathetic activation
‘Adrenergic storm’
* Tachycardia, hypertension
* Anxiety, panic attacks, agitation
* Fever, profuse sweating
* Cardiac arrhythmia, risk of stroke,
heart attack
133
Chronic alcohol consumption is a
huge financial, health, and social
burden
134
High comorbidities of alcohol abuse in psychiatric illness
* Depression
* Schizophrenia
* Bipolar disorder
* Developmental disorders – including FAS / FASD
135
Chronic heavy drinking can lead to
cognitive impairment (some
reversible) and peripheral health effects
136
Cognitive deficits occur with prolonged heavy drinking (6)
* Abstract problem solving
* Visuospatial abilities
* Verbal learning
* Perceptual motor skills
* Motor skills
* Memory
137
brain structure changes include
Decreased brain volume
Neuronal loss in cortex
Ventricular enlargement
138
Decreased brain volume especially in
white matter, hippocampus
139
Neuronal loss in cortex
superior frontal association cortex, hypothalamus, pons, thalamus, brainstem,
cerebellum
140
Brain damage mechanisms 3
NMDA-mediated excitotoxicity
Homocysteine accumulation
Neurotrophic factors
141
NMDA-mediated excitotoxicity and brain damage
Sensitization of neuronal cells due to compensatory upregulation of glutamate and NMDAR
142
Brain damage mechanisms Homocysteine accumulation
Neurotoxic amino acid due to low folates
143
Homocysteine is an
agonist at glutamate and glycine sites of NMDAR (exacerbates excitotoxicity)
144
Homocysteine levels are a marker for
severity of withdrawal
145
Brain damage mechanisms Neurotrophic factors
Reduced levels of brain-derived neurotrophic factor (BDNF) and altered receptor function
146
Acetaldehyde
General damage to protein function and DNA
147
Formation of aldehyde adducts correlates with
liver damage
148
Acetaldehyde also shown to cause increased
reinforcing effects
in the mesolimbic dopamine pathway
149
Acetaldehyde microinjection to VTA can demonstrate
self-administration in rats
150
Wernicke
-Korsakoff Syndrome - Alcoholism causes
B1-vitamin deficiency
151
Alcoholism causes
B1-vitamin deficiency
Poor diet and impaired absorption of B
1
(thiamine)
152
Thiamine required for
brain glucose metabolism
153
thiamine deficit causes
t causes cell death in mammillary bodies, thalamus,
periaqueductal grey
154
WKS presents as
confusion, disorientation, tremors, and
ataxia
155
Wernicke
-Korsakoff Syndrome Leads to significant
memory impairment
156
Wernicke
-Korsakoff Syndrome - recall for past events
intact
157
Wernicke
-Korsakoff Syndrome - Encoding is
inhibited
158
Wernicke
-Korsakoff Syndrome - inhibited encoding
repeatedly reading same page,
repeating same stories or asking same questions
159
Wernicke
-Korsakoff Syndrome - can be stopped with
thiamine supplement
but damage is irreversible
160
Liver toxicity is a well characterized effect of
chronic consumption
161
At lower levels alcohol leads to
fatty liver
162
Metabolism of alcohol decreases fat metabolism
leading to
reversible accumulation of fats
163
Prolonged use leads to
alcoholic hepatitis
164
alcoholic hepatitis
* Inflammation, fever, jaundice
* Potentially fatal
165
Liver injury leads to
scarring
166
Liver injury leads to scarring
* Liver cirrhosis
* Scar tissue reduces blood flow – secondary
damage due to ischemia
167
Fetal alcohol syndrome / fetal alcohol spectrum disorder results from
developmental
injury to the fetal brain
168
Alcohol effects on the developing fetus - cytotoxin
Pre- and post-natal growth disorders
169
Alcohol effects on the developing fetus - Teratogen
typical craniofacial changes and variable malformations
170
Alcohol effects on the developing fetus - Neurotoxin
structural changes to the CNS and multiple cerebral dysfunctions
171
Alcohol effects on the developing fetus - Behavioural
dramatic increase in risk of addictions
