Pharmacology 11b – Alcohol
Anil Chopra
1.
Describe the dose-dependent effects of acute ethanol ingestion on
(a) CNS function and put forward theories to explain the underlying
mechanism of action
(b) Other body systems
2.
Describe the consequences of long-term excessive ethanol consumption
3.
Outline the main pharmacokinetic features of ethanol
4.
Explain how tolerance to the effects of ethanol is produced. What symptoms
are associated with alcohol withdrawal in dependent subjects
Alcohol
 Alcohol = ethanol (C2H5OH
 1 unit = 8g or 10ml
 %ABV x 0.78 = g alcohol/100ml
 Units = %ABV x volume (ml) / 1000
 Recommended maximums – Men = 21 units, Women = 14 units a week
 Responsible for 1/3 of all A&E admissions – costs £3bn a year
Alcohol Related Injuries
 28,000 hospital admissions/year
 33,000 deaths/year
 Cost to NHS; £3bn/year
 1/3 of all A&E attendances
Dosing
In order to calculate the amount of alcohol drunk, you multiply the alcohol by volume
by 0.78.
ABV x 0.78 = g alcohol/100ml
Therefore 1 unit is 10ml or 8g of absolute ethanol.
The supposed “safe level” is:
- Men  21 units/week
- Women  14 units/week
20-40mg/ml (Minimal effects)
Up to 50mg/ml
Up to 80mg/ml (Legal driving limit)
Up to 150mg/ml (90% - gross intoxication)
300mg/ml (Coma)
4-500mg/ml (Death)
 Likelihood of
car accident


x4
x 25
Alcohol is absorbed in the stomach (20%) and in the duodenum (80%).
First pass metabolism occurs in the liver (90%) and in the GI tract (10%):
Alcohol
(alcohol dehydrogenase)
(mixed function oxidase)
acetoaldehyde
Females have 50% less alcohol dehydrogenase in their stomachs as well as less
circulating water.
Second pass metabolism occurs entirely in the liver:
Acetoaldehyde
(aldehyde dehydrogenase)
Acetic Acid
Effects of Alcohol
Ethanol itself has a low pharmacological potency. Effects generally start occurring at
40-100mg/100ml – 10-20x this can be lethal. Longer chain alcohols are more lipid
soluble and so would be more potent but are not in drinks as do not dissolve in water.
Central Nervous System
Its acute effects are as a CNS depressant. Its initial stimulatory effect results from
depression of the INHIBITORY control pathways. The excitability may depend on
the patients personality or the setting which they are in. It does this by:
- increasing amounts of pre and post synaptic allopregnenolone (which has
inhibitory effects on neurones),
- decreasing allosteric modulation of NMDA receptors (NMDA acts like
glutamate)
- decreasing Ca2+ release
- enhancement of GABA-mediated inhibition.
Some areas of the brain are more sensitive than others:
 Cortical regions – impairs sensory function (mood changes, memory loss, loss of
co-ordination. Euphoria, increased self confidence) and impairs motor function
(slurred speech, prolonged reaction time, loss of co-ordination)
 Corpus callosum – passes info from left (rules, logic) to right (impulse, feelings)
and vice versa
 Hippocampus – role in memory
 Hypothalamus – controls appetite, temperature, emotions and pain sensation
 Cerebellum – movement and co-ordination
 Basal ganglia – time perception
 Reticular activating system - conciousness
It induces euphoria mainly via its effects on the ventral tegmental area.
Also leads to
- memory loss
- mood changes
- reduced powers of discrimination and concnentration
Cardiovascular System
It can cause cutaneous (near the skin) dilation of blood vessels by decreasing Ca2+
entry into smooth muscle cells and increasing the production of prostaglandins.
It has been proven that in moderate drinkers, it is shown to have positive effect on
HDL cholesterol and a reduction in mortality from heart disease and thrombosis due
to its effects on reducing platelet aggregation and tPA (tissue plasminogen activator)
levels.
Chronic effects:
» Atrial arrhythmias:
o Prolongation of conductance times and increase in refractory period
o Acute negative inotropic effects mediated by direct interaction with cardiac
muscle cells
» Alcoholic cardiomyopathy:
o Myocyte and nuclear hypertrophy, interstitial necrosis and myocyte necrosis
Motor Function
- Slurred speech
- Prolonged reaction delay
- Loss of co-ordination
Endocrine System
Its acute effects are diuresis (polyuria) caused by reduced vasopressin secretion. In
chronic use however it can lead to increase ACTH secretion (therefore increases in
cortisol), as well as decreases in testosterone production (can lead to feminisation).
Gastro-Intestinal Tract
Chronic use is shown to cause damage to gastric mucosa and increase the risk cancer
development.
Acute:
 Increased salivary and gastric acid secretions:
 Taste increase salivary production
 Irritant effect → histamine release → increases gastric acid (may also be due to
fermentation products)
 Also due to stimulation of sensory nerve endings
Chronic:
 Direct damage to gastric mucosa – directly related to dose → increased risk of
peptic ulcers
 Increased gastric bleeding – gastrititis
Effects on lipid metabolism/platelet formation:
 In small doses – reduced thrombosis formation → reduced risk of
atherosclerosis/ischaemic heart disease
 MOA: Increased HDL → increased cholesterol esterification → reduced plaque
formation → reduced thromboxane A2 → reduced platelet aggregation
Effect on Foetal Development
 Foetal alcohol syndrome – if mother drinks at least 4 units/day
 Abnormal facial development (and other anatomical abnormalities)
 Growth retardation
 Mental retardation
 Caused by inhibition of cell division and migration
Liver
Alcohol has few acute effects on the liver, however its chronic use can lead to fatty
liver. In order to metabolise alcohol, its is first oxidised to acetaldehyde, which results
in the production of NADH. The excess NADH can have a number of fates. It can be
used to in lipogenesis, this results in more triglycerides in liver cells. It can also be
used in the electron transport chain to produce ATP from ADP. This therefore means
that the Krebs cycle has to slow down and therefore other fats and glucose cannot be
metabolised. It can also be used in the conversion of lactic acid to pyruvic acid.
This results in fat vesicles accumulating in liver cells which results in fatty liver. The
acetaldehyde produced can also leak into the blood and cause a decrease in normal
metabolism.
The free radicals produced can also lead to an increase in the production of certain
cytokines (IL-6 and TNFα) and ultimately liver inflammation – hepatitis.
The increase in activation of fibroblasts and decrease in hepatocyte regeration can
also cause liver cirrhosis, characterised by the replacement of liver tissue with scar
tissue.
Pharmacokinetics
 Uncharged and so highly lipid soluble
 Rapidly absorbed through the mucus membranes of the stomach and gut (slowed by
food)
 Rapidly distributed throughout body tissues – dependant on tissue blood flow
 Substantial amounts removed in first pass metabolism
 Demonstrates saturation kinetics – rapid absorption → high portal vein
concentration → liver enzyme saturation → escape into systemic circulation
 90% metabolised in body (mainly by liver) 5-10 % is excreted unchanged in the
urine (variable) and expired by the lungs (constant – 80mg/ml in blood =
35µg/100ml of expired air – hence breathalysers
Metabolism of ethanol
Ethanol is 90% metabolised in the body – mainly liver
LIVER
Ethanol
C2H5OH
(NAD+)
75%
Alcohol
Dehydrogenase
(NADH)
(NAD+)
75%
(NAD+)
25%
Mixed function
oxidase
Acetaldehyde
CH3CHO
Aldehyde
Dehydrogenase
Induction
(NADH)
25%
Aldehyde
Oxidase
(+ O2)
EXTRA-HEPATIC
(NADH)
Acetic acid
CH3COOH
1. Disulfiram (aversion therapy)
2. Genetic variant (50% asians)
 Mixed function oxidase can be increased/induced by exposure to alcohol and other
compounds
 NAD+ is needed as a co-factor for all reactions
 Disulfiram inhibits aldehyde dehydrogenase → high levels of acetaldehyde →
flushing, tachycardia, hyperventilation, panic/distress. Used in aversion therapy for
recovering alcoholics – no effect without alcohol
 50% of Asians do not have aldehyde dehydrogenas → therefore alcohol intolerant
 Also rare variation in alcohol dehydrogenase → increased alcoholism risk
 Tolerance to the effects of alcohol occurs within 1-3 weeks of continuous
administration
 Due to:
o Pharmacokinetic tolerance
o Tissue tolerance
o Cellular adaptation
 Dependence = overpowering craving for alcohol
 Physical withdrawal from dependence is characterised by:
o Tremor
o Hallucinations
o Convulsions
o Behaviour disturbances
o Nausea
o Fever
The Hangover
The symptoms peak as blood alcohol level tends toward 0:
 Nausea: caused by vagus stimulation to the vomiting centre.
 Headache: caused by vasodilation
 Fatigue: caused by sleep deprivation
 Tremors: “rebound” – increased glutamate production by neurones to compensate
for its inhibition by the alcohol.
 Polyuria: caused by decreased vasopressin secretion.