P&T 14: Alcohol

ALCOHOL: DOSING ABV: alcohol by volume Absolute amount = % ABV 0.78 [g of alcohol/100 ml] Units = % ABV volume [ml] 1000 1 unit = 10 ml or 8 g of absolute alcohol There is very little consistency

Recommended maximums: Men: Low risk: <4 units at least 1/7 days High risk: <8 units at least 1/7 days Low risk: <3 units at least 1/7 days High risk: <6 units at least 1/7 days

Women:

Blood levels: The depressant effect of alcohol is dose-related: it increases exponentially as dose increases
Blood levels 20-40 mg/ml Up to 80 mg/ml Up to 150 mg/ml 300 mg/ml 400-500 mg/ml Effect Minimal effects Legal driving limit Gross intoxication (for 90% of people) Coma Death

ALCOHOL: PHARMACOKINETICS Uncharged; highly lipophilic Rapidly absorbed from the mucous membranes of the stomach and gut (food slows this) Rapidly distributed throughout the body water (its distribution depends on blood flow to individual tissues) A significant proportion is removed from portal vein blood to due first pass hepatic metabolism Demonstrates saturation kinetics: rapid absorption high concentration in portal vein blood saturation of liver enzymes escapes into the systemic circulation 90% is metabolised in the body (mainly in the liver) 5-10% is excreted unchanged in the urine and in expired air (this is the basis of breathalysers)

Alcohol: absorption Stomach (80%) Small intestine (20%) Speed of onset is proportional to gastric emptying Food slows gastric emptying; therefore if you drink on a full stomach, alcohol remains in the stomach 90% metabolised o o Hepatic metabolism (85%) GI tract metabolism (15%)

Alcohol: metabolism

10% exhaled (excreted unchanged by the lungs)

Hepatic metabolism: alcohol acetaldehyde Alcohol dehydrogenase (75%) Mixed function oxidase (25%): induced by chronic drinking; therefore tolerance develops Acetaldehyde: toxic metabolite Bolus dose: liver enzymes become saturated and alcohol enters the systemic circulation Several smaller doses: give the liver time to metabolise alcohol

Alcohol undergoes extensive first pass hepatic metabolism:

GI tract metabolism: alcohol acetaldehyde Alcohol dehydrogenase: present in the stomach lining Females are less tolerant to alcohol since they have less alcohol dehydrogenase in their stomach lining (and hence less capacity to metabolise alcohol)

Females vs. males: The effects of alcohol are more pronounced in females

Females have less body water than males; therefore they dilute alcohol to a lesser extent Females (50%); males (59%) They have less alcohol dehydrogenase in their stomach lining They have less body water by weight

Blood levels of alcohol are higher in females since:

Hepatic and GI metabolism: Acetaldehyde acetic acid Aldehyde dehydrogenase Acetaldehyde is the 1st metabolite of alcohol metabolism Acetic acid is non-toxic Disulfiram: inhibits aldehyde dehydrogenase; therefore acetaldehyde builds up o Used as aversion therapy in alcoholics; very effective in alcoholics who are motivated to quit

Aldehyde dehydrogenase is affected by:

Genetic polymorphism: found in Asian populations; impairs alcohol metabolism

ALCOHOL: PHARMACODYNAMICS Alcohol has low pharmacological potency (i.e. vast amounts are required for its effects to be seen) The CNS is functionally complex Alcohol has low potency and hence low selectivity Alcohol does not have a drug target due to its simple structure (it binds to everything) Effects generally occur between 40-100 mg/100 ml Nicotine: 20 ng/ml Cocaine: 200 ng/ml Alcohol: 200 g/ml

Doses at which effects are seen:

Alcohol: acute CNS effects Depressant effect: Alcohol is classed as a depressant (the initial stimulatory effect results from depression of inhibitory control pathways) CNS agitation may occur (due to disinhibition) The degree of CNS excitability depends on environment (social/non-social setting) and personality Enhances GABA mediated inhibition sedative/anxiolytic effects Presynaptic and postsynaptic neurons: binds to GABA receptors Cl influx hyperpolarisation

Alcohol affects many systems:

Increases allopregnenolone production Blocks NMDA receptors reduced firing memory loss Blocks voltage sensitive Ca2+ channels reduced neurotransmitter release Alcohol is associated with euphoria Enhances GABA firing inhibition of dopamine release Reduces NMDA firing inhibition of dopamine release Mechanism of action of euphoria is unknown

Euphoria:

Cortical region: highly sensitive to alcohol Alcohol impairs: Sensory function Motor function Mood changes, e.g. increased self confidence; euphoria Memory loss Reduced powers of discrimination and concentration Slurred speech Prolonged reaction time Loss of coordination Corpus callosum: passes info from the left brain (rules, logic) to the right brain (impulses, feelings) & v.v. Hypothalamus: controls appetite, emotions, temperature and pain sensation Reticular Activating System: controls consciousness Hippocampus: important in memory Cerebellum: important in movement and coordination Basal ganglia: play a role in time perception

Impaired sensory function:

Impaired motor function:

Brain regions: alcohol influences various anatomical structures

Certain brain regions appear to be more sensitive to alcohol The cortical region and reticular activating systems are the most sensitive regions: Cortical damage sensory/motor impairment Damage to the Reticular Activating System sensory impairment/loss of consciousness

The CNS is functionally more complex than any other system in the body; therefore the relationship between the behaviour of individual cells and the organ as a whole is often unclear 150 mg/100 ml gross intoxication 300 mg/100 ml coma (probably via the Reticular Activating System)

400-500 mg/100 ml respiratory failure & death (due to depression of central respiratory centres)

Alcohol: acute CVS effects Cutaneous vasodilation flushing: Flushing causes a warm feeling (despite increased heat loss) Flushing occurs due to: o o Decreased Ca2+ entry Increase in prostaglandins

Baroreceptor activation stimulates parasympathetic outflow and inhibits sympathetic outflow to the heart When BP increases, baroreceptor firing increases parasympathetic activation Alcohol increases heart rate

Alcohol: acute endocrine effects Diuresis (polyuria): Alcohol inhibits vasopressin secretion diuresis dehydration Mechanism of action: decreased K+ entry into the posterior pituitary May be mediated by alcohol/acetaldehyde

Alcohol: chronic CNS effects CNS changes occur due to chronic alcohol intake: Dementia: due to cortical atrophy; reduced volume of cerebral white matter Ataxia: due to degeneration of the cerebellar cortex Wernicke-Korsakoff syndrome: due to thiamine deficiency/alcohol intake Wernickes encephalopathy: due to degeneration around the 3 rd ventricle and aqueduct Korsakoffs psychosis: due to changes in the dorsomedial thalamus

Peripheral neuropathy Myopathy Direct effects of ethanol or its metabolites, e.g. acetaldehyde or fatty acid esters Thiamine deficiency due to malnutrition Caused by excessive alcohol consumption Fatty liver hepatitis cirrhosis Increased release of fatty acids from adipose tissue (due to increased sympathetic discharge) Impaired fatty acid oxidation (due to the metabolic load imposed by alcohol) Chronic malnutrition is also a contributory factor Glycerol + fatty acids (in the blood) triacylglycerol (in the liver) Blood and changes in hepatic cytokines (e.g. increase in IL-6 and TNF- ) Free radicals Fibroblasts form a supportive framework Reduced regeneration of hepatocytes Increase in fibroblasts Reduction in active liver tissue

Causes:

Alcohol: chronic effects on the liver

Causes:

Fatty liver: increased fat accumulation in the liver Hepatitis: liver inflammation

Cirrhosis: irreversible hepatic necrosis/fibrosis

Alcohol: chronic CVS effects Beneficial effects: Decreased mortality from coronary artery disease (in men who consume 2-4 units/day) Increase in HDLs Increase in tPA levels; decrease in platelet aggregation

Polyphenols??? Acute GI effects: Increased salivary and gastric acid secretions Psychic: the taste of alcohol increase salivary production Irritant effects increased histamine release increased HCl secretion Stimulation of sensory nerve endings Damage to the gastric mucosa gastric/duodenal ulcers Causes:

Chronic GI effects:

Carcinogenic Increased ACTH secretion adrenal steroid production Cause: direct action at the anterior pituitary Reduced plasma testosterone levels feminisation in males Causes: o o Impaired testicular steroid synthesis Enhanced testosterone inactivation by hepatic enzymes

Chronic endocrine effects:

Effects on lipid metabolism/platelet formation: Effect of small doses of alcohol: Reduced thrombosis formation reduced risk of atherosclerosis/ischaemic heart disease

Cause: increased HDL increased cholesterol esterification decreased plaque formation decreased thromboxane A2 decreased platelet aggregation Effects on foetal development: Foetal alcohol syndrome (in mothers who consume at least 4 units/day) Abnormal facial development (and other anatomical abnormalities) Growth retardation Mental retardation Small degrees of ethanol-related abnormality may occur very frequently

Cause: inhibition of cell division/migration Hangover: Symptoms peak as blood alcohol concentrations 0 Nausea: irritation stimulation of the vagus nerve activation of the vomiting centre Headache: due to vasodilation Fatigue: due to sleep deprivation and rebound Restlessness and muscle tremors: due to rebound Polyuria and polydipsia: due to decreased vasopressin secretion

Disulfiram (aversion therapy): Inhibits aldehyde dehydrogenase acetaldehyde accumulation High acetaldehyde levels flushing, tachycardia, hyperventilation, panic/distress Useful in discouraging recovering alcoholics from drinking (no effect without alcohol) Common variation in aldehyde dehydrogenase alcohol intolerance Rarer variation in alcohol dehydrogenase increased risk of alcoholism

Genetic polymorphisms (within the Asian population):

ALCOHOL: TOLERANCE AND DEPENDENCE Tolerance: Tolerance to the effects of alcohol occurs rapidly (within 1-3 weeks of continuous administration) Causes of alcohol tolerance: Pharmacokinetic tolerance Tissue tolerance Cellular adaptation

Dependence: Dependence: overpowering craving for alcohol Physical withdrawal is characterised by: Tremor Hallucinations Convulsions Behavioural disturbances Nausea Fever