A/Prof. Ken Rodgers School of Life Sciences
References
- Rang HP, Dale MM, Ritter JM & Flower RJ (2015) Pharmacology, 8th Edition, Churchill Livingstone, Sydney.
- Drug addiction, dependence and abuse – Chapter 49
- Therapeutic Guidelines: Psychotropic, Therapeutic Guidelines Ltd, Melbourne
- Roberts C, Robinson SP (2007) Alcohol concentration and carbonation of drinks: the effect on blood alcohol levels. J Forensic Legal Med 14:398-405
Alcohol…A Short History
Evidence From China
- Mixed fermented beverage of rice, honey, and fruit (hawthorn fruit and/or grape) was being produced 7,000 BC in China
- Preserved as liquids inside sealed bronze vessels of the Shang and Western Zhou Dynasties.
- These findings provide direct evidence for fermented beverages in ancient Chinese culture, which were of considerable social, religious, and medical significance
Fermented beverages of pre- and proto-historic China
PNAS. 2004,101(51): 17593–17598
Why?
“Alcohol is the anaesthesia by which we endure the operation of life.” George Bernard Shaw (1856-1950)
“Beer makes you feel the way you ought to feel without beer” Henry Lawson
“Beer, more than just a breakfast drink.” Homer Simpson
“Lechery, sir, it provokes, and unprovokes; it provokes the desire, but it taketh away the performance” aphrodisiac – from Macbeth
Ethanol (ethyl alcohol; CH3CH2OH)
- Fermentation is a metabolic process in which an organism converts a carbohydrate, such as starch or a sugar, into an alcohol or an acid
- Yeast perform fermentation to obtain energy by converting sugar into alcohol (and CO2)
- Maximum concentration = 12–14%, concentrations greater than 12% are toxic to yeast but higher alcohol concentrations are attained by distillation
Impact and co$t
Tobacco
56 %
Alcohol
27 %
Illicit Drugs
15 %
Alcohol + illicits
2 %
- Second only to tobacco as a cause of drug-related deaths (~3300 deaths and ~ 1 mil hospital bed days in Australia[1]).
- Total social cost of alcohol abuse was $15.3 billion in 2004/05[1]
- Over 80% of Australia population consumed alcohol last year (11% males and 6% females drink daily)
- State/Federal governments made $1.4 billion from alcohol (net revenue minus social/health costs)[1]
[1] Collins DJ, Lapsley HM (2008) The Costs of Tobacco, Alcohol and Illicit Drug Abuse to Australian Society in 2004/05
Effects of ethanol on the CNS
Effects of ethanol on the CNS 1
- Alcohol is a CNS depressant (not a stimulant!)
- Characteristic response: euphoria, impaired thought processes, decreased motor control
Effects of ethanol on the CNS 2
- Main effects of ethanol are on the brain
- It has depressant actions similar to the volatile general anaesthetics (ion channels)
- At a cellular level ethanol is a depressant – but neuronal activity can be increased! – this is due to disinhibition in some parts of the CNS
- activates the mesolimbic dopaminergic (reward) pathway.
- At a cellular level ethanol is a depressant – but neuronal activity can be increased! – this is due to disinhibition in some parts of the CNS
Effects of ethanol on the CNS 3
- Enhancement of the action of GABA on GABAA receptors (the major inhibitory neurotransmitter receptors in mammalian brain)
- GABAA receptors are ligand-gated ion channels selective for Cl− ions. Classical benzodiazepines like valium are positive allosteric modulators of the response to GABA.
- Ethanol enhances CNS inhibition (similar to benzodiazepines) but has smaller and less consistent effects than benzodiazepines (may only act at GABAA subtypes)
- Ethanol can also enhance GABA release
- Ethanol might have a similar effect on glycine receptor function (another inhibitory receptor)
Effects of ethanol on the CNS 4
- Other mechanisms of action
- Inhibition of transmitter release in response to nerve terminal depolarisation (blocks opening of voltage-gated Ca2+ channels)
- Inhibitory action at NMDA glutamate receptors
- blocks excitation
- Inhibition of adenosine uptake
- adenosine actions on A1 receptors in neurons cause depression
Effects on the CNS
ACUTE EFFECTS
- Euphoria, slurred speech, ataxia (unsteady gait), increased self-confidence, decreased mental acuity and physical coordination
- Thought and motor processes that are most dependent on training, judgement and previous experience are first affected
- Effect on mood varies – most are louder and outgoing some are morose and withdrawn
- Higher concentrations – unconsciousness, respiratory depression is usual cause of death
Stages of alcohol intoxication
* The number of standard drinks it would take a 60 kg woman, or a 80 kg man, to get this concentration of alcohol in her/his blood.
Number of Standard Drinks
1 unit = 10ml alcohol = 8g alcohol
Effects on the CNS: Driving
Effects on the CNS: Driving1
Effects on the CNS: Driving1
- Probability of being involved in road accident
- Little correlation up to 0.04%, 11 x increase in probability at 0.08%, 25 x increase at 0.16%
- NSW has determined 0.05% (g/100 ml of blood) as legal limit
- Male ~2 std drinks, females ~1 std drink per hour
Effects on the CNS: Driving 2
Table: BACs in males, 1 standard drink in 1 hour, assuming rapid absorption, BAC can be 20-30% higher for females
Effects on the CNS: Driving 3
ALCOHOL ALSO INTERACTS WITH THE FOLLOWING DRUGS TO IMPAIR DRIVING SKILLS:
- antihistamines
- antidepressants
- benzodiazepines
- opiates
- antipsychotics
- cannabis
- amphetamines
Effects on the CNS: Toxicity
Effects on the CNS: Toxicity
CHRONIC EFFECTS
- Irreversible neurological abnormalities
- Due to ethanol or metabolites such as acetaldehyde or FA esters
- Loss / damage to neurons and glia (seen in pathology)
- Tissue shrinkage, CSF increases (ventricles enlarge on CT / MRI)
- Lower glucose metabolism, reduced blood flow and neuronal viability
Effects on the CNS: Chronic Toxicity 2
CHRONIC EFFECTS OF HEAVY DRINKING
- Peripheral neuropathies
- Cerebellar degeneration
- Dementia
- Wernicke-Korsakoff’s syndrome (thiamine deficiency)
Other Effects of Alcohol
Effects on the cardiovascular system
- Vasodilatation due to central vasomotor depression
- sense of warmth but loss of body heat (drop in core temperature)
- Positive association between alcohol consumption and hypertension
- EtOH withdrawal increases sympathetic activity
- Myocardial problems
- major cause of cardiomyopathy in the Western world
- conduction defects and rhythm disturbances
- Negative association between chronic use of low amounts of alcohol (up to 2-3 drinks/day) and coronary heart disease
Effects on lipids, platelets and blood vessels
- Decreases atheroma formation
- EtOH ⇧[HDL] (protective) and ⇩[LDL]
- But <50% of lower risk for CHD can be explained by altered levels of these lipoproteins
- Decreases clotting
- ⇧ Production of endogenous tissue-type plasminogen activator (t-PA)
- Decreased production of arachidonic acid production by PLA2
- Decreases platelet aggregation
- However protective effect is offset by increased risk of haemorrhagic stroke
Is Alcohol’s Role Causal or Incidental?
“Alcohol is the cause of the lower risk for CHD in moderate drinkers”?
Prevalence of regular exercise is higher among moderate and heavy drinkers than nondrinkers
“Wine (particularly red) affords more CHD protection than beer or liquor”?
Drinkers who prefer wine tend to smoke and drink less and have a more healthy diet than those who prefer beer / liquor
Effects on the Liver 1 (high alcohol intake)
- Increased fat accumulation (fatty liver) due to ↑synthesis of lipids and ↓synthesis of lipoprotein
- Release of fatty acids from adipose tissue and impaired fatty acid oxidation (due to EtOH)
- Hepatitis (inflammation of the liver) due to choked off nutrient supply by enlarged cells
- Irreversible liver necrosis and fibrosis
- liver failure (50% chance of death in 4 yrs)
Effects on the Liver 2
- Direct cellular toxicity of EtOH metabolites most important, but malnutrition also contributes
- 300 g of EtOH (1 bottle of whisky) = 2000 kcal (8370 kJ) but no vitamins, AAs or FAs
- May lead to vitamin deficiencies eg thiamine deficiency – chronic neurological damage (Wernicke-Korsikoff Syndrome)
Beer Belly: Myth or Reality?
Effects on the Kidney and GIT
Kidney
- Acts as diuretic by ⇩ release of ADH from pituitary resulting in ⇩ reabsorption of water in renal tubules = diuresis
GI tract
- 15-20% incidence of mucosal irritation
- 30% alcoholics suffer from chronic gastritis, inflammation of pancreas / gall bladder
- Duodenal / oesophageal varices (dilated veins that bleed)
Foetal Alcohol Syndrome
- Foetal alcohol syndrome (FAS) due to placental transfer
- Frequency of 1:3 in alcoholic mothers
- Microcephaly, abnormal facial structure, growth deficiencies, cardiac defects, mental retardation, impaired immune system
- Risk when consumption is > 4 drinks/day or binge drinking
Pharmacokinetics: Absorption
Pharmacokinetics: Absorption 1
- Rapidly absorbed primarily from duodenum
- Peak levels reached in 30-90 minutes
- Peak blood alcohol conc. (BAC) depends on:
- Rate of drinking
- Gastric and hepatic first pass metabolism (minor – ca. 9%)
- Amount and alcohol concentration of beverage
- High concentrations irritate gastric mucosa, stimulating mucus secretion, and delaying gastric emptying – reduces absorption
- Increase in duration of contact between the alcohol and the gastric alcohol dehydrogenase (ADH) results in an increased gastric metabolism
- Carbonation of beverages
- Carbonation increases gastric emptying rate due to gas causing distension of stomach (more rapid absorption; eg. champagne)
Pharmacokinetics: Absorption 2
Pharmacokinetics: Absorption 3
- Peak blood alcohol conc. (BAC) depends on:
- Food consumption and composition (minimal effect)
- Food in the stomach lowers peak BAC by as much as 20–57%
Pharmacokinetics: Distribution
Pharmacokinetics: Distribution
Peak blood alcohol conc. (BAC) depends on:
- Gender
- Distributes into total body water not fat – Vd is 0.6 L/kg in females and 0.7 L/kg in males due to fat:water ratio differences between sexes
- Smaller volume (Vd) means higher peak BAC in females for the same dose
- Weight
- Bigger individual means lower peak BAC (mean weight of males is 80 kg vs. 60 kg for females)
- Obese individuals (eg. BMI >30) have lower Vd(eg 0.45 L/kg) and therefore higher BAC[1]
Pharmacokinetics: Metabolism
Pharmacokinetics: Metabolism 1
- Metabolism (90-95% metabolized in liver)
- Acute
- EtOH → acetaldehyde → acetic
acid - 1st step is oxidation by alcohol
dehydrogenase – rate-limiting and
zero order (constant amount/unit
time) - Availability of cofactor
nicotinamide adenine dinucleotide (NAD+) is rate-limiting (NAD+) step - Metabolism can be SLIGHTLY enhanced by fructose and amino acids (TPN) – increase supply of NAD+
Pharmacokinetics: Metabolism 2
- Normal rate of metabolism is 100 mg/kg/hr or 0.015–0.02%/hr = ~8g/hr in a 80 kg individual
- 1 to 1.5 hours to eliminate 1 std drink (10g)
- Accumulation of acetaldehyde is associated with headache, gastritis, nausea, dizziness (hangover)
- 5-10% excreted unchanged in urine, faeces, breath and sweat
- At [high] increased metabolism by mixed function oxidase – more sensitive to barbiturates, warfarin, steroids when drunk (competition for enzymes ie two substrates)
- H2 histamine receptor blockers (ranitidine, cimetidine) inhibit gastric ADH to increase peak BAC
Pharmacokinetics: Metabolism 3
Chronic
- ⇧ Oxidative metabolism – inducer (less sensitive to barbiturates when sober)
Genetic factors
- 50% Asians express inactive genetic variant of aldehyde dehydrogenase (ALDH2*2) – disulfiram-like reaction (alcoholism is low)[1]
- Low expression of ADH2*2 isoform of alcoholdehydrogenase with reduced activity is also seen in Asians – associated with alcoholism[1]
Pharmacokinetics: Metabolism 4
Sex differences
- Women achieve high blood EtOH than men given same dose on weight/weight basis
- Much of first-pass metabolism occurs in gastric tissue
- 50% less in women than men due to low alcohol dehydrogenase activity
- Also Vd is smaller in women (0.55 l/kg) than men (0.68 l/kg)
Pharmacokinetics: Excretion
Pharmacokinetics: Excretion 1
- Excretion
- Kidney – since most EtOH is metabolised, very little is excreted by kidney (can’t hasten excretion with diuretics)
- Lung – a constant % of plasma alcohol levels (1:2100) – basis for breathalyser
- Issue with:
- mouthwashes containing alcohol
- cough syrups containing alcohol
- gastric reflux of any alcohol in stomach
- immediate prior consumption of alcohol
- acetone in breath of diabetics (with some simpler devices)
Acute Overdose
Acute overdose 1
- Potentially fatal
- Average lethal BAC is ca. 0.3% (lower if sedatives have been taken) – respiratory failure
Acute Overdose 2
- Generally a self-limiting process since individual passes out before reaching lethal ethanol concentrations
- Rapid consumption of large amount or may overcome this process
- Unconscious patient may aspirate vomitus and suffocate
Alcohol Dependence
Tolerance and dependance 1
- No two people respond exactly the same to equal amounts of alcohol
- People develop tolerance with chronic use of alcohol
- Tolerance (2-3 fold loss of potency) develops over 1-3 weeks due to:
- Tissue tolerance (two-fold decrease in potency)
- proliferation of Ca2+ channels
- proliferation of NMDA receptors
- reduction in density of GABA receptors
- Small component due to more rapid elimination
- Tissue tolerance (two-fold decrease in potency)
Tolerance and dependence 2
- Alcohol dependence (‘alcoholism’) is common – 4-5% of population
- Strong physical dependence
- Potentially life-threatening withdrawal syndrome
- Strong psychological dependence
- Strong cravings to continue drinking / get drunk
Acute Alcohol Withdrawal 1
Drug treatment of Acute alcohol withdrawal
BENZODIAZEPINES EG. DIAZEPAM – FIRST LINE AGENTS, BEST EFFICACY, SAFETY AND COST
– ↑ GABAAR function
– ↓ Seizures: ~90%
– ↓ Delirium: ~70%
FOR WERNICKE-KORSIKOFF SYNDROME
– Alcoholics are usually deficient in Vit B1 so give thiamine
FOR PSYCHIATRIC SYMPTOMS
– Use antipsychotics such as haloperidol or droperidol (not phenothiazines as they can precipitate seizures)
Long-term management of alcohol dependence 1
TO REDUCE CRAVING
- acamprosate
- NMDA receptor antagonist and GABA agonist (taurine analogue) to reduce hyperexcitability in withdrawal
- Given after withdrawal
TO REDUCE ALCOHOL-INDUCED REWARD
- naltrexone
- Opioid receptor antagonist (alcohol ingestion releases endogenous opioids reinforcing drinking behaviour)
- Will precipitate opioid withdrawal in addicts
Long-term management of alcohol dependence 2
TO RENDER ALCOHOL CONSUMPTION UNPLEASANT
- disulfiram (ANTABUSE®)
- Only in suitably motivated alcoholics after detox
- Presence of EtOH + disulfiram makes person very sick
- Disulfiram interferes with aldehyde dehydrogenase – leads to excessive acetaldehyde levels
- Headache, sweating, dizziness, nausea, vomiting, respiratory difficulties, orthostatic hypotension
- Cephalosporins and sulphonylurea antidiabetic drugs produce a similar effect
