Alcoholism Flashcards
What are the primary neurotransmitters of the brain?
GABA -inhibitory
Glutamate - stimulatory
What are the secondary neurotransmitters?
Dopamine Serotonin Noradrenaline ACh Endogenous opiods These add tone, valence and emotion to the primary process
How do full agonist opiates work? (E.g. Heroin)
Act on the neurotransmitter pathway, but with a much greater effect than the natural transmitter
- the drug hijacks the natural transmitter system
- normal levels of stimulation are now not enough in comparison = addiction
How does alcohol cause addiction?
It indirectly stimulates the endogenous opiate system
- enhances the action of the inhibitory neurotransmitter GABA
This enters the synaptic cleft and binds to its receptors, opening chloride channels and hyperpolarising the membrane, lowering cell excitability
Some drugs work by acting on dopamine, how do they do this?
Stimulant drugs increase energy and stamina by increasing synaptic levels of dopamine
Some drugs increase dopamine availability in other brain regions; nucleus accumbens and prefrontal cortex
Normally the reward circuit in the brain is activated by food, water and sex
- drug abuse produces a greater effect on the reward system, and so the brain directs normal drives away from the natural reinforces and towards the drug
Define alcohol dependence?
An individual is physically or psychologically dependent on drinking alcohol - access to alcohol is the thing that takes on greatest value in their life
What criteria must someone fit to be diagnosed as alcohol dependent?
3 out of the 7 following things
- tolerance
- withdrawal symptoms
- used in larger amounts or for longer periods than intended
- persistent desire or unsuccessful efforts to cut down
- time is spent obtaining alcohol
- social, occupational and recreational pursuits are given up or reduced due to alcohol use
- use is continued despite knowledge of alcohol related harm
What is the difference between dependence and abuse?
Dependence includes tolerance and withdrawal
Abuse can still include binge drinking
What is tolerance?
Reduced sensitivity requires that higher quantities of alcohol must be consumed in order to reach the same effects as before tolerance was established
What is reverse tolerance?
A liver damaged by chronic alcohol use, builds up fat and scar tissue
This reduces the ability of the liver to metabolise or break down alcohol and small amounts can lead to high blood alcohol concentrations
What does a persons alcohol tolerance depend on?
Activity of alcohol dehydrogenase - found in the liver and in the blood
What is a unit of alcohol?
10ml or 8g of pure alcohol
- equates the amount the average adult can process in one hour
What are the normal alcohol limits?
Advised not to drink more than 14 units a week, and should be spread out over a few days
- should include some days of abstinence
What substance is most alcohol metabolised to?
Acetaldehyde
- a highly reactive and toxic substance
- responsible for physical damage caused by excessive alcohol consumption
What is acetaldehyde metabolised to?
Acetate
- non toxic and concentrations in tissues is low
What is produced during oxidation of excess alcohol?
Lactic acid Keto acid Retention of uric acid Hyperlipidaemia Accumulation of fat in the liver
What are the two pathways of alcohol metabolism?
Cytoplasmic alcohol dehydrogenase (CDH)
Microsomal ethanol oxidising system (MEOS)
Describe the cytoplasmic alcohol dehydrogenase system
It is the main, non-inducible route.
Alcohol is metabolised to acetaldehyde by alcohol dehydrogenase in the cytosol of cells
Acetaldehyde is then oxidised to acetate by acetaldehyde dehydrogenase in the mitochondria
Describe the Microsomal ethanol oxidising system
This is an inducible system, and takes excess alcohol the CAD system can’t handle
Alcohol is oxidised in acetaldehyde by the action of CYP2E1 in the SER
This reaction gives of a ROS as a byproduct
Then, acetaldehyde is oxidised to acetate in the mitochondria by the action of acetaldehyde dehydrogenase
Describe the acute physical injuries associated with drinking alcohol.
Accident and injuries Acute alcohol poisoning Aspiration pneumonia Oesphagitis Malory-Weiss syndrome Gastritis Pancreatitis Cardiac abnormalities Cerebrovascular accidents Neuropraxia Myopathy
List the chronic problems that can arise from alcohol abuse.
Accidents and injuries Oesphagitis Gastritis Malabsorption Pancreatitis Malnutrition Liver damage Systemic hypertension Cardiomyopathy Coronary heart disease Cerebrovascular accidents Brain damage Peripheral neuropathy Osteoporosis - alcohol directly onto bone reduces bone mass Skin disorders Malignancy Sexual dysfunction Foetal damage
Describe the relationship between alcohol and chronic pancreatitis.
Alcohol use can cause progressive and irreversible damage to the pancreas gland
Pancreatic calcification and gland distortion
Main clinical features are pain coupled with malabsorption/maldigestion and diabetes - main problem is continuous epigastric pain
Describe how alcohol can cause fatty liver.
Decreased mitochondrial fatty acid beta-oxidation (alcohol metabolism prioritised)
Increased endogenous fatty acid synthesis
Enhanced delivery of fatty acids to the liver
Deficient incorporation or export of triglycerides as VLDL
Describe how alcohol can cause hepatitis.
Some present with jaundice, poor clotting and fluid retention
Acetaldehyde damages liver cell membranes
Free radical production also causes hepatocellular damage
Describe how alcohol can cause cirrhosis.
Damaged membranes prevents detoxification of chemicals, causing scarring and necrosis
Acetaldehyde causes fibrosis by stimulating collagen deposition by hepatic Stellate cells
Inflammation is caused by acetaldehyde and ROS, damages the cell membrane
Which brain damages are likely to occur during alcohol abuse?
Korsakoff-Wernicke’s syndrome
Dementia
Cerebellar atrophy
Central pontine myelinosis
What is Wernicke-Korsakoff syndrome?
Confusion, nystagmus and ataxia
Caused by thiamine deficiency
- lack of thiamine means the mitochondria are less protected against free radicals, and damage occurs
Describe cerebellar atrophy.
Characterised by various degrees of ataxia - affects trunk and lower limbs (upper limbs are little affected)
Atrophy of the cerebellum - mainly in anterior and superior vermis
List the general characteristics of alcohol abuse.
Spider nevi - found only in distributions of the IVC/SVC
Telangiectasia - broken veins
Facial mooning - face appears round and eye-lids appear puffy
Parotid hypertrophy
Palmar erythema - beginning on hypothenar border of the hand
Dupytren’s contracture - thick palmar fascia
Gynaecomastia
What are the social effects of alcohol?
Social problems
Psychological problems
Cognitive impairment
When is the most vulnerable period for alcohol abuse during pregnancy?
Weeks 4-10
What effects does alcohol exposure have during the 1st and 3rd trimester?
1st - Organ and craniofacial development
3rd - significant effect on growth
What are the symptoms of foetal alcohol syndrome?
Small head Small ridge between nose and upper lip Small, wide-set eyes Thin upper lip Hyperactivity Below average height and weight Lack of focus Poor coordination Delayed development and problems in thinking, speech, movement and social skills Poor judgement Problems seeing/hearing Learning disabilities Intellectual disability Heart problems Kidney defects and abnormalities Deformed limbs and fingers Mood swings
What psychological therapies are available for alcohol addicts?
Brief intervention
Barriers to change
Aims
Describe a brief intervention
Focused on those who drink at hazardous levels
Consists of
- an assessment of recent alcohol intake
- provision of information on harmful drinking
- clear advice on options supported by relevant literature
- contact details of local agencies
Motivational interviewing - let patient arrive at their own decision
Try to avoid arguments and confrontations
Describe common barriers to change.
Dependence
- psychical (careful withdrawal from alcohol)
- psychological (find trigger for drinking)
- devise techniques for refusing drinks, develop and rehearse diversionary activities
Stress
- alcohol relaxes people in stressful situations (counselling and cognitive behavioural therapy)
- environment
Habit
- difficult to break a habit (keep a diary during problem times)
- hopelessness and pessimism (no point in trying because they won’t be able to sustain it)
What are the aims at the end of the interview?
Set goals - specific, attainable and instantly rewarding
Involve the family - reinforce decisions
Identify underlying psychiatric or psychological problems
Identify barriers to changes - eliminating these makes treatment easier
Engender a positive attitude
Describe all thecognitive and behavioural therapies.
Cognitive and behavioural therapies
- individual learns to identify triggers to drinking and finds new ways to cope with them
Solution focused relapse prevention therapy
Stress management and relaxation therapy
Counselling
- seeks to clarify psychosocial factors underlying alcoholism
Family therapy
Describe the mechanism of Disulfiram.
Inhibitor of alcohol dehydrogenase
If someone on this drug imbibes alcohol, blood acetaldehyde concentrations increase significantly, producing a flushing reaction
May be accompanied by nausea, vomiting and tachycardia
Describe the mechanism of action of Naltrexone.
Opiate receptor antagonist - stops alcohol ingestion firing the pleasure pathway, and the experience has no joy for the person
50mg daily dose for 3-4 months
Describe the mechanism of action of Acamprosate.
Functional glutamate antagonist
- again, modification the activity of the neurotransmitter in order to decrease the ‘reward effects’ from consumption of alcohol
What are the self-help groups available for alcohol addicts?
Alcoholics Anonymous
AIAnon
AITeen
Online websites
What is the sneaky third option for alcohol metabolism?
Alcohol is oxidised to acetaldehyde via catalases in the peroxisomes
ROS is also given off in this pathway
What are the consequences of acetaldehyde production?
Binds to proteins and DNA; immunogenic
Stimulates collagen production by Stellate cells
What are the consequences of acetate production?
Increased acetyl-CoA promotes inflammation by histone acetlyation
What are the consequences of an increasing NADH/NAD ratio?
Increased fatty acid synthesis
Reduced fatty acid oxidation
Promotion of steatosis
What are the consequences of non-oxidative metabolism?
Fatty acid ethyl ester production and increases steatosis
What are the consequences of ROS production?
Largely through MEOS, but catalase activity may also contribute
Production of hydrogen peroxide and superoxide ions
Activates redox-sensitive transcription factors, which leads to increase TNF-alpha production
Promotes lipid peroxidation which promotes inflammation and damages mitochondrial membranes = apoptosis
What is another factor in how alcohol can cause liver damage?
Increased intestinal permeability leads to portal circulation endotoxaemia
This promotes the action of Kupffer cells which in turn promot liver injury
What molecules does the hepatocyte produce when activated by alcohol?
TNF - activates ceramide - increases ROS concentrations IL-8 - activates neutrophils - increases ROS concentrations
Describe the intrinsic pathway of apoptosis.
Initiated by oxidative stress
Leads to leakage of pro-apoptotic factors from the mitochondria (I.e.cytochrome-c) regulated by Bcl-2 proteins
Pro-apoptosis factors from mitochondria activate cascades leading to cell degradation
Describe the extrinsic pathway of apoptosis.
Initiated by TNF-alpha
Binding to TNF receptors leads to caspase activation via FADD (FAS-associated death domain) and TNF receptor-associated death domain proteins
What is the difference between apoptosis and necrosis?
Apoptosis is a natural cell death, stimulated by signals and is to the benefit of the organism as a whole
While necrosis is traumatic cell death, stimulated by factors external to the cell and is fatal
What is glutathione?
A molecule that protects mitochondria
- requires zinc for its synthesis
How does alcohol affect glutathione?
Chronic liver disease affects the synthesis of glutathione, leaving the mitochondria more susceptible to damage by the ROSs
