Biochem 2 Flashcards
How does ethanol act on the brain?
It is a small molecule which can cross the BBB
Ethanol makes nerve membranes leaky
Impaired nervous function and even in severe cases death
What part of the brain is affected first by alcohol?
Cerebral cortex - leading to impaired judgement
What part of the brain is affected second and third by alcohol?
Forebrain - memory and emotions
Cerebellum - balance and movement
What part of the brain is affected fourth by alcohol? What are the consequences?
Brain stem breathing circulation (can be suppressed and cause death)
What is considered low medium ad high risk drinking per day for a male?
2
4-6
6+
What is considered low medium ad high risk drinking per day for a female?
Up to 2
2-4
4+
Where is alcohol dependence most common?
Dependence is generally higher in rural and colder states
What are the symptoms of severe dependence?
Severe Dependence exists when withdrawal causes tremors, anxiety, sweating or vomiting
Dependence is a continuum from mild to severe. It is more likely when family or social groups exhibit high drinking patterns. People who cannot stop drinking, when they realise that they should, are dependent
How many Australians likely have brain damage from alcohol consumption at current levels?
2 Million
What is Wernicke Korsakoff Syndrome?
Neurotoxicity due to thiamine deficiency
What percentage of Australians are affected by Wernicke Korsakoff Syndrome?
2%
What cause Wernicke Korsakoff Syndrome?
Dietary deficiency (little fruit and veg) - no thiamine. Also alcohol metabolises thiamine further reducing its level
How can Wernicke Korsakoff Syndrome be reversed?
Thiamine injection
What are the symptoms of Wernicke Korsakoff Syndrome?
Eyes uncoordinated (nystagmus), Wide step, Confusion, Hypothermia, Amnesia and confabulation
What are some signs of alcoholism?
Neurological disturbances Brain damage Heart disease - Irregular heart beat Jaundice Altered breath Oesophageal varices Feminization (altered sex hormones - development of breasts) Extensively scarred liver Portal Hypertension Enlarged collateral vessels Ascites Hand tremor Hypogonadism Infertility in women Impotence in men Osteoporosis East bruising Muscle wasting Oedema
What is fatty liver?
Fatty liver occurs rapidly and is reversible (detected by ultrasound).
What is alcoholic hepatitis?
Alcoholic hepatitis with widespread inflammation. This occurs in up to 50% of heavy drinkers and may be recognised by the presence of fever, jaundice and abdominal pain. This condition carries a mortality of between 15 - 20%.
What is alcoholic cirrhosis?
Alcoholic cirrhosis is diagnosed in some 15-30% of heavy drinkers. The cirrhotic liver is characterised by extensive fibrosis that distorts the internal structure of the liver.
What percentage of the liver is required for normal function?
Only 40% of a liver’s functioning hepatocytes are required for its adequate performance. This is due to their efficiency and their ability to regenerate
How is serum albumin concentration affected by liver disease?
Usually normal in chronic liver diseases until cirrhosis is present.
Where is alcohol metabolised and where does it pass?
> 90% is metabolised in liver.
Where does alcohol enter the blood?
~30% enters blood from stomach.
~70% enters blood from gut
What happens to alcohol in the stomach?
Some undergoes first pass metabolism (alcohol dehydrogenase is gastric mucosa)
The rest either passes into the SI or enters the blood
How is alcohol absorption slowed?
Fatty in foods
What pathways are used to metabolise alcohol?
Alcohol dehydrogenase (ADH) MEOS Catalase (don't worry about it)
What is the pathway of ethanol breakdown using ADH?
(NAD+ → NADH + H+)
Ethanol → Acetaldehyde
(ADH)
(NAD+ → NADH + H+) Acetaldehyde → Acetate
(ALDH)
Acetate → Acetyl CoA (can enter the TCA cycle or be stored as fat
What is a consequence of the ADH pathway?
The breakdown of ethanol leads to the production of NADH which represses gluconeogenesis and can lead to hypoglycaemia
What cytochrome is is recruited in the MEOS pathway?
CYP2E1
It can be induced
What can be said about MEOS and catalase?
They are minor pathways in moderate drinkers
How much alcohol in 1 standard drink?
10g
How much does 1 standard drink raise blood alcohol?
0.015 g/l
How much alcohol can a human clear per hour?
Most humans clear alcohol at approximately one standard drink (10g alcohol) per hour. This is equivalent to a decrease of 0.015% blood alcohol per hour.
Is alcohol cleared at a consistent rate?
Yes - ADH is absolutely saturated at a concentration of 3-4mM which is about 1 standard drink or 0.015g/l
Are breath tests accurate?
Blood alcohol is measured with high accuracy by gas chromatography. Breath tests usually give slight underestimates.
What effects does alcohol have on drug clearance?
Alcohol has two alternate effects on drugs:
1. Prevents drug clearance when alcohol is present.
- Promotes drug clearance by elevated CYP 2E1 when alcohol is not present
Name a few common drugs which use the CYP 2E1 pathway?
Warfarin, paracetamol
What change needs to be made to those taking warfarin if also using alcohol?
Need to increase protective dose when patient is also taking alcohol (increases warfarin destruction by CYP 2E1)
What are the causes of Alcohol Induced Liver damage?
Damaged cells release inflammatory agents such as eicosanoids, cytokines and endotoxins. Damaged tissue is destroyed by the immune system.
What happens to sex hormones in chronic alcohol consumption?
Affected by chronic alcohol consumption, probably by stimulating microsomal modification or destruction of steroids
What are the outcomes of low testosterone?
Testicular atrophy
Gynaecomastia
Loss of libido
Feminisation of hair patterns
In women libido is lowered and breast cancer risk increases
What happens if someone inherits an inactive variant of ALDH2 enzyme?
The ALDH2 enzyme is the more important aldehyde dehydrogenase (located in the mitochondria)
Increased circulating acetaldehyde produces general vasodilatation with a striking facial flushing response.
What does Disulfiram do?
Irreversible inhibitor of aldehyde dehydrogenase
Ingestion of alcohol → acetaldehyde accumulation causing tachycardia, flushing, dyspnoea, nausea & vomiting.
Are genes thought to play a role in alcohol addiction?
Yes
We talked about Dopamine D2 receptor
What is naltrexone?
Opioid receptor antagonist Blocks alcohol induced release of dopamine in Nucleus Accumbens. Diminishes pleasurable effects and craving for alcohol. The most clinically successful drug when used with the Sinclair method
What is nalmefene?
µ and α opioid receptor antagonist – less hepatotoxic than naltrexone.
What do dopaminergic drugs do?
Tiapride: a D2 receptor antagonist. Eases symptoms of withdrawal for treatment of acute & chronic alcoholism
What is Acamprosate (trade name CAMPRAL)?
GABA receptor agonist that normalises glutamanergic mediated reaction to alcohol withdrawal. Trials show 60% abstinence compared with 22% for placebo
What is Fetal Alcohol syndrome?:
Birth disorders brought on by alcohol consumption during pregnancy.
Children with FAS typically have small heads, small eyes and certain facial malformations.
How does alcohol cause dehydration?
Production of antidiuretic hormone by the brain (pituitary) signals the kidney to take water back from the urine. Alcohol interferes with pituitary function. Low antidiuretic hormone levels result in more body water passing into the urine. Despite high fluid intake with the alcoholic drinks even more is lost. The body becomes dehydrated.
What impact does dehydration have on the brain?
Dehydration of the brain (the brain shrinks!) leads to headache and the death of brain cells
What is GGT?
Gamma-glutamyltranspeptidase (GGT)
When is GGT elevated?
May be elevated in virtually any liver disease and even sometimes in normal individuals. GGT is induced by many drugs, including alcohol, and its serum activity may be increased in heavy drinkers even in the absence of liver damage or inflammation.
What is ALT?
Alanine transaminase
When is ALT elevated?
is elevated in all types of hepatitis (viral, alcoholic, drug-induced, etc.) due to hepatocyte damage.
What is a clear marker of elevated alcohol consumption?
carbohydrate deficient transferrin (CDT)
