Alcohol III Flashcards
What is the link between ethanol and cancers?
chronic consumption leads to alot of upper GI cancers, liver, colorectum and female breast tissue
how many percent of all cancers are linked to ethanol?
3.6%
in men its as high as 10%
how many % of all cancers (both sexes) are linked to alcohol consumption?
50% of all cancers in both sexes are linked to alcohol consumption
what are the main culprits of cancer causing in ethanol? and what is the safe the safe threshold of ethanol consumption for it to cause cancer?
main culprits are ROS and acetalaldehyde and there is no safe threshold for some cancers
what are the two types of upper GI cancers that are the most common and increase highly as the intake of alcohol goes higher in one day?
esophagus cancer and oral cavity and pharynx cancer
if you drink 10g or even less than that in one setting per day, u increase (increase in relative risk)
how does acetaldehyde cause cancer?
acetaldehyde binds to DNA and changes its shape and structure. The problem arises when the DNA has to replicate itself with the new structure and can cause mutation in replicating itself the wrong way… which can lead to cancer.
also when the DNA tries to repair itself on the new structure produced, it can make mistakes which can lead to cancers
a structure called ethyldenndoxyguanosine is made from acetylaldehydes modification of DNA
if you add ADH then you see less DNA alterning because ADH metabolizes acetylaldehyde into acetate
why are some reasons for cancer being in the upper digestive tract that have to do with ethanol?
ethanol is metabolized to acetaldhyde by microbes in the saliva that can be 10-100 times higher in concentration than in the blood
poor dental hygiene increases the concentraiton of this because theres more microbes on the tongue
smoking shifts the microbes towards the types that produce higher (50%) acetaldehyde levels
aka u need to brush ur teeth often if ur drinking alot
How does liver cancer occur in chronic alcoholics?
chronic alocholics often have higher CYP2E1 enzymes and catalase enzymes.
CYP2E1 causes more acetaldehyde and increase ROS
CYP2E1 also metabolizes retinoic acid (RA) aka vitamine A which is thought to act as a negative regulator of maliganant/cancer cells and prevent cancer cells from proliferating
low RA levels as a result of high CYP2E1 can result in lower RA receptors, and changes the levels of proteins involved in gene regulation and proteins involved in liver cell proliferation which causes an increase risk of cancer
what causes brain damage in chronic alcoholics (5)?
- ROS and acetaldehyde
- nutiritional deficiency… as a result of inflammated gut
- repeated head trauma
- hyperactivity of glutametergic systems leading to excitotoxicity
- alcohol induced neuroinflammation… BBB is compromised when immune cells enter the brain and cause same problems as they do in the liver
what are 3 main differences in the MRI scans of individuals who are chronic drinkers and individuals who are not?
- larger ventricles
- less space between cerebellum and skull
- larger gap between skull and cortex
overall just a total loss of neurons
What is Wernicke’s disease? what does it result from?
Wernicke’s disease is a result of B1 (thiamine) deficiency and can be partially reversible by IV of B1
deficiency is due to the fact that B1 isnt absorbed well in the gut of chronic alcoholics due to inflammation
- thiamine is involved in myelin formation, glucose utilization and amino acid production
- this is why in B1 deficiency you see ataxia (motor movement problems), confusion, abnormal eye movement, shaky eyes and paralysis of eye muscles due to myelin damage
what is korsakoff’s psychosis? what does it result from?
korsakoff’s psychosis results from wernicke’s disease going untreated.
it involves short and long term memory loss, inability to learn new information
it is NON-reversable and associated with neuronal loss
What did the study from Center for ADdictions Reseach tells us in 2016 about the studies done in the past about alcohol increasing lifespan?
tells us that the abstainer group (the control group) used in those experiments were actually made up of previous drinkers who stopped rinking because they were so unhealthy… this made the drinking group look healthy
when they corrected those experiments, they found that the risk of mortality in even casual drinking is higher than previously imagined
this makes more sense and is in par with the cancer data from ethanol
what are some potential cardioprotective effects of ethanol? (4)
AT LOW ETHANOL DOSES
- it increases density of the good lipoprotein (transports fats from blood to liver for metabolism)
- decreases platelet aggregation and caogulation
- decreased inflammation in blood vessels
- improved endothelial function, balance between blood vessel constriction and dialation
what are some cardiotoxic effects of ethanol?
high doses of ethanol causes caridomyopathy (diseas of heart muscle)
- alcohol is a direct myocardial depressant… slows down the heart
acetaldehyde inhibits myocyte function by altering calcium homeostasis and myocardial protein synthesis … the heart muscles need calcium to contract
calcium release from the sarcoplasmic reticulum is inhibited, which has a neg. effect on calcium sensitive contractility protiens
- ethanol metabolites result in mitochondrial dysfunction and poor energy use… (low energy for the heart)
alcohol slows down the heart by preventing muscle cells from contracting…
what is fetal alcohol syndrome?
it is the leading cause of brian damage in the USA (1 in 10 births)
it is a spectrum and it is on the severe end
what did the study on mouse fetus exposure to alcohol and the human fetus affects on alcohol show us? what three things occur abnormally in the development of the fetus in the presence of ethanol?
mouse gestiational day 7 is equivalent to third week of human gestation
at this time, ethanol expsure effects the median part of the face and forebrain
this causes poor impulse control, planning, impaired mental function and seizures
synaptogensis occurs in the third trimester and was believed that this was the critical worst time for exposure to ethanol
three things that occur abnormally in the fetus of the mouse and the human at 7day/third week gestation is:
- palpebral fissures (eye slits) are not formed properly due to lack of apoptosis in that area so it appears they have shorter eye openings
- lack of philtrum: groove between the upper lip and nose .. also very thin upper lip
- skull is smaller (microcephaly)
What effect does binge (non chronic) alcohol exposure have on fetal development (as shown in gest. day 17 of mouse)?
binge exposure even first time exposure can cause massive apoptic programmed cell death
- researchers found that different brain regions were sensitive to ethanol during different time periods
- the researchers divided these brain areas to those that are affected etiher early, mid or late in fetal development
theres no specific window of vulnerability because specific brain regions are vulnerable at points of development in the fetus
What did binge exposure show about the areas of the brain that are affected by ethanol in early, mid and late developmental stages?
in early developmental stage, the ventromedial hypothalamus is affected
in mid development, the laterodorsal thalamus is affected
in late development, the prefrontal cortex is affected
what is the severity of apoptosis linked to in rat embryos equavalent to the in the third trimester in humans?
During the third trimester, synaptogensis is occuring
so a BAC of 0.2 for 4 hours triggered enough to be apoptic and result in cell death in rat fetus
severity of it is not linked to total dose of ethanol but rather the peak concentration of it (the highest amount of it in the blood stream).
the fetus is effected because its liver isnt functioning properly like a human one, so it receives MORE ethanol than humans which can possibly cause excitotoxicity quicker in them and cell death
neuronal death was reflected in the loss of weight of the fetus
represents millions of neurons
how does ethanol cause apoptosis in developing fetuses? How is affected by MK-801 receptors and phenobarbital?
- apoptosis occurs due to a combo of GABA-A receptor activation and NMDA receptor block
- MK-801 is an NMDA receptor antagonist and binds inside the ion channel receptor and prevents flow of ions including calcium through, and phenobarbital activates GABA-A receptors
ethanol dose produced peak of approx 300mg/100ml
How does alcohol induced neuronal death in the fetus occur?
ethanol produces effects on GABA-A and NMDA receptor responses
ethanol exposure can result in lack of ERK (extracellular signal- related kinase) phosphorylation (so it inhibits its movement of ERK to the nucleus) and mitochondrial damage…
this seems to trigger the activation of enzymes called caspase 3 and caspase 9 that are important triggers for apoptosis
this can occur with a single exposure
What are two other effects of alcohol on fetal development?
- ethanol exposure alters the migration of survivng neurons and heterotopias form as a result of clumps of neurons in the wrong part of the brain
- genes associated with receptors for thyroid hormone and retinoic acid are affected and this leads to increased bioological reactions to stress which is linked to increase anxiety and depression coupled with poor coping skills
What are the 4 steps to alcohol withdrawl?
stage 1: tremors, rapid heart beat, hypertension, heavy sweating, no apeptite, insomnia
stage 2: hallucinations
stage 3: delusions, delirium, disorientation, amneisa
stage 4: seizure activity
What is delirium tremens?
it occurs three or four days into the withdrawal of alcohol cold turkey
includes physical effects like shaking, shaking, shivering, irregular heart rate, and sweating. Occasionally, a very high body temperature or seizures may result in death.
also includes people seeing and hearing things
what are some drugs used to treat withdrawl (3)?
- sedatives such as benzodiazepines .. prevents stages 3 and 4
- clonidine –> agonist at presynaptic adrenergic alpha 2 receptors) prevents excessive NT release
- propranolol –> a beta adrenergic receptor antagonist that blocks excessive sympathetic activity and slows heart rate and reduces tremour.
these drugs all have in common the fact that they are inhbitory because the effect of alcohol withdrawl is mainly from too many excitatory neurons
what is a drug used to prevent use of alcohol?
disulfiram
- prevents aldehyde dehydrogensase from working
- results in high levels of acetaldehyde
- causes headaches, neausea, flusing etc..
- questionable over time
- does not stop cravings and could cause cancer
- this was used so it can imediately cause affect of a hangover after drinking and punish the person from drinking by having aversive effect to ethanol
how do opiod antagonists help reduce alcohol cravings? what is an example of a opiod antagonist and what does it do to stop cravings?
- alcohol increases release of endogenous opiod, endorphin in VTA and NA
- naltrexone is an opiod antagonist at mu opiod receptors
- it prevents beta endorphin from activatating presynaptic receptors and causing hyperpolarization of GABA
- so it prevents inhibition of GABA release in VTA
- some people say that it recudes cravings but others say that theres problems with neg mood
what is acamprosate? what does it do?
acamprosate is an antagonist at glutamate receptors
it is thought to address the hyperexcitability in chronic alcoholics due to up-regulation of glutamate receptors especially in withdrawal
it is through to prevent cravings
european studies showed success while american studies are mixed
