Midterm II Flashcards
alcohol production
- eth synth from scratch is inconvenient, instead, depend on yeast fermentation (converts sugar to glucose, then pyruvate, the ethyl alcohol then CO2 (which also causes some fizziness in drinks) in order to regenerate NAD+, a glycolysis cofactor)
- ethanol is toxic to the yeast though, and they can only produce up to ~15% before it kills them (higher percentage requires distillation)
the three “steps” of fermentation
- glycolysis converts glucose to 2 pyruvate, generating 2 ATP from 2 ADP (this also reduces 2 NAD+ to 2 NADH)
- pyruvate decarboxylase converts 2 pyruvate to 2 acetaldehyde, generating CO2
- alcohol dehydrogenase regenerates 2 NAD+ from 2 NADH by converting 2 acetaldehyde to 2 ethanol
what is a drink?
in can, one shot of hard liquor (1.5 oz), one glass of wine (5 oz) and one can of beer (12 oz) each contain approx 0.6 oz of ethanol
since there are 22.3 g ethanol/oz, a standard drink then has 13.38 g eth, which puts huge stressor on metab
alcohol absorption
- food DOES slow the absorption of alcohol, not by binding the ethanol itself, but by slowing the emptying of the stomach, in which absorption is slow
- most of the absorption of alcohol takes place in the small intestine (after passing through the stomach)
- by holding the alcohol in the stomach longer, it also gives alcohol dehydrogenase enzymes a chance to partially metabolize the ethanol
- ethanol remains neutral despite the pH of the stomach, so no change in absorption as a result on that front
- peak ethanol conc is lower than it would be when drinking on empty stomach
Mellanby Effect
when BAC is increasing, clinical effects tend to be greater than at the same BAC when it’s decreasing (ppl on the downslope test, clinically, as less impaired when compared to same BAC on the up slope of intoxication)
Biphasic effects of ethanol
at low doses: increases locomotion (motor stimulant-this effect is the first to peak and drop off)
-likely due to increased DA lvls in ventral striatum (where the reward pathway lies)
-thought that the stimulating, bubbly effect is rewarding and motivates the desire to ingest more, while the depressant effect is likely aversive
at high doses: sedative/depressant
-effect mediated at GABA (inhib NT) and Glu (excit. NT) receptors
-> potentiates inhibitory effect of GABA at GABA-A R, at very high doses impaired Glu signaling
-always peaks after stimulant effect
-not thought to be rewarding component, as often reported as unpleasant likely independent of reward pathway
-effect continues to increase even as BAC decrease
Alcohol: Stimulatory effects
- are DA mediating
- those who experience more stimulant vs sedative effects are at greater risk as they tend to report more positive effects/experience
- we can also reliably measure increased heart rate as a marker of pshysiological stimulation, which correlates quite well with reporting positive effects
- also, the more activation in the NAc (reward pathway), the more intoxicated users tend to judge themselves on self-reports
Alcohol: anxiolytic effects
- ethanol is linked to decreased (social) anxiety, likely due to effects on amyg (which is involved in storing + retrieving emotional mem, esp fear mems)
- normally, amy becomes more active when confronted w threatening imagery, but when treated with alcohol it not only responds less to scary stim but we lose the ability to distinguish btw threatening and non-threatening stiches (ppl who are drunk can’t asses envs end up in fights, etc)
- > alcohol may also disrupt threat detection circuitry
BAC
- blood alcohol concentration (g eth/100 ml blood)
- lethality: 0.4-0.5 BAC
- calculated by dividing number of g eth ingested by vol in which it can distribute
- > take g eth ingested, divide by L of blood in the body, and multiply by .806 (bc blood is 80.6% water)
ethanol metabolism
2% excreted unchanged in breath/skin/urine, some metab’d in stomach, 90% metab’d in liver over the course of several passes
- our enzymes, alcohol dehydrogenase (converts eth to acetaldehyde) and aldehyde dehydrogenase (converts acetaldehyde to acetate) aren’t sufficent to deal with recreational eth use
- the CYP2E1 enzyme plays little role in alc naive, but is upregulated in heavy drinkers, so the mircosomal ethanol oxidizing system comes into play more and more
- body has a hard time keeping up w demand for NAD+ needed to metab eth (availability limits metab to ~8 g/hr); depletion can also cause other NAD+ dependent systs to fail
kinetics of ethanol metabolism
-hepatic metab shows zero order kinetics (enzymes are saturated before a single drink is finished, and regardless of amt/dose of eth ingested, metab removes it in fixed amounts as opposed to proportions)
metabolism and BAC
metab will depend on alcohol experience (experienced drinkers tend to metab more quickly due to built up tolerance), which also makes estimating/extrapolating BAC tricky
- average metab rate predicts 0.017 BAC decline/hr (tho more conservative value of 0.015 BAC/hour widely accepted in CAN)
- because males have more blood for alcohol to distribute into, they generally need to drink more than a woman to reach the same BAC and also metab eth faster
breathalyzer
ethanol is somewhat volatile and can escape blood vessels in lungs to be excreted unchanged in the breath at a ratio of 2100blood:1lung
-in a study, inhalation of eth from 70% eth hand-san caused 2 minute false positives in hospital workers who had zero BAC
Aldehyde dehydrogenase
this is the enzyme that clears acetaldehyde (a toxic product of eth metab by alc. dehyd.) by converting it to acetate
-ppl of asian descent tend to have a single mutation that leads to low aldehyde dehyd. activity; accumulation of toxic acetaldehyde from drinking leads to nausea, blushing, sweating (flushing syndrome/asian glow), increased risk of esophageal cancer
antifreeze metabolism
antifreeze (ethylene glycol) is very sweet tasting
- init, leads to CNS depression; the indv appears drunk or even comatose
- then, the body begins metab-ing; alc. dehyd. converts ethylene glycol to glycoaldehyde, which ald. dehyd. converts to glycolic and oxalic acids
- this causes cardiopulmonary disfunction, acidosis, low blood pH (which can be fatal as messes w O2-heme binding and leads to hyperventillation, heart arrythmia, pulmonary edema)
- ox. acid can bind w Ca to form crystals that ppte out thr/out body in kidneys, lungs, etc
- final stage: renal dysfunction, kidney failure, cessation of urine production (all of which may manifest days after init contact)
- just 30 ml can cause death
methanol metabolism
- alc dehyd converts meth. to formaldehyde, which on its own can cross-link proteins and DNA and produces acidosis
- ald. dehyd then converts formald. to formic acid, which disrupts mito function in optic nerves (hence why as little as 10 ml meth. can cause blindness)
- init symptoms aren’t as sever as ethanol, but can be lethal at just 30 ml
- most common cause of meth. related death is resp. failure/sudden respiratory arrest
isopropanol (rubbing alcohol) metabolism
(note: acetone, the solvent in nail poslish remover, leaves a fruity scent on the breath)
- alc. dehyd. converts isoprop. to acetone
- both are CNS depressants that are rel. safe at low levels, but at high levels can result in vomiting and coma
how to prevent poisoning from alcohols other than ethanol?
flood the system with ethanol, which will out-compete the methanol/etc at the alcohol dehydrogenase binding sites, instead producing ethanol metabolism products (which the body is slightly better equipped to deal with) and leaving the other alcohol to be excreted unchanged OR introduce fomepizole (a competitive inhibitor of alc. dehyd. which will prevent the metabolism of chemicals like methanol and ethylene glycol -minimal adverse health effects as compared to flushing w eth and longer acting, but also more expensive
GABA-A receptors
- ligand gated Cl- ion channels composed of 5 subunits (2a, 2b, one other (often gamma)) that open when activated by GABA (and some other drugs) binding at a-b interface, allowing -ve charge to flow into and hyperpolarize the post-syn cell
- ethanol can bind at the a-gamma/a-delta interfaces, where the receptor interfaces w the lipid bilayer, to potentiate (increase) the inhibitory activity of GABA
- receptors containing delta as opposed to gamma subunits seem to be particularly susceptible to eth (respond at low levels)
NMDA Repectors
- Glu receptors that are selectively activated by synthetic compound called N-methyl D aspartate (NMDA)
- has 4 subunits; 2 NR1, and two NR2 (A/B/C/D)
- Glu binds not at subunit interfaces but at internal pockets, causing the ion channel to open and let +ve ions (Ca, Na) into the post-syn cell and cause depolarization
- eth doesn’t bind to the same sites as NMDA, rather likely smwh w/in the transmembrane domains that interface the lipid bilayer, and inhibs receptor activity at high concs (inhibiting excitation)
- bc of pharmacodyn. tol, the body will upregulate NMDAR, but w/o ethanol in the system Ca floods all of these cells and we get excitotoxicity, thought to lead to the neuronal loss in alcoholics
ethanol: overall mechanism of action at receptors
-at rel low doses (tho still higher than those that affect DA release), eth strongly potentiates effects of GABA (inhib NT) at GABAAR containing delta subunits, which interestingly may not be in the syn cleft
-at high doses, the above continues, but also inhibs effects of Glu (excit NT) at NMDA receptors , and may also inhib Ca entry thr its own volt-gated ion channels (reducing NT release)
net effect: less Ca entering nerve endings gives rise to neuronal inhib and gen lack of NT release, which causes drowsiness and anesthetic like properties (shut down basic autonom. f(x)s like breathing or even death)
ethanol and the mesolimbic circuit
ethanol does increase DA release, but:
- if release eth directly on NA, see v little (if any) increase in DA release, suggesting ethanol likely isn’t acting on nerve endings
- if release eth directly on VTA we see tonic DA release shift to phasic, dense firing, leading to increased DA release fr VTA neurons that synapse on NAc
- this excitatory DA release occurs at much lower conc eth than the inhib effects of eth (GABA potentiation, decreased Glu signaling), which is why ethanol can activate the reward pathway and stimulate to some extend while still being classified as a depressant
GABA release in VTA
eth increases relase of beta-endorphin, nat occuring/endogenous mu opiod agonist, from hypothalamal projections
- interact w mu-opiod receptors on GABA releasing neurons in VTAcausing the same inhibitory effects a D2/A1 receptors (inhib Ca channel and increase K channel activity (allows positive efflux w/o rebalancing, hyperpolarizing the membrane and shutting down GABA release
- this disrupts balance btw Glu + GABA signaling to VTA neurons, givnig rise to phasic DA bursts fr VTA/NAc
alcohol: physiological effects
- vasodilation (expansion/contraction of blood vessels) thr/out central vasomotor control mech. in brainstem (when contracted, move closer to skin and radiate more heat, resulting in feeling of warmth, tho core temp may decrease)
- increased salivary + gastric secretion which may promote hunger
- damage to gastric mucosa, bleeding via constant irritation of stom. lining (eth can attack lipids in stom-this damage leaves underlying cells vulnerable to stom acid)
alcohol: tolerance
pharmacodynamic:
- GABAAR (which are potentiated) are downregulated, and see change in the types of subunits incorporated (thought to be ones less sensitive to alcohol)
- NMDAR and CA channels (which are inhibited by alc) are upregulated
behavioural: somehow, drinkers devel. abil. to overcome/mask the effects of ethanol
metabolic: in heavy drinkers, CYP2E1 is significantly upregulated (which is problematic, bc in coverts acetaminophen, indust. solvents, some anesthetics to toxic metabolites (so normal dose of tylenol could e hella toxic)); in animal studies, increased CYP2E1 also correlates w increased ROS lvls and more eth-induced liver damage
Reactive Oxygen Species (ROS)
- covalently bind to things and change structure (rendering non-funct), tear away e-, etc
- interact w and damage DNA, lipids, proteins
- one form of production is from eth metab; byproduct if CYP2E1 reaction btw eth and molecular O2 to produce acetaldehyde doesn’t go to completion (w the oxygen not being incorporated)
- at high lvls, the body just can’t mop it all up
- ROS can directly damage DNA, and can also be produced by increased lvls of acetaldehyde, and can also damage cell membranes creating reactive lipid species that damage DNA
- this damage can lead to cell death or cancer
hangovers
symptoms:
physical (in descending order of pervasiveness) are headache, diarrhea, fatigue, tremulousness, nausea-psychological are decreased cognition, ability to perform tasks, impaired visuospatial skills
-seems to be manifestation of body-wide, ethanol-triggered inflammatory response
-symptoms peak when BAC=0%
-likely not mainly caused by dehydration
-may increase cytokine prod. via thromboxane B2 pathway (these are important in immune cell signaling/function, and hangovers seem to resemble viral infections which also increase cytokine lvls)
-prostglandin synthesis inhibitor decreases some symptoms by preventing cytokine production
-also see some mito dysfunct. esp in cebrebellum (integration of sens. + motor paths); can lead to neuronal dysfunct/death
congeners
toxic byproducts of alcohol production/storage (ex. leech in from barrels, peat in whiskey)
- include acetone, methanol, acdtaldehyde, tannins furfural, fusel oil
- darker drinks tend to contain more congeners, and are associated w increased severity of hangover symptoms
ethanol and energy use
- at 7 cal/g, eth is more cal-dense than carbs/protein (4 cal/g), and only slightly less than fat (9 cal/g)
- in the average canadian drink then, approx 10% of daily caloric intake is from alcohol (8% for women, 13 for men)
- in heavy drinker brains, neurons may switch fr glucose to acetate as primary E source during intox.
- when both exposed to same amt eth, intoxicated heavy drinkers metab less glucose than non-drinkers in brain tissue
fatty liver/cirrhosis
- ethanol metab by alc. dehyd converts NAD+ to NADH; high NADH lvls signal body to synth fatty acids and stop oxidizing them (start storing what it interprets as excess E)
- these fats stored as droplets in hepatocytes that can lyse if they get too full, causing inflammation (nasty yellow, cirrhoic liver)
- reversible until significant cell death begins occurring
- once irreversible, increase cytokine prod, which leads to increated growth factor (TGF-beta) in liver; this binds to receptors on surface of liver cells and stims intracell. pathways that upregulate gene transcription and therefore stim collagen synth
- eventually funct. liver cells completely replaced w non-functioning connective tissue (mostly that collagen), and liver loses abil. to detox. blood
immune system and liver inflammation
ROS/acetaldehyde can mod. lipids/proteins such that the body sees them as foreign and devel. antibodies to fight them (which contributes to chronic liver inflam.)
-immune cells infiltrate liver and release ROS, RNS (nitrogen species), enzymes, that destroy liver cells (bc they think they’re invading pathogens)
bed spins
- positional alc. vertigo
- when the cupula moves in the fluid of the inner ear, it deforms the cilia receptors that stick into in, which tells your brain that you’re accelerating
- w/in 30 min of drinking/at BAC ~0.04, eth. diffuses into cupula, making it lighter than surrounding endolymph (other sens. info such as vision override any odd effects)
- 3-5 hrs after drinking, eth. accumulates in endolymph, balancing densities again (silent phase)
- as drinking stops (5-10 hrs after ingestion), eth. diffuses out of cupula 1st, making it heavier; it flops over in the endolymph (esp when u lie down), deflecting and activating cells; w/o other sens. info, brain assumes you’re spinning
ethanol and cancer
- clear link btw chronic consum. of alc and all cancers (but esp upper GI, liver, colorectal, female breast tissue
- in upper GI, 50% of all cancers in both sexes linked to alc. consum.
- main culprits are acetaldehydes, ROS
- data suggests there’s no safe alc. threshold for some cancers (in order of increasing risk vs increasing intake study, alc linked to pancreatic, colorectal, laryxn, oral cavity/pharynx and esophageal cancers)
acetaldehyde and cancer
- covalently bind to and irreversibly modify deoxyguanosines in DNA which can introduce weird errors and prevent repair thereby causing mutation w/in strands that can lead to chromosomal damage, shortening, translocation
- if after reaction with dG, the ring doesn’t close, it can lead to interstrand and/or DNA-protein crosslinks
Alcohol and upper-digestive tract cancers
- eth. is metab’d to acetaldehyde by microbes in saliva; acetald. conc. can therefore be 10-100x higher in saliva than in blood
- substance abusers also tend to have poorer dental hygene, which increases the acetald. conc. as even more microbes present in saliva
- smoking also shifts those microbes towards types that produces higher (50%) acetald. lvls
cancer of the liver
- main factor is is ROS from CYP2E1 metab. processes; ROS cause lipid damage, producing reactive lipid species that covalently modify DNA (which is highly mutagenic)
- CYP2E1 also metab’s retinoic acid (RA), which is thought to act as -ve regulator of malignant cells (prevents their proliferation); this also results in fewer RA receptors, which changes lvls of proteins involved in gene reg and liver cell proliferation
alcohol and brain damage
- alcoholic brains are clearly smaller tan expected and much smoother, due to loss of neurons/brain density; we also see larger ventricles (which typically indicates neuronal die off) and larger gaps between the brain and the skull
- same culprits as liver damage (acetaldehyde and ROS are toxic to neurons but also nutritional deficiency (not having vitamins important in myelin formation, etc), repeated head trauma, excitotoxicity (from hyperactive NMDARs that let in excessive Ca and inappropriately activate Ca-sensitive signaling pathways (and cell death)), alcohol induced-inflammation seen in liver makes manifests in the brain
Wernicke-Korsakoff syndrome
Wernicke: const. irritation/inflam. of GI tract makes it harder to absorb vit. B1 (thiamine) and leads to deficiency; bad bc involved in myelin formation, glucose utlization, AA production, and can result in confusion, ataxia and abnormal eye movement if not addressed; partially reversible if u can just get that B1 into the blood
Korsakoff: (progress of Wernicke) short + long term mem loss, inabil to learn new info, non-reversible and as’d w neuronal loss
ethanol: cardioprotective effects
at low doses, and in isolated tissue/cell cultures, eth:
- increases good, high density lipoprotein
- decreases platelet aggregation/coagulation (reduce likelihood of clotting)
- decreases inflam. in blood vessels
- improves endothelial function by balancing blood vessel dilation (and by exten. decrease BP) ((although tends to be risk for increased BP in mod-heavy users so maybe nah))
cardiotoxic effects
at high eth doses:
- cardiomyopathy (disease of heart muscle in which it’s weak and doesn’t function properly)
- alc. is direct myocardial depressant
- acetald. inhibs function of myocytes (heart muscle cells) by altering Ca homeostatis and myocard. protein synth
- Ca release fr scaroplasmic retic. is inhib’d (had -ve effect of Ca-sensitive contractory proteins in heart)
- metabolties cause mito dysfunction and poor E use
