Midterm II Flashcards
1
Q
alcohol production
A
- 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)
2
Q
the three “steps” of fermentation
A
- 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
3
Q
what is a drink?
A
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
4
Q
alcohol absorption
A
- 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
5
Q
Mellanby Effect
A
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)
6
Q
Biphasic effects of ethanol
A
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
7
Q
Alcohol: Stimulatory effects
A
- 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
8
Q
Alcohol: anxiolytic effects
A
- 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
9
Q
BAC
A
- 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)
10
Q
ethanol metabolism
A
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
11
Q
kinetics of ethanol metabolism
A
-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)
12
Q
metabolism and BAC
A
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
13
Q
breathalyzer
A
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
14
Q
Aldehyde dehydrogenase
A
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
15
Q
antifreeze metabolism
A
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
16
Q
methanol metabolism
A
- 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
17
Q
isopropanol (rubbing alcohol) metabolism
A
(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
18
Q
how to prevent poisoning from alcohols other than ethanol?
A
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
19
Q
GABA-A receptors
A
- 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)
20
Q
NMDA Repectors
A
- 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
21
Q
ethanol: overall mechanism of action at receptors
A
-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)
22
Q
ethanol and the mesolimbic circuit
A
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
23
Q
GABA release in VTA
A
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
24
Q
alcohol: physiological effects
A
- 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)
25
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
26
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
27
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
28
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
29
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
30
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
31
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)
32
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
33
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)
34
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
35
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
36
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
37
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
38
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
39
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))
40
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
41
FASD (fetal alcohol spectrum disorder)
- leading cause of brain dam. in US, w FAS at the severe end of the spectrum
- collection of eth-related damage during development; effects are esp. prominent at the midline of the face, cn also result in poor impusle control, planning, impaired mental function, seizure
- exposure in 3rd trimester may be particularly harmful to brain is that's when synaptogensis (forming of neural connections) occurs
42
fetal neuronal death and time of alcohol exposure
binge exposure causes massive apoptotic (programmed) death
- diff brain regions are sensitive to ethanol during diff stages of the 3rd trim. (early-ventromedial hypthalamus, mid-laterodorsal thalamus, late-PFC)
- differential effect likely reflects timing of devel/connections made by diff. regions
- embryonic BAC of 0.2 for 4hrs triggered apoptosis, severity linked to peak conc (not tot. dose)
43
fetal apoptosis
- occurs due to combo of GABAAR activation and NMDA blocking (which is found from studying MK-801 (NMDAR antag), phenobarbital (GABAAR activator), neither of which produces quite the same cell death seen in ethanol
- eth exposure results in lack of ERK phophr. (inhib-ing mvmt to nuc.) and mito damage
- triggers activation of capase 3 + 9 enzymes that trigger apoptosis
44
additional effects of prenatal alc. exposure
- alters migration of surviving neurons (see heterotopias (clumps of neurons in the wrong part of the brain)
- genes as'd w thyroid hormone + retionoic acid receptors affected; increased biol rxns to stress, linked to increased risk of anx, depression, poor coping skills
45
alcohol withdrawal
-severe, more likelyl to cause death than w/drawal fr heroin/other hard drugs
4 stages
1. tremors, rapid heart beat, hypertension, heavy sweating, apeptite loss, insomnia
2. hallucinations
3. delusions, delirium, dosirientation, amnesia
4. seizure activity
-delirium tremens, DT, (stage 3/4) peaks 3-4 days after last drink
46
drugs to treat alcohol withdrawal
- sedatives such as benzodiazepines can prevent stages 3/4
- clonidine (agonist at presyn. adrenergic alpha2 recept) prevent excessive NT release
- propanolol (beta adrenergic receptor antagonist) blocks excess. sympa. activity, slowing heart r8 + reducing tremors
- disulfiram (inhibits aldehyde dehyd., but results in high lvls of cetal theat cause headache, nausea, flushing-questionable efficacy + morality (will it cause cancer??), doesn't stop craving)
47
alcohol and opiods
- alc increases release of endog. opiod endorphin in VTA and NAc
- na
48
solvents and inhalents
products w volatile chemicals
solvents-used to remove grease and oil
fuels-propane, gasoline
propellants-nitrous oxide, fluorinated HC
anesthetics-chloroform + ether, nitrous oxide (whipped cream cartridges)
-grouped by admin. method (they have little structural similarity)
49
sedative/inhalant effects
-init, ethanol-like inebriation effect
-seems to be 2 phases of intox, like eth(low dose-DA excitation, inhib of inhib circuits, high
dose inhib neuronal activity, stop breathing, induce coma)
-init, euphoria, dizziness, disinhibiton, impaired judgment, recklessness, lasts 15-45 min and followed by 1-2 hrs drowsiness
-low lvls: motor excitation (sedate/anesthetize high lvls, also hallucinations/coma/death)
-the only depressants that produce hallucin.
50
solvents
typically contain a mixture of compounds, including aliph. HCs, aro. HCs, chlorinated HCs (tetra and trichloroethylene, used in dry cleaning supplies ), ketones (acetone)
51
solvent administration
- direct inhalation from container (risk of lung damage from the pressure)
- soak cloth and hold over face
- fill bag/balloon/etc + inhale (sniffing, bagging, huffing)
- can cause asphyxiation, lung damage, hypoxia (nc ur breathing in a ton of NOT oxygen)
52
solvent absorption and excretion
- highly lipophil, so quickly delivered to and removed from brain; short acting, so need constant admin for sustained effects
- rate of abs/excr. determined for most volatile substances down a conc gradient (enter the blood when lung conc is high and diffuse out vice versa)
- highest amts delivered to fatty tissues w good blood flow (brain, liver)-body fat has poor blood flow so get rel. little
53
solvent metabolism
less volatile solvents (that are not exhaled) are metab'd by CPY2E1 enzymes in liver to hydrophil. + excreted in urine (ex. solvent toluene is only 20% exhaled-instead, metab'd to benzoic acid but this can conjugate w glycine to form hippuric acid which can lead to acidosis)
54
inhalants and NMDAR
- inhalants decrease activity of NMDA (Glu) receptors, esp those which contain NR2B subunits
- the prevents less ions from flowing thr the integral ion channels
55
nicotinic Ach receptors AHHHH
-expressed in xenopus oocytes
56
inhalants at GABAA and glycine receptors
-inhalants seem to produce sim. effects as alc.
-oppose what's seen w NMDA and nicotinic receptors
-in presence of GABA, produce direct enhancement of GABAAR
in present of glycine, direct enhancement of glyrice R func.
57
adverse effects of inhalants
- risk of burns and suffocation as most are heavier than air + pool in lungs
- 'sudden sniffing death' due to cardiac arrhythmia (esp w toluene, which inhibs cardiac volt-activ. Na channels + butane, which sensitizes heart to effects of adrenaline
- freezing of vagal nerve (from release directly into throat) which irritates the nerve, resulting in more Ach release than normal w acts at Ach receptors in heart tissue to event. slow heart + produce cardiac arrest
58
acute toluene (solvent) exposure
- ado. + adult rats treated w toluene and periodically measured loss of pyram. neuronal cells in hippo.
- day after treatment, adults saw little death while ados saw stat. sig decrease
- after 40 days, ado neuronal loss had mostly stabilizes, while adult loss had increased
- neuronal death also correlated w mem loss
59
chronic toluene (solvent) exposure
- as hippocampal neurons adapt (4 days), NMDA receptor agonists have greater response (which may cause excitotoxicity and brain dam.)
- response of GABAAR recpetors to GABA is decreased
- overall, hyperexcitable brain in absence of solvent; cessation can therefore lead to seizure + death
- see an increase in size and density of NR1-containing NMDAR cluster levels (opposite response in GABAAR)
60
solvent/inhalant brain damage
-imaging shows more structural damage caused than in many other drugs
-dam. conc'd in white matter (demyelination)
-corpus callosum (biggest white matter tract) most severely affected
-defects in white matter -vely affect mem, lang., processing speed, + manifesr as type of dementia
-early destruction of cerebellar white matter linked to cerebellar ataxia
chronic damage: 2-5 hexanedione, a hexane metabolite, cross-links lysine (AA) in neuronal cytoskel. proteins (cuasing axonal damage), esp in neurons w long processes (periph.); result in tingling in hands/feet as cell body projections damaged, + if no nerves reach muscles in arms/legs they eventually atrophy
61
sedative hypnotics
depressants, which generally increase effects of GABA in CNA + depress neuronal excitability, and clinically used to some degree
ex.
- benzodiazepines (Librium, Xanax, Valium, Ativan)
- benzodiazepine-like (zopiclone/lunesta, zolpidem/ambien, zalepon)
- GHB (Gamma-hydrocybutyrate and precursors), used to treat narcol.
62
sedatives and GABAAR
* reminder that GABA binding site is at the alp-beta interface*
- benzodiazepines bind at alph-gam interface (most commonly a1 +g2)
- benzo binding increases recept. affin. for GABA and increases freq. of channel opening (allostery)
- benzo-binding GABAAR conc'd in cerebral cortex, striatum, cerebellum
63
benzodiazepines: clinical use
high dose: sedation, hypnosis (madazolam also a common anesthetic agent)
low-med dose: muscle relaxant
low dose: anxiolysis
-also treat seizures in emergencies
-at peak of use, 10-20% of N. americans taking benzos on the daily
64
benzodiazepines: structure
7-membered rings, Ns in pos. 1 + 4 (diazepine structure), pendant phenyl (benzo)
-librium and valium are long acting
(they form active metabolites)
-those w triazole grps allow rapid metab + clearance w/o form. of active metabolites
-trialozobenzos also linked to more adverse CNS effects (amnesia, cog. impairment) bc of high high affin. for receptors
65
benzodiazepines: effects and use
- along w clinical effects, some report eupohria, tho that seems to be linked to ppl w history of sedativy or opiod abuse
- tolerant abusers can take up to 40x clinically rec'd dose
- abuse linked to impaired driving, car + other accidents due to sedative effects
- cocktails of benzos + opiods can be incredible dangerous
66
benzodiazepines: memory
- can cause complete loss of recent events (useful for surgical anesthetics)
- prevent transferrence fr short to long term mem
- mem issues can persist moths after discontinuation
- mediated mostly through receptors w a1 subunits
- along w sedative effects (and esp when combined with alcohol, these become effective date rate drugs (rohypnol/flunitrazepam)
67
floppy infant syndrome
- benzos have rapid placental transfer bc they're highly lipophyl.
- since fetal liver metab is minimal, half life of drugs is increased, resulting in sig. accum. in the fetus, typ. 2x the lvl found in the mother
- causes loss of muscle tone, making them unable to nurse which can result in malnutrition
- effects can persist for months following birth
68
benzos and the VTA circuit
- normally, GABA acts on GABAAR to produce some inhib. tone
- in presence of benzos, magnified inhib at GABA-releasing neuron (less inhibitory GABA released onto DA releasing neurons)
- result: increased DA release from the VTA onto the NAc
69
what genetically engineered mice tell us about benzo effects on GABAAR
-mice engineered to prevnt binding to a-subunits tell us that:
a1 must be important in anti-convulsion, amnesia, and sedation
a2 must be important in anxiolysis (also myo-relaxation)
a3 must be midly involed in myo-relaxation
a5 must be moderately involved in myo-relaxation
70
benzodiazepines: tolerance
- benzos notorious for producing tol (need increasing doses to achieve same effects)
- tol to antiseizure/hypnotic/sedative effects devs quickly (days-weeks)
- tol to anxiolytic effects devs mch slower (3-4 months if at all)
- repeated exposure changes types/numbers of GABAAR
- chronic use linked to depression + violence
71
benzodiazepines: withdrawal
- can be fatal (hyperexcitable brain in absence (pharmacodyn tol))
- short acting drugs produce worst but shortes w/drawal symptoms
- cold turkey on long lasting drugs: sympts may dev. weeks later, last longer, but are milder
- tapering fr rel. short acting (ex. midazolam) to long acting (diazepam) tbest to avoid mini-w/drawals
72
flumazenil
a GABAAR benzodiazepine site antag which can treat benzo overdose
73
GHB; 1,4-butanediol; gamma-butyrolactone
- sedatives
- at low doses, lower inhibitions and produce euphoria
- all structurally similar to GABA, which produces strong sedative effect
- seem to act as antagonists at GABABR
- 1,4-butanediol (less lipophyl. than GHB, longer acting but lower potentcy) , gam-butyrolactone (more lipophyl. than GHB, enters + exists brain more quickly, more potent) and GABA are all metab'd to GHB in the body
- GHB also called Grievous Bodily Harm, liquid ecstasy, liquid X, liquid E, E2), Georgia Home Boy
- all cause unconsciousness + mem loss when combined w alc, maybe even coma/death due to resp. depression
- w/drawal sympts: anxiety, muscle cramps, twitching
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where does GHB act?
- at nat. occuring low doses, activates the postsyn GHB receptor (unclear whether that's a sodium channel, specific receptor, etc)
- at high doses, see activation of pre and postsyn a4, b3 or b3-containing GABAAR that decrease excitability by inhib-ing Ca influx + opening K channels; seems to inhibit Glu release
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dangers of GHB
TI may be as low as 2, means can easily reach dose that results in coma, resp. depression, and death, esp if taken in combo w other depressants
-users have hard time judging correct dose + can often be injured when they lose consciousness
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an overview of tobacco use
- globally, 47% of men and 12% of women smoke
- use in industrialized nations is decreasing while it increases in developing nations; by 2020 85% of smokers will be in devel. countries
- 9% of canadians smoke
- smoking linked to 5.4 mil. death/yr (9% of all deaths)
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tobacco
most N. american products fr Nicotiana tabacum species
- contains nat occuring chems (nicotine (the addictive substance, a neurotoxin made by plants to kill insects (a naturally occurring pesticide), carotenoids), side products from curing process, chems added for palatability
- 4000 new chemical combustion products are created by burning tobacco and many are linked to cancer
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what's in the tobacco smoke?
- tar (particulates of combustion product, rich in polycy. aro HCs, nitrosamines, other harmful chems); single cigarette exposes lungs to 10-40mg particulate while a heavy smoker will have ~1g of tar deposited/day
- >the tar coats everything, binds in the alveoli, no good way to remove; maximal lung damage found in biopsies is nearest tar deposits
- ROS + RNS (ex notric oxide, NO, which can react w other radicals to dam.lungs cells and is a key mediator of lung injury) (tar deposits have high density of rel stable forms)
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cigarettes: intentional additives
-theobromine + glycyrrhizin are brochodilators (impart sm flavor but also increase amt nic that delivered w each inhalation)
sugar-containing additives (harmless on their own, but when burned can make acrolein (modifies DNA + protein) and acetaldehyde (though to inhibit MAO and boost NT lvls)
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menthol
- "counter-irritant" (cooling/icy cold feeling, from interaction w TRPM8)
- TRPA1 (nerve ending that sense pain + temp) in airways are acted on by acrolien, triggering coughing reflex; menthol interacts w TRPA1R to inhibit activation by acrolein + other irritants, reducing coughing)
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cigarettes: unintentional additive
- from growing, handling, processing
- conveyor fragments, insect bits, pest + herbicide, heavy metals (which nic plants are v good at concentrating fr soil), bacterial + mold toxins, radioactive elements (to stop N fr getting into nic plants and ensure flavor is most appealing to customers, 'starve' by feeding P-rich fertilizer (apatite) which contains radium/rad. isotopes of Pb/polonium (poten. carcinogenic))
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electronic cigarettes
- don't contain tobac/require combustion; designed to deliver pure, inhalable nic, to help ppl quit cigs
- battery-powered atomizer heats up and vaporizes a nic-containing liq. stored in a cartridge
- satisfy lots of behav. cues as'd w smoking (raising cig, puffing (as opposed to say nic gum)) but we're seeing kids start here and graduate to full-blown tobac use
- concerns abt inhalation of propylene glycol (the nic solvent in some cartridges), evidence of some nitrosamines (DNA-mod-ing chems), also increasing evidence that nic itself may enhance cancer growth, may also increase vuln. to viral infect.
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popcorn lung
- obliteration of respiratory tissues (bronchiolitis oblierans) in workers in buttered popcorn factories from inhaling so much diacetyl in the flavouring
- diacetyl also found in many flavoured e-cigs
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hookah
- shisha often tobacco base w added ingredients use via hookahs (water pipes)
- the shisha is heated but not burned (so theor. no combustion products??) then passed thr the water to cool and this ther. removes some of the irritants before inhalation
- 1 g shisha produces 11x more CO than 1 g cig tobac tho, which can displace O2 from hemoglobin and put stress on cardiovasc system
- smoke still contains certain carcinogens at same or higher lvls than in cigs, causes increased heart r8, BP, risk of oral + lung cancer, leads to lung disease
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nicotine
-facilitates addiction
mimics Ach at AchR (agonist, binds to same site on the receptor as Ach)
-charged at low pH
-doesn't appear to initiate cancer growth, but may enhance it
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nicotine and pH
-nic is a weak base and its charge depends on pH; cigs w high customer retenion generally have nic in its unprotonated, free-base form, which is highly lipophyl (most easily crosses the lipid bilayer and is most quickly taken up into the blood) and volatile (easily release fr burnt tobacco) ((tho once in blood, some will likely be converted to monoprotonated for)) (((diprotonated form doesn't occur while smoking)))
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nicotine administration
- a few drops (60g) of pure nic on the tongue will kill a healthy adult
- 1 cig contains 0.5-2 mg nic; smoker gets a fraction (sidestream spoke, pyrolysis, filter, etc)
- most ppl smoke 1-2 puffs/min, each lasting ~2s and delivering 1-2 micro g/kg body weight (ppl smoking a pack a day then take 100-200 puffs)
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24 hours nicotine levels
- peak at end of smoking day
- see accumulation thr/out as new drug is added before previous drug removed
- constant nic exposure desensitizes receptors; they resensitize overnight which is likely why the first few puffs of the day are the most euphoric
- a study using a tracer that bind a4b2 receptors indicates that 1-2 puffs sufficient to occupy 50% of receptors, one full cig=80% occupancy (avail. receptors are quickly saturated)
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Nicotine Replacement Therapy (NRT)
- aim to give pure, safer version of the addictive ingredient
- huge industry (800 mil/yr) but efficacy is questionable + many studies show no improvement in relapse r8 compared to quitting w/o NRT
- none of the replacement options give the same peak conc of nic, nor do they satisfy behavioural cues
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nicotine metabolism
CYP2A6 converts 80% of nic (w a 1/2 life of 2 hrs) to cotinine (more water soluble, w a 1/2 of 16 hrs-can be used as marker for direct + 2nd-hand smoking)
- monooxygenases convert sig. smaller percent to nicotine-1'-N-oxide
- mutation in CYP2A6 that slows metab results in lower tobacco use and an easier time quitting bc nicotine builds up and high nic lvls are aversive
- either nic or other components of the tar induce these enzymes to metab the nic, and therefore may be responsible for some tol.
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neuronal nicotinic Ach receptor
- from the same family as glycine and GABA receptors, composed of alpha and beta subunits
- integral cation channel opens when triggered by nic, letting Na + K flow into the cell and depolarize
- each has 2 nic binding sites at the a-b interface (same site where Ach usually binds)
- can be pre and postsyn in CNS, and postsyn at neuromusc. junctions
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mechanism: nicotine at nicotinic receptors
when activated:
- postsyn neurons will quickly depolarize and cause cellular excitation (neuromuscular)
- presyn neurons will induce release of NTs (DA, Glu, GABA, nora, 5HRT, and others) ((neuronal))
- either way, neurons quickly desensitize (w/in s/min) if continually exposed to the agonist
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nicotinic receptor subtypes, reinforcement and reward
- mutations in a4 make animals hypersensitive to nic effects (either by increasing OR decreasing behaviour)
- if you knock out the b2 subunit, nic no longer causes DA release and self-administering behav. ceases
- antagonists for a4b2 receptors block rewarding effect of nic (so this subtype likely most important in DA release)
- a7 also plays a role in controlling Glu release
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nicotinic receptor desensitization
- those that are on GABA releasing neurons, typically a4b2, are v sensitive to nic-induced desensitization (desens. in under 60s) , leading to decreased GABA release; desens'd state lasts 1 hr
- those on Glu releasing neurons, usually a7-containing, aren't sensitive (in fact nic still activates them)
- indirectly, this stimulates release of DA from dopaminergic neurons under control of both GABA and Glu
- receptors directly on cell bodies of DA-releasing neurons in the VTA can be activated by nic which shifts them into a burst-firing mode (greater DA release to NAc)
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effects of cigarettes and nicotine on other systems
- cig smoke inhibs monamine oxidase (MAO) via acetaldehyde (which forms beta-carbolines like harman known to inhib MAOs); this prevents degradation of NTs and results in increased DA, adrenaline + nora. lvls whic boosts the reinforcing effect of nic
- nicotine itself isn't directly involved in that
- note than many (archaic) antidepressants work by inhibiting MAO
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nicotine tolerance
w chronic exposure, nicotinic receptor numbers increase, w a4b2-containing receptors being the most strongly upregulated
-may cause increases sensitization to nic esp. when receptors are resensitized (BUT Ach is meant to act at those receptors and desens. renders them mostly non-functional so the brain tries to compensate by making more even tho nic is an agonist)
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tar
- sticky, adheres to cells in and disrupts airways (plugging fine ones, causing mechanical issues, etc)
- full of carcinogens such as planar, polycyclic aros that can insert themselves btw bps in DNA and introduce mutations
- causes cilia that line airways to stop beating in unison, prevent debris from being cleared from lungs (overnight, cilia partially recover which is why heavy smokers cough so much in the morning before they've had their first cig of the day)
- also see inhib of phagocytes (immune cell) so less able to fight out invading orgs, more prone to pneumonia + other lung diseases
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nicotine and cancer
-nic seems to support pro-cancer effects in non-neuronal cells (can inhib programmed cell death (by activating a7 receptors in mito that prevent apoptotic initiation), promote cell prolif, perhaps cause mutations by stiming prod. of ROS), but doesn't init.
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benzo[a]pyrene
- planar, polycyclic aro produced by incomplete combustion of tobacco and is a procarcinogen; lots ends up in tar
- gets metab'd to active form w highly reactive epoxide group; inserts into DNA and covalently binds guanine, causing bulge in helix + faulty replication
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NNN + NNK
- nicotine derivates found in cig smoke formed during curing + burning
- nitrosamines formed by nitrosation of nicotine
- can cause cancer directly (covalent mod. of DNA after further metab.) and indirectly (init. prolif. pathways, inhib repair pathways via nicotinic Ach receptors; they bind more tightly than nic and are agonistic)
- originally thought that they were only formed fr curing/smoking, but nic may be directly metab'd to NNN + NNK in the body as ecig users still seem to show trace amts (albeit like 3% of what cig. smokers see) ((see also: exposure to e-cig smoke induces lung cancer))
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bupropion (zyban)
- originally used as an antidepressant
- seems to produce moderate inc. in DA + nora lvls by inhib-ing removal fr synapse or increasing releast
- bupropion and at least one of its metabolites lock the nicotinic receptor in closed state (by binding in the channel itself), preventing ions from entering even in present of nic, which seems to address some craving issues
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varenicline (champix)
- partial agonist at a4b2 nicotin. receptors (results in 30-60% of max possible activation) which blocks effects of nic added to system
- seems to reduce craving and reinforcing effects of smoking by partially substituting for nic, but now has warning bc of increased risk of suicide, hostility, aggression, and bc drinking may make neurophsychiatric events worse
- success may be as low as 14%
