Class notes
Study guide post midterm-end of course
- Course
- PCTH 201 (201)
- Institution
- University Of British Columbia (UBC )
Study guide including all lecture notes and reading notes post midterm
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PCTH STUDY GUIDE CONT’DALCOHOL - Class of compounds in science
- In society= specific drug (ethyl alcohol or ethanol)
- Fermentation byproduct of yeast and sugar
**consumption exceeds any other drug consumption including medicinal
15g/drink
- 1unit —volume of drink containing ~14g ethanol
ETHANOL DOSING - Effects proportional to concentration
- Blood alcohol concentration (BAC) = % (wgt/vol= g/100mL)
ETHANOL - Difficult to classify due to non specificity
PHARMACODYNAMICS - Effects occur in concentration manner
- Effects start from
frontal cortex to limbic At low doses = can be used as anxiolytic —higher logic areas of brain affected
structure and brain
stem last Higher doses (BAC)= role as sedative/depressant —CNS activity, slows you down, does not always
- Higher areas of brain mean feelings of depression
affected last (related to
survival) Very high doses= hypnotic role—passing out
*around legal limit= start to see greater inc in navigating heavy machinery (vehicles)
- Legal limit= .05
Has other non CNS effects
1. cutaneous vasodilation
- Inc blood flow to peripheries
- Feelings of warmth
2. Inhibition of antidiuretic hormone = more frequent urination
- Impacts preference for alcohol
- Ability to drink a lot vs less
GENETICS AND ALCOHOL - ~10% excreted unchanged
- Majority of ethanol metabolized via central pw: metabolizes any alcohol (ethanol, methanol) via
alcohol dehydrogenase (ADH) and produces = 2-C AcetAldehyde from which aldehyde
dehydrogenase = acetate (Can enter CAC)
METABOLISM OF ETHANOL - ~20% metabolized by CYP2E1
- Upregulation of this pathway is how pharmacokinetic tolerance is built
- Some metabolized through breathing
CYP2E1 pathway is easily saturated
- Zero order metabolism when this pathway gets saturated —constant amount of ethanol
metabolized per unit time (15g/hour)
- Processing speed of enzymes determines rate
Zero order kinetics = constant amount of ethanol metabolized per unit time (~15g (or 1 unit) per
hour)—this is amount enzymes can metabolize
- Alcohol dehydrogenase (ADH1) — found mainly in liver but also in stomach (men have more in
stomach than women)
Normally alcohol dehydrogenase variant 1 (ADH1) expressed —mostly in liver, some in stomach
VARIABILITY IN (males>>females in stomach)
METABOLISM - When ADHB*2 (variant 2) expressed instead = inc metabolism of ethanol
- Leads to greater production of acetaldehyde
, - This variant does NOT impact second enzyme, so there is an accumulation of acetaldehyde
- Mild toxicity = flushing of skin, tachycardia, nausea
Another variant (affects aldehyde dehydrogenase):
- Aldehyde dehydrogenase 2 (ALD2) metabolizes acetaldehyde
- ALD2 Most common isozyme expressed in liver
- ALDH*2 substituted with E487K (Lysine replaces glycine) substitution = 23x dec in affinity of
acetaldehyde to aldehyde dehydrogenase enzyme
- Completely kills enzyme’s job of eliminating acetaldehyde (97% reduction rate)
- Acetaldehyde cannot be metabolized as aldehyde dehydrogenase function
**acetaldehyde toxicity produced
- Chance of getting these variants depends if homozygous or heterozygous
- Both variants protective from alcoholism = less likely to attribute ethanol to pleasurable feelings
because you get sick every time you ingest(conditioned aversion)
- Prevalent in asians
Widmark formula (accounts for wgtm gender and amount of alc consumed)
CALCULATING BAC
- Females have lower amount of water volume for ethanol to distribute = higher BAC
eX: 120 pound woman, ingests 3 ounces of 40% vodka
30mL, alc .8/mL,
- Biphasic
- But in actual study there is only one peak —because does not account for tolerance and other
factors
Assumptions in calculating BAC:
BAC for population - Absorption —occurs in stomach and SI
- If big meal prior=slower absorption (delays gastric emptying), lower peak BAC
- Distribution —distributes total body water
- Hydration state causes variations
- Age, gender, body type
- Metabolism —goes through dehydrogenase enzymes
- Genetic variability
- Enzyme leads to induction
- Predominantly through liver = hepatic func.
- Also gastric enzyme effect
- Will also affect absorption through effects on 1st pass metabolism
- Excretion primarily through kidneys, little amount through lungs
- Fatigue, nausea, headache
- Can arise prior to full ethanol elimination—so not fully associated with withdrawal
Causes:
Dehydration = inhibition of antidiuretic hormone (ADH/vasopressin)
HANGOVER—veisalgia - Inhibition of concentration of urine by less reabsorption of water in kidneys
- Less water returned to plasma
- Effects sugar, electrolyte levels in body
, sleep disruption= reduced REM sleep—impacts learning, memory and mood
- Reduced onset of sleep, affects first half of sleep
- Restlessness due to glutamine = multifunctional AA/natural stimulant inhibited by alcohol
- Body responds by creating more (Acute tolerance)
- As alc dec, its inhib effect wears off = excessive glutamine prevents quality sleep
congeners/impurities
- Other chemicals/substances in drink
- methanol=competes with ethanol for metabolism= toxic metabolites
- Amines, amides, esters and tannins
- Most studies correlate darker drinks with worse hangovers
genetics 5-25% are hangover resistant
**acetaldehyde depletion likely contributes to occurrence of hangovers
LONG-TERM EFFECTS Tolerance:
- 2-3 fold reduction in effect of dose over 1-3 wk of admin
- Inc tissue tolerance and induction of enzymes
- Narrowed TI, but lethal dose does NOT change
dependence/withdrawal
- hangover=acute effects
- Chronic use 8-24 h post consump=severe symptoms include tremors, sweating nausea and
fever
Delirium tremens = confusion, agitated, aggressive, hallucinations
Supportive treatment = benzodiazepines
ALCOHOLISM
- Largest detriment to recreational use
- ~8% americans meet criteria
ALCOHOLISM HEALTH - Nutritional deficiency
EFFECTS - Irreversible neurological syndromes: dementia, amnesia
- Liver disease/cirrhosis = inhibit Citric acid cycle , NADH accumulation
- Inc FA release due to SNS stim = fat accumulation, hepatitis, necrosis/fibrosis,
- cirrhosis (fatty liver)
1st line treatments
ALCOHOLISM TREATMENT Naltrexone - Antagonist of opioid receptor
- Break associated - Longer half life, so better - Blocks reward cycle
reward - Dec urge to drink
Acamprosates - Mechanism not fully understood
- Multiple receptor effects
- Possibly NMDA antagonist or dec
GABAa activation
- Dec cravings/withdrawal
DISULFIRAM - Irreversible inhibition of aldehyde dehydrogenase enzyme = inc flushing, nausea, panic,
tachycardia
- Mimics ALDH2*2 polymorphism effect = protective against alcoholism
- Effective but NOT first line use = people would be resistant to taking it because wont receive
pleasurable feeling
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