Unit 3 - Non-Medicinal Drug Use

Question 1

what are the CNS depressants and how do they work?

Answer 1

augment activity at GABA-A receptor complex, increasing Cl- influx, hyperpolarizing cell (inhibitory)
-include alcohol, barbiturates, benzodiazepines, and inhalants

Question 2

alcohol absorption?

Answer 2

very rapidly absorbed by diffusion through membranes

• very small molecule that easily crosses membranes
• -mouth mucus membrane, stomach, small intestine (most here)
• -lungs absorb alcohol vapor

Question 3

what does the rate of alcohol absorption depend on?

Answer 3

1. concentration of alcoholic beverage

2. stomach (empty has higher and faster peak, slower drop; full has lower and slower peak)

Question 4

what does food in the stomach do to alcohol?

Answer 4

1. dilutes alcohol
2. delays stomach emptying
3. increases effective rate of alcohol metabolism
   - some enzyme oxidation in stomach
   - slower delivery to liver through portal circulation > liver oxidation

Question 5

what are blood alcohol units?

Answer 5

BAC (blood alcohol concentration)

• based on plasma or serum in hospital, or whole blood legally
• 100 mg% = 100 mg/dL = 1 mg/mL = 0.10% (wt/vol) = 22 nM

Question 6

explain alcohol distribution?

Answer 6

total body water, as small molecule can easily cross all membranes

Question 7

how is alcohol eliminated?

Answer 7

90-98% metabolized (oxidized)

-routes are urine, breath, and sweat

Question 8

how is alcohol metabolized?

Answer 8

mostly in liver, some stomach

• small intestines > portal circulation > liver
• alcohol dehydrogenase, acetaldehyde dehydrogenase, and microsomal ethanol oxidizing system

Question 9

what is alcohol dehydrogenase?

Answer 9

ADH - dimeric Zn-containing metallo-enzyme in liver cytoplasm, and a bit in gastric mucosa
-ethyl alcohol + NAD+ –> acetaldehyde + NADH + H+

Question 10

what is acetaldehyde dehydrogenase?

Answer 10

ALDH - 1 in liver cytoplasm, 2 in liver mitochondria

-acetaldehyde + NAD+ + H2O –> acetate + NADH + H+

Question 11

what is the “Asian flush” due to?

Answer 11

1. “atypical” B2 allele with enhanced rate of hepatic ADH (increases metabolism to acetaldehyde)
2. lack of functional ALDH2 causes build-up

Question 12

what happens if there is a high magnitude of alcohol consumed?

Answer 12

tremendous load for liver, causing dramatic change in redox state

• all NAD-dependent reactions in liver are affected by alcohol
• -impaired gluconeogenesis leads to hypoglycemia
• -increased lactic acid and ketone body production
• -inhibits uric acid excretion (hyperuricemia)
• -decreases fatty acid oxidation and increases TG and FA synthesis

Question 13

what is the rate-limiting factor in alcohol oxidation?

Answer 13

supply of NAD+; causes saturation (zero-order) kinetics results

Question 14

what is microsomal ethanol oxidizing system?

Answer 14

MEOS P450 (esp. CYP2E1)

• smooth ER mixed function oxidase
• more important factor at high levels of alcohol, and with chronic alcohol consumption
• induced by chronic exposure to alcohol and barbiturates

Question 15

what three drugs have cross-tolerance and what is it for?

Answer 15

alcohol, barbiturates, and benzodiazepines have X-tolerance for inhibitory neurotransmitter GABA-A and intrinsic Cl- channel
-opens Cl- channel –> hyperpolarizatin –> inhibition

Question 16

effects of alcohol on CNS

Answer 16

1. potency as a drug is very weak
2. CNS depressant - dose-related graded effects
   - mild mood alteration –> intoxication –> coma –> death
3. acute intoxication (mild or moderate)

Question 17

what is “mild intoxication” from alcohol?

Answer 17

“impairment”; 25-100 mg% BAC

• loss of inhibitions, altered mood, impaired cognition, incoordination, sedation
• due to preferential involvement of polysynaptic neuronal pathways in reticular formation (cerebral cortex, brain stem, cerebellum)

Question 18

what is “intoxication” from alcohol?

Answer 18

> 100 mg%

• diplopia, nystagmus, dysarthria, ataxia
• vestibular and cerebellar dysfunction –> stupor –> death
• blackouts are dangerous outcome
• temporal correlation between peak BAC and peak bheavioral effects, thus behavioral effects correlate with BAC

Question 19

between males and females, which have higher BAC?

Answer 19

women have higher BAC due to gastric metabolism and less body H2O

Question 20

what happens to the liver if chronic heavy drinking?

Answer 20

fatty liver, although uncertain pathology
-progression: lipid metabolism alteration –> fatty liver –> hepatitis –> necrosis –> fibrosis –> cirrhosis –> hepatic failure –> death

Question 21

what happens if there is constant exposure to acetaldehyde?

Answer 21

increase lipid peroxidation and damage to membranes and mitochondria

• depletion of glutathione and some vitamins
• alteration in protein transport

Question 22

wwhat are cardiovascular effects of alcohol?

Answer 22

most studies show moderate alcohol consumption is protective

• increases HDL to decrease CDH
• but all-cause mortality has U-shaped relationship (as other causes of mortality, caused by actions while intoxicated)

Question 23

effect of alcohol on dementia?

Answer 23

decreased dementia with 1-6 drinks/week compaired to abstaining

Question 24

what are GI and endocrine effects of alcohol?

Answer 24

1. GI irritation –> inflammation –> chronic gastritis
2. well-known diuretic effect from decreased secretion of antidiuretic hormone
3. stressor to stimulate adrenal cortex
4. decreased testosterone synthesis
   - male alcoholics –> hypogonadism and feminization, gynecomastia
5. suppresses uterine motlity and milk ejection

Question 25

explain what fetal alcohol syndrome causes

Answer 25

1. growth deficiency (pre- and postnatal body length and weight below mean) 2. dysmorphic characteristics (facial features, limb abnormalities) 3. CNS manifestations (neurobehavioral effects) - microcephaly, tremor, seizures, slow development, hyperactivity, learning problems, memory problems

Question 26

what are drug interactions with alcohol

Answer 26

1. pharmacokinetic interactions with many drugs - acute (while alcohol is on board): metabolism of other drugs will be inhibited if they undergo oxidative metabolism - chronic (induces P450, thuus metabolism of some other drugs may be enhanced, which also contributes to tolerance of alcohol) 2. pharmacodynamic interactions - additive CNS depression with other CNS depressants

Question 27

what is methyl alcohol and treatment?

Answer 27

windshield washer antifreeze - formaldehyde and formic acid are highly toxic metabolites --> severe acidosis - visual disturbances --> blindness - treatment = ethyl alcohol (to tie up alcohol dehydrogenase) + bicarbonate (to decrease acidosis state)

Question 28

what is ethylene glycol and treatment?

Answer 28

autommotive antifreeze - oxidized to oxalic acid, which is very toxic to kidney - -renal insufficiency - -acidosis - -CNS excitement --> depression

Question 29

what does disulfiram do?

Answer 29

inhibit acetaldehyde dehydrogenase, so that acetaldehyde cannot be converted into acetic acid -worsens their toxic effects, so used as alcoholism treatment

Question 30

what is treatment for both methanol and ethylene glycol poisoning?

Answer 30

1. ethyl alcohol (vodka; maintain 100 mg/dL) | 2. alcohol dehydrogenase inhibitor (4-methylpyrazole)

Question 31

what is isopropyl alcohol and treatment?

Answer 31

rubbing alcohol - causes gastritis, acidosis, and CNS symptoms - no antidote, so must use symptomatic and supportive treatment

Question 32

what are barbiturates?

Answer 32

multi-use, generally replaced by benzodiazepines - augment activity at GABA-A receptor complex to produce CNS inhibition - cause drowsiness, confusion, impaired judgement, slurred speech

Question 33

what are phenobarbital and thiopental?

Answer 33

barbiturates still in use today - phenobarbital: anti-seizure - thiopental: induce anesthesia

Question 34

what are benzodiazepines?

Answer 34

augment activity at GABA-A receptor complex to produce CNS inhibition - many benzos, and widely used to induce anesthesia, treat anxiety, sleep aids, and for recreation - cause alcohol-like drunkenness with relaxation, loss of inhibition, impaired judgement, and loss of short-term memory

Question 35

what are CNS stimulants?

Answer 35

amphetamine and cocaine | -increase CNS catecholamine, especially dopamine, directly or indirectly by several mechanism