Alcohol: The Biology, Chemistry, & Pharmacology Rochelle D. Schwartz-Bloom, PhD J. Suzanne Sikes, PhD Myra J. Halpin, PhD

Pharmacology principles Pharmacokinetics Absorption Distribution Metabolism Excretion

Pharmacology principles Pharmacodynamics How alcohol works Adverse effects Toxicity Drug interactions

Pharmacology is biology cell types cell membrane structure filtration, passive diffusion, active tr. R vs L circulatory system genetics

Pharmacology is chemistry polarity bond formation concentration gradient chemical reactions enzymes as catalysts

Alcohol Absorption

Absorption: Stomach vs Intestine greater surface area

Alcohol moves into the blood passively

Water moves through pores

Ethanol is small and polar

Ethanol has some non-polar character

Alcohol moves by filtration & passive diffusion

Alcohol moves into the blood passively

Water & small solutes move through holes in capillaries

Ethanol is distributed everywhere

Ethanol distributes into water spaces Males: low fat:water Females: high fat:water BAC: males < females

The blood-brain-barrier: Not for alcohol!

The blood-brain-barrier: Not for alcohol! Passive diffusion is key

Symptoms of intoxication

Symptoms of intoxication depend on brain region affected motor memory pleasure judgment risk impulsivity balance vomiting breathing, heart rate

Neurons fire electrical impulses

glutamate receptors GABA receptors

Alcohol depresses neuron firing

How does alcohol work? Glutamate increases firing Alcohol blocks glutamate receptors affects judgment reduces memory

How does alcohol work? GABA decreases firing Alcohol opens GABA receptors incoordination reduces memory slurred speech disinhibits (obnoxious!)

Alcohol increases Cl- entry into neurons through GABA receptor channels More negative charges inside the cell decreases firing

Blackouts: Disruption in the hippocampus Hippocampus = memory!

Alcohol can shrink the hippocampus

Alcohol decreases neurogenesis

Alcohol causes cell suicide (apoptosis)

….5 minute break

Getting rid of alcohol

The “first pass” effect: Metabolism in the stomach guys yes, girls no

The “first pass” effect: Metabolism in the liver guys +++, girls ++

Ethanol metabolism: oxidation x 2

All about acetaldehyde H3C C O H sweating rapid heart rate nausea dizziness headache hangover symptoms cellular damage

ethanol ---> acetaldehyde acetaldehyde ---> acetic acid Ethanol Oxidation Alcohol Dehydrogenase (ADH) ethanol ---> acetaldehyde Acetaldehyde Dehydrogenase (ALDH) acetaldehyde ---> acetic acid coenzymes : small non-protein ligands that catalyze reactions… +/- electrons,  transfer a group,  form or break a covalent bond

Ethanol binds to an active site London forces N What does an ES Complex do?             - holds substrate out of aqueous solution             - holds substrate in specific orientation, close to transition state to allow reaction to occur             - reduces ability of free rotation & molecular collisions with non-reactive atoms             - allows amino acid side chains to alter local environment:                         changes ionic strength, pH, adds or removes H-bonds to substrate   

Oxidation: ethanol loses 2 e- (a H atom) London forces N What does an ES Complex do?             - holds substrate out of aqueous solution             - holds substrate in specific orientation, close to transition state to allow reaction to occur             - reduces ability of free rotation & molecular collisions with non-reactive atoms             - allows amino acid side chains to alter local environment:                         changes ionic strength, pH, adds or removes H-bonds to substrate   

Many types of ADH & ALDH ADH: 7 proteins ALDH: 2 major proteins

ethanol ---> acetaldehyde Genetic Polymorphisms ADH1 ADH2 ADH3 ADH4 ADH5 ADH6 ADH7 Polymorphic (in liver) Monomorphic (in stomach) *1 *2 *3 ethanol ---> acetaldehyde Slow: increased risk of Alcoholism (Caucasians) Fast: decreased risk of alcoholism (Asians)

Exhaling alcohol and the Breathalyzer

Alcohol vaporizes in the airsacs

Alcohol vaporizes easier than water Less H bonds to break

Why teach about alcohol?

Biology….. cell types cell membrane structure filtration, passive diffusion, active tr. DNA structure, protein synthesis R vs L circulatory system genetics

& Chemistry polarity bond formation concentration gradient chemical reactions enzymes as catalysts