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Hypnotics

Alcohol - The most commonly used Sedative- Hypnotic. • Probably the oldest psychoactive used by humans. • use is common our society. • ≈ 2/3 of people drink. • ≈ 10% are “problem drinkers” • ≈ 5% are “alcoholics”

What is alcohol? • A compound composed of Carbons, Hydrogens, and a Hydroxy group. • Ethyl alcohol is only one of many different .

H HH H H H CCCH H CCOH H OH H H H Ethyl Alcohol Isopropyl Alcohol ()

1 Production of ethanol • Produced by fermentation. • Yeast converts sugar (glucose) into ethanol. • Type of sugar determines beverage. • Fermentation is limited to producing ≈ 12% ethanol. • Distillation produces higher ethanol concentrations (distilled spirits). • Ethanol concentration measured in “proof”.

Measuring the amount of ethanol in the body. • Alcohol Content (BAC) • grams of ethanol / 1 ml of blood. • .001 g ethanol / 1 ml blood = 0.10% BAC

• 0.08 BAC - Legal driving limit in CA.

Crude method for calculating 0.08 BAC • 1 “standard drink” / 50 lbs. of body weight. • 1 drink = .6 ounces of pure ethanol. • 1.5 Ounce of distilled spirits. • 5 Ounces of wine. • 12 Ounces of beer.

2 Problems with estimating BAC • Body weight isn’t a good measure. • Fat contains less ethanol. • More fatty tissue = higher BAC.

• The “standard drink” may not be standard.

Behavioral Effects of Ethanol

Low Dose of Ethanol • 0.05 BAC Disinhibition Light Impairment of judgement Lowered Alertness Feelings of

Behavioral Effects of Ethanol

Moderate Dose of Ethanol • 0.08 BAC Legally intoxicated in CA

• 0.10 BAC Slowed reaction times. Impaired motor coordination Gross judgement impairment.

3 Behavioral Effects of Ethanol

High Dose of Ethanol • 0.2 BAC Severe motor disturbances. Severe sensory disturbances. Memory Deficits

Behavioral Effects of Ethanol

Very High Dose of Ethanol • 0.3 BAC Stupor. • 0.35 BAC Surgical • 0.4 BAC LD50 by respiratory depression.

Ethanol is a “dangerous” drug. • Therapeutic Index is < 10

•ED50 of ≈.05 BAC (or greater)

•LD50 of ≈ .4 BAC

4 Pharmacokinetics of Ethanol • Lipid soluble enough to be easily absorbed. • Crosses the BBB easily. • Not lipid soluble enough to dissolve into fat. • Circulates until metabolized.

Ethanol Absorption •Stomach ≈ 10% • Small intestine ≈ 90%

• Duration in the stomach can affect the onset of intoxication. • Food • Carbonation

Ethanol

Ethanol Alcohol dehydrogenase

Acetaldehyde Aldehyde dehydrogenase

Acetic Acid

HO2 CO2

5 Site of Ethanol Metabolism •Stomach (≈10%-20%) via alcohol dehydrogenase in stomach. • Stomach metabolism is affected by: • Duration of drug in stomach. • Amount of alcohol dehydrogenase. •Liver (≈ 80% - 90%) via alcohol dehydrogenase and other enzyme systems. • First pass metabolism eliminates ≈ 40% of ethanol.

Ethanol is metabolized at a fixed rate. • Doesn’t follow half-life rule. • Limited by amt of alcohol dehydrogenase. • BAC drops ≈ 0.015 points / hour • ≈ 1/4 drink for every 50 pounds of body weight.

Pharmacodynamics of ethanol. • Ethanol has a VERY low potency. • Moderate dose of 30 grams. • 1500X less potent than cocaine.

• This is evidence for very nonspecific effects.

6 Ethanol is a “Dirty” Drug. • Membrane Fluidity • Glutamate Antagonist • GABA • R015-4513 - GABA antagonist that “reverses” ethanol intoxication. • Acutely facilitates release. • Naltrexone (ReVia) as treatment of alcholism. • Facilitates dopamine release.

Other notable physical effects: • Suppresses release of antidiuretic hormone (ADH). • ADH causes the kidneys to retain water. • So the effect of suppressing ADH is...

Acute Toxicity • Death through respiratory depression. • Vomiting or “passing out” usually prevents death. • Consuming large amounts very quickly can defeat this protective mechanism.

7 The dreaded “” • Symptoms: • Headache • Thirst • Body Aches • Nausea and Vomiting

Possible causes of • Toxic byproducts of ethanol metabolism. • Acetaldehyde • Congeners • Dehydration • Digestive Tract Irritation • Deprivation

• Acute Ethanol Withdrawal? • “hair of the dog that bit you”

Chronic Toxicity • Liver Disease • Alcohol-Related Fatty Liver • Alcoholic Hepatitis Normal Liver • Cirrhosis (scarring) • ≈75% of alcohol related deaths.

Cirrhotic Liver

8 Chronic Toxicity continued... • Brain Damage - Heavy, chronic use probably leads to death of brain cells.

Chronic Toxicity continued... Organic Brain Syndromes • Wernicke’s Disease • Confusion and deficits of coordination. • Caused by a (thiamin) deficiency.

• Korsakoff’s Psychosis • Loss of memory for recent and new events. • Confabulation

Brain Damage continued...

Besides organic brain syndromes are there less obvious impairments? • No effect on Verbal Intelligence. • Deficits in Abstract Reasoning. • Visual-Spatial Abilities • Logical Thinking • Cognitive Shifts • Card Sorting Tasks

9 Other examples of chronic toxicity • Damage to most other organs. • Heart • Pancreas • Production • , especially when combined with use. • Harm to the fetus.

Beneficial Effects of Ethanol

• 1-2 drinks a day might prevent heart disease and strokes. • Reduces blood clotting. • Raises HDL cholesterol. • Psychological benefits?

• However, risk due to accidents, cancer, etc… negate all or most of this benefit.

Tolerance, Addiction, and Withdrawal • Tolerance developed from regular use. • Due to all 3 mechanisms.

• WARNING: Tolerance to lethal effects develops slower than tolerance to other effects.

10 Psychological and • Alcoholics account for 20% of people treated by psychiatric facilities. • Animals will self-administer. • Promotes DA transmission in nucleus accumbens.

• Ethanol withdrawal can be serious. • Starts within a day and lasts for 1-2 weeks.

Mild symptoms of ethanol withdrawal: • Anxiety, Tremor, Rapid Heartbeat,

Serious symptoms of ethanol withdrawal (5-10%) • (DTs) • Hallucinations, Delusions, Seizures • About 30% of untreated DTs are fatal. • Preferred treatment for DTs: • Long acting (e.g., ) before DTs develop.

Barbiturates • Earliest medically prescribed sedative- hypnotic. • Originally used to reduce anxiety, produce and anesthesia.

11 3 categories determined by lipid solubility and fat depot binding.

Category Onset Duration Example Ultra short 10-20s 20-30 min Thiopental Acting (Pentothal)

Intermediate 20-40 min 5-8 hrs Acting (Nembutal)

Long Acting 1+ hrs 10-12 hrs (Luminal)

Pharmacokinetics determine clinical use. Class Used for/treats Ultra short preanesthesia

Intermediate anesthesia, insomnia (formerly)

Long Acting seizure disorders, anxiety (formerly)

Safety • are fairly dangerous. • High Risk of overdose (low TI). • Risk is much higher when combined with other sedative-hypnotics. • Shared pharmacokinetic and pharmacodynamic features. • Strong potential for tolerance and addiction. • Medical use has greatly diminished.

12 of barbiturates. • GABA binding normally causes Cl- influx and IPSPs.

• At low-moderate doses, barbiturates increase the duration of Cl- channel opening. • At high doses, barbiturates activate GABA receptor directly.

Inhalants - Psychoactive substances that are volatile (a gas) at room temperature.

Categories of • Gas (e.g., Nitrous Oxide, Halothane) • Easier and safer than barbiturates for general anesthesia.

Inhalants of Abuse • (glue, paint thinner, correction fluid. • Aerosols (hair spray, butane) • Anesthetics (nitrous oxide, halothane)

13 abuse can cause: • Euphoria • Hallucinations • “Ethanol-like” intoxication

High doses or chronic use can cause: • Heart or liver failure. • Anoxia (lack of oxygen to brain) • Seizures • Brain Damage

“Date-Rape” • (Rohypnol) • Benzodiazepine used in other countries as a sleep aid. • Very potent. • Defensive beverage selection. • Gamma Hydroxy Butyrate (GHB) • Endogenous . • Can be illegally synthesized. • May be useful for narcolepsy.

These drugs exert classic sedative-hypnotic effects. • Euphoria • Disinhibition • (Blackouts) • Unconsciousness • Respiratory Depression

• Effects are greatly enhanced when mixed with alcohol.

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