Depressant DrugsPart 1

Kim Edward Light, Ph.D.

Professor, College of Pharmacy

University of Arkansas for Medical Sciences

Objectives – part 1 Discuss general nature of depressant drugs. Discuss origins and effects of ethyl alcohol. Determine alcohol dosage of different beverages. Discuss the ADME of alcohol. Discuss alcohol pharmacology. Relate alcohol effects with blood alcohol

concentrations (BAC). Discuss the nature of alcohol impairment. Identify the time course of BAC and estimate the time

for total alcohol elimination. Discuss the impact of alcohol use on society.

Depress-ant® Drugs

Alcohol Barbiturates Benzodiazepines Non-benzodiazepines Methaqualone Meprobamate Glutethimide Chloral hydrate Antihistamines (some) Narcotics – opiates

Depressant Drugs - Depress Cognition, judgment, self-control Vision, hearing, touch, smell, taste Coordination – speech, balance, movement Awareness and wakefulness Memory (amnesia) Consciousness

Depressant Drugs

Therapeutic Uses (does not apply to all) Anxiety & nervousness. Sedation. Acute panic disorder. Seizures. Insomnia and related sleep disorders. Acute and chronic pain (opiates).

Adverse Effects - Acute

Impaired ability to operate machinery or motor vehicles.

Social disinhibition CNS depression Increased risk of accidental injury or death Amnesia Coma Respiratory arrest

Adverse Effects – Chronic

Synergistic effects when used in combination with other drugs

Prolonged CNS depression Dependance and withdrawal

Ethyl Alcohol

2 carbon simple molecule. Fermentation of sugar by yeast. Alcohol concentration ~14%. Distillation required for higher

concentrations.

Proof Alcohol content expressed as

“proof” Ignition of gunpowder soaked

with the beverage Requires at least 50% alcohol.

Proof is twice the % of alcohol 100% alcohol = 200 proof 80 proof = 40% alcohol

Alcohol Availability

Wide variety of products beverages medications (cough syrups, cold medicines) mouthwashes

Beverage alcohol ranges

3% → 150% Size of a single “drink” is inverse proportion to

alcohol content.

Alcohol Dose Cannot be standardized into a simple unit or

“drink.” Compute grams:

%alcohol (as a decimal) x total volume (in mL, 1 oz = 29.6 mL) x density of ethyl alcohol (0.789 g/mL).

Formula: (mL consumed) x (%alcohol) x 0.789 = grams of alcohol consumed.

Dose Per Drink 1 can (12 oz or 360 mL) beer at 5%

contains 14.2 grams {(360mL*0.05)*0.789=14.2}

1 shot (1.5 oz or 45 ml) 80 proof spirits (40%) contains 14.2 grams

{(45mL*0.40)*0.789=14.2}

1 glass (5 oz or 150 mL) of 12% wine contains 14.2 grams

{(150mL*0.12)*0.789=14.2}

Absorption Primarily absorbed in the duodenum Rate is extremely variable Peak blood alcohol concentration (BAC)

depends on: Volume & %alcohol Rate of drinking Food consumption and composition Gastric emptying (CO2 promotes) Gastric metabolism Hepatic first pass metabolism

Distribution

Total Body Water BAL or BAC (blood alcohol level or

concentration) is expressed as grams alcohol per unit volume g/100mL -- g% -- %

Total Body Water

Total body water based on size and sex. Males more water/pound than females

♂ ♀ ♀

Alcohol Concentration

[Alc] = (dose x 100) / (bw x r)

The “r” (Widmark's rho) represents the percent of body weight that is composed of water. r=0.55 (SD +/- 0.055) for females; r=0.68 (SD +/- 0.085) for males; Dose and body weight (bw) in grams; 1 pound= 454 gms

BAC = [Alc] x 0.81 Adjusts for percent of blood that is water.

Less than 5% of total dose is excreted unchanged urine, breath, sweat, etc.

Liver is primary metabolic site Alcohol dehydrogenase (ADH) +

Aldehyde dehydrogenase (ALDH) Genetic differences – Asians, Am. Indians Calories - 7.1 kcal/g Calories - 7.1 kcal/g

(protein & carbohydrates = 4.1 kcal/g; fat=9.0 kcal/g)

Metabolism

Metabolism

Catalase system & Cytochrome P450 system (esp. CYP2E1)

Methanol, isopropanol, or ethylene glycol, and diethylene glycol (antifreeze) poisonings

Increases Acetaminophen toxicity

Elimination

Elimination driven by metabolism Metabolism is usually saturated

Zero-order elimination BAC decreases 0.015% per hour on

average Range is 0.012 - 0.020 %/hr

Alcohol - Mechanism

Many actions via GABA receptor.

Associates with receptor

Increases effectiveness of GABA

Results in more inhibition

Alcohol - Low Doses Apparent stimulation

inhibition of inhibitory brain functions (or dis-inhibition)

Reduced anxiety Euphoria Impaired thought processes Decreased mechanical efficiency

Alcohol - Moderate Doses Altered heart rate, Flushing of skin - sensation of warmth, Lowered body temperature, Increased secretion of saliva and gastric

juices, Increases urination, Slowing of the electroencephalogram

(EEG), Slowed reactions and reflexes, and reduced

muscular coordination.

Alcohol - Moderate Doses

Impairment of complex and recently learned tasks.

Reduced performance on tests that require a high degree of attention concentration vigilance

Alcohol - High Doses Drunkenness, disorientation & confusion Slurred speech & blurred vision Poor muscular control Nausea and vomiting Respiratory depression Unconsciousness (general anesthesia)

“Passed out”

Death due to respiratory & circulatory failure.

Alcohol - Intoxication

Mellanby effect Greater impairment when BAC is

increasing rather than decreasing. Acute tolerance

Alcohol Impairment

Four General Impairments1. Loss of Judgment and Self Control

2. Impairment of Vision and Hearing

3. Clumsiness of Voluntary Muscles

4. Decreased Awareness of Surroundings

Blackouts

Alcohol-induced antegrade amnesia.

The individual may appear normal and able to function

Associated with alcoholism

Hangover

Nausea, weakness, dizziness, poor coordination, multiple aches and pains.

Hypersensitivity to sensory stimulation

Acute withdrawal syndrome

BAC & Intoxication

BAC % Effects

0.02-0.03 Mood elevation, Slight muscle relaxation.

0.05-0.06 Relaxation & warmth, slowed reactions, Decreased fine muscle coordination.

0.08-0.09 Impaired balance, speech, vision, hearing, gross muscle coordination.

0.10-0.15 Gross impairment of physical & mental control.

0.20-0.30 Severely intoxicated, Very little control of mind or body.

0.40-0.50 Unconscious, Deep coma, Death from respiratory depression

BAC – Time Course200 lb male 125 lb female One drink each hour beginning at 6 PM.

Male, one drink = BAC of 0.019.Female one drink = BAC of 0.037.

Alcohol Forensics

Retrograde Extrapolation (“backward estimation”) Assumption is that no further alcohol

consumption or absorption occurred. Important in traffic & other types of

transportation accidents.

BAC & Driving

National Highway Traffic Safety Administration, DOT HS 809 050 April 2000

BAC

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Underage Drinkers

Underage Drinkers at Higher Risk of Brain Damage than Adults – American Medical Association Report, 2004 http://www.ama-assn.org/ama/pub/category/9416.html

Verbal and nonverbal information recall most

affected, with a 10% performance decrease in alcohol users

Significant neuropsychological deficits in early to middle adolescents (ages 15 and 16) with histories of extensive alcohol use

Brain Imaging Studies

New Developments

Alcohol administration by inhalation “Alcohol-without-liquid” AWOL

Involves vaporization of alcohol and the inhalation of the vapor.

Rapidly absorbed in the lungs. False Claims:

No hangover? Low carbohydrates?

Summary

General nature of depressant drugs. Origins and effects of ethyl alcohol. Alcohol content of different beverages. Discuss the ADME of alcohol. Discuss alcohol pharmacology. BAC, relationship to effects, and how to calculate. Nature of alcohol impairment, acute and chronic. Time course of BAC and how to estimate the time

for total alcohol elimination. Discussed the impact of alcohol use on society