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Sedative Hypnotics

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Sedative Hypnotics Sedative Hypnotics Alcohol - The most commonly used Sedative- Hypnotic. • Probably the oldest psychoactive drug used by humans. • Alcohol 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 alcohols. H HH H H H CCCH H CCOH H OH H H H Ethyl Alcohol Isopropyl Alcohol (Ethanol) 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. • Blood 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 Euphoria 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 Anesthesia • 0.4 BAC Unconsciousness 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 Metabolism 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 Agonist • R015-4513 - GABA antagonist that “reverses” ethanol intoxication. • Acutely facilitates opioid 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 “hangover” • Symptoms: • Headache • Thirst • Body Aches • Nausea and Vomiting Possible causes of Hangovers • Toxic byproducts of ethanol metabolism. • Acetaldehyde • Congeners • Dehydration • Digestive Tract Irritation • Sleep 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 vitamin (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 • Sex Hormone Production • Cancer, especially when combined with tobacco 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 Physical Dependence • 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, Insomnia Serious symptoms of ethanol withdrawal (5-10%) • Delirium Tremens (DTs) • Hallucinations, Delusions, Seizures • About 30% of untreated DTs are fatal. • Preferred treatment for DTs: • Long acting benzodiazepine (e.g., diazepam) before DTs develop. Barbiturates • Earliest medically prescribed sedative- hypnotic. • Originally used to reduce anxiety, produce sedation and anesthesia. 11 3 barbiturate 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 Pentobarbital Acting (Nembutal) Long Acting 1+ hrs 10-12 hrs Phenobarbital (Luminal) Pharmacokinetics determine clinical use. Class Used for/treats Ultra short preanesthesia Intermediate anesthesia, insomnia (formerly) Long Acting seizure disorders, anxiety (formerly) Safety • Barbiturates 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 Mechanism of action 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 Inhalants • Gas Anesthetics (e.g., Nitrous Oxide, Halothane) • Easier and safer than barbiturates for general anesthesia. Inhalants of Abuse • Solvents (glue, paint thinner, correction fluid. • Aerosols (hair spray, butane) • Anesthetics (nitrous oxide, halothane) 13 Inhalant 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” Drugs • Flunitrazepam (Rohypnol) • Benzodiazepine used in other countries as a sleep aid. • Very potent. • Defensive beverage selection. • Gamma Hydroxy Butyrate (GHB) • Endogenous neurotransmitter. • Can be illegally synthesized. • May be useful for narcolepsy. These drugs exert classic sedative-hypnotic effects. • Euphoria • Disinhibition • Amnesia (Blackouts) • Unconsciousness • Respiratory Depression • Effects are greatly enhanced when mixed with alcohol. 14.
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