Download 220 Sedative Hypnotics

Sedative Hypnotics
Alcohol - The most commonly used SedativeHypnotic.
• 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
H
H
H
C
C
C
H
OH H
H
Isopropyl Alcohol
H
H
H
C
C
H
H
OH
Ethyl Alcohol
(Ethanol)
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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.
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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.
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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
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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
H2O
CO2
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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.
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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.
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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
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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
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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.
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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 sedativehypnotic.
• Originally used to
reduce anxiety,
produce sedation and
anesthesia.
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3 barbiturate categories determined by lipid
solubility and fat depot binding.
Category
Ultra short
Acting
Onset
10-20s
Duration
20-30 min
Example
Thiopental
(Pentothal)
Intermediate
Acting
20-40 min
5-8 hrs
Pentobarbital
(Nembutal)
Long Acting
1+ hrs
10-12 hrs
Phenobarbital
(Luminal)
Pharmacokinetics determine clinical use.
Class
Ultra short
Used for/treats
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.
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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)
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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.
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