Represent the most widely used and abused drugs in the U.S. CNS depressants are popular for their...

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Transcript of Represent the most widely used and abused drugs in the U.S. CNS depressants are popular for their...

Page 1: Represent the most widely used and abused drugs in the U.S.  CNS depressants are popular for their stress reducing and anxiety relieving (anxiolytic)
Page 2: Represent the most widely used and abused drugs in the U.S.  CNS depressants are popular for their stress reducing and anxiety relieving (anxiolytic)

Represent the most widely used and abused drugs in the U.S.

CNS depressants are popular for their stress reducing and anxiety relieving (anxiolytic) effects.

Medicinal uses include ◦ Sleep disorders◦ Anxiety disorders◦ Seizure disorders◦ Anesthesia

Second only to caffeine, alcohol is one of the most widely used and abused of all psychoactive drugs.

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Types of Alcohol◦ Ethyl alcohol (ethanol)◦ Methyl alcohol (methanol)◦ Isopropyl alcohol (rubbing alcohol)

Fermentation of fruits or grains by yeasts◦ Beer and wine products◦ 10-15 % maximum ethanol content

Distillation, heating and condensation process◦ Liquors and liqueurs

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Alcohol is legal. Advertising & media promote

drinking as normal. Widespread distribution and sales

of alcohol Very long history of alcohol use

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Early evidence of brewing alcohol dates as far back as ~9000 years ago.

Early Roman empire (wine in lead vessels) Distillation process not widely used in

England until 16th century In 17th century, use of distilled spirits

increased dramatically The Temperance Movement (1830-1850)

◦ Benjamin Rush (1785) An Inquiry into the Effects of Ardent Spirits

◦ His writings inspired temperance societies and the early 19th century temperance movement in the U.S.

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Prohibition Era (1920-1933)◦ State by state: The temperance movement led

to the enactment of alcohol prohibition laws in 11 states and 2 territories.

◦ Federal (18th amendment to constitution)◦ Repealed (21st amendment)

Regulation after 1933◦ Taxation

Consumption in U.S. tracked since ~1850◦ Repeating cycles with peaks every 60-70 years,

followed by declines in use◦ Periods of decline are accompanied by social

concerns about health and morality.

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Cultural influences on drinking Trends in U.S. alcohol consumption Regional Differences Gender Differences College and University Students and

Alcohol Use:◦ Binge Drinking◦ Gender and Collegiate Alcohol Use 

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Relationship between blood alcohol concentration and alcohol intake.

Absorption◦ Alcohol doesn’t ionize; pH doesn’t

influence absorption◦ Readily dissolved in water, most

rapid absorption from small intestine.

◦ “First pass” metabolism by alcohol dehydrogenase in digestive system

BAC (BAL) depends on: presence of food in the stomach rate of alcohol consumption concentration of alcohol drinker’s body composition

e.g., age, gender

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Although high in calories, alcohol beverages have almost no vitamins, minerals, protein, or fat.

Distribution◦ Distributed mainly in body’s water◦ Estimating BAC (BAL) depends on body

water/fat proportions Due to differences in body composition,

women tend to have a higher BAL than men, even when controlling for body weight.

Body composition changes with age (more so in men).

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Standardized definition of an one alcohol “drink”

Blood alcohol concentration (BAC) after the rapid consumption of different amounts of alcohol by eight adult fasting male subjects.* (Adapted from Wilkinson et al., Journal of Pharmacokinetics and Biopharmaceutics5(3):207-224, 1977.)Retrieved from http://alcoholism.about.com/cs/alerts/l/blnaa35.htm

http://www.ou.edu/oupd/bac.htmhttp://www.ga-drunkdrivinglawyer.com/dui-general-information/bac.htmhttp://www.ctduiattorney.com/dui_information/calculating_bac.html

Resources for calculating BAC

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Metabolism & Excretion◦ Three step metabolic process

1st (rate-limiting) step: alcohol dehydrogenase converts alcohol to acetaldehyde. Rate is limited by availability of a coenzyme (NAD) required

for the activity of ADH, relatively independent of alcohol concentration.

2nd step: acetaldehyde converted to acetic acid by aldehyde dehydrogenase

3rd step: Acetic acid metabolized to CO2 and H2O

◦ MEOS (microsomal ethanol-oxidizing system)◦ Alcohol is metabolized at a constant rate (zero

order kinetics), which varies among individuals. Range 10-20 mg/100 ml per hour Rate influenced by drinking experience, faster rate in light to

moderate drinkers than nondrinkers.

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GABAA receptor agonist◦ Low to moderate doses enhance GABA’s

inhibitory effects Glutamate (NMDA receptor) antagonist

◦ Higher doses block glutamate receptors Multiple neurotransmitter systems

affected◦ Second messenger systems◦ Monoamine oxidase (enzyme that metabolizes

monoamines)◦ Alters responsiveness of endorphin system

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RO 15-4513: alcohol antagonist discovered in 1985◦ GABA antagonist◦ Not likely to have medical use

Blocks alcohol intoxication, but does not prevent lethal effects of alcohol and can cause seizures.

Serotonin Antagonists 5-HT3 receptor antagonists block reinforcing and

discriminative effects of alcohol. Opiate Antagonists

◦ Naltrexone reduces alcohol consumption and may assist in relapse prevention following treatment.

Caffeine◦ May reverse some impairments (e.g., slowed reaction

time) produced by low BAL but no effect at higher BALs.◦ Not a specific antagonist of alcohol’s effects.

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BAC Stage Clinical symptoms

0.01 - 0.05 Subclinical Behavior nearly normal by ordinary observation

0.03 - 0.12 EuphoriaMild euphoria, sociability, talkativeness

0.09 - 0.25 Excitement

Emotional instability; loss of critical judgmentImpairment of perception, memory and comprehension, increased reaction time

0.18 - 0.30 ConfusionDisorientation, mental confusion; dizzinessExaggerated emotional states

0.25 - 0.40 StuporGeneral inertia; approaching loss of motor functionsMarkedly decreased response to stimuli

0.35 - 0.50 ComaComplete unconsciousness, Depressed or abolished reflexes

0.45 + Death Death from respiratory arrest

Acute Alcohol Effects Acute Alcohol Effects

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Low to moderate doses◦ produce disinhibition◦ interfere with motor activity, reflexes, and

coordination◦ disrupt complex or poorly learned behaviors◦ reduce anxiety

The social setting, mental state, and previous learning history clearly influence the behavioral effects of alcohol.◦ Some may be euphoric, friendly, and talkative

while others are aggressive and hostile under alcohol’s influence.

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Higher doses of alcohol◦ cause difficulties with walking, talking, and

thinking◦ induce drowsiness and promote sleep◦ High BAC causes severe depression of the brain

systems and motor control areas of the brain Lack of coordination, confusion, & disorientation Stupor, anesthesia, coma, and even death

The lethal level of alcohol is between 0.4 and 0.6% BAC

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Moderate quantities of alcohol◦ slightly increase heart rate◦ slightly dilate blood vessels in arms, legs,

skin◦ moderately lower blood pressure◦ stimulate appetite◦ increase production of gastric secretions◦ increases urine output

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Anecdotal reports vs. scientific research findings

Role of expectancies, placebo effects Psychological vs. physiological effects Alcohol use is linked with risky sexual

behaviors◦ e.g. unprotected sex, early sexual experience,

increased sexual assault◦ Findings from lab studies using date rape

scenarios Chronic alcohol use can lead to

impotence in men.

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Light or moderate drinking does little permanent harm (exception - FAS)

Chronic heavy drinking◦ seriously damages the heart (cardiomyopathy

and coronary artery disease)◦ causes kidney and liver damage◦ associated with cancers of mouth, throat,

stomach, liver, lungs, pancreas, colon, rectum◦ associated with mental disorders, irreversible

damage to the brain and peripheral nervous system

◦ lowers resistance to pneumonia and other infectious diseases

◦ causes irritation of the gastrointestinal tract

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A collection of physical and behavioral abnormalities caused by the presence of alcohol during fetal development◦ Craniofacial Abnormalities

e.g., small head, wide set eyes, flattened bridge and shortened nose, flattened philtrum

◦ Low IQ, Mental Retardation

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Withdrawal Syndrome during detoxification◦ Stage 1: tremors, cardiovascular irregularities,

sweating, loss of appetite, insomnia◦ Stage 2: hallucinations◦ Stage 3: delusions, disorientation, delirium◦ Stage 4: seizures

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Management of withdrawal ◦ Benzodiazepines◦ Antipsychotics◦ Anticonvulsants

Relapse prevention◦ Alcohol sensitizing drugs

e.g., disulfiram (Antabuse) and calcium carbimide (Temposil)

◦ Anti-craving drugs e.g., Opioid antagonist naltrexone e.g., acamprosate

normalizes GABA basal concentrations and blocks glutamate receptors

Alcoholics with co-morbid depression or anxiety◦ SSRIs and other serotonin agonists

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CNS depressants reduce CNS activity and diminish the brain’s level of awareness

Depressant drugs include:◦ Benzodiazepines◦ Barbiturates◦ Other barbiturate-like drugs◦ Alcohol◦ Antihistamines◦ GHB (gamma hydroxybutyrate)

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Before Barbiturates:◦ Chloral hydrate

first synthesized in1832 but not used clinically until 1870– for sleep

◦ Paraldehyde first synthesized in1829 but not used clinically

until 1882 – very safe – very, very bad taste and odor

◦ Bromides to induce sleep in the 19th century, used until

1960s in OTC meds

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Barbiturates◦ First synthesized in 1864, introduced in early

1900s◦ Thousands of compounds, about 50 marketed◦ Grouped according to onset and duration of

action ◦ Main concerns: dependence and overdose

risks Meprobamate

◦ Happy pills of the 1950s, later found to create dependence

◦ Safety not properly evaluated

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Methaqualone◦ The big disaster

Benzodiazepines◦ Librium and Valium◦ Introduced in late 1950s, first marketed in 1960s

◦ Generally considered safer than barbiturates

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Medical Uses◦ Anxiolytic (anxiety reducing)◦ Sedative (sleep inducing)◦ Anticonvulsant (seizure inhibiting)◦ Alcohol Dependence (relief from withdrawal)◦ Chronic Pain (muscle relaxant)◦ Pre-surgical Anesthesia (induction of amnesia)

Four top-selling prescription drugs in the U.S.◦ Xanax (alprazolam)◦ Halcion (triazolam)◦ Ativan (lorazepam)◦ Valium (diazepam)

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Several benzodiazepines: Distinguished primarily by their duration of

action Short-acting (short half-lives, no active metabolites)

e.g., triazolam, temazepam, alprazolam Intermediate-acting (intermediate half-lives, some

have active metabolites,) e.g., lorazepam, clonazepam

Long-acting (long half-lives and active metabolites) e.g., chlordiazepoxide, diazepam, flurazepam

Short-acting agents commonly prescribed as sedatives, long-acting more agents commonly used as anticonvulsants.

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Relative time course of two barbiturates and two benzodiazepines after oral administration.

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The clinical value of CNS depressants is dose dependent:◦ Low dose (sedatives, relieve anxiety and

promote relaxation)◦ Higher doses (hypnotics, can cause drowsiness

and promote sleep)◦ At even higher doses (anesthetics, can cause

anesthesia and are used for patient management during surgery)

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GABA receptor complex Benzodiazepines

enhance GABA’s actions on chloride channels.

Barbiturates act in a similar manner at different binding sites, and are also capable of opening chloride channels in the absence of GABA.

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Memory◦ Risks: date rape◦ Benefits: surgery, experimental tools to study

memory Driving

◦ Residual Effects◦ Additive Effects with Alcohol

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Unconditioned Behavior◦ Reduce defensive aggression

Conditioned Behavior◦ Escape-Avoidance tasks◦ Increase punished behavior, with little effect on

positively motivated behavior Discriminative Stimulus Effects

◦ Generalization between barbiturates and benzodiazepines

◦ Blocked by GABA antagonists, not blocked by CNS stimulants

◦ Partial generalization to alcohol

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Acute Tolerance Chronic Tolerance

◦ Lab studies in nonhumans: Tolerance develops to many of the behavioral effects.

◦ Tolerance to anxiolytic effects in humans is variable and related to dosing regimen.

◦ Short-acting agents tend to exhibit tolerance more readily than long-acting agents.

Cross Tolerance◦ Evident among benzodiazepines, barbiturates,

and alcohol

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Dependence Liability◦ Psychological dependence

Shorter acting substances more readily establish dependence than longer acting substances.

◦ Physical dependence Withdrawal symptoms following chronic use of large

doses Symptoms similar to alcohol withdrawal: anxiety,

insomnia, confusion, disorientation, agitation, delusions, tremors, alcohol-like DTs

Toxicity◦ Alcohol-like intoxication◦ Decreased respiration can lead to death◦ Increased toxicity when combined with alcohol

Patterns of Abuse

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Volatile Solvents◦ Toluene, tetracholorethylene, ether

Fuels◦ Butane, propane, isopropane

Propellants◦ Chlorofluorocarbons, Nitrous oxide

Nitrites◦ Amyl nitrite, butyl nitrite

Gaseous Anesthetics◦ Nitrous oxide

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Nausea Cough/sneeze Light-headedness Damage heart, kidneys, brain Hypoxia/death

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SSD (sudden sniffing death syndrome)

Damage brain, liver, kidney, heart, fetus

Accidents associated with “intoxication” and fires

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GHB is an endogenous substance found in small amounts in the brain:◦ putative neurotransmitter with specific receptor

sites and mechanisms for its synthesis, release and reuptake in the CNS

Sedative and intoxicating effects, similar to alcohol and other GABA agonists.

GHB abuse increased after being banned from OTC use in 1990

Several reports of date-rape (Schedule I in 2000)

Xyrem® (sodium oxybate) FDA approved for cataplexy (symptom of narcolepsy) in 2002◦ Only this form of GHB listed as Schedule III

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GBL and 1,4-BD: precursors and metabolites of GHB.

Once ingested, converted to GHB. GBL and 1,4-BD are found in some industrial

solvents and also present a potential health hazard because their supply is not easily controlled.