Represent the most widely used and abused drugs in the U.S. CNS depressants are popular for their...
-
Upload
antony-parsons -
Category
Documents
-
view
213 -
download
1
Transcript of Represent the most widely used and abused drugs in the U.S. CNS depressants are popular for their...
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.
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
Alcohol is legal. Advertising & media promote
drinking as normal. Widespread distribution and sales
of alcohol Very long history of alcohol use
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.
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◦ Federal (18th amendment to constitution)◦ Repealed (21st amendment)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.
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
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
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).
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
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.
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
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.
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
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.
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
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
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.
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
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
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
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
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)
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
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
Methaqualone◦ The big disaster
Benzodiazepines◦ Librium and Valium◦ Introduced in late 1950s, first marketed in 1960s
◦ Generally considered safer than barbiturates
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)
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.
Relative time course of two barbiturates and two benzodiazepines after oral administration.
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)
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.
Memory◦ Risks: date rape◦ Benefits: surgery, experimental tools to study
memory Driving
◦ Residual Effects◦ Additive Effects with Alcohol
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
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
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
Volatile Solvents◦ Toluene, tetracholorethylene, ether
Fuels◦ Butane, propane, isopropane
Propellants◦ Chlorofluorocarbons, Nitrous oxide
Nitrites◦ Amyl nitrite, butyl nitrite
Gaseous Anesthetics◦ Nitrous oxide
Nausea Cough/sneeze Light-headedness Damage heart, kidneys, brain Hypoxia/death
SSD (sudden sniffing death syndrome)
Damage brain, liver, kidney, heart, fetus
Accidents associated with “intoxication” and fires
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
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.