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) 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.

3.  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

4.  Alcohol is legal.  Advertising & media promote drinking as normal.  Widespread distribution and sales of alcohol  Very long history of alcohol use

5.  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 16 th century  In 17 th 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 19 th century temperance movement in the U.S.

6.  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 ◦ Federal (18 th amendment to constitution) ◦ Repealed (21 st amendment)  Regulation after 1933 ◦ Taxation  Consumption in U.S. tracked since ~1850 ◦ Repeating cycles with peaks every 60-70 years, followed by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.

7.  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

8. 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

9.  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).

10. 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.htm http://www.ga-drunkdrivinglawyer.com/dui-general-information/bac.htm http://www.ctduiattorney.com/dui_information/calculating_bac.html Resources for calculating BAC

11.  Metabolism & Excretion ◦ Three step metabolic process  1 st (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.  2 nd step: acetaldehyde converted to acetic acid by aldehyde dehydrogenase  3 rd step: Acetic acid metabolized to CO 2 and H 2 O ◦ 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.

12.  GABA A 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

13.  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-HT 3 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.

14. BACStageClinical symptoms 0.01 - 0.05SubclinicalBehavior nearly normal by ordinary observation 0.03 - 0.12Euphoria Mild euphoria, sociability, talkativeness 0.09 - 0.25Excitement Emotional instability; loss of critical judgment Impairment of perception, memory and comprehension, increased reaction time 0.18 - 0.30Confusion Disorientation, mental confusion; dizziness Exaggerated emotional states 0.25 - 0.40Stupor General inertia; approaching loss of motor functions Markedly decreased response to stimuli 0.35 - 0.50Coma Complete unconsciousness, Depressed or abolished reflexes 0.45 +DeathDeath from respiratory arrest Acute Alcohol Effects

15.  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.

16.  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

17.  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

18.  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.

19.  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

20.  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

21.  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

22.  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

24.  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)

25.  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

26.  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

27.  Methaqualone ◦ The big disaster  Benzodiazepines ◦ Librium and Valium ◦ Introduced in late 1950s, first marketed in 1960s ◦ Generally considered safer than barbiturates

28.  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)

29.  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.

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

31.  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)

32.  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.

33.  Memory ◦ Risks: date rape ◦ Benefits: surgery, experimental tools to study memory  Driving ◦ Residual Effects ◦ Additive Effects with Alcohol

34.  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

35.  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

36.  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

37.  Volatile Solvents ◦ Toluene, tetracholorethylene, ether  Fuels ◦ Butane, propane, isopropane  Propellants ◦ Chlorofluorocarbons, Nitrous oxide  Nitrites ◦ Amyl nitrite, butyl nitrite  Gaseous Anesthetics ◦ Nitrous oxide

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

39.  SSD (sudden sniffing death syndrome)  Damage brain, liver, kidney, heart, fetus  Accidents associated with “intoxication” and fires

40.  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

41.  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.