CNS Depressants Alcohol Other Sedatives Introduction to CNS

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CNS Depressants Alcohol & Other Sedatives

CNS Depressants Alcohol & Other Sedatives

Introduction to CNS Depressants Represent the most widely used and abused drugs in the

Introduction to CNS Depressants 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.

Sources of Alcohol Types of Alcohol ◦ Ethyl alcohol (ethanol) ◦ Methyl alcohol (methanol)

Sources of Alcohol 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

Some People Consider Alcohol a Non-Drug Alcohol is legal. Advertising & media promote drinking

Some People Consider Alcohol a Non-Drug Alcohol is legal. Advertising & media promote drinking as normal. Widespread distribution and sales of alcohol Very long history of alcohol use

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

History 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.

History Prohibition Era (1920 -1933) Regulation after 1933 Consumption in U. S. tracked since

History Prohibition Era (1920 -1933) Regulation after 1933 Consumption in U. S. tracked since ~1850 ◦ 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 ◦ Federal (18 th amendment to constitution) ◦ Repealed (21 st amendment) ◦ Taxation ◦ Repeating cycles with peaks every 60 -70 years, followed by declines in use ◦ Periods of decline are accompanied by social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.

Who Drinks and Why? Cultural influences on drinking Trends in U. S. alcohol consumption

Who Drinks and Why? 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

Alcohol Pharmacology Absorption ◦ Alcohol doesn’t ionize; p. H doesn’t influence absorption ◦ Readily

Alcohol Pharmacology Absorption ◦ Alcohol doesn’t ionize; p. H 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 Relationship between blood alcohol concentration and alcohol intake.

Alcohol Pharmacology Although high in calories, alcohol beverages have almost no vitamins, minerals, protein,

Alcohol Pharmacology 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).

Estimating BAC Blood alcohol concentration (BAC) after the rapid consumption of different amounts of

Estimating BAC 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 Biopharmaceutics 5(3): 207 -224, 1977. ) Retrieved from http: //alcoholism. about. com/cs/alerts/l/blnaa 35. htm Standardized definition of an one alcohol “drink” Resources for calculating BAC http: //www. ctduiattorney. com/dui_information/calculating_bac. html http: //www. ga-drunkdrivinglawyer. com/dui-general-information/bac. htm http: //www. ou. edu/oupd/bac. htm

Alcohol Pharmacology Metabolism & Excretion ◦ Three step metabolic process 1 st (rate-limiting) step:

Alcohol Pharmacology 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.

Neuropharmacology of Alcohol GABAA receptor agonist ◦ Low to moderate doses enhance GABA’s inhibitory

Neuropharmacology of Alcohol 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

Neuropharmacology of Alcohol RO 15 -4513: alcohol antagonist discovered in 1985 ◦ GABA antagonist

Neuropharmacology of Alcohol 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.

Acute Alcohol Effects BAC Stage Clinical symptoms 0. 01 - 0. 05 Subclinical Behavior

Acute Alcohol Effects BAC Stage Clinical symptoms 0. 01 - 0. 05 Subclinical Behavior nearly normal by ordinary observation 0. 03 - 0. 12 Euphoria 0. 09 - 0. 25 Excitement 0. 18 - 0. 30 Confusion 0. 25 - 0. 40 Stupor Mild euphoria, sociability, talkativeness Emotional instability; loss of critical judgment Impairment of perception, memory and comprehension, increased reaction time Disorientation, mental confusion; dizziness Exaggerated emotional states General inertia; approaching loss of motor functions Markedly decreased response to stimuli 0. 35 - 0. 50 Coma Complete unconsciousness, Depressed or abolished reflexes 0. 45 + Death from respiratory arrest

Behavioral Effects Low to moderate doses ◦ produce disinhibition ◦ interfere with motor activity,

Behavioral 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.

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

Behavioral Effects 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

Acute Physiological Effects Moderate quantities of alcohol ◦ slightly increase heart rate ◦ slightly

Acute Physiological Effects 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

Alcohol and Sexual Behavior Anecdotal reports vs. scientific research findings Role of expectancies, placebo

Alcohol and Sexual Behavior 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.

Chronic Toxicities of Alcohol Light or moderate drinking does little permanent harm (exception -

Chronic Toxicities of Alcohol 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

Fetal Alcohol Syndrome A collection of physical and behavioral abnormalities caused by the presence

Fetal Alcohol Syndrome 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

Alcohol Dependence Withdrawal Syndrome during detoxification ◦ Stage 1: tremors, cardiovascular irregularities, sweating, loss

Alcohol Dependence 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

Pharmacotherapies for Alcohol Dependence Management of withdrawal Relapse prevention ◦ Benzodiazepines ◦ Antipsychotics ◦

Pharmacotherapies for Alcohol Dependence Management of withdrawal Relapse prevention ◦ Benzodiazepines ◦ Antipsychotics ◦ Anticonvulsants ◦ 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 Sedative-Hypnotics, Anesthetics, Inhalants

CNS Depressants Sedative-Hypnotics, Anesthetics, Inhalants

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

Effects of CNS Depressants 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)

History Before Barbiturates: ◦ Chloral hydrate first synthesized in 1832 but not used clinically

History Before Barbiturates: ◦ Chloral hydrate first synthesized in 1832 but not used clinically until 1870– for sleep ◦ Paraldehyde first synthesized in 1829 but not used clinically until 1882 – very safe – very, very bad taste and odor ◦ Bromides to induce sleep in the 19 th century, used until 1960 s in OTC meds

History Barbiturates ◦ First synthesized in 1864, introduced in early 1900 s ◦ Thousands

History Barbiturates ◦ First synthesized in 1864, introduced in early 1900 s ◦ 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 1950 s, later found to create dependence ◦ Safety not properly evaluated

History Methaqualone ◦ The big disaster Benzodiazepines ◦ ◦ ◦ Librium and Valium Introduced

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

Benzodiazepines Medical Uses ◦ ◦ ◦ Anxiolytic (anxiety reducing) Sedative (sleep inducing) Anticonvulsant (seizure

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

Types of CNS Depressants § Several benzodiazepines: § Distinguished primarily by their duration of

Types of CNS Depressants § 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.

Time Course of Some Barbiturates and Benzodiazepines Relative time course of two barbiturates and

Time Course of Some Barbiturates and Benzodiazepines Relative time course of two barbiturates and two benzodiazepines after oral administration.

Effects of CNS Depressants The clinical value of CNS depressants is dose dependent: ◦

Effects of CNS Depressants 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)

Pharmacological Mechanism of Action GABA receptor complex Benzodiazepines enhance GABA’s actions on chloride channels.

Pharmacological Mechanism of Action 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.

Effects on Performance Memory ◦ Risks: date rape ◦ Benefits: surgery, experimental tools to

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

Behavioral Effects Unconditioned Behavior ◦ Reduce defensive aggression Conditioned Behavior ◦ Escape-Avoidance tasks ◦

Behavioral Effects 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

Tolerance Acute Tolerance Chronic Tolerance ◦ Lab studies in nonhumans: Tolerance develops to many

Tolerance 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

Causes for Concern Dependence Liability ◦ Psychological dependence Shorter acting substances more readily establish

Causes for Concern 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 Patterns of Abuse ◦ Alcohol-like intoxication ◦ Decreased respiration can lead to death ◦ Increased toxicity when combined with alcohol

Types of Inhalants Volatile Solvents ◦ Toluene, tetracholorethylene, ether Fuels ◦ Butane, propane, isopropane

Types of Inhalants Volatile Solvents ◦ Toluene, tetracholorethylene, ether Fuels ◦ Butane, propane, isopropane Propellants ◦ Chlorofluorocarbons, Nitrous oxide Nitrites ◦ Amyl nitrite, butyl nitrite Gaseous Anesthetics ◦ Nitrous oxide

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

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

Dangers of Inhalants SSD (sudden sniffing death syndrome) Damage brain, liver, kidney, heart, fetus

Dangers of Inhalants SSD (sudden sniffing death syndrome) Damage brain, liver, kidney, heart, fetus Accidents associated with “intoxication” and fires

Gamma-Hydroxybutyrate GHB is an endogenous substance found in small amounts in the brain: ◦

Gamma-Hydroxybutyrate 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

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

GHB Precursors 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.