Tranquilizers & Sedative-Hypnotics• Introduction – Terms • Tranquilizer or anxiolytic: • drugs used therapeutically to treat agitation or anxiety • Sedative-Hypnotic: • drugs used to sedate and aid in sleep
Tranquilizers & Sedative-Hypnotics1) Barbiturates: barbital, phenobarbital, secobarbital, etc2) Benzodiazepines: diazepam (Valium), clordiazepoxide(Librium), alprazolam (Xanax), clonazepam (Klonopin), lorazepam(Ativan), etc…3) Z-Drugs: zopiclone (esopicone is an optical isomer marketedas Lunesta), zolpidem (Ambien), zaleplon •able to target specific symptomsOthers: meprobamate (Miltown) methaqualone (Quaalude),abecarnal, alpidem•All have same ultimate effect, medical use depends on pkproperties •sedative-hypnotics: fast action, short effect •tranquilizers: slow action and long effect
Baeyer, discovererBarbiturates: History of barbituratesOriginal sedatives (before development of barbiturates) - brandy, chloral hydrate, bromides, opium - only marginally effective, unwanted side-effectsBarbiturates (1860s) - 1000s of different barbiturates developed - 50 marketed - treat 77 disorders (from arthritis to bed-wetting!)By 1990s, barbiturates replaced by benzodiazepines - exceptions: phenobarbital – seizures butalbital - headaches
Barbiturates: HistoryBarbiturates were widely diverted frommedical use and used on the street inthe 60s where they were called“downers” and sold under a variety ofdifferent names.Illicit use has declined as medical usehas declined.They had a low therapeutic index andwere often used for suicide. Marilyn Monroe died of barbiturate overdose in 1962
Barbiturates: HistoryGeneric Name Street NameAmobarbital Downers, blue heavens, blue velvet, blue devilsPentobarbital Nembies, yellow jackets, abbots, Mexican yellowsPhenobarbital Purple hearts, goof ballsSecobarbital Reds, red birds, red devils, lilly, F-40s, pinks, pink ladies, seggyTuinal Rainbows, reds and blues,(Combination of Amobarbital andSecobarbital) tooies, double trouble, gorilla pills, F-66s
Tranquilizers & Sedative-HypnoticsBarbiturates: History Psychotherapy - Psychological Truth Facilitate Conditioned Aversion learning (1950s) http://archneurpsyc.ama- assn.org/cgi/content/summary/63/4/579 Case Study of Dissociative OCD Interview (2009) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184566/Robert DeNiro in Meet the Parents with Sodiumthiopental or pentothal (truth serum)Higher cortical function is suppressed; chatty andcooperative; not necessarily “truth”
History - Benzodiazepines Leo SternbackIn the 1930s, Leo Sternback synthesized a class of drugsknown as heptoxdiazines (benzo-heptox-diazine).•1950s, Hoffman - LaRoche in the US • new tranquilizer/sedative• 1957, he tested Ro 5-0690, chlordiazepoxide; it wasbehaviorally active. • It was eventually marketed as Librium. • Diazepam was marketed as Valium. • Alprazolam marketed as Xanax • Many more were developed; replaced the barbituratesSternback is credited with the invention of chlordiazepoxide (Librium), diazepam(Valium), flurazepam (Dalmane), nitrazepam (Mogadon), clonazepam (Klonopin), andtrimethaphan (Arfonad).Flunitrazepam (Rohypnol), most widely abused BDZ. Sold as roofies, roaches,Mexican Valium. Possible date rape drug.
History - BenzodiazepinesRohypnol (flunitrazepam)Mexican Valium, roofies, roaches •Not licensed for medical use in US and Canada, but used in Europe and South America •Widely smuggled into U.S. •Used as a club drug. Used at raves •Known as a date rape drug
History – Others and Z DrugsMethaqualone (Quaalude) and meprobamate(Miltown) were used in the 60s as “non Quaaludesbarbiturate tranquilizers”.They were widely sold on the street.Methaqualone no longer in use, butmeprobamate is still being used. MiltownZ drugs: now replacing the BDZs.Can be targeted to specific symptoms,insomnia and anxiety. Zopiclone
Tranquilizers & Sedative-Hypnotics• Route of Administration and Absorption Barbiturates and Benzodiazepines are weak acids, readily absorbed after injection and oral administration routes Wide range in lipid solubility Barbiturates pKa = 4.1 – 8.4 BZD pKa = 1.5 – 10 Different Forms: Short-acting, intermediate-acting, long-acting Diazepam: fast acting; peak concentration 30-60 minutes http://en.wikipedia.org/wiki/List_of_benzodiazepines Z drugs: Absorbed orally and reach peak in about an hour Pka ~6.6 Absorption from the digestive system may be greatly increased by the drinking of alcohol; risk of overdose increases when drugs are
Tranquilizers & Sedative-Hypnotics• Distribution and Excretion – Distribution and Duration of Action determined by Lipid Solubility – More lipid soluble = fast onset & short duration of action, BUT… – sequestered by body fat – and as brain levels fall, released slowly from fat cells back into blood – Two-Phase Excretion Curve – 2 Half-Lives – Rapid drop in blood level as drug is redistributed; 2-10 hr half-life – Released from body fat; 27-48 hr half-life
Tranquilizers & Sedative-Hypnotics• Metabolism of Benzodiazepine – Mainly Liver CYP450 (also Glucoronidation) • Active Metabolites & Half-Lives – Alprazolam (Xanax) CYP3A4 » Hydroxylated in liver to α-hydroxyalprazolam » Active metabolite; lesser degree than parent drug • What effects would you expect if you inhibited CYP3A4? – Alcohol Consumption & BDZ Metabolism • Half-life of chlordiazepoxide increased by 60% – clearance is already slow (5-30 hr)
Tranquilizers & Sedative-Hypnotics• Neurophysiology – Barbiturates and Benzodiazepines • Positive GABAA Modulators • Affects GABAA only; not GABAB Receptors • Receptor Sites on GABA-Chloride Ionophore Complex • GABA Neurotransmitter Made More Effective • No direct alteration of levels of GABA and no binding to GABA receptor site • In high enough dosage, barbiturates can open GABAA Cl- channel on their own • Affinity of drug to site will determine level of modulation
Tranquilizers & Sedative-Hypnotics Barbiturate and Benzodiazepine• GABA is responsible for overall level of inhibitory tone in the brain.• GABA binds to receptor site and chloride ions entering the cell stabilize the membrane and make it more difficult for excitatory transmitters to fire the cell.• Barbiturates and BDZs have their own receptor sites on the complex.• At low doses, both BDZ and barbiturates enhance the effect of GABA by increasing GABA affinity for receptor• At high doses, barbiturates can open the ion channel; upper limit of facilitating effect of BDZ but not Barbiturate A schematic drawing of the GABA receptor-chloride ionophore complex.
Tranquilizers & Sedative-Hypnotics How do Z Drugs Work at GABAA receptor?Z-drugs like Ambien 1 5targets GABAaReceptors withAlpha-1 subunit 2 4 3 Different types of alpha, beta, gamma subunits means we can have a large variety of GABAa receptor types.
Tranquilizers & Sedative-Hypnotics How do Z Drugs Work at GABAA receptor•The GABAA is made of 5 subunits • alpha (α), beta (β) and gamma (δ)•There are many subtypes of alpha, beta and gamma. •Making possible a large variety of possible GABAA receptor types.•Different brain mechanisms mediate a variety ofbehaviors via different types of GABAA receptors •Receptor types are differentially sensitive (affinity) to different molecules.•Therefore - design a drug to target GABAA receptors in specific parts of thebrain •Drug will have different affinities for receptors with different subunits responsible for specific actions, such as sedationZ-drugs: Zolpidem (Ambien) high affinity for receptors with the α -1 subunit;sedatives without anti-anxiety effects. Drugs that can block anxiety without making a person sleepy are being developed.
Tranquilizers & Sedative-HypnoticsEffects on the nucleus accumbens (NAcc)•Net effect of other drugs of abuse (i.e., cocaine, amphetamine) isto increase DA release in NAcc•If positive GABAA modulators decrease dopamine release inthe NAcc, how can these drugs be reinforcing?•DA has an inhibitory effect on cells of the NAcc; when DA isreleased, the cells of the NAcc are inhibited and so is thereoutput.•Activation of GABA cells in the NAcc may have the sameinhibitory effect on cells of the NAcc.•Thus, positive GABAA modulators are reinforcing.
Tranquilizers & Sedative-Hypnotics• Effects on the Body• Respiratory depression caused by barbiturates which is lethal at high doses. •BDZs have few effects on respiration, heart rate or blood pressure.• BDZs increase appetite & relax muscles - useful in treating muscle spasms, back pain (CNS effect), etc.• Seizures •Barbiturates are useful as anticonvulsants in the long term •BDZs (particularly clonazepam) can treat petit mal seizures and infantile spasms
Tranquilizers & Sedative-Hypnotics• Effects on Sleep 1. BDZs and Z drugs are useful in treating insomnia. •Decrease the time to go to sleep •Decreased wakefulness and increased sleeping time depending on speed of absorption and half-life. 2. BDZs decrease REM sleep, but this effect shows tolerance with continued use. •REM rebound with drug discontinuance •increased REM causes rebound insomnia, increased wakefulness, increased, bizarre dreaming, restlessness •Stopped instantly with resumption of drug. • Rebound less with Z drugs and flunitrazepam after short term use.
Tranquilizers & Sedative-Hypnotics• Effects on Behavior and Performance of Humans – Subjective Effects of BDZ In General – Subjects report euphoria and liking along with sedation and fatigue
Tranquilizers & Sedative-Hypnotics• Effects on Behavior and Performance of HumansSubjective Effects of Benzodiazepines•Diazepam: Increase POMS scores of sedation andconfusion and decreased arousal and vigor scores•Reports of Increase liking and take again scores:people with a history of sedative alcohol, or opiate use(people on methadone maintenance).•Flunitrazepam most likely to generate increased likingscores in normal volunteers•Effectiveness: in relieving anxiety in 60 to 70% of cases;current and prior exposure to stress is a factor
Tranquilizers & Sedative-Hypnotics• Effects on Performance 1. BDZs & Anterograde Amnesia – memory for events that happen while people are under the influence of the drug 2. Explicit Memory vs. Implicit Memory – people can use information, but not recall it to working memory 3. Sedation – Decrease working memory, attention and psychomotor performance 4. Residual Effects – impairment can last after the drug is gone. Sleeping pills can interfere with performance (driving) the next day after use.
Tranquilizers & Sedative-Hypnotics• Effects on Driving 1. Simulated Driving Task – Impaired ability to navigate – Increased collision – Risk increases with alcohol use 2. Impairments are greatest in first time users – People not able to detect the impairment – Effects can last up to 7 days after use (lorazepam) – Effects can last up to 3 weeks after use (diazepam) – Residual effect on driving due to active metabolites? 3. In combination with Alcohol – BDZs in some studies do not seem to be contributing factors to accidents after the effects of alcohol have been eliminated
Tranquilizers & Sedative-Hypnotics• Effects on Behavior and Performance of non-Humans1. Unconditioned BehaviorTaming effect –reduces defensive aggression. No change in unprovoked aggression• Conditioned BehaviorAvoidance behavior blocked at doses 1/4 to 1/6 of doses that block escape.Increase punishment-suppressed behavior.
Tranquilizers & Sedative-HypnoticsDiscriminative Stimulus Properties1. BDZs easily discriminated – potentiated by alcohol2. Generalize to barbiturates and other BDZs, but not to ketamine and antipsychotics.3. Animals can be trained to discriminate BDZs from barbiturates and alcohol4. Not blocked by stimulants.5. Blocked by GABA receptor blockers6. Z drugs – only partial generalization to BDZs and none to alcohol.
Tranquilizers & Sedative-Hypnotics Tolerance1. Acute tolerance: •Some effects of BDZs and barbiturates may show acute tolerance.2. Chronic tolerance: •Effect of BDZs on GABA modulation shows tolerance •Demonstrated for avoidance blocking in nonhumans. •Slow development of tolerance to anticonvulsant effect and drowsiness in humans •Tolerance to hypnotic effect in of zolpidem and BDZs - about 4 weeks •Short acting hypnotics develop tolerance faster than fast acting.
Tranquilizers & Sedative-Hypnotics• Cross Tolerance1. Overall Effect of Drug -Barbiturate tolerance crosses to alcohol and BDZs -BDZ tolerant subjects are tolerant to alcohol • only partially tolerant to barbiturates.2. Effect of Drowsiness Alcohol and barbiturate abusers show less drowsiness to therapeutic doses of BDZs.• Ataxic effects of alcohol, barbiturates and BDZs show tolerance after one administration in mice.
Tranquilizers & Sedative-Hypnotics• Withdrawal in General – Sedative-Hypnotic Type • Tremors, delirium, cramps, and convulsions – Low-Dose Withdrawal • Anxiety, panic, irregular heartbeat, increased blood pressure, impairment of memory, feelings of unreality, muscle spasm, and a sensitivity to light and sounds
Tranquilizers & Sedative-Hypnotics WithdrawalLaboratory animals there iswithdrawal frombarbiturates and BDZs.Cross dependence:withdrawal from one can beblocked by the other.Barbiturates have beenknown to cause withdrawalin humans since the 1930s,but what of therapeuticdoses of benzodiazepines?
Benzodiazepine withdrawal in Humans• High doses of BDZs would cause withdrawalsymptoms similar to barbiturates and alcohol • Agitation, depression, abdominal pain, DTs, insomnia and seizures • Most people believed that there was no withdrawal from therapeutic doses.• In 1981, Halstrom and Later • Found withdrawal symptoms in low dose patients. • different from alcohol-barbiturate withdrawal: sleep disturbances, anxiety, intolerance of bright lights and noises, weight loss, unsteadiness, numbness and tingling feelings.Peaked at 5 days and were gone in 2 weeks.
Tranquilizers & Sedative-HypnoticsSmith and Wesson (1983) suggested that there are twotypes of withdrawal from BDZs;B)Sedative-Hypnotic typeC)Low dose withdrawalSedative-Hypnotic Type: tremors, delirium, cramps,convulsions.Higher than therapeutic doses for more than one month.
Tranquilizers & Sedative-HypnoticsLow dose withdrawalTherapeutic doses longer than three months.Emerge slowly15-44% of usersAnxiety, panic, irregular heart beat, increased bloodpressure, impairment of memory and concentration, feelingsof unreality, muscle spasms, sensitivity to light and sounds.Last 2 weeks to a yearOccur in cycles (10 days?)Should not be confused with symptom reemergence.
Tranquilizers & Sedative-Hypnotics Withdrawal• Two types of withdrawal symptoms that may be seen after use of the benzodiazepines People who take high doses for longer than 6 months may report both types of withdrawal.
Tranquilizers & Sedative-Hypnotics• Self-Administration in Humans – Laboratory Studies • Choice Experiments – Johanson and Uhlenhurth (1980): no preference for diazepam vs. placebo in normal sample. – High doses avoided BDZ, chose placebo – Highly anxious subjects also did not prefer diazepam • Self-Administration – Griffiths and colleagues (1979): pentobarbitol acted as positive reinforcer in male volunteers with history of sedative use
Tranquilizers & Sedative-HypnoticsPatterns of abuse of benzodiazepine outsideof the laboratoryIatrogenic Use (physician caused):People escalate prescription use taking larger doses for than longer thannecessary. Sometimes escalates to street use. Physical dependenceDoctor shopping. Early requests for refills, etcSome surveys show that most users of benzodiazepines do have amedical condition, e.g. anxiety. Much anxiety goes untreated.Many people in BDZ abuse clinics have a legitimate medical need, but taketoo large a dose.Many use BDZs in conjunction with other drugs like alcohol, cocaine andopiates.Flunitrazepam preferred by methadone users, but no special property offlunitrazepam has been identified.
Tranquilizers & Sedative-HypnoticsSTREET USE: BDZs often used on the street by opiate users. Diazepamhas been shown to enhance the effects of opiates.Use is increasing by High School students in the US.
Tranquilizers & Sedative-Hypnotics • Self-Administration in Nonhumans•Rats and monkeys will self-administerbarbiturates. •Short acting barbiturates better reinforcers.•BDZs are effective reinforcers, but not as effective asbarbiturates.•Prior exposure to BDZs enhances reinforcing ability.•Human preference for flunitrazepam has not beendemonstrated in non-humans
Tranquilizers & Sedative-HypnoticsHarmful EffectsHuman birth defects have not been confirmedBehavioral teratology in ratsPrenatal administration causes absence ofstartle response and immobility. Altersresponse to stressors.Newborn infants show withdrawal if motherused BDZsBDZs during labor can have effects on Floppy Baby syndromenewborn Depressed respiration and feeding Floppy baby syndrome Low Apgar scores.
Tranquilizers & Sedative-HypnoticsOverdoseBarbiturates, meprobamate and methaqualone have low TIs. Causedeath by depressing the respiratory centre. Widely used for suicide.Benzodiazepines are much safer. Very few deaths have been causedby BDZs alone. Short acting BDZs are more dangerousOverdose causes Drowsiness No coma or respiratory depressionSymptoms disappear within 48 hrs.Treated with flinazemil – BDZ receptor antagonistBDZ overdoses are fatal when combined with alcohol or otherdepressant.
Tranquilizers & Sedative-HypnoticsTreatmentLong term high dose withdrawal should be medically supervisedbecause of possible convulsionsUsually accomplished by gradual dose reduction in conjunction withcounseling, self-help groups and family and social support.Reemergence of symptoms need to be handledMost severe symptoms when last few mg are withdrawn.Iatrogenic overuse treatment usually successful (88+%).Invloves counseling, education, 12-steps program, and sympatheticphysician supervision.Street users – BDZ use is usually secondary to another drug.Primary addiction needs to be treated.