DepressantsHistory: Before BarbituratesBarbituratesExamples of BarbituratesConcerns About BarbituratesMeprobamateMethaqualoneBenzodiazepinesRohypnolNonbenzodiazepine HypnoticsMechanism of ActionBeneficial UsesConcernsAnxiolyticsHypnoticsAnticonvulsantsDependence LiabilityAcute ToxicityPatterns of AbuseInhalantsExamples of InhalantsGaseous InhalantsNitritesVolatile SolventsDangers of Inhaling SolventsGamma Hydroxybutyric AcidDepressants and Inhalants Depressants A class of drugs that decrease CNS activity Have a widespread effect in the brain- As a group, also called sedative-hypnotics Sedatives treat anxiety Hypnotics treat insomnia- Widely used depressants include: Alcohol Benzodiazepines (prescription)History: Before Barbiturates- Chloral hydrate “knockout drops,” “Mickey Finn” Synthesized in 1832; used clinically in 1870 Induces sleep in less than an hour  Repeated use leads to gastric irritation - Paraldehyde  Synthesized in 1829; used clinically in 1882 Effective with a wide safety margin Noxious taste and odor- Bromides  Widely used as a sleep agent in patent medicines Remained in OTC drugs through the 1960s Accumulates in the body and cause toxic effectsBarbiturates- First introduced in 1903 So popular and useful that over 2500 examples were synthesized Popular barbiturates included phenobarbital, amobarbital and secobarbital- Grouped based on the time of onset and duration of activity  Short-acting and rapid onset: used to induce sleep and often prescribed in high doses Long-acting and delayed onset: used to reduce anxiety and often prescribed in low dosesExamples of Barbiturates- Short-acting pentobarbital, secobarbital Time of onset: 15 minutes Duration of action: 2 to 3 hours- Intermediate-acting amobarbital, butabarbital Time of onset: 30 minutes Duration of action: 5 to 6 hours- Long-acting mephobarbital, phenobarbital Time of onset: 1 hour Duration of action: 8 hours or longerConcerns About Barbiturates- Overdose Deaths Intentional and accidental Caused by respiratory depression- Abuse and dependence Reinforcing effects of a drug are related to the rapidity of onset of effects Short-acting drugs are more likely to lead to psychological dependence- Concerns led to search for safer medicationsMeprobamate- Widely prescribed beginning in the 1950s Used as an anxiolytic- Like barbiturates, can produce psychological and physical dependence- Still available as a prescription drug However, largely replaced by benzodiazepinesMethaqualone- Other names: Brand = Quaalude or Sopor Slang = “ludes” or “sopors”- Despite problems in other countries, drug was introduced in the U.S. (1965) Package insert read “Addiction potential not established” Physicians overprescribed, thinking the drug was a safe alternative to barbiturates Widely misused and abused - Scheduling history: 1973: Schedule II 1985: Schedule IBenzodiazepines- First introduced in 1960: Chlordiazepoxide (Librium), the first commercially marketed benzodiazepine Reduces anxiety without inducing sleep Much larger safety margin than barbiturates  Physical dependence was rare Overdose was rare (only when combined with other depressants like alcohol)- 1970s: Diazepam (Valium) became the best seller among all prescription drugs - However, dependence and overdose can occur- Dose level and time course are critical factors Overdose deaths more likely for drugs sold in higher doses Psychological dependence more likely with drugs that have a rapid onset of effects Physical dependence more likely with drugs that have a short duration of action- Are benzodiazepines safer than barbiturates? More differences among drugs within each class Fewer differences between these two classes of drugsRohypnol- A 1990s version of a “Mickey Finn”- Produces profound intoxication when mixed with alcohol- Reportedly used as a “date-rape” drug  Slipped into drinks 1997 change in the formulation causes a distinctive color when dissolved in a drinkNonbenzodiazepine Hypnotics- “Z-drugs” Similar to benzodiazepines but with a different chemical structure- Zolpidem (Ambien) became the most widely prescribed hypnotic Short duration Rapid onset- Initially thought to be safer than benzodiazepines Withdrawal symptoms have been reportedMechanism of Action- Benzodiazepines and barbiturates  Bind with receptors on GABA receptor complex Separate binding site for barbiturates and benzodiazepines Enhances the normally inhibitory effects of GABA- Nonbenzodiazepine hypnotics Entirely new class of drugs that may selectively bind to different sites on the receptor complexBeneficial Uses- As anxiolytics Sedatives often prescribed to reduce anxiety  Four benzodiazepines are among the top 100 most commonly prescribed medications in the United Stateso Xanaxo Ativano Klonopino Valium - As hypnotics Sedatives (at large enough doses) decrease sleep onset time About a third of American adults report trouble sleeping- As anticonvulsants Barbiturates and benzodiazepines may be prescribed for seizure disorders (epilepsies)ConcernsAnxiolytics- Sedatives are not appropriate for all anxiety disorders Example: OCD or specific phobias- Overprescribed? Most sedatives are not prescribed by psychiatrists Most patients do not have a clearly defined anxiety disorder or physical ailmentHypnotics- Concerns about the nonbenzodiazepine hypnotics include: Sleepwalking Sleep-eating Driving while in a semi-waking state- In 2008, all hypnotic drugs were required to carry a safety labelAnticonvulsants- Potential concerns Tolerance can make it difficult to find a dose that is effective but doesn’t cause excessive drowsiness Abrupt withdrawal is likely to cause seizuresDependence Liability- Psychological dependence Especially associated with short-acting sedatives- Physical dependence Withdrawal syndrome is similar to alcohol and potentially life-threatening Barbiturate withdrawal symptoms: o anxiety, insomnia, tremulousness, weakness, nausea and vomiting, seizures, disorientation, agitation, delusions, and visual and auditory hallucinations Benzodiazepine withdrawal is similar but less severe Cross-dependence occurs among the barbiturates, the benzodiazepines, and alcoholAcute Toxicity- Behavioral Alcohol-like intoxication