Depressant Drugs Part II Kim Edward Light, Ph.D. Professor, College of Pharmacy University of Arkansas for Medical Sciences

Objectives Sedative/Hypnotics Identify the different pharmacological families of sedative/hypnotic drugs. For each family Outline the general physiological alterations produced Identify the common therapeutic uses Identify the pharmacological mechanisms Discuss the possible negative consequences Discuss tolerance, dependance and withdrawal for each Identify their role in addiction and any unique features

Sedative-Hypnotic Drugs Anxiety, insomnia, panic disorder, seizures Cross-tolerance Cross-dependence Synergism Combined use gives more than either drug alone (i.e. 2+2 > 4)

Sedative-Hypnotic – Families Based on chemistry and/or actions Barbiturates - early 20th century Benzodiazepines – early 1960’s Non-benzodiazepines/non-barbiturates Antihistamines Older agents

Barbiturates Mild relief of anxiety or nervousness induction of anesthesia. Primary difference and classification based on duration of action, including: ultrashort, short, intermediate, and long-acting

Barbiturates - Agents Ultrashort-acting barbiturates (15-30 minutes duration) methohexital (Brevital®) thiamylal (Surital®) thiopental (Pentothal®) Short-acting (2-4 hours duration) pentobarbital (Nembutal®) secobarbital (Seconal®) pentobarbital secobarbital

Barbiturates - Agents Intermediate-acting barbiturates (4-5 hours duration) amobarbital (Amytal®) butalbital (Fiorinal®) butabarbital (Butisol®) aprobarbital (Alurate®) Long-acting barbiturates (6-8+ hours duration) phenobarbital (Luminal®) mephobarbital (Mebaral®) phenobarbital

Barbiturates - Indications Current indications Seizure prophylaxis & treatment (long acting) Anxiety (short-intermediate acting) Insomnia (short-intermediate acting) Anesthesia (ultra-short acting for induction).

Barbiturates - Intoxication Acute intoxication Accidental injury Amnesia (blackouts) Coma Chronic damage to the liver and delirium. Withdrawal syndrome seizures that may be life threatening.

Barbiturates - Slang Street names barbs red devils (esp. Seconal®) goof ball yellow jacket (esp. Nembutal®) block busters pinks reds blues Christmas trees

Barbiturate - Abuse Abuse decreased after the introduction of the benzodiazepines Notable individuals such as rock musician Jimmy Hendrix and actress Marylyn Monroe died as a result of barbiturate overdose.

Benzodiazepines “Valium-like” agents Chlordiazepoxide (Librium®) - first of this class introduced into medical use 1960. Diazepam (Valium®) was introduced a few years later. Chlordiazepoxide

Benzodiazepines - Agents Some 30-50 available world-wide Roughly 15 used in U.S. Significant differences Potency Duration of action (T½ from 4 to 100+ hours) Indications Renal or Liver based metabolism

Benzodiazepines - Therapy Many therapeutic uses: Anti-anxiety, Anticonvulsant Obsessive-compulsive, Panic attacks & Phobic disorders Post-traumatic stress disorder Extrapyramidal disorders Muscle tremors & spasticity Sedation for medical procedures Skeletal muscle relaxant  Insomnia & Parasomnias

Benzodiazepine - Categories Primarily Anxiolytics Alprazolam - Xanax® Chlordiazepoxide - Librium® Clonazepam - Klonopin® Clorazepate - Tranxene® Diazepam - Valium® Halazepam - Paxipam® Lorazepam - Ativan® Midazolam - Versed® Oxazepam - Serax® Prazepam - Centrax® Primarily Hypnotics Estazolam - ProSom® Flurazepam - Dalmane® Temazepam - Restoril® Triazolam - Halcion® Quazepam - Doral®

Benzodiazepines - Duration Short Duration of Action Onset (hours) T½ (hours) MIDAZOLAM 0.25-0.8 1-12 TRIAZOLAM 1-2 1.7-5.5 Intermediate Duration of Action ALPRAZOLAM 9-20 ESTAZOLAM 2 10-24 LORAZEPAM 0.5-3 10-20 OXAZEPAM 2-3 4-20 TEMAZEPAM 1-3

Benzodiazepines - Duration Long Duration of Action Onset (hours) T½ (hours) CHLORDIAZEPOXIDE 1-4 5-30 CLONAZEPAM 20-80 CLORAZEPATE 1-2.5 44-46 DIAZEPAM 0.5-2 FLUNITRAZEPAM** 1-2 20-30 FLURAZEPAM 0.5-6 47-100 HALAZEPAM 1-3 50-100 PRAZEPAM 6 120++ QUAZEPAM 2-2.6 25-41 ** not approved in US

Benzodiazepines - Actions Tolerance Physical dependence Most people can be gradually withdrawn from the medication Effective for managing withdrawal from alcohol

Benzodiazepines – Use ~11-15% of Americans use. Abuse & dependence More likely with faster-acting, high-potency agents Less likely with longer acting agents Significant contributor to falls and injury of elderly patients.

Benzodiazepines - Abuse Among the most abused of prescription drugs. Potentiates effect of alcohol. Health care professionals. Relaxation, sleepiness, sluggishness and in-coordination.

Benzodiazepines & Sleep Insomnia is a serious and potentially debilitating medical condition. Mood changes, psychosis, irritability. Decreased cognitive function. Physiological regeneration

Other Sedative-Hypnotics Non-benzodiazepines Buspirone - BuSpar® Zaleplon - Sonata® & Zolpidem - Ambien® Meprobamate - Miltown®, Equanil® Methaqualone - "Quaalude" Sopor® Glutethimide - Doriden® Chloral hydrate - Noctec® Antihistamines Diphenhydramine - Benadryl® Hydroxyzine - Atarax® or Vistaril®

Buspirone - BuSpar® Acts on 5HT1A receptors and to a lesser extent DA2 receptors. No anti-seizure or muscle relaxing activity. Little sedation. Buspirone is not currently subject to scheduling under the CSA. Three to four weeks delay

Zaleplon Sonata® Zolpidem Ambien® Short term treatment of insomnia Anticonvulsant, anxiolytic, and myorelaxant Cross-tolerance and cross-dependence with benzodiazepines Amnesia

Meprobamate Miltown® Equanil® Introduced 1955 Anxiety, tension, muscle spasms. Effective with less sedation than barbiturates Carisoprodol (Soma®) metabolized to meprobamate.

Methaqualone ("Quaalude" Sopor®) 1965 “safe barbiturate substitute” 1972 "luding out" – taking with wine was a popular college pastime. Marketing in the US stopped in 1984 transferred to Schedule I of the CSA.

Glutethimide (Doriden®) Introduced in 1954 Similar to those of barbiturates. Used for treatment of insomnia In 1991, transferred into Schedule II Little medical use today

Chloral Hydrate Oldest of the sedative hypnotics Synthesized in 1832 Introduced in 1869 Used for insomnia Cross tolerance & dependence “Mickey Finn”

Antihistamine Sedative-Hypnotics Diphenhydramine - Benadryl® Hydroxyzine - Atarax® or Vistaril®

Summary Identified the several pharmacological families of sedative/hypnotic drugs. Discussed the properties and actions of each family. Discussed the different members of each family. Overview of the therapeutic uses of each. Role of each in abuse and addiction.