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

2. 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

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

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

5. 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

6. 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

7. 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

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

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

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

11. 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.

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

13. Benzodiazepines - Agents
Some 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

14. 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

15. 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®

16. Benzodiazepines - Duration
Short Duration of Action
Onset (hours)
T½ (hours)
MIDAZOLAM
1-12
TRIAZOLAM
1-2
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

17. 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

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Most people can be gradually withdrawn from the medication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

19. 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.

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

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

22. 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®

23. 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

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

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

26. 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.

27. 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

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

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

30. 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.