Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Chapter 34 Sedative-Hypnotic Drugs

2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Sedative-Hypnotic Drugs  Drugs that depress CNS function  Primarily used to treat anxiety and insomnia  Antianxiety agents or anxiolytics  Distinction between antianxiety effects and hypnotic effects is often a matter of dosage

3Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Sedative-Hypnotic Drugs  Benzodiazepines  Benzodiazepine-like drugs  Ramelteon: a melatonin agonist  Barbiturates

4Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Benzodiazepines  Drugs of choice to treat insomnia and anxiety  Used to induce general anesthesia  Used to manage seizure disorders, muscle spasm, panic disorder, and withdrawal from alcohol  Most familiar member: diazepam (Valium)  Most prescribed: lorazepam and alprazolam  Safer than general CNS depressants  Lower potential for abuse  Produce less tolerance and physical dependence  Fewer drug interactions

5Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Benzodiazepines  Overview of pharmacologic effects  Central nervous system  Cardiovascular system  Respiratory system  Molecular mechanism of action  Pharmacokinetics  Absorption and distribution  Metabolism  Time course of action

6Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Benzodiazepines  Therapeutic uses  Anxiety  Insomnia  Seizure disorders  Muscle spasm  Alcohol withdrawal  Panic disorder  Perioperative applications

7Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Benzodiazepines  Adverse effects  CNS depression  Anterograde amnesia  Sleep driving  Paradoxical effects  Respiratory depression  Abuse  Use in pregnancy and lactation  Other adverse effects

8Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Benzodiazepines  Drug interactions  CNS depressants  Tolerance and physical dependence  Tolerance With prolonged use, tolerance develops to some effects but not others With prolonged use, tolerance develops to some effects but not others  Physical dependence Can cause physical dependence, but the incidence of substantial dependence is low Can cause physical dependence, but the incidence of substantial dependence is low

9Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Benzodiazepines  Acute toxicity  Oral overdose  Intravenous toxicity  General treatment measures  Treatment with flumazenil  Preparations, dosage, and administration  Preparations and dosage  Routes Orally Orally Parenterally (IM and IV) Parenterally (IM and IV)

10Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Benzodiazepine-like Drugs  Zolpidem (Ambien)  Sedative-hypnotic  Short-term management of insomnia  Zaleplon (Sonata)  New class of hypnotics, pyrazolopyrimidines  Short-term management of insomnia  Prolonged use does not appear to cause tolerance  Eszopiclone (Lunesta)  Is the S-isomer of zopiclone  For treating insomnia  No limitation on how long it can be used

11Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Ramelteon: Melatonin Agonist  Brand name: Rozerem  Relatively new hypnotic  Activation of melatonin receptors  Approved for chronic insomnia: difficulty with sleep onset  Rapid onset (about 30 minutes)

12Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Barbiturates  Three classifications  Ultrashort-acting (thiopental)  Short- to intermediate-acting (secobarbital)  Long-acting (phenobarbital)  Mechanism of action  Binds to the GABA receptor–chloride channel complex

13Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Barbiturates  Pharmacologic effects  CNS depression  Cardiovascular effects  Induction of hepatic drug-metabolizing enzymes  Tolerance and physical dependence  Tolerance Develops to many—but not all—of the CNS effects Develops to many—but not all—of the CNS effects Very little tolerance develops to respiratory depression Very little tolerance develops to respiratory depression  Physical dependence

14Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig. 34 – 2. Induction of hepatic microsomal enzymes by barbiturates.

15Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Barbiturates  Pharmacokinetics  Lipid solubility has a significant impact  Rapid onset and brief duration  Therapeutic uses  Seizure disorders  Induction of anesthesia  Insomnia  Other uses

16Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Barbiturates  Drug interactions  CNS depressants  Interactions resulting from induction of drug-metabolizing enzymes  Chloral hydrate  Meprobamate

17Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Barbiturates  Adverse effects  Respiratory depression  Suicide  Abuse  Use in pregnancy  Exacerbation of intermittent porphyria  Hangover  Paradoxical excitement  Hyperalgesia

18Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Barbiturates  Acute toxicity  Symptoms Respiratory depression Respiratory depression Coma Coma Pinpoint pupils Pinpoint pupils  Treatment Removal of barbiturate from the body Removal of barbiturate from the body Maintenance of an adequate oxygen supply to the brain Maintenance of an adequate oxygen supply to the brain  Administration  Oral  Intravenous  Intramuscular

19Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig. 34 – 3. Development of tolerance to the toxic and subjective effects of barbiturates.

20Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Miscellaneous Sedative-Hypnotics  Basic pharmacologic profile  Nonselective CNS depressants  Actions much like those of barbiturates  Acute overdose resembles poisoning with barbiturates  Avoid during pregnancy and lactation  Chloral hydrate  Meprobamate  Paraldehyde

21Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Management of Insomnia  Sleep physiology  Sleep phases  Basic management principles  Cause-specific therapy  Nondrug therapy  Drugs used for treatment  Hypnotic drugs

22Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Sleep Physiology  Sleep phases  Rapid-eye-movement (REM)  Non–rapid-eye-movement sleep (NREM) I = Relatively light sleep I = Relatively light sleep II = Relatively light sleep II = Relatively light sleep III = Deep sleep III = Deep sleep IV = Deep sleep IV = Deep sleep

23Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Basic Management Principles  Cause-specific therapy  Treatment is highly dependent on the cause  Nondrug therapy  Therapy with hypnotic drugs

24Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Drugs Used for Treatment of Insomnia  Drugs used for treatment  Benzodiazepines  Benzodiazepine-like drugs: zolpidem, zaleplon, and eszopiclone  Ramelteon  Trazodone  Doxepin  Antihistamines  Alternative medicines