1. Sedative-Hypnotic-Anxiolytics: Benzodiazepines & others Tracy A. Womble, Ph.D Florida A&M University College of Pharmacy and Pharmaceutical Sciences

2. SEDATIVE-HYPNOTICS

3. History of Sedatives Alcohol, the oldest known sedativeAlcohol, the oldest known sedative –“When Noah left the Ark he planted a vineyard, drank the wine, and was drunken, and he was uncovered within his tent.” Genesis 9:21 Barbiturates: narrow TI1900 Barbiturates: narrow TI 1960’s Chlordiazepoxide (Librium)1960’s Chlordiazepoxide (Librium)

4. SEDATIVE-HYPNOTIC DRUGS SEDATION Reduction of anxiety Calming effect ANXIOLYTIC Drug that reduces anxiety Sedative HYPNOSIS Induce sleep –go to sleep fast, feel refreshed tomorrow !!!

5. What is Anxiety ? an unpleasant state of tension, apprehension, or uneasiness; a fear that seems to arise from a sometimes unknown source.

6. Classification of Anxiety Disorders Generalized Anxiety Disorder (GAD) Panic Disorder Social Phobia Simple Phobia Obsessive Compulsive Disorder (OCD)

7. Classification of Anxiety Disorders Generalized Anxiety Disorder (GAD) exaggerated autonomic response, irritability, difficulty in concentrating and swallowing, and insomnia. Panic Disorder - autonomic symptoms, hot flashes, and fear of dying or going crazy. Social Phobia - f ear of eating, writing or speaking in public.

8. Simple Phobia - Phobias of heights, animals, driving, or air travel. Obsessive Compulsive Disorder (OCD) : Obsessions are persistent ideas –e.g., recurrent thoughts of contamination. Compulsions are repetitive behaviors –e.g., repetitive hand-washing. Significantly interfere with the patient’s social and practical life. Classification of Anxiety Disorders (Cont)

9. Anxiolytics Benzodiazepines Buspirone SSRIs (Those FDA approved for Anxiety) SNRIs (Those approved for Anxiety) Hydroxyzine Clomipramine

10. Sedative/Hypnotic/Anxiolytic Because many of the antianxiety drugs also cause some sedation, the same drugs often function clinically as both anxiolytic and hypnotic (sleep-inducing) agents. In addition, some have anticonvulsant activity.

11. Dose Response Curve for Sedative/Hypnotics

12. EFFECTIVE SEDATIVE- HYPNOTIC DRUGS Lipid soluble Absorbed well from the GIT Good distribution to the brain Metabolized before elimination from the body

13. SEDATIVE-HYPNOTIC DRUGS Benzodiazepines Barbiturates Miscellaneous agents Short Ultra short acting Intermediate Short Buspirone acting acting Chloral hydrate Long Long Zaleplon acting acting Zolpidem

14. Actions of Sedative Hypnotics Sedation / Anxiolytics –Amnesia during surgical procedure Hypnosis (insomnia) Adjunct to Anesthesia Anticonvulsant effects (i.v.) Muscle Relaxation Respiration and Cardiovascular Control of ethanol, sedative-hypnotic withdrawal

15. Action Potential of a Neuron

16. SEDATIVE-HYPNOTIC DRUGS BENZODIAZEPINES receptors  Form part of GABA A receptor-chloride ion channel macromolecular structure  Binding facilitates the inhibitory actions of GABA  Increased GABA mediated chloride ion conductance

17. Benzodiazepine Receptor Located on the GABA A receptor –Divided into 3 main types (A,B and C) GABA A,B,C –GABA A - ligand-gated Cl - ion channel (ionotropic) GABA,B,C are metabotropic Hippocampus, striatum, spinal cord, mediate anxiolysis –Most common throughout CNS, mediate sedation

18. Benzodiazepine Indications Sedation/Hypnotic Anxiety Anesthesia Alcohol withdrawal syndrome Anticonvulsant Muscular disorders

19. Benzodiazepine Receptor Ionotropic receptor – (GABA A ) form ion channels –Metabotropic receptor – (GABA B ) BZP’s have very low affinity for GABA B GABA A receptor- contains 5 subunits found in many regions of brain, different regions of CNS contain different combinations –(6) α, (3) β, (3) γ and (2) δ

21. Benzodiazepines (BZP) Mechanism of Action BZP receptor linked to GABA A receptor complex (bound to Cl - channels). –BZP enhance GABA A effect. –GABA: an inhibitory neurotransmitter Open Cl - channels in response to GABA activation, hyperpolarization, decrease neuronal firing Effects: Sedative, Hypnotic, Anticonvulsant, Muscle- Relaxant, Anxiolytic

23. Pharmacokinetics of Benzodiazepines Pharmacokinetics of Benzodiazepines Lipid-soluble: fast cross blood-brain- barrier: rapid onset of action. –obese, elderly Biotransformation & Half-Life: –Hepatic oxidation: long-t½, active metabolites –Glucuronidation: short-t½, no active metab.

24. Pharmacokinetics of Benzodiazepines Pharmacokinetics of Benzodiazepines Diazepam, Chlordiazepoxide, Clorazepate and Flurazepam –Converted initially to active metabolites with long half-lives  After several days of therapy accumulation of active metabolites can lead to excessive sedation

25. Pharmacokinetics of Benzodiazepines BENZODIAZEPINES Diazepam, Chlordiazepoxide, Clorazepate * desmethyldiazepam active oxazepam metabolites conjugation * Prodrug

26. SEDATIVE-HYPNOTIC DRUGS BENZODIAZEPINES Lorazepam and oxazepam  Undergo extrahepatic conjugation and do not form active metabolites

27. Biotransformation of BZPs

28. BenzodiazepineClassificationHalf Life (t½) (hrs.)Therapeutic Use Midazolam (Versed) Short Acting2-6Preanesthetic, intraoperative Triazolam (Halicon) Short Acting2-3Insomnia Alprazolam (Xanax) Intermediate Acting12-15Anxiolytic, agoraphobia Estazolam (Prosom) Intermediate Acting10-24Insomnia Lorazepam (Ativan) Intermediate Acting10-20Anxiolytic, preanesthetic Temazepam (Restoril) Intermediate Acting10-40Insomnia Clonazepam (Klonipin) Long Acting18-50Anticonvulsant Clorazepate (Tranxene) Long Acting40-50Anxiolytic, anticonvulsant Diazepam (Valium) Long Acting20-80Anxiolytic, status epilepticus, muscle relaxant, anesthetic premed Flurazepam (Dalmane) Long Acting40-100Insomnia

29. BZD: Adverse Effects BZD few SE Sedation, CNS Depression –Worse if combined with EtOH Behavioral disinhibition –Irritab, excitement, aggression Psychomotor & Cognitive Impairment –coordination, attention (driving) –poor visual-spatial ability (not aware of it) –Ataxia, confusion

30. BZD: Adverse Effects Overdose: Rare fatalities if BZD alone Hypnotic dose of BZP may worsen snoring/OSA Severe CNS & Respiratory Depression if combined –alcohol, barbiturates, narcotics,TCA’s

31. Benzodiazepine Antagonist Flumazenil (Romazicon)  Reverses the CNS effects of benzodiazepines, Eszopiclone, Zaleplon and Zolpidem  Antagonist at the BZP receptor, no effect on barbiturates.  Management of BZP overdose  t½ 0.7-1.3 hr – sedation commonly recurs, requires repeated admin.

32. Barbiturates Not used for anxiety or insomnia –Used for induction of anesthesia Potentially Fatal Respiratory Depression –narrow TI Induce P450 system: interactions

33. Barbiturates Gen Anesthesia (induction) - thiopental Sedative - Amobarbital, pentobarbital Anticonvulsant – Phenobarbital Abrupt withdrawal after physical dependence may result in death Increase porphyrin synthesis, contraindicated in pts. w/ acute intermittent porphyria

35. Action of Barbiturates CNS– –Low dose, sedation. High dose, hypnosis, anesthesia, finally coma and death. CNS depression dependent on dose. No analgesic properties. Respiratory Depression –Suppress hypoxic and chemoreceptor response to CO 2 Enzyme Induction – induce P450 microsomal enzymes.

36. Barbiturate Poisoning Lethal dose >10x hypnotic dose Tx of acute barbiturate poisoning is supportive –Hemodialysis or hemoperfusion –Purging of stomach –Diuresis/alkalinization of urine –Airway ventilation –Gastric lavage if < 24hr since ingestion Admin. Activated charcoal to shorten t½ CNS stimulants contraindicated, increases mortality

37. Non-Benzodiazepine Sedative Hypnotics Zolpidem (Ambien) Zaleplon (Sonata) Eszopiclone (Lunesta Buspirone (Buspar) Chloral Hydrate (Aquachloral) Propofol (Diprivan )

38. Benzodiazepine-Receptor Agonists Zolpidem (Ambien), Zaleplon (Sonata), Eszopiclone (Lunesta) Structurally similar to BZPs Sedation and hypnosis Effects reversed by Flumazenil

39. Zolpidem (Ambien) Ambien, Ambien CR, Zolpimist Acts at subset of BZP receptors no anticonvulsant or muscle relaxation properties no withdrawal effect, Minimal rebound insomnia, t½ 2-3 hrs, Little to no tolerance with prolonged use Adverse effects - nightmares, agitation, h/a, GI upset, dizziness and daytime drowsiness

40. Zaleplon (Sonata) Similar to Zolpidem hypnotic action Less residual s/e on psychomotor and cognitive than zolpidem and BZPs Causes fewer cognitive side effects t½ < 1 hr.

41. Eszopiclone (Lunesta) Used in tx of insomnia Effective up to 6 months Rapidly absorbed (1 hour) metabolized by oxidation /demethylation t½ ~ 6 hrs Adverse effects – anxiety, dry mouth, chest pain, h/a, migraine, peripheral edema, somnolence, unpleasant taste

42. Buspirone (Buspar) mediated by serotonin ((5-HT 1A ) minimal sedation, no physical dependence or tolerance, no withdrawal Not a BZP, not hypnotic, no CNS depression w/ alcohol no anticonvulsant or muscle relaxant, minimal sedation

43. Buspirone (Buspar) tx of GAD, onset of action – 1 wk Effects not reversed by Flumazenil hypothermia, inc. prolactin, GH release < motor function interference (important in elderly) < nicotine cravings in tobacco users

44. Chloral Hydrate Prodrug - active. metab. inc. anticoagulant effect – (displace form protein binding site) Sedative / hypnotic –onset ~ 30 min. DOA 6 - 10 hrs. Irritating to GI tract –Produces unusual, unpleasant taste sensation, synergizes w/ alcohol

45. Propofol (Diprivan ) i.v. sedative/hypnotic induction/maintenance of anesthesis smooth onset ~ 40s, facilitates CNS depression no postaneshetic n/v