Sedative-Hypnotic- Anxiolytics : Benzodiazepines & others

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 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 • 1900 Barbiturates: narrow TI • 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 - fear of eating, writing or speaking in public.

8. Classification of Anxiety Disorders (Cont) 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.

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 BenzodiazepinesBarbiturates Miscellaneous agents ShortUltra short actingacting Intermediate Short Buspirone actingacting Chloral hydrate Long LongZaleplon actingactingZolpidem

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 GABAA 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 GABAA receptor • Divided into 3 main types (A,B and C) • GABA A,B,C • GABAA - 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 – (GABAA)form ion channels • Metabotropic receptor – (GABAB ) BZP’s have very low affinity for GABAB • GABAA 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 GABAAreceptor complex (bound to Cl-channels). • BZP enhance GABAAeffect. • 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 • 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 • 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* desmethyldiazepamactive oxazepammetabolites conjugation *Prodrug

26. SEDATIVE-HYPNOTIC DRUGS BENZODIAZEPINES • Lorazepamandoxazepam • Undergo extrahepatic conjugation and do not form active metabolites

27. Biotransformation of BZPs

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 CO2 • 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-HT1A) • 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