Sedatives and hypnotics (1)

Sedatives and hypnotics (1)

1. Presented By: Maryam Manzoor Lecturer Pharmacology Rashid Latif College of Pharmacy SEDATIVES AND HYPNOTICS

2. What is anxiety Study and explain sedatives and hypnotics Differentiate between sedatives and hypnotics Actions of sedatives-hypnotics Classifications of sedatives/hypnotics with mechanism of actions, clinical uses and side effects. OBJECTIVES

3. Anxiety is an unpleasant state of tension or uneasiness, a fear that seems to arise from a sometimes unknown source. The physical symptoms of severe anxiety are similar to those of fear (such as tachycardia, sweating, trembling, and palpitations) and involve sympathetic activation. The term anxiolytic is sometimes applied to a sedative-hypnotic. ANXIETY

4. Sedative refers to a substance that moderates hyperactivity and excitement while inducing a calming effect Hypnotic refers to a substance that causes drowsiness and facilitates the onset and maintenance of natural sleep. SEDATIVE/HYPNOTIC

5. SEDATIVE/HYPNOTIC An effective sedative (anxiolytic) agent should reduce anxiety and exert a calming effect. Graded dose-dependent depression of central nervous system function is a characteristic of sedative-hypnotics

6. SEDATIVES HYPNOTICS A drug that reduces excitement and calms the patient without inducing sleep. A drug which produces sleep resembling natural sleep. Sedatives in therapeutic doses are anxiolytic agents. They are used for initiation or maintenance of sleep. Most sedatives in larger doses produce hypnosis. Hypnotics in larger doses produce anesthesia. Site of action is limbic system which regulates thought and mental functions. Site of action is on mid brain and ascending RAS which maintains awake fullness.

7. At still higher doses, these sedative-hypnotics may depress respiratory and vasomotor centers in the medulla, leading to coma and death

8. NORMAL  ANXIETY _________  _________________ SEDATION  HYPNOSIS  Confusion, Delirium, Ataxia  Surgical Anesthesia  COMA  DEATH

9. SEDATIVE-HYPNOTICS M ajor therapeutic use is to cause sedation (with concomitant relief of anxiety) or to encourage sleep.

10. ACTIONS OF SEDATIVE AND HYPNOTIC DRUGS Sedation Benzodiazepines, barbiturates, and most older sedative-hypnotic drugs exert sedative or calming effects with concomitant reduction of anxiety at relatively low doses . Hypnosis By definition, all of the sedative-hypnotics will induce sleep if high enough doses are given.

11. ACTIONS OF SEDATIVE AND HYPNOTIC DRUGS Anesthesia certain sedative-hypnotics in high doses will depress the central nervous system to the point known as stage III of general anesthesia e.g Benzodiazepines—including diazepam, lorazepam , and midazolam—are used intravenously in anesthesia. Barbiturates like thiopental and methohexital are also used in III stage anesthesia

12. ACTIONS OF SEDATIVE AND HYPNOTIC DRUGS Anticonvulsant Effects Most of the sedative-hypnotics are capable of inhibiting the development and spread of epileptiform activity in the central nervous system. This effect is partially, although not completely,mediated by GABA A receptors.

13. ACTIONS OF SEDATIVE AND HYPNOTIC DRUGS Muscle Relaxation Some sedative-hypnotics, at high doses may also depress transmission at the skeletal neuromuscular junction that lead to muscle relaxation

14. ACTIONS OF SEDATIVE AND HYPNOTIC DRUGS Effect on Respiratory Functions Effects on respiration are dose-related, and depression of the medullary respiratory center is the usual cause of death due to overdose of sedative-hypnotics.

15. ACTIONS OF SEDATIVE AND HYPNOTIC DRUGS Effect on cardiovascular Functions At doses up to those causing hypnosis, no significant on CVS. At toxic doses, myocardial contractility and vascular tone may both be depressed by central and peripheral effects, leading to circulatory collapse. Respiratory and cardiovascular effects are more marked when sedative-hypnotics are given intravenously.

16. CLASSIFICATION OF SEDATIVE-HYPNOTICS Benzodiazepines Barbiturates Antihistamines Other sedative- hypnotics

17. 3-8 hours 10-12 hours 1-3 days

18. BARBITURATES

19. THE BENZODIAZEPINES & BARBITURATES Pharmacokinetics Absorption and Distribution The rates of oral absorption of benzodiazepines differ depending on a number of factors, including lipophilicity . Oral absorption of triazolam is extremely rapid, and that of diazepam. The more the lipid solubility, the more enterance to CNS

20. THE BENZODIAZEPINES & BARBITURATES Biotransformation Metabolic transformation to more water-soluble metabolites is necessary for clearance of sedative-hypnotics from the body. The microsomal drug-metabolizing enzyme systems of the liver are most important.

21. THE BENZODIAZEPINES & BARBITURATES Excretion The water-soluble metabolites of benzodiazepines and other sedative-hypnotics are excreted mainly via the kidney.

22. GABA A receptor-chloride ion channel macromolecular complex

23. Gamma- aminobutyric acid Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system.

24. GABA A receptor The GABA A receptor (in which the receptor is part of a ligand-gated ion channel complex ), which functions as a chloride ion channel, is activated by the inhibitory neurotransmitter GABA

25. BENZODIAZEPINES First choice as sedative - hypnotic

26. MECHANISM OF ACTION Bzs facilitate GABA-induced chloride channels hyperpolarization = GABA-mediated inhibitory neurotansmission , by binding to BZ receptors.

27. ADVERSE EFFECTS OF BENZODIAZEPINES Drowsiness and confusion: These effects are the two most common side effects of the benzodiazepines. Ataxia occurs at high doses and precludes activities that require fine motor coordination, such as driving an automobile. Cognitive impairment (decreased long-term recall and acquisition of new knowledge) can occur with use of benzodiazepines.

28. ADVERSE EFFECTS OF BENZODIAZEPINES Triazolam , one of the most potent oral benzodiazepines with the most rapid elimination, often shows a rapid development of tolerance, early morning insomnia, and daytime anxiety, along with amnesia and confusion.

29. PRECAUTIONS Alcohol and other CNS depressants enhance the sedative-hypnotic effects of the benzodiazepines.

30. FLUMAZENIL a selective competitive antagonist of BZD receptors (Bz1). Blocks action of benzodiazepines but not other sedative /hypnotics.

31. BARBITURATES S econd choice as sedative - hypnotic Mechanism of Action Facilitation of GABA action on the brain. increase the duration of the GABA gated channel opening.

32. MECHANISMS OF ACTION 1) Enhance GABAergic Transmission  frequency of openings of GABAergic channels. Benzodiazepines  opening time of GABAergic channels. Barbiturates  receptor affinity for GABA. BDZs and BARBS

33. BARBITURATES Barbiturates are less selective in their actions than benzodiazepines, T hey also depress the actions of excitatory neurotransmitters ( eg , glutamic acid) and exert nonsynaptic membrane effects in parallel with their effects on GABA neurotransmission. This multiplicity of sites of action of barbiturates may be the basis for their ability to induce full surgical anesthesia----------------- less safety margin.

34. ADVANTAGES OF BZD OVER BARBITURATES 1. Selective: minimal respiratory and cardiovascular depression. 2. High therapeutic index. 3. Less dependence with minimal withdrawal symptoms 4. Has specific antagonist

35. Anesthesia: The ultrashort -acting barbiturates, such as thiopental, are used intravenously to induce anesthesia. Anticonvulsant: Phenobarbital is used in long-term management of tonic- clonic seizures, status epilepticus , and eclampsia . Anxiety : Barbiturates have been used as mild sedatives to relieve anxiety, nervous tension, and insomnia. THERAPEUTIC USES

36. ADVERSE EFFECTS

37. ANTIHISTAMINES Diphenhydramine Dimenhydrinate Hydroxyzine Promethazine

38. ANTIHISTAMINES Act on H1 receptors by blocking them . H istamine depolarizes human cortical neurons via action at an H1 receptor---- generates action potential and increase excitatory post synaptic potential. Treat mild insomnia and anxiety disorder Tolerance ----long term use

39. OTHER SEDATIVE-HYPNOTICS Zolpidem Zaleplon Chloral hydrate Ethanol Buspirone Ramelteon Eszopiclone

40. ZOLPIDEM A cts on benzodiazepine receptors (BZ 1) & facilitate GABA mediated neuronal inhibition. Its action is antagonized by flumazenil. R apidly absorbed from GIT and metabolized to inactive metabolites via liver CYT P450. Short duration of action ( 2- 4 h).

41. ZOLPIDEM Respiratory depression occur at high doses in combination with other CNS depressant as ethanol. Uses A hypnotic drug for short term treatment of insomnia

42. ZALEPLON Action same to that of Zolpidem . I nteracts with the GABA receptor complex and shares some of the pharmacological properties of the benzodiazepines. Rapid absorption Short onset of action Short duration of action (1 hr ) Metabolized by liver microsomal enzymes .

43. ZALEPLON Little effect on sleep pattern Potentiates action of other CNS depressants (alcohol). Used as hypnotic drug.

44. CHLORAL HYDRATE It is a prodrug Metabolized to active metabolite( trichloroethanol ). Short onset of action Short duration of action T 1/2 = 6- 8 hours It synergizes with alcohol.

45. CHLORAL HYDRATE Chloral hydrate exerts its pharmacological properties via enhancing the GABA receptor complex Disadvantages 1. GIT irritation 2. Bad taste 3. Tolerance Use - Short term treatment of insomnia

46. Buspirone is useful in the treatment of generalized anxiety disorder. Acts via serotonin (5-HT 1A ) receptors. Causes only mild sedation BUSPIRONE

47. Buspirone undergoes metabolism by CYP3A4. The most common effects being headaches, dizziness, and nervousness . D ependence is unlikely. S low onset of action. BUSPIRONE

48. Used in patients with concerns for addiction or dependence or a history of addiction or dependence to other substances. The SSRIs, TCAs, venlafaxine, duloxetine and MAOIs all have potential usefulness in treating anxiety ANTI DEPRESSANTS

49. Ramelteon is a selective agonist at the MT 1 and MT 2 subtypes of melatonin receptors . Stimulation of MT 1 and MT 2 receptors by melatonin in the SCN is able to induce and promote sleep and is thought to maintain the circadian rhythm underlying the normal sleep-wake cycle. RAMELTEON

50. F or the treatment of insomnia in which falling asleep (increased sleep latency ). Low addiction Common adverse effects of ramelteon include dizziness, fatigue, and somnolence. RAMELTEON

51. The precise mechanism of action of eszopiclone as a hypnotic is unknown, but its effect is believed to result from its interaction with GABA receptor complexes at binding domains located close to benzodiazepine receptors . Eszopiclone is an oral non benzodiazepine hypnotic and is also used for treating insomnia. Rapid absorption (peak time= 1 hour) ESZOPICLONE

52. Metabolism by oxidation. Excretion in urine. Elimination half-life is approximately 6 hours. Adverse events include anxiety, dry mouth, headache, peripheral edema, somnolence, and unpleasant taste ESZOPICLONE

53. Ethanol (ethyl alcohol) has anxiolytic and sedative and hypnotic effects, but its toxic potential outweighs its benefits. It is readily absorbed orally. Ethanol is metabolized primarily in the liver, first to acetaldehyde by alcohol dehydrogenase and then to acetate by aldehyde dehydrogenase. ETHANOL

54. Elimination is mostly through the kidney, but a fraction is excreted through the lungs . Inhibits the NMDA glutamate receptor (inhibits an excitatory effect) ETHANOL