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Sedative hypnotic drugs arf

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Sedative hypnotic drugs arf

  1. 1. SEDATIVE HYPNOTIC DRUGS Aditia Retno Fitri
  2. 2. OUTLINES <ul><li>Sleep </li></ul><ul><li>Hypnotic vs Sedative </li></ul><ul><li>Hypnotic Sedative Drugs </li></ul><ul><li>Benzodiazepine </li></ul><ul><li>Barbiturates </li></ul><ul><li>Miscellaneous Agents </li></ul><ul><li>Summary </li></ul>
  3. 3. SLEEP
  4. 4. Normal sleep cyclic and repetitive , consists of distinct stages,based on three physiologic measures: the electroencephalogram, the electromyogram, and the electronystagmogram. <ul><li>Non-rapid eye movement(NREM) sleep : 70%-75% </li></ul><ul><li>Stage 1,2 </li></ul><ul><li>Stage 3,4:slow wave sleep, SWS </li></ul><ul><li>Rapid eye movement(REM) sleep </li></ul>Normal sleep
  5. 7. <ul><li>SEDATIVE - HYPNOTIC </li></ul>
  6. 8. SEDATIVE <ul><li>Drugs that have an inhibitory effect on the CNS to the degree that they reduce: </li></ul><ul><ul><li>Nervousness </li></ul></ul><ul><ul><li>Excitability </li></ul></ul><ul><ul><li>Irritability without causing sleep </li></ul></ul><ul><ul><li>(McKenry et al., 2003) </li></ul></ul><ul><li>An effective sedative (anxiolytic) agent should reduce anxiety and exert a calming effect with little or no effect on motor or mental functions. </li></ul><ul><li>(Katzung et al., ed 11) </li></ul>
  7. 9. HYPNOTICS <ul><li>Calm or soothe the CNS to the point that they cause sleep </li></ul><ul><li>A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep that as far as possible resembles the natural sleep state. </li></ul><ul><li>A sedative can become a hypnotic if it is given in large enough doses  dose dependent </li></ul><ul><li>(Katzung; Goodman & Gilman) </li></ul>
  8. 10. CNS Depression <ul><li>Sedation </li></ul><ul><li>Hypnosis </li></ul><ul><li>General Anesthesia </li></ul><ul><li>Poisoning </li></ul><ul><li>Death </li></ul>
  9. 11. Anxiolytics: reduce anxiety Sedatives: decrease activity, calming effect Hypnotics: induce sleep Some drugs have anxiolytic and sedative/hypnotic effects.
  10. 12.
  11. 13. SEDATIVE-HYPNOTIC DRUGS
  12. 14. SEDATIVE-HYPNOTIC DRUGS <ul><li> SEDATIVE-HYPNOTICS </li></ul><ul><li>Benzodiazepines Barbiturates Miscellaneous agents </li></ul><ul><li>Short Ultra </li></ul><ul><li>action action </li></ul><ul><li> Intermediate Short Buspirone </li></ul><ul><li> action action Chloral hydrate </li></ul><ul><li> Long Long Zaleplon </li></ul><ul><li> action action Zolpidem </li></ul><ul><li>Ramelteon </li></ul>
  13. 15. GABA System <ul><li>is the major inhibitory neurotransmitter in the brain. </li></ul><ul><ul><li>It has specific receptors in chloride channels present on the membrane of post synaptic neurons. </li></ul></ul><ul><ul><ul><li> regulates the entrance of chloride into the postsynaptic cells. </li></ul></ul></ul><ul><li>Binding of GABA to its receptor (GABA A receptor) </li></ul><ul><ul><li>results in opening of the chloride channel and increased conductance of cl¯ ions to inside the post-synaptic neuron.  hyperpolarization of the postsynaptic neuron and decreased synaptic neurotransmission. </li></ul></ul>
  14. 16. Site and Structure of Action <ul><li>Site of action is the GABA A receptor </li></ul><ul><li>Structure of GABA A receptor </li></ul><ul><ul><li>Comprised of 5 subunits </li></ul></ul><ul><ul><ul><li>2 α subunits (to which GABA binds) </li></ul></ul></ul><ul><ul><ul><li>2 β subunits (to which barbiturates bind) </li></ul></ul></ul><ul><ul><ul><li>1 γ subunit (to which benzodiazepines bind) </li></ul></ul></ul>
  15. 17.
  16. 18.
  17. 19. Characteristics of an “Ideal” Hypnotic <ul><li>Rapid absorption </li></ul><ul><li>No active metabolites </li></ul><ul><li>Optimal half-life </li></ul>Adapted from Bartholini G. In: Sauvanet JP, Langer SZ, Morselli PL, eds. Imidazopyridines in Sleep Disorders . 1988:1-9. <ul><li>Rapid sleep induction </li></ul><ul><li>Physiological sleep pattern </li></ul><ul><li>Mechanism other than general CNS depression </li></ul><ul><li>Sleep maintenance </li></ul><ul><li>Improved Daytime Function </li></ul><ul><li>No residual sedation </li></ul><ul><li>No respiratory depression </li></ul><ul><li>No ethanol interaction </li></ul><ul><li>No tolerance </li></ul><ul><li>No physical dependence </li></ul><ul><li>No rebound insomnia </li></ul><ul><li>No effect on memory </li></ul>Ideal Hypnotic Pharmacokinetic Properties Pharmacokinetic Effect Side Effect
  18. 20. Sedative/hypnotics death surgical anesthesia coma unconsciousness sleep sedation Drug dose Most non-benzodiazepine sedative/hypnotics Benzodiazepines, Zolpidem, Zaleplon
  19. 21.
  20. 22.
  21. 23. BENZODIAZEPINES
  22. 24. BENZODIAZEPINES : Pharmacodynamic <ul><li>act selectively on gamma-aminobutyric acid A (GABA A ) receptors , which mediate fast inhibitory synaptic transmission through the CNS. </li></ul><ul><ul><li>bind to the gamma sub-unit of the GABA-A receptor. </li></ul></ul><ul><ul><ul><li> causes an allosteric (structural) modification of the receptor that results in an increase in GABA A receptor activity. </li></ul></ul></ul><ul><ul><li>not substitute for GABA, which bind at the alpha sub-unit, but increase the frequency of channel opening events which leads to an increase in chloride ion conductance and inhibition of the action potential </li></ul></ul><ul><li>The antagonist – f l u m a z e n i l </li></ul>
  23. 25. BENZODIAZEPINES : Pharmacodynamic
  24. 26. BENZODIAZEPINES: Pharmacokinetics <ul><li>A bsorption: </li></ul><ul><ul><li>well absorbed if given orally , Cma x reached in about 1 h </li></ul></ul><ul><li>B inding: </li></ul><ul><ul><li>strongly bound to plasma proteins </li></ul></ul><ul><li>D istribution: </li></ul><ul><ul><li>large Vd: accumulation in body fat (high lipid solubility) </li></ul></ul><ul><li>M etabolism : </li></ul><ul><ul><li>Hydroxylation </li></ul></ul><ul><ul><li>conjugation with glucuronic acid </li></ul></ul><ul><ul><li>short-, medium- and long-acting BZ </li></ul></ul><ul><ul><li>the role of N-desmethyldiazepam </li></ul></ul>
  25. 27. BENZODIAZEPINES : Biotransformation
  26. 28.
  27. 29.
  28. 30. BENZODIAZEPINES: Short Acting and the Elderly <ul><li>Short-lasting benzo’s are not converted to active intermediates; they are metabolized directly into inactive products </li></ul><ul><li>The elderly have a reduced ability to metabolize long-acting benzo’s (and their active metabolites) </li></ul><ul><li>Pharmacokinetics are not drastically altered with the short-acting benzo’s </li></ul>
  29. 31. <ul><li>Benzodiazepine Binding Site Ligands </li></ul><ul><li>Three types of ligand-benzodiazepine receptor interactions have been reported: </li></ul><ul><li>Agonists </li></ul><ul><li>facilitate GABA actions  occurs at multiple BZ binding sites </li></ul><ul><li>nonbenzodiazepines zolpidem, zaleplon, and eszopiclone are selective agonists at the BZ sites that contain an  1 subunit. </li></ul><ul><li>(2) Antagonists </li></ul><ul><li>are typified by the synthetic benzodiazepine derivative flumazenil, which blocks the actions of benzodiazepines, eszopiclone, zaleplon, and zolpidem </li></ul><ul><li>(3) Inverse agonists </li></ul><ul><li>act as negative allosteric modulators of GABA-receptor function. </li></ul><ul><li>Their interaction with BZ sites on the GABAA receptor can produce anxiety and seizures, an action that has been demonstrated for several compounds, especially the  -carbolines, eg, n-butyl-  -carboline-3-carboxylate (  -CCB ). In addition to their direct actions, these molecules can block the effects of benzodiazepines. </li></ul>
  30. 32. Pharmacological effects <ul><li>Those compounds that bind and enhance the inhibitory actions of GABA are complete agonists </li></ul><ul><ul><li>(Ex) Lorazepam, midazolam, etc. </li></ul></ul><ul><li>Those compounds that bind with “less than complete agonist action” are termed partial agonists </li></ul><ul><ul><li>(Ex) Ambien (zolpidem) </li></ul></ul><ul><ul><li>Those compounds that bind and decrease the inhibitory actions of GABA are inverse agonists </li></ul></ul>
  31. 33. Receptor Ligands
  32. 34. Benzodiazepines: Main Effects <ul><li>The main effects of benzodiazepines are: </li></ul><ul><ul><li>reduction of anxiety and aggression </li></ul></ul><ul><ul><li>sedation and induction of sleep </li></ul></ul><ul><ul><li>reduction of muscle tone and coordination </li></ul></ul><ul><ul><li>anticonvulsant effect </li></ul></ul><ul><ul><li>anterograde amnesia. </li></ul></ul>
  33. 35. Benzodiazepines: Unwanted Effects <ul><li>Unwanted effects </li></ul><ul><li>acute overdosage </li></ul><ul><li>effects occuring during normal therapeutic use </li></ul><ul><li>tolerance and dependence </li></ul><ul><li>acute overdosage (BZs are relatively safe in overdose) </li></ul><ul><ul><li>BZs produce prolonged sleep, without serious depression of respiration or cardiovascular function </li></ul></ul><ul><ul><li>Severe even life-threatening respiratory depression may appear in BZ combination with other CNS depressants, particularly alcohol . </li></ul></ul><ul><ul><li>Acute overdosage can be counteracted with flumazenil </li></ul></ul>
  34. 36. Benzodiazepines: Unwanted Effects <ul><li>unwanted effects occuring during therapeutic use </li></ul><ul><ul><li>Influence of manual skills (such as driving performance) due to drowsiness, confusion, amnesia and impaired coordination </li></ul></ul><ul><ul><li>enhance of depressant action of other drugs (in a more than additive way ) </li></ul></ul><ul><li>tolerance , dependence </li></ul><ul><ul><li>Tolerance (gradual escalation of dose needed to produce the required effect) occurs with all BZs. T.appears to represent a change at the receptor level. </li></ul></ul><ul><ul><li>Dependence – In human subjects and patients, stopping BZ treatment after weeks and months causes an increase in symptoms of anxiety, together with tremor and dizziness. </li></ul></ul><ul><ul><li>The withdrawal syndrome : short acting BZs cause more abrupt withdrawal effects </li></ul></ul><ul><ul><li>Addiction (-craving -severe psychological dependence) is not a major problem. </li></ul></ul>
  35. 37. Benzodiazepine Therapy
  36. 38.
  37. 39. Effects on Pregnancy <ul><li>Benzodiazepines (and their metabolites) can freely cross the placental barrier and accumulate in fetal circulation </li></ul><ul><ul><li>Administration during the first trimester can result in fetal abnormalities </li></ul></ul><ul><ul><li>Administration in third trimester (close to the time of birth) can result in fetal dependence, or “floppy-infant syndrome” </li></ul></ul><ul><li>Benzodiazepines are also excreted in the breast milk </li></ul><ul><li>  </li></ul>
  38. 40.
  39. 41. BARBITURATES
  40. 42. Barbiturates: Pharmacodynamic <ul><li>BA: the sleep-inducing properties were discovered early </li></ul><ul><li>in the 20th century . Until the 1960s, they formed the largest </li></ul><ul><li>group of hypnotics and sedatives in clinical use. </li></ul><ul><li>Pharmacodynamics: </li></ul><ul><li>increase the duration of the GABA-gated chloride channel openings. </li></ul><ul><li>At high concentrations, the barbiturates may also be GABA-mimetic, directly activating chloride channels. </li></ul><ul><li>β subunits binding site in GABA receptor </li></ul><ul><li>more pronounced central depressant effects </li></ul>
  41. 43. <ul><li>Absorption </li></ul><ul><ul><li>small intestine </li></ul></ul><ul><li>Distribution </li></ul><ul><ul><li>lipid solubility </li></ul></ul><ul><ul><li>rapidly cross placenta </li></ul></ul><ul><li>Elimination </li></ul><ul><ul><li>liver microsomal enzymes </li></ul></ul><ul><ul><li>renal tubular reabsorption </li></ul></ul>Barbiturates : Pharmacokinetics
  42. 44. <ul><li>CNS depression </li></ul><ul><li>Respiratory depression </li></ul><ul><li>CV depression </li></ul><ul><ul><li>decreased myocardial contractility, vasodilation, hypotension </li></ul></ul><ul><li>GI motility inhibition </li></ul><ul><li>Poor safety , easy to cause dependence </li></ul><ul><li>The application has been declining and is mainly used for anticonvulsant , antiepilepsia and anaesthesia . </li></ul>Barbiturates : Clinical Effect
  43. 45. Table 12-3 Barbiturates: Onset and Duration
  44. 46.
  45. 47. Barbiturates: Disadvantage of use <ul><li>if given in a large dose </li></ul><ul><ul><li>death from respiratory and cardiovascular depression (flumazenil not effective) </li></ul></ul><ul><li>a high degree of tolerance: </li></ul><ul><ul><li>BA strongly induce the synthesis and activity of hepatic CYP450 and conjugating enzymes thus increasing the rate of metabolic degradation of many other drugs </li></ul></ul><ul><li>drug-drug interactions </li></ul><ul><li>dependence </li></ul><ul><li>BA are now little used </li></ul><ul><li>as anxiolytic and hypnotic drugs </li></ul>
  46. 48. <ul><li>CNS system </li></ul><ul><ul><li>consciousness change </li></ul></ul><ul><ul><li>respiratory depression </li></ul></ul><ul><ul><li>areflexia </li></ul></ul><ul><li>CV system </li></ul><ul><ul><li>low cardiac output </li></ul></ul><ul><li>GI system </li></ul><ul><ul><li>ileus </li></ul></ul>Barbiturate Poisoning
  47. 49.
  48. 50. MISCELLANEOUS AGENTS
  49. 51. Ramelteon : Melatonin receptors <ul><li>Pharmacodynamic: </li></ul><ul><ul><li>Melatonin receptors  circadian rhythms </li></ul></ul><ul><ul><li>an agonist at MT 1 and MT 2 melatonin receptors located in the suprachiasmatic nuclei of the brain. </li></ul></ul><ul><ul><li>no direct effects on GABAergic neurotransmission </li></ul></ul><ul><li>Indication </li></ul><ul><ul><li>reduced the latency of persistent sleep with no effects on sleep architecture and no rebound insomnia or significant withdrawal symptoms. </li></ul></ul>
  50. 52. Ramelteon: Melatonin Receptors ....cont’d <ul><li>Pharmacokinetic </li></ul><ul><ul><li>rapidly absorbed per oral administration </li></ul></ul><ul><ul><li>first-pass metabolism !!!! </li></ul></ul><ul><ul><ul><li>f orming an active metabolite with longer half-life (2–5 hours) </li></ul></ul></ul><ul><ul><ul><li>The CYP1A2 isoform and CYP2C9of cytochrome P450 are involved. </li></ul></ul></ul><ul><li>Drug Interaction </li></ul><ul><ul><li>should not be used in combination with : </li></ul></ul><ul><ul><ul><li>inhibitors of CYP1A2 (eg, ciprofloxacin, fluvoxamine, tacrine, zileuton) or CYP2C9 (eg, fluconazole) </li></ul></ul></ul><ul><ul><ul><li>The CYP inducer rifampin markedly reduces the plasma levels of both ramelteon and its active metabolite. </li></ul></ul></ul><ul><ul><li>caution in patients with liver dysfunction. </li></ul></ul><ul><li>Adverse effects </li></ul><ul><ul><li>dizziness, somnolence, fatigue, and endocrine changes as well as decreases in testosterone and increases in prolactin. </li></ul></ul>
  51. 53. Buspirone : 5 -HT1A -receptor agonists <ul><li>Pharmacodynamic: </li></ul><ul><ul><li>selective anxiolytic effects  relieves anxiety without causing marked sedative, hypnotic, no anticonvulsant or muscle relaxant properties. </li></ul></ul><ul><ul><li>does not interact directly with GABAergic systems. </li></ul></ul><ul><ul><li>a partial agonist at brain 5-HT 1A receptors , but it also has affinity for brain dopamine D 2 receptors. </li></ul></ul><ul><ul><li>no rebound anxiety or withdrawal signs on abrupt discontinuance. </li></ul></ul><ul><ul><li>not effective in blocking the acute withdrawal syndrome from abrupt cessation of use of benzodiazepines </li></ul></ul><ul><ul><li>minimal abuse liability . </li></ul></ul><ul><ul><li>anxiolytic effects of buspirone may take >1 week to become established  less effective in panic disorders </li></ul></ul>
  52. 54. Buspirone : 5 -HT1A -receptor agonists <ul><li>Pharmacokinetic: </li></ul><ul><ul><li>rapidly absorbed orally  extensive first-pass metabolism </li></ul></ul><ul><ul><li>The elimination half-life of buspirone is 2–4 hours, and liver dysfunction may slow its clearance. </li></ul></ul><ul><ul><li>Rifampin, an inducer of cytochrome P450, decreases the half-life of buspirone; inhibitors of CYP3A4 (eg, erythromycin, ketoconazole, grapefruit juice, nefazodone) can markedly increase its plasma levels. </li></ul></ul><ul><li>A dverse effect: </li></ul><ul><ul><li>causes less psychomotor impairment than benzodiazepines </li></ul></ul><ul><ul><li>does not potentiate effects of conventional sedative-hypnotic drugs, and elderly patients do not appear to be more sensitive to its actions. </li></ul></ul><ul><ul><li>Nonspecific chest pain, tachycardia, palpitations, dizziness, nervousness, tinnitus, gastrointestinal distress, and paresthesias and a dose-dependent pupillary constriction </li></ul></ul><ul><ul><li>FDA category B drug in terms of its use in pregnancy. </li></ul></ul>
  53. 55. <ul><li>Differences between buspirone and benzodiazepines: </li></ul><ul><li>1- The full anxiolytic effect of buspirone takes several weeks to develop , whereas the anxiolytic effect of the benzodiazepines is maximal after a few days of therapy. </li></ul><ul><li>2- In therapeutic doses, buspirone has little or no sedative effect and lacks the muscle relaxant and anticonvulsant properties of the benzodiazepines. </li></ul><ul><li>3- Buspirone does not potentiate the central nervous system depression caused by sedative–hypnotic drug or by alcohol </li></ul><ul><li>4- Buspirone does not prevent the symptoms associated with benzodiazepine withdrawal. </li></ul>
  54. 56. Zolpidem <ul><li>Effect: </li></ul><ul><ul><li>binds selectively to the BZ 1 subtype of BZ receptors and facilitates GABA-mediated neuronal inhibition </li></ul></ul><ul><ul><li>Useful for the short-term treatment of insomnia </li></ul></ul><ul><ul><li>Primarily a sedative (rather than an anxiolytic) </li></ul></ul><ul><ul><li>are antagonised by f l u m a z e n i l </li></ul></ul><ul><ul><li>risk of tolerance and dependence < BZ </li></ul></ul><ul><li>Pharmacokinetics : </li></ul><ul><ul><li>Rapidly absorbed in the GI tract following oral administration (75% reaches plasma) </li></ul></ul><ul><ul><li>Metabolized in the liver and excreted by the kidney’s </li></ul></ul><ul><ul><li>Dosage reduction in hepatic dysfuction, elderly </li></ul></ul>
  55. 57. Zaleplon & Zopiclone <ul><li>Short half-life resembles zolpidem, t 1/2 = 1h </li></ul><ul><li>Rapid onset and short duration of action are favorable properties for those patients who have difficulty falling asleep. </li></ul><ul><li>Only approx. 30% of an orally administered dose reaches the plasma, and most of that undergoes first-pass elimination </li></ul><ul><li>Half as potent as zolpidem </li></ul><ul><li>Improves sleep quality w/o rebound insomnia, and little chance of developing dependency </li></ul>
  56. 58. Sedative-Hypnotic: Misuse and Abuse <ul><li>Motivational Factors </li></ul><ul><ul><li>The search for sleep </li></ul></ul><ul><ul><li>Coping with stress </li></ul></ul><ul><ul><li>Appetitive drug use-motivated by desire for pleasurable responses and sensations </li></ul></ul><ul><ul><li>Escape-avoidance drug use-motivated by desire for relief from an unpleasant sensation, tension, fear, or anxiety </li></ul></ul><ul><ul><li>Potentiating (synergistic)- exaggerated depressant effect </li></ul></ul><ul><ul><li>Offset effects of stimulant drugs </li></ul></ul>
  57. 59. Sedative-Hypnotic : Withdrawal Syndrome <ul><li>First 12-15 hours, patient appears to improve </li></ul><ul><li>16+ hours </li></ul><ul><ul><li>Restless, anxious, tremulous, weak, abdominal cramping </li></ul></ul><ul><ul><li>Vomiting, orthostatic hypotension, tremors, increased deep tendon flexion, convulsions </li></ul></ul><ul><li>Days 2-3 </li></ul><ul><ul><li>Delirium, hallucinations (persecutory) disorientation to time & place </li></ul></ul><ul><ul><li>Once delirium starts can’t be reduced by administration of other sedative hypnotics-has to run its course </li></ul></ul><ul><ul><li>Includes hyperthermia (increased body temp), exhaustion, cardiovascular collapse & sometimes death </li></ul></ul><ul><li>Depending upon type of drug, withdrawal symptoms reach peak severity at days 2-3 & last upwards of a week ( & in some cases, some of the symptoms may last several weeks) </li></ul>
  58. 60. Sedative-Hypnotics : Clinical Uses <ul><li>For relief of anxiety </li></ul><ul><li>For insomnia </li></ul><ul><li>For sedation and amnesia before and during medical and surgical procedures </li></ul><ul><li>For treatment of epilepsy and seizure states </li></ul><ul><li>As a component of balanced anesthesia (intravenous administration) </li></ul><ul><li>For control of ethanol or other sedative-hypnotic withdrawal states </li></ul><ul><li>For muscle relaxation in specific neuromuscular disorders </li></ul><ul><li>As diagnostic aids or for treatment in psychiatry </li></ul>
  59. 61.
  60. 62.
  61. 63. TIME IN BED HOURS AFTER BEDTIME DRUG METABOLISM: TOO SHORT: EARLY AWAKENING. TOO LONG: HANGOVER. SOMETIME BOTH!
  62. 64. SUMMARY
  63. 65.
  64. 66. Summary
  65. 67. Summary
  66. 68. Summary
  67. 69. THANK YOU

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