Anxiolytics Ol 2002
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Anxiolytics Ol 2002 Presentation Transcript

  • 1. SEDATIVE/HYPNOTICS ANXIOLYTICS Martha I. D ávila-García, Ph.D. Howard University Department of Pharmacology
  • 2.
    • Optimal
    • Performance
    Sedated Nervous Breakdown Performance Anxiety GOAL
  • 3.
    • Normal
          • Relief from Anxiety
      • _________  _________________
        • SEDATION
        • (Drowsiness/decrease reaction time)
          • HYPNOSIS
            • Confusion, Delirium, Ataxia
            • Surgical Anesthesia
            •  Depression of respiratory and vasomotor center in the brainstem
            • COMA
            • DEATH
  • 4. SEDATIVE/HYPNOTICS ANXIOLYTICS
    • Major therapeutic use is to relief anxiety (anxiolytics) or induce sleep (hypnotics).
    • Hypnotic effects can be achieved with most anxiolytic drugs just by increasing the dose.
    • The distinction between a "pathological" and "normal" state of anxiety is hard to draw, but in spite of, or despite of, this diagnostic vagueness, anxiolytics are among the most prescribed substances worldwide.
  • 5. Manifestations of anxiety :
    • Verbal complaints. The patient says he/she is anxious, nervous, edgy.
    • Somatic and autonomic effects . The patient is restless and agitated, has tachycardia, increased sweating, weeping and often gastrointestinal disorders.
    • Social effects . Interference with normal productive activities.
  • 6. Pathological Anxiety
    • Generalized anxiety disorder (GAD) : People suffering from GAD have general symptoms of motor tension, autonomic hyperactivity, etc. for at least one month.
    • Phobic anxiety :
      • Simple phobias. Agoraphobia, fear of animals, etc.
      • Social phobias.
    • Panic disorders : Characterized by acute attacks of fear as compared to the chronic presentation of GAD.
    • Obsessive-compulsive behaviors : These patients show repetitive ideas (obsessions) and behaviors (compulsions).
  • 7. Causes of Anxiety
    • 1). Medical :
      • Respiratory
      • Endocrine
      • Cardiovascular
      • Metabolic
      • Neurologic .
  • 8. Causes of Anxiety
    • 2). Drug-Induced :
      • Stimulants
        • Amphetamines, cocaine, TCAs, caffeine.
      • Sympathomimetics
        • Ephedrine, epinephrine, pseudoephedrine phenylpropanolamine.
      • AnticholinergicsAntihistaminergics
        • Trihexyphenidyl, benztropine, meperidine diphenhydramine, oxybutinin.
      • Dopaminergics
        • Amantadine, bromocriptine, L-Dopa, carbid/levodopa.
  • 9. Causes of Anxiety
      • Miscellaneous:
        • Baclofen, cycloserine, hallucinogens, indomethacin .
    • 3). Drug Withdrawal :
        • BDZs, narcotics, BARBs, other sedatives, alcohol.
  • 10. Anxiolytics
      • Strategy for treatment
      • Reduce anxiety without causing sedation.
  • 11. Anxiolytics
      • Benzodiazepines (BZDs).
      • Barbiturates (BARBs).
      • 5-HT 1A receptor agonists.
      • 5-HT 2A , 5-HT 2C & 5-HT 3 receptor
      • antagonists.
    • If ANS symptoms are prominent :
      • ß-Adrenoreceptor antagonists.
      •  2 -AR agonists (clonidine).
  • 12. Anxiolytics
    • Other Drugs with anxiolytic activity.
      • TCAs (Fluvoxamine). Used for Obsessive compulsive Disorder.
      • MAOIs. Used in panic attacks.
      • Antihistaminic agents. Present in over the counter medications.
      • Antipsychotics (Ziprasidone).
    • Novel drugs . (Most of these are still on clinical trials).
      • CCK B (e.g. CCK 4 ).
      • EAA's/NMDA (e.g. HA966).
  • 13. Sedative/Hypnotics
      • A hypnotic should produce, as much as possible, a state of sleep that resembles normal sleep.
  • 14. Sedative/Hypnosis
    • By definition all sedative/hypnotics will induce sleep at high doses.
    • Normal sleep consists of distinct stages, based on three physiologic measures: electroencephalogram, electromyogram, electronystagmogram.
    • Two distinct phases are distinguished which occur cyclically over 90 min:
    • 1) Non-rapid eye movement (NREM). 70-75% of total sleep. 4 stages. Most sleep  stage 2.
    • 2) Rapid eye movement (REM). Recalled dreams.
  • 15. Properties of Sedative/Hypnotics in Sleep
    • 1) The latency of sleep onset is decreased (time to fall asleep).
    • 2) The duration of stage 2 NREM sleep is increased.
    • 3) The duration of REM sleep is decreased.
    • 4) The duration of slow-wave sleep (when somnambulism and nightmares occur) is decreased.
    • Tolerance occurs after 1-2 weeks .
  • 16. Other Properties of Sedative/Hypnotics
    • Some sedative/hypnotics will depress the CNS to stage III of anesthesia.
    • Due to their fast onset of action and short duration, barbiturates such as thiopental and methohexital are used as adjuncts in general anesthesia.
  • 17. Sedative/Hypnotics
      • Benzodiazepines (BZDs):
      • Alprazolam, diazepam, oxacepam, triazolam
      • 2) Barbiturates:
      • Pentobarbital, phenobarbital
      • 3) Alcohols:
      • Ethanol, chloral hydrate, paraldehyde, trichloroethanol,
      • 4) Imidazopyridine Derivatives:
      • Zolpidem
      • 5) Pyrazolopyrimidine
      • Zaleplon
  • 18. Sedative/Hypnotics
      • 6) Propanediol carbamates:
      • Meprobamate
      • 7) Piperidinediones
      • Glutethimide
      • Azaspirodecanedione
      • Buspirone
      • 9)  -Blockers**
      • Propranolol
      • 10)  2-AR partial agonist**
      • Clonidine
  • 19. Sedative/Hypnotics
    • Others:
    • 11) Antyipsychotics **
    • Ziprasidone
    • 12) Antidepressants **
    • TCAs, SSRIs
    • 13) Antihistaminic drugs **
    • Dephenhydramine
  • 20. Sedative/Hypnotics
    • All of the anxiolytics/sedative/hypnotics should be used only for symptomatic relief.
    • *************
    • All the drugs used alter the normal sleep cycle and should be administered only for days or weeks, never for months.
    • ************
    • USE FOR
    • SHORT-TERM TREATMENT
    • ONLY!!
  • 21. Sedative/Hypnotics
    • Relationship between
    • Older vs Newer Drugs
    • Barbiturates Benzodiazepines
    • Glutethimide Zolpidem
    • Meprobamate Zaleplon
    • ** All others differ in their effects and therapeutic uses. They do not produce general anesthesia and do not have abuse liability.
  • 22. SEDATIVE/HYPNOTICS ANXYOLITICS GABAergic SYSTEM
  • 23. Sedative/Hypnotics
    • The benzodiazepines are the most important sedative hypnotics.
    • Developed to avoid undesirable effects of barbiturates (abuse liability).
  • 24. Benzodiazepines
    • Diazepam
    • • Chlordiazepoxide
    • Triazolam
    • Lorazepam
    • Alprazolam
    • Clorazepate => nordiazepam
    • Halazepam
    • Clonazepam
    • Oxazepam
    • Prazepam
  • 25. Barbiturates
    • Phenobarbital
    • Pentobarbital
    • Amobarbital
    • Mephobarbital
    • Secobarbital
    • Aprobarbital
  • 26.
    • NORMAL
          • ANXIETY
      • _________  _________________
        • SEDATION
          • HYPNOSIS
            • Confusion, Delirium, Ataxia
            • Surgical Anesthesia
            •  COMA
            • DEATH
  • 27. Respiratory Depression Coma/ Anesthesia Ataxia Sedation Anxiolytic Anticonvulsant DOSE RESPONSE BARBS BDZs ETOH
  • 28. Respiratory Depression Coma/ Anesthesia Ataxia Sedation Anxiolytic Anticonvulsant DOSE RESPONSE BARBS BDZs
  • 29. GABAergic SYNAPSE GABA glutamate glucose Cl - GAD
  • 30. GABA-A Receptor
    • Oligomeric (  glycoprotein.
    • Major player in Inhibitory Synapses.
    • It is a Cl - Channel.
    • Binding of GABA causes the channel to open and Cl - to flow into the cell with the resultant membrane hyperpolarization.
    GABA AGONISTS BDZs    BARBs  
  • 31. 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
    • 2) Stimulation of 5-HT 1A receptors.
    • 3) Inhibit 5-HT 2A , 5-HT 2C , and 5-HT 3 receptors.
  • 32. Patch-Clamp Recording of Single Channel GABA Evoked Currents From Katzung et al., 1996
  • 33. Benzodiazepines
    • PHARMACOLOGY
    • BDZs potentiate GABAergic inhibition at all levels of the neuraxis.
    • BDZs cause more frequent openings of the GABA-Cl - channel via membrane hyperpolarization, and increased receptor affinity for GABA.
    • BDZs act on BZ 1 (  1 and  2 subunit-containing) and BZ 2 (  5 subunit-containing) receptors.
    • May cause euphoria, impaired judgement, loss of cell control and anterograde amnesic effects.
  • 34. Pharmacokinetics of Benzodiazepines
    • Although BDZs are highly protein bound (60-95%), few clinically significant interactions.*
    • High lipid solubility  high rate of entry into CNS  rapid onset.
    • *The only exception is chloral hydrate and warfarin
  • 35. CNS Effects (Rate of Onset) Lipid solubility
  • 36. Pharmacokinetics of Benzodiazepines
    • Hepatic metabolism. Almost all BDZs undergo microsomal oxidation (N-dealkylation and aliphatic hydroxylation) and conjugation (to glucoronides).
    • Rapid tissue redistribution  long acting  long half lives and elimination half lives (from 10 to > 100 hrs).
    • All BDZs cross the placenta  detectable in breast milk  may exert depressant effects on the CNS of the lactating infant.
  • 37. Pharmacokinetics of Benzodiazepines
    • Many have active metabolites with half-lives greater than the parent drug.
    • Prototype drug is diazepam (Valium), which has active metabolites (desmethyl-diazepam and oxazepam) and is long acting (t½ = 20-80 hr).
    • Differing times of onset and elimination half-lives (long half-life => daytime sedation).
  • 38. Biotransformation of Benzodiazepines From Katzung, 1998
  • 39. Biotransformation of Benzodiazepines
    • Keep in mind that with formation of active metabolites, the kinetics of the parent drug may not reflect the time course of the pharmacological effect.
    • Estazolam, oxazepam, and lorazepam, which are directly metabolized to glucoronides have the least residual (drowsiness) effects.
    • All of these drugs and their metabolites are excreted in urine.
  • 40. Properties of Benzodiazepines
    • BDZs have a wide margin of safety if used for short periods. Prolonged use may cause dependence.
    • BDZs have little effect on respiratory or cardiovascular function compared to BARBS and other sedative-hypnotics.
    • BDZs depress the turnover rates of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in various brain nuclei.
  • 41. Side Effects of Benzodiazepines
    • Related primarily to the CNS depression and include: drowsiness, excess sedation, impaired coordination, nausea, vomiting, confusion and memory loss. Tolerance develops to most of these effects.
    • Dependence with these drugs may develop.
    • Serious withdrawal syndrome can include convulsions and death.
  • 42. Sedative/Hypnotics
      • They produce a pronounce, graded, dose-dependent depression of the central nervous system.
  • 43. Toxicity/Overdose with Benzodiazepines
    • Drug overdose is treated with flumazenil (a BDZ receptor antagonist, short half-life), but respiratory function should be adequately supported and carefully monitored.
    • Seizures and cardiac arrhythmias may occur following flumazenil administration when BDZ are taken with TCAs.
    • Flumazenil is not effective against BARBs overdose.
  • 44. Drug-Drug Interactions with BDZs
    • BDZ's have additive effects with other CNS depressants (narcotics), alcohol => have a greatly reduced margin of safety.
    • BDZs reduce the effect of antiepileptic drugs.
    • Combination of anxiolytic drugs should be avoided.
    • Concurrent use with ODC antihistaminic and anticholinergic drugs as well as the consumption of alcohol should be avoided.
    • SSRI’s and oral contraceptives decrease metabolism of BDZs.
  • 45. Pharmacokinetics of Barbiturates
    • Rapid absorption following oral administration.
    • Rapid onset of central effects.
    • Extensively metabolized in liver (except phenobarbital), however, there are no active metabolites .
    • Phenobarbital is excreted unchanged. Its excretion can be increased by alkalinization of the urine.
  • 46. Pharmacokinetics of Barbiturates
    • In the elderly and in those with limited hepatic function, dosages should be reduced.
    • Phenobarbital and meprobamate cause autometabolism by induction of liver enzymes.
  • 47. Properties of Barbiturates
    • Mechanism of Action.
      • They increase the duration of GABA-gated channel openings.
      • At high concentrations may be GABA-mimetic.
    • Less selective than BDZs, they also:
      • Depress actions of excitatory neurotransmitters.
      • Exert nonsynaptic membrane effects.
  • 48. Toxicity/Overdose
    • Strong physiological dependence may develop upon long-term use.
    • Depression of the medullary respiratory centers is the usual cause of death of sedative/hypnotic overdose. Also loss of brainstem vasomotor control and myocardial depression.
  • 49. Toxicity/Overdose
    • Withdrawal is characterized by increase anxiety, insomnia, CNS excitability and convulsions.
    • Drugs with long-half lives have mildest withdrawal (.
    • Drugs with quick onset of action are most abused.
    • No medication against overdose with BARBs.
    • Contraindicated in patients with porphyria .
  • 50. Sedative/Hypnotics
      • Tolerance and excessive rebound occur in response to barbiturate hypnotics.
    NREM III and IV REM 1 2 3 NIGTHS OF DRUG DOSING SLEEP PER NIGHT (%) CONTROL WITHDRAWAL
  • 51. Miscellaneous Drugs
    • Buspirone
    • Chloral hydrate
    • Hydroxyzine
    • Meprobamate (Similar to BARBS)
    • Zolpidem (BZ 1 selective)
    • Zaleplon (BZ 1 selective)
  • 52. BUSPIRONE
    • Most selective anxiolytic currently available.
    • The anxiolytic effect of this drug takes several weeks to develop => used for GAD.
    • Buspirone does not have sedative effects and does not potentiate CNS depressants.
    • Has a relatively high margin of safety, few side effects and does not appear to be associated with drug dependence.
    • No rebound anxiety or signs of withdrawal when discontinued.
  • 53. BUSPIRONE
    • Side effects:
      • Tachycardia, palpitations, nervousness, GI distress and paresthesias may occur.
      • Causes a dose-dependent pupillary constriction.
  • 54. BUSPIRONE
    • Mechanism of Action:
      • Acts as a partial agonist at the 5-HT 1A receptor presynaptically inhibiting serotonin release.
      • The metabolite 1-PP has  2 -AR blocking action .
  • 55. Pharmacokinetics of BUSPIRONE
    • Not effective in panic disorders.
    • Rapidly absorbed orally.
    • Undergoes extensive hepatic metabolism (hydroxylation and dealkylation) to form several active metabolites (e.g. 1-(2-pyrimidyl-piperazine, 1-PP)
    • Well tolerated by elderly, but may have slow clearance.
    • Analogs: Ipsapirone, gepirone, tandospirone .
  • 56. Zolpidem
    • Structurally unrelated but as effective as BDZs.
    • Minimal muscle relaxing and anticonvulsant effect.
    • Rapidly metabolized by liver enzymes into inactive metabolites.
    • Dosage should be reduced in patients with hepatic dysfunction, the elderly and patients taking cimetidine.
  • 57. Properties of Zolpidem
    • Mechanism of Action:
      • Binds selectively to BZ 1 receptors.
      • Facilitates GABA-mediated neuronal inhibition.
      • Actions are antagonized by flumazenil
  • 58. GABA ? NE DA 5-HT ACh (-) (-) (-) (-) (-) ANXIOLYTIC ? SEDATION ? ANTICONVULSANT/ MUSCLE RELAXANT ?
  • 59. Properties of Other drugs .
    • Chloral hydrate
    • Is used in institutionalized patients. It displaces warfarin (anti-coagulant) from plasma proteins.
    • Extensive biotransformation .
  • 60. Properties of Other Drugs
    •  2-Adrenoreceptor Agonists (eg. Clonidine)
      • Antihypertensive.
      • Has been used for the treatment of panic attacks.
      • Has been useful in suppressing anxiety during the management of withdrawal from nicotine and opioid analgesics.
      • Withdrawal from clonidine, after protracted use, may lead to a life-threatening hypertensive crisis .
  • 61. Properties of Other Drugs
    •  -Adrenoreceptor Antagonists
    • (eg. Propranolol)
      • Use to treat some forms of anxiety, particularly when physical (autonomic) symptoms (sweating, tremor, tachycardia) are severe.
      • Adverse effects of propranolol may include: lethargy, vivid dreams, hallucinations.
  • 62. OTHER USES
    • 1. Generalized Anxiety Disorder
    • D iazepam, lorazepam, alprazolam, buspirone
    • 2. Phobic Anxiety
        • a. Simple phobia. BDZs
        • b. Social phobia. BDZs
    • 3. Panic Disorders
    • TCAs and MAOIs, alprazolam
    • 4. Obsessive-Compulsive Behavior
    • C lomipramine (TCA), SSRI’s
    • 5. Posttraumatic Stress Disorder (?)
        • Antidepressants, buspirone
  • 63. Other Properties of Sedative/Hypnotics
    • BDZs on the other hand, with their long half-lives and formation of active metabolites, may contribute to persistent postanesthetic respiratory depression.
    • Most sedative/hypnotics may inhibit the development and spread of epileptiform activity in the CNS.
    • Inhibitory effects on multisynaptic reflexes, internuncial transmission and at the NMJ.
  • 64.
    • ANXYOLITICS
    • Alprazolam
    • Chlordiazepoxide
    • Buspirone
    • Diazepam
    • Lorazepam
    • Oxazepam
    • Triazolam
    • Phenobarbital
    • Halazepam
    • Prazepam
    • HYPNOTICS
    • Chloral hydrate
    • Estazolam
    • Flurazepam
    • Pentobarbital
    • Lorazepam
    • Quazepam
    • Triazolam
    • Secobarbital
    • Temazepam
    • Zolpidem
  • 65. References:
    • Katzung, B.G. (2001) Basic and Clinical Pharmacology . 7 th ed. Appleton and Lange. Stamford, CT.
    • Brody, T.M., Larner,J., and Minneman, K.P. (1998) Human Pharmacology: Molecular to Clinical. 2 nd ed. Mosby-Year Book Inc. St. Louis, Missouri.
    • Rang, H.P. et al. (1995) Pharmacology . Churchill Livingston. NY., N.Y.
    • Harman, J.G. et al. (1996) Goodman and Gilman's The Pharmacological Basis of Therapeutics . 9 th ed. McGraw Hill.