sedative hypnotics anxiolytics n.
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  1. SEDATIVE/HYPNOTICSANXIOLYTICS Martha I. Dávila-García, Ph.D. Howard University Department of Pharmacology

  2. Optimal Performance Nervous Breakdown Sedated Performance Anxiety GOAL

  3. 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.

  4. 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).

  5. Causes of Anxiety 1). Medical: • Respiratory • Endocrine • Cardiovascular • Metabolic • Neurologic.

  6. Causes of Anxiety 2). Drug-Induced: • Stimulants • Amphetamines, cocaine, TCAs, caffeine. • Sympathomimetics • Ephedrine, epinephrine, pseudoephedrine phenylpropanolamine. • Anticholinergics\Antihistaminergics • Trihexyphenidyl, benztropine, meperidine diphenhydramine, oxybutinin. • Dopaminergics • Amantadine, bromocriptine, L-Dopa, carbid/levodopa.

  7. Causes of Anxiety • Miscellaneous: • Baclofen, cycloserine, hallucinogens, indomethacin. 3). Drug Withdrawal: • BDZs, narcotics, BARBs, other sedatives, alcohol.

  8. Anxiolytics Strategy for treatment Reduce anxiety without causing sedation.

  9. Anxiolytics • Benzodiazepines (BZDs). • Barbiturates (BARBs). • 5-HT1A receptor agonists. • 5-HT2A, 5-HT2C & 5-HT3 receptor antagonists. If ANS symptoms are prominent: • ß-Adrenoreceptor antagonists. • 2-AR agonists (clonidine).

  10. 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). • CCKB (e.g. CCK4). • EAA's/NMDA (e.g. HA966).

  11. Sedative/Hypnotics • A hypnotic should produce, as much as possible, a state of sleep that resembles normal sleep.

  12. 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.

  13. Sedative/Hypnotics • Benzodiazepines (BZDs): Alprazolam, diazepam, oxazepam, triazolam 2) Barbiturates: Pentobarbital, phenobarbital 3) Alcohols: Ethanol, chloral hydrate, paraldehyde, trichloroethanol, 4) Imidazopyridine Derivatives: Zolpidem 5) Pyrazolopyrimidine Zaleplon

  14. Sedative/Hypnotics 6) Propanediol carbamates: Meprobamate 7) Piperidinediones Glutethimide • Azaspirodecanedione Buspirone 9) -Blockers** Propranolol 10) 2-AR partial agonist** Clonidine

  15. Sedative/Hypnotics Others: 11) Antyipsychotics ** Ziprasidone 12) Antidepressants ** TCAs, SSRIs 13) Antihistaminic drugs ** Dephenhydramine

  16. 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!!

  17. Sedative/Hypnotics Relationship between Older vs Newer Drugs Barbiturates Benzodiazepines GlutethimideZolpidem MeprobamateZaleplon **All others differ in their effects and therapeutic uses. They do not produce general anesthesia and do not have abuse liability.


  19. Sedative/Hypnotics The benzodiazepines are the most important sedative hypnotics. Developed to avoid undesirable effects of barbiturates (abuse liability).

  20. Benzodiazepines • Diazepam • Chlordiazepoxide • Triazolam • Lorazepam • Alprazolam • Clorazepate => nordiazepam • Halazepam • Clonazepam • Oxazepam • Prazepam

  21. Barbiturates • Phenobarbital • Pentobarbital • Amobarbital • Mephobarbital • Secobarbital • Aprobarbital

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

  23. Respiratory Depression BARBS BDZs Coma/ Anesthesia Ataxia RESPONSE ETOH Sedation Anticonvulsant Anxiolytic DOSE

  24. Respiratory Depression BARBS Coma/ Anesthesia BDZs Ataxia RESPONSE Sedation Anticonvulsant Anxiolytic DOSE

  25. GABAergic SYNAPSE glucose glutamate GAD GABA Cl-

  26. GABA-A Receptor BDZs • Oligomeric (abdgepr) 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. BARBs GABA AGONISTS   d  e

  27. 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-HT1A receptors. 3) Inhibit 5-HT2A, 5-HT2C, and 5-HT3 receptors.

  28. Patch-Clamp Recording of Single Channel GABA Evoked Currents From Katzung et al., 1996

  29. 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 BZ1 (1 and 2 subunit-containing) and BZ2 (5 subunit-containing) receptors. • May cause euphoria, impaired judgement, loss of cell control and anterograde amnesic effects.

  30. 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

  31. CNS Effects (Rate of Onset) Lipid solubility

  32. 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.

  33. 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).

  34. Biotransformation of Benzodiazepines From Katzung, 1998

  35. 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.

  36. 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.

  37. 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.

  38. Sedative/Hypnotics • They produce a pronounce, graded, dose-dependent depression of the central nervous system.

  39. 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.

  40. 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.

  41. 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.

  42. 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.

  43. 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.

  44. 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.

  45. 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.

  46. WITHDRAWAL CONTROL SLEEP PER NIGHT (%) NIGTHS OF DRUG DOSING Sedative/Hypnotics Tolerance and excessive rebound occur in response to barbiturate hypnotics. REM NREM III and IV 1 2 3

  47. Miscellaneous Drugs • Buspirone • Chloral hydrate • Hydroxyzine • Meprobamate (Similar to BARBS) • Zolpidem (BZ1 selective) • Zaleplon (BZ1 selective)

  48. 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.

  49. BUSPIRONE Side effects: • Tachycardia, palpitations, nervousness, GI distress and paresthesias may occur. • Causes a dose-dependent pupillary constriction.

  50. BUSPIRONE Mechanism of Action: • Acts as a partial agonist at the 5-HT1A receptor presynaptically inhibiting serotonin release. • The metabolite 1-PP has 2 -AR blocking action.