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Sedative Hypnotic Drugs Lecture

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Sedative Hypnotic Drugs Lecture

  1. 1. CNS DEPRESSANTS SEDATIVE-HYPNOTIC DRUGS Dr. Hiwa K. Saaed, BSc, HD, MSc. PhD Department of Pharmacology & Toxicology College of Pharmacy/ University of Sulaimani 2014-2015
  2. 2. ANXIETY • Unlike other mental disorders, anxiety can be both: – a normal emotion – and a psychiatric illness. • It is a universal human emotion, and a certain amount is useful to the individual, acting as a stimulant and increasing efficiency. • but when it becomes excessive and disproportionate to the situation, an anxiety state develops; it becomes a pathological (disabling) and needs treatment. 11/3/2014 2
  3. 3. ANXIETY DISORDERS It usually involves both: • Mental features – worry, fear, difficulty concentration, sleep problems. • Physical symptoms – Tachycardia; muscle aches, nausea, shortness of breath, trembling, pacing 11/3/2014 3
  4. 4. ANXIETY CLASSIFICATION #Primary • Generalized anxiety disorder (GAD): apprehensive and tense for no particular reason. • Panic disorder: unexpected attacks of anxiety. • Phobic disorders: fears certain situation “agoraphobia” • Obsessive compulsive disorder: repetitive, anxiety driven behavior or obsessive thoughts and doubts (check things more than once) • Post-traumatic stress disorder (rape or warefare) #Secondary due to medical causes or substances 11/3/2014 4
  5. 5. SEDATIVE-HYPNOTIC DRUGS The sedative-hypnotics belong to a chemically heterogeneous class of drug. The most important are: • Benzodiazepines (BZs), Diazepam, • Non benzodiazepines: buspirone, zolpidem, and Zaleplon • Barbiturates: phenobarbital, • Miscellaneous: carbamates, alcohol 11/3/2014 5
  6. 6. SEDATIVE-HYPNOTIC DRUGS SEDATIVE-HYPNOTICS Benzodiazepines Barbiturates Miscellaneous agents Short Ultrashort acting acting Intermediate Short Buspirone acting acting Chloral hydrate Long Long Zaleplon acting acting Zolpidem Ramelteon Tasimelteon 11/3/2014 6
  7. 7. THE EFFECTS OF CNS DEPRESSANTS – Sedatives cause mild depression and relaxation • Anxiolytic—drugs that relieve anxiety Site of action is on the limbic system which regulates thought and mental function. – Hypnotics induce drowsiness and encourage sleep • Amnesiac effects can cause the loss of memory Site of action is on the midbrain and ascending RAS which maintain wakefulness. 11/3/2014 7
  8. 8. THE EFFECTS OF CNS DEPRESSANTS (continued) • The same drug can cause different effects based on dose. – Low dose (sedatives—relieve anxiety and promote relaxation) – Higher doses (hypnotics—can cause drowsiness and promote sleep) – Even higher doses (anesthetics—can cause anesthesia and are used for patient management during surgery) 11/3/2014 8
  9. 9. DOSE-DEPENDENT DEPRESSION OF CNS 11/3/2014 9
  10. 10. SEDATIVE HYPNOTIC MECHANISMS OF ACTION • Most S-H drugs facilitate the actions of GABA, a major inhibitory transmitter in the CNS, • GABAA receptor activation leads to increased Cl- ion influx; • GABAB receptor activation causes increased efflux of K+. • Both mechanisms result in membrane hyperpolarization. 11/3/2014 10
  11. 11. GABAA RECEPTOR The pentapeptide structure of the GABAA receptor has binding sites for BZs and for other drugs, including Barbiturates and ethanol. 11/3/2014 11
  12. 12. BENZODIZEPINES  Sedative (Anxiolytics) : Alprazolam Chlordiazepoxide oxazepam Diazepam lorazepam  Hypnotics : Triazolam Diazepam Alprazolam Lorazepam Estazolam Temazepam Flurazepam Nitrazepam Quazepam  Preanesthetics : Diazepam - Midazolam Leo sternback 11/3/2014 12
  13. 13. DURATION OF ACTION OF BZS • Short acting (2-8 hrs) midazolam triazolam • Intermediate (10-20 hrs) temazepam, lorazepam, alprazolam, oxazepam, nitrazepam, estrazolam • Long acting (1-3 days): chlordiazepoxide, diazepam, flurazepam, clonazepam, chlorazepate 11/3/2014 13
  14. 14. BENZODIAZEPINE MECHANISMS OF ACTION Affect neurons that have receptors for the neurotransmitter GABA BZs potentiate GABA → increase frequency of Cl- ion channel opening→ causes hyperpolarization→ raise firing threshold→ and thus inhibits the formation of action potentials  inhibitory effect on different sites of the brain especially motor cortex, and limbic system. GABA—inhibitory transmitter in brain regions – Limbic system (alter mood) – RAS (cause drowsiness) – Motor cortex (relax muscles) 11/3/2014 14
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  16. 16. PHARMACOKINETICS  Most of them are well absorbed orally.  Bzs are lipid soluble and widely distributed  Redistribution from CNS to skeletal muscles, adipose tissue.  Cross placental barrier during pregnancy and are excreted in milk (Fetal & neonatal depression).  Highly bound to plasma protein. 11/3/2014 16
  17. 17. PHARMACOKINETICS  All Bzs are metabolized in the liver Phase I: ( liver microsomal system) Phase II: glucouronide conjugation and excreted in the urine.  Many of Phase I metabolites are active: Increase elimination half life of the parent compound , cumulative effect with multiple doses.  EXCEPT No active metabolites are formed for (LEO) Lorazepam, Estazolam, Oxazepam. 11/3/2014 17
  18. 18. METABOLISM 11/3/2014 18
  19. 19. ACTIONS AND THERAPEUTIC DOSES: BZs have neither antipsychotic activity nor analgesic. They don’t affect ANS Reduction of anxiety at low dose: alprazolam, lorazepam, oxazepam, diazepam and chlordiazepoxide.  Alprazolam has anxiolytic-antidepressant effect.  Diazepam is preferred in acute panic-anxiety.  Chlordiazepoxide is preferred in chronic anxiety states. Sedative and hypnotic actions at higher dose: not all, three most commonly prescribed BZs are: – long acting flurazepam, – intermediate temazepam – short acting triazolam. and Two non BZs: – Zolpidem & Zaleplon. 11/3/2014 19
  20. 20. ACTIONS AND THERAPEUTIC DOSES: • Anterograde amnesia: short acting BZs used in premedication for endoscopic, bronchoscopic, angioplasty. In anesthesia : Preanesthetic medication diazepam Induction of balanced anesthesia (Midazolam) • Anticonvulsant: Treatment of epilepsy Diazepam – Lorazepam: Status epilepticus Clonazepam-Clorazepate: absence , myoclonic seizures. 11/3/2014 20
  21. 21. ACTIONS AND THERAPEUTIC DOSES: • To control Alcohol withdrawal symptoms: chlordiazepoxide, chlorazepate, diazepam & oxazepam • Muscle relaxant at higher doses; diazepam is useful in the Rx of skeletal muscle spasm • Other actions: in higher doses BZs decrease BP and increase HR. diazepam decreases nocturnal gastric acid secretion 11/3/2014 21
  22. 22. INDICATIONS AND DRUG CHARACTERISTICS 11/3/2014 22
  23. 23. TOLERANCE • Tolerance: reduction in drug effect requiring an increase in dosage to maintain the same response. • Chronic use leads to tolerance (cross with other S-H drugs), possibly via downregulation of BZ receptors. • The antianxiety effects of the BZ are less subject to tolerance than sedative and hypnotic effects. 11/3/2014 23
  24. 24. DEPENDENCE • Physiological dependence: removal of the drug evokes unpleasant symptoms, usually the opposite of the drugs effects • Psychological dependence: the drug taker feels compelled to use the drug & suffers anxiety when separated from drug. 11/3/2014 24
  25. 25. WITHDRAWAL SYMPTOMS Abrupt discontinuation, particularly if high doses used for prolong period. 1. Confusion, 2. anxiety, 3. agitation, 4. restlessness, 5. insomnia 6. tension WD symptoms with BZs are less intense than with ethanol or barbiturates; 11/3/2014 25
  26. 26. ADVERSE EFFECTS OF BZS • Drowsiness and confusion • Ataxia at high doses-precludes activities like driving • Cognitive impairment: ↓long term recall, ↓acquisition of knowledge 11/3/2014 26
  27. 27. FLUMAZENIL BZS ANTAGONIST Flumazenil: I.V only, reverses the effect of the BZs (competitive antagonist), onset is rapid, and duration is short. 11/3/2014 27
  28. 28. MISCELLANEOUS; NON BENZODIAZEPINES Zolpidem and Zaleplon they: • act on BZ1 (a subtype of BZ receptor family), • are more selective hypnotics • are not effective in chronic anxiety, seizure disorders, or muscle relaxing. • Possibly less tolerance occur with prolong use • and lower abuse liability and dependence than BZs. • they show no withdrawal effects, Minimal rebound insomnia 11/3/2014 28
  29. 29. ZOLPIDEM AND ZALEPLON • Rapidly absorbed, rapid onset with short duration (2-3 hrs) • Zaleplon is very similar to zolpidem in its hypnotic action, • but ZALEPLON causes fewer residual effect on pseudomotor and cognitive function compared with zolpidem or the BZs due to short t1/2 < 1hr 11/3/2014 29
  30. 30. BUSPIRONE totally different anxiolytic from BZs, no effects on GABA systems, possible partial agonist at 5- HT1A receptors some affinity for D2 & 5-HT2A. Indication: • Indicated for generalized anxiety disorders but takes 1 to 2 weeks to exert anxiolytic effects. 11/3/2014 30
  31. 31. BUSPIRONE Buspirone lucks anticonvulsant and Muscle relaxant property of BZs and cause minimal sedation. • No additive CNS depression with other drugs. Adverse effects: hypothermia, increase prolactin, headache, dizziness, nervousness 11/3/2014 31
  32. 32. BARBITURATES • Formerly used as sedative hypnotic replaced by BZs, because barbiturates induce: 1. tolerance, 2. drug metabolizing enzyme, 3. physical dependence 4. and very severe withdrawal symptom. 5. Flumazenil does not block the effects of barbiturates. Bayere dicoverer of barbiturates. 11/3/2014 32
  33. 33. BARBITURATES MECHANISM OF ACTION • interact with GABA receptors, the binding site is distinct from that of the BZs. • potentiate GABA action on Cl- entry into the neuron by increase the duration of Cl- ion channel opening. • In addition, barbiturates can block excitatory glutamate receptor (sub anesthetic dose). • at high doses (anesthetics conc. of pentobarbital-reticular activating system inhibition), also – open Cl- ion channels directly – and block high frequency Na+ channels). 11/3/2014 33
  34. 34. Duration of Action of Barbiturates • Long acting (1-2 days) Anticonvulsant Phenobarbital; • Short (3-8hrs) Sedative & Hypnotic Pentobarbital, secobarbital and amobarbital: • Ultrashort (20 min) I.V induction of anesthesia Thiopental 11/3/2014 34
  35. 35. ADVERSE EFFECTS OF BARBITURATES • Dose-dependent CNS depression, with nystagmus and ataxia progressing to respiratory depression, coma, and possible mortality. • no specific antidote in overdose. • Additive CNS depression with other drugs. 11/3/2014 35
  36. 36. PHARMACOKINETICS  All barbiturates are weak acids, lipid soluble, absorbed orally. distribute throughout the body  Thiopentone is highly lipid soluble (high rate of entry into CNS- quick onset of action).  Redistribute in the body from the brain to skeletal muscles- adipose tissues.  metabolized in the liver to inactive metabolites  Excreted in the urine.  Alkalinization increases excretion (NaHCO3)  Cross the placenta ( pregnancy). 11/3/2014 36
  37. 37. METABOLISM • Hepatic metabolism (some to active metabolite). • Induction of Cytochrome P450 is characteristic and may lead to drug interactions. • Because of increase heme synthesis, they are contraindicated in porphyrias • Porphyrias: a hereditary disorder of hemoglobin metabolism causing: -mental disturbance, -extreme sensitivity to light -and excretion of dark pigments in the urine. 11/3/2014 37
  38. 38. WHY BENZODIZEPINES HAS REPLACED BARBITURATES? BZS BARBITURATES  They do not produce anesthesia in high doses & patient can be aroused.  These are not enzyme inducers,  Very low abuse liability.  Lesser distortion of normal hypnogram.  Bzs have no hyperalgesia.  Bzs can be used as day time anxiolytic.  Do not effect respiratory or cvs function.  There is a specific antagonist- Flumazenil.  Produce loss of consciousness and have low margin of safety  enzyme inducers.  High abuse liability.  Marked suppression of REM sleep.  Hyperalgesic action.  Unacceptable drowsiness is seen.  Causes respiratory and depression & hypotension.  No specific antagonist. 11/3/2014 38
  39. 39. MISCELLANEOUS • Antihistamines: it has low tendency for habituation and thus is useful for patients wit anxiety who have a history of drug abuse. – hydroxyzine, – diphenhydramine – doxylamine; • Melatonin: synthesized from 5HT, significant role in diurnal cycles and sleep-wake behavior. 11/3/2014 39
  40. 40. MISCELLANEOUS • Ramelteon: melatonin receptor (MT1 and MT2) agonist with sleep promoting activities. – It has been approved for chronic insomnia and considered free from dependence potential. • Tasimelteon • PROPRANOLOL has efficacy in performance anxiety and social phobias. • Tricyclicantidepressants (TCA) and SSRI • Opiod analgesics • Ethanol 11/3/2014 40
  41. 41. SOME OUTDATED HYPNOTICS: • Chloral hydrate: – is a trichlorinated derivative of acetaldehyde that is converted to the active metabolite, trichloroethanol in the body. • Paraldehyde: – little effect on respiration and BP in therapeutic dose. – Large doses suppress all type of convulsions with rapid onset of action. – It has strong aromatic odor and unpleasant taste. 11/3/2014 41
  42. 42. 11/3/2014 Thank you 42

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