1 / 23

Sedative-Hypnotics

Teresita N. Avendano-Batanes, M.D., DPBA Department of Anesthesiology College of Mediciane UERMMMCI. Sedative-Hypnotics. Sedative - Hypnotics. Sedative Anxiolytic exerts a calming effect makes one less responsive to stimulation with decreased spontaneous activity Hypnotic

yestin
Download Presentation

Sedative-Hypnotics

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Teresita N. Avendano-Batanes, M.D., DPBA Department of Anesthesiology College of Mediciane UERMMMCI Sedative-Hypnotics

  2. Sedative - Hypnotics • Sedative • Anxiolytic • exerts a calming effect • makes one less responsive to stimulation with decreased spontaneousactivity • Hypnotic • encourages onset • maintains sleep • usually attained at higher doses of a sedative

  3. Sedative - Hypnotics • Death • Coma A • Anesthesia B • Hypnosis • Sedation Increasing Dose • Drug A: older Sed.-hypnotics, e.g. Barbiturates • Drug B: greater margin of safety, e.g. benzodiazepines

  4. Benzodiazepines •  aryl-1,4-benzodiazepines •  7-position substituent: halogen or nitro-group • - required for sedative-hypnotic activity

  5. Benzodiazepine • • Flumazenil (Anexate) – antagonist of benzodiazepine • • a synthetic benzodiazepine derivative

  6. Benzodiazepines • for sedative-hypnotic activity • Diazepam (Valium) 4. substitution in the 7-position, such as with a halogen or nitro group is required Triazolam (Halcion) • Flurazepam (Dalmane) 5. Midazolam (Dormicum) • Lorazepam (Ativan) 6. Estazolam (Esilgan) • *Flumazenil (Anexate) – antagonist of benzodiazepine • MOA: competitive antagonism at the GABAA receptor • a synthetic benzodiazepine derivative

  7. Barbiturates • Structure – Activity Relationships • 1. Substitution at C5 determines • a. Hypnotic potency: long-branched chain > short straight chain • b. Anti-convulasant activity: phenyl group is anti-convulsive •  2. Replacing O2 at C2 (Oxybarbiturate) with • S (Thiobarbiturate) •  lipid solubility  onset of action •  3. Short duration of action–methyl substitution at N1

  8. Barbiturates

  9. Sedative-Hypnotics • Alcohols: Ethanol, Chloral Hydrate • Ethers • New Drugs:Other Drugs with • *Buspirone - anxiolytic Sedative Effects • * Zolpidem - hypnotic 1. Clonidine • * Zaleplon – hypnotic 2. Antipsychotic tranquilizeres 3. Tricyclic Antidepressants 4. Antihistamines

  10. Benzodiazepines and Barbiturates • Pharmacokinetics • Routes of Admi/Absorption: po, rectal, IV, IM, SQ • Distribution • major role of lipid solubility to gain entry into CNS • thiobarbiturates more lipid vs. oxybarbiturates • rapid redistribution which termination CNS effects • all cross placental barrierneonatal depression • (+) in breast milk depression in breastfed babies • extensive protein binding: benzodiazepines: 60 – 90% • chloral hydrate displaces warfarin from plasma protein binding site anticoagulant effect of warfarin

  11. Benzodiazepines • Biotransformation/Excretion • by microsomal drug metabolizing enzymes (liver)to water-soluble metabolites excretion via the kidneys • Table M. Some benzodiazepines with their metabolites:

  12. Barbiturates • -  inactive metabolites w/ few exceptions • *Phenobarbital – 20 – 30% excreted unchanged; elimination half-life of 4 – 5 days • multiple dosing  cumulative CNS effects • biodisposition affected by hepatic changes due to: • old age, diseases, microsomal enzyme activity

  13. Benzodiazepines and Barbiturates • Pharmacodynamics • Mechanism of Action: bind • Benzodiazepines molecular components of • barbiturates*GABAA receptors in CNS  opening of Chloride ion channels  Chloride ion conductance • *Do not substitute for GABA but appear to enhance effects of GABA

  14. Organ Level Effects • Sedation • may be with by euphoria, impaired judgement • anterograde amnesia – cannot recall events happening during the drug’s action (benzodaazepines) 2. Hypnosis • time to fall asleep is , duration of stage 2 NREM sleep is ; duration of REM sleep is  • use of sedative-hypnotics for > 1 – 2 weeks may lead to some tolerance to their effects on sleep patterns 3. Anesthesia • some sedative-hypnotics  stage III of GA • large doses contribute to post-op resp. depression • no analgesic property, used as adjuncts, “conscious sed.”

  15. Organ Level Effects • Anti-Convulsant Effect - inhibit development and spread of seizure activity in CNS • - benzodiazepines: clonazepam (for absence seizure), lorazepam, diazepam (drug of choice for status epilepticus) • - barbiturates: Phenobarbital, metharbital 2. Muscle Relaxation • inhibitory effects:polysynaptic reflexes/internuncial trans. • relax contracted skel. muscle/muscle spasm: treat spasticity 3. Effects on Respiratory and Cardiovascular Functions • significant resp. depression in pxs with pulmonary disease • significant CV depression in pxs who are hypovolemic, w/ congestive heart failure or w/ impaired CV function

  16. Benzodiazepine Antagonist: Flumazenil • MOA: competitive antagonism at GABAA receptor • 1,4- benzodiazepine (synthetic) derivative • does not antagonize the CNS effects of other sedative-hypnotics, ethanol, opioids or general anesthetics • IV; half-life = 0.7 – 1.3 hrs. due to rapid hepatic clearance • Watch/O for recurrence of benzodiazepine-caused CNS dep. • Adverse Effects: agitation, confusion, dizziness, nausea, abstinence symptoms in dependent patients •  Drug Interaction: benzodiazepine + tricyclic antidep. + flumazenil Sz, cardiac arrhythmias

  17. New Anxiolytic • BUSPIRONE: for relief of Anxiety • no marked sedation/euphoria; less psychomotor impair. • does not potentiate CNS actions of other drugs • Mechanism of Action: partial agonist at 5-HT1A receptor • Onset of Action: > one week to establish • Not for panic states, only for general anxiety states • Liver dysfunction may decrease clearance • Drug Interactions: • Buspirone + MAOI  BP • antagonized by flumazenil

  18. New Hypnotics • ZOLPIDEM (Stilnox):a hypnotic •  Mechanism of Action: binds selectively with BZ1 (omega1) subtype of benzodiazepine receptor •  facilitate GABA-mediated neuronal inhibition • antagonized by flumazenil; elim.half-life: 1.5 – 3.5 hrs. • DI: •  dose in pxs w/ liver dysfunction, elderly, on cimetidine • Rifampicin (C P450 inducer) half-life of zolpidem • C/I: children <15 yrs., pregnant/lactating pxs • Prep: tab 10mg

  19. New Hypnotics • 2. ZALEPLON: a hypnotic, resembles zolpidem • Mechanism of Action: binds selectively with BZ1 receptor subtype of benzodiazepine receptor •  facilitate GABA inhibitory action • decreases sleep latency, has little effect on total sleep time • SE: amnestic effects; next-day impair. of psychomotor fx • may potetiate CNS depression from ethanol • no reports of tolerance or withdrawal symptoms • Pharmacokinetics: • absorbed rapidly from the GIT • metabolized by hep.aldehyde oxidase, cytochrome p450 • metabolism is inhibited by cimetidine

  20. Sedative - Hypnotics • DRUG INTERACTIONS • 1.  Additive Effects with Other CNS Depressants • alcoholic beverages, opioidcs, anti-convulsants, phenothiazines, antihistamines, TCAD, antihypertensives •  2.  Altered Activity of Hepatic Drug-Metabolizing Enzyme System • Barbiturates - metabolism of dicumarol, phenytoin, digitalis, griseofulvin • Diazepam – half-life doubled by cimetidine (inhib. metab Chloral Hydrate – may displace warfarin from plasma protein binding sites  anticoagulant effect of warfarin

  21. Clinical Toxicology of the Sed-Hyps • CNS Depression • - severe toxicity: resp. dep., aspiration, loss of vasomotor control from brainstem, direct myocardial depression • - treatment:secure airway and breathing, maintain plasma volume, renal output,maintain cardiac function, • reversal of benzodiazepine effects by flumazenil 2. Hypersensitivity Reactions – skin rashes 3.  Teratogenicity – piperidindiones, some benzodiazepines 4.  Enhance Porphyrin Synthesis • - barbiturates are contraindicated in patients with acute intermittent porphyria, variegated porphyria, hereditary coproporphyria or symptomatic porphyria

  22. Alterations in Drug Response • 1. Tolerance - decreased responsiveness to a drug following repeated exposure • depends on dosage, duration of use, chronic abusers consume very large doses w/o experiencing severe toxicity • Cross-Tolerance – exists between different sedative-hypnotics, including ethanol •  2.      Physiologic Dependence • altered physiologic state requiring continued drug administration to prevent the appearance of abstinence Sx • withdrawal Sx: restlessness, anxiety, weakness, orthostatic hypotension, hyperactive reflexes, generalized seizures • Cross-Dependence – the ability of a substituted drug to suppress abstinence Sx from D/C of another drug

More Related