Introduction:Sedation: | Reduction of anxiety | Hypnosis: | Induction of sleep | Sedative: | Synonym=anxiolytic, Reduces anxiety and has a calming effect | Hypnotic: | Produces drowziness, Induces and maintains sleep |
Dose-Responsive Curve for S-H Agents:
Classification:Benzodiazepines:
>Short-acting: Triazolam
>Intermediate-acting: alprazolam,lorazepam,oxazepam,temazepam
>Long acting: pentobarbitone, phenobarbitone,secobarbitone MOA: BenzodiazepinesReceptors for BZ present = Thalamus, limbic structures, cerebral cortex
BZ receptors =
> Part of GABAA receptor chloride ion channel macromolecular complex
> Major GABAA receptor isoform
>Five subunits: 2α1, 2β2, and 1Υ2 |
Benzodiapines bind between α1 and Υ2 subunits
Increase the FREQUENCY of GABA-mediated chloride ion opening | | MOA:Barbiturates:> Depress neural activity in midbrain reticular formation
>Bind to α and β subunits of the GABAA receptor
>Prolong the action of GABA and glycine |
Increase the DURATION of GABA-mediated chloride ion channel opening
>may also block glutamate receptors and sodium channels at higher doses MOA: Other Agents:Zolpidem, Zaleplon, Eszopiclone = not Benzaodiazepines
>Bind to benzodiazepine receptor (BZ1 or ω1)
More selective to GABAA isoforms that contain α1 subunits
-Fewer adverse effects than benzodiazepines
-Minimal effects on sleep patterns, less likely to cause dependence
>Increase the FREQUENCY of GABA-mediated chloride ion opening |
Effects:Sedation | Anticonvulsant actions | Tolerance | Hypnosis | Muscle relaxation | Psychological dependence - Compulsive use | Anaesthesia | Medullary depression | Physiological dependence - withdrawl symptoms if drug is discontinued |
CNS Effects:Clinical Uses:
> Anxiety states
> Sleep disorders
> Anesthesia
> Epilepsy
> Alcohol withdrawal state | | Adverse Effects:Psychomotor Dysfunction: | Cognitive impairment, decreased psychomotor skills, daytime sedation | Additive CNS Depression: | Alcohol, antihistamines, antipsychotic agents, opioids, tricyclic antidepressants | Overdose: | CVS and respiratory depression, Antidote: Flumazenil |
Pharmacokinetics:> Most are lipid soluble, absorbed well from GIT | > May cross the placental barrier during pregnancy - may depressed neonatal vital functions | > Detectable in breast milk - may exert depressant effects in nursing infant | > Metabolism by hepatic enzymes - renal function = no significant effect on elimination |
Pharmacokinetics:Benzodiazepines:
-Converted to active metabolites with long half-lives
--Potential for accumulation
-Lorazepam and oxazepam do not form active metabolites
-Metabolized mainly by CYP3A4
Barbiturates:
-Extensively metabolized
--Except pentobarbital
---Excreted partly unchanged in urine |
Zolpidem: No active metabolites
Drug Interactions:
-Inducers/inhibitors of CYP3A4 interact with sedative hypnotics
--E.g. rifampicin (inducer), ketoconazole, cimetidine (inhibitors)
-Barbiturates induce metabolic enzymes Atypical Sedative-Hypnotics:Buspirone:
>Partial agonist at 5-HT1A receptors
>Selective anxiolytic effects:
-Minimal CNS depressant effects = No anticonvulsant or muscle relaxation effect
>Minimal tolerance, dependence, and abuse potential |
Ramelteon, Tasimelteon:
> Melatonin receptor agonists
>Minimal rebound or withdrawal symptoms
>Minimal abuse potential |
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