SEDATIVE-HYPNOTIC DRUGS

Sedative Hypnotic Drugs• The sedative-hypnotic produce dose

dependent CNS depressant effect• Sedation : Reduction of anxiety

Hypnosis : Induction of sleep• Subgroup :

- Benzodiazepine (Chlordiazepoxide, diazepam, temazepam)- Barbiturat (Phenobarbital, pentobarbital,

thiopental)- Others (buspirone, zolpidem, chloralhydrate, zaleplon)

Sedative Hypnotic Drugs• Benzodiazepine :

- short acting (triazolam)- intermediate acting (estazolam,

temazepam)- long acting (flurazepam, quazepam)

Sedative Hypnotic Drugs• Barbiturates :

- Ultra short acting - Short acting - Long acting

Sedative Hypnotic Drugs(Pharmacokkinetics)

• All sedative hypnotic are lipid soluble and absorbed well from GI tract

• Good distribution to the brain in oral administration

Sedative Hypnotic Drugs(Metabolism and Excretion)

• Metabolized mainly by hepatic enzymes

• Many benzodiazepine are converted to active metabolitesAccumulation of active metabolites can lead to excessive sedation

• The barbiturates are extensively metabolized,except phenobarbital

Sedative Hypnotic Drugs(Mechanisms of Action)BENZODIAZEPINES• Receptors for benzodiazepines (BZ

receptors) are present in the thalamus,limbic structures,and the cerbralcortex.

• Binding of Benzodiazepines facilitates the inhibitory actions of GABA,which are exerted through increased chloride ion conductance.

• GABA is the major inhibitoric neurotransmitter in the CNS

Sedative Hypnotic Drugs(Mechanisms of Action)Barbiturates• Barbiturates depress neuronalactivity in the

midbrain reticular formation, facilitating and prolonging the inhibitory effects of GABA

Other drugs• Mechanism of anxiolytic effect of buspirone

is unknown, but buspirone interact with the 5-HT as partial agonist

• Zolpidem & zaleplon interact with BZ1 bind selectively with GABAA receptor

Sedative Hypnotic Drugs(Pharmacodynamics)• The CNS effect depend on dose• Effects : sedation & relief of anxiety,

through hypnosis (facilitation of sleep) to anesthesia and coma

• When 2 or more drugs are given togetherdepressant effect +++

• Sedation : sedative action with relief of anxiety

• Hypnosis : promote sleep onset and duration of the sleep state

Sedative Hypnotic Drugs(Pharmacodynamics)• Anesthesia : conscious with amnesia &

supressions of reflexes (at highdose). Can produce by most barbiturates (eg,thiopental) & certain benzodiazepines (eg,midazolam)

• Anticonvulsant actions : supression of seizure activity (high dose),usually accompany by sedation effect.Selective anticonvulsant (supression of convulsion at dose that do not cause severe sedation is Phenobarbital, clonazepam

Sedative Hypnotic Drugs(Pharmacodynamics)• Muscle relaxation : relaxation of skeletal

muscle (at high dose)Diazepam at sedative dose effective for spasticity statesSelective muscle relaxant : Meprobomate

• Medullary depression : High dose can cause depression of medullarry neurons,leading to respiratory arrest, hypotension & CV collapse death

Sedative Hypnotic Drugs(Pharmacodynamics)

• Tolerance& dependence :tolerance – a decrease in responsiveness, occurs when used chronically or in high dose

physiologic dependence– an altered state that leads to an abstinence syndrome (withdrawal state) when the drug is discontinued Sign : anxiety, tremors,hyperreflexia, seizure

Sedative Hypnotic Drugs(Clinical Uses)• Anxiety states (alprazolam,

clonazepam, buspirone)The anxiolityc effect of buspirone occur without sedation or cognitive impairment

• Sleep disorder (estazolam,flurazepam, triazolam)

• Induction of anesthesia (thiopental, diazepam, midazolam)

• Management of seizure disorders (clonazepam,phenobarbital)

Sedative Hypnotic Drugs(Clinical Uses)• Management of withdrawal states

in persons physiologically dependent on ethanol & sedative hypnotics (chlordiazepoxide, diazepam)

Sedative Hypnotic Drugs(Toxicity)

• Cognitive impairment• Decreased psychomotor skills• Unwanted daytime sedation• Anterograde amnesia• Additive CNS depression

when used with other drugs in the class (antihistamines,antipsychotic drugs, opioid analgesics, tricyclic antidepressants)

• Overdosage severe respiratory & CV depressionFlumazenil may reverse CNS depressant effect of

benzodiazepines, zolpidem & zaleplon