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SEDATIVE AND HYPNOTICS

By:Dr. Usman Younis

SEDATIVE Drugs that calm the patient and reduce anxiety without inducing normal sleep.

HYPNOTICSDrugs that produce drowsiness and encourage the onset of sleep

CLASSIFICATION OF DRUGSBarbiturates. Benzodiazepines ( BDZ ). Miscellaneous agents.BuspironeChloral hydrateZolpidemZaleplon.zopiclon

BARBITURATESARE

CNS depressants which produce effects ranging from Sedation Reduction of anxiety Hypnosis and Unconsciousness.

Barbiturates were in the past the mainstay of treatment.

BARBITURATESClassification: Long acting( 24-28 h): PhenobarbitoneIntermediate (8-24h): AmylobarbitoneShort-acting(3-8h): PentobarbitoneSecobarbitoneAmobarbitalUltrashort acting (25 minutes): Thiopentone, Methohexitone.

Bayere dicoverer of barbiturates.

MECHANISM OF ACTIONGABA the major inhibitory neurotransmitter in the brain.It has specific receptors in chloride channels present on the membrane of post synaptic neurons. regulates the entrance of chloride into the postsynaptic cells.

MECHANISM OF ACTION

Binding of GABA to its receptor (GABA A receptor) Results in opening of the chloride channel and Increased conductance of cl ions to inside the post-synaptic neuron. hyperpolarization of the postsynaptic neuron and decreased synaptic neurotransmission.

MECHANISM OF ACTIONBarbiturates increases the cl ion channel opening (at higher doses open cl ion channels and block Na+ channels) Increased conductance of cl ions to inside the post-synaptic neuron. hyperpolarization of the postsynaptic neuron and decreased synaptic neurotransmission.

PHARMACOKINETICSLipid solubility and ionization influence the onset and duration of action. The ultra-short acting Drug; Thiopentone is highly lipid soluble (high rate of entry into CNS- quick onset of action). b/cRedistribute in the body from the brain to skeletal muscles- adipose tissues.

PHARMACOKINETICSLong-acting agents (less lipid soluble) have slower onset and longer duration of action.

metabolized in the liver to inactive metabolites Excreted in the urine. Alkalinization of urine increases excretion (NaHCO3)

Cross the placenta ( pregnancy).

PHARMACOLOGICAL ACTIONSAt Low Doses : Barbiturates produce sedation At Higher Doses :Produce hypnosis Anaesthesia.

Overdosage may cause respiratory depression and death.

USESANTICONVULSANT: Phenobarbitone. (tonic-cronic seizures and eclampsia)INDUCTION OF ANESTHESIA: thiopentone and methohexitone.HYPNOTIC: pentobarbital (used as sleeping pills).HYPERBILIRUBINEMIA : pentobarbitalTo lower serum bilirubin : a) Patients with chronic cholestasis b) Neonatal jaundice (kernicterus)

ADVERSE EFFECTSRespiratory depression. Hangover: residual sedation after awakening. Tolerance. Physical dependence with prolonged use. Teratogenicity. Allergic reaction: urticaria and skin rash.

Toxicity : Respiratory depression, Cardiovascular collapse, coma and death.

BENZODIZEPINES The most widely used anxiolytic drugs. They have largely replaced barbiturates in the treatment of anxiety, Since BZs are more effective and safer. BZs induce sleep when given in high doses at night.provide sedation. reduce anxiety when given in low, divided doses during the day.

BENZODIZEPINESSedative (Anxiolytics) : Alprazolam Chlordiazepoxide lorazepam Diazepam lorazepam

Hypnotics : Triazolam Diazepam AlprazolamLorazepam Estazolam Temazepam Flurazepam Nitrazepam Quazepam Preanesthetics :Diazepam- Midazolam

Leo sternback

MECHANISM OF ACTIONGABA the major inhibitory neurotransmitter in the brain.It has specific receptors in chloride channels present on the membrane of post synaptic neurons. regulates the entrance of chloride into the postsynaptic cells.

MECHANISM OF ACTIONBZs bind to specific, high affinity BZ receptors present in CNS. These receptors are separate but adjacent to the receptor for GABA. The binding of BZ enhances the affinity of the GABA receptors for GABA neurotransmitter. Resulting in a more frequent opening of adjacent chloride channels. The increased influx of Cl- into the neuron results in enhanced. Hyperpolarization and inhibition of neuronal firing

PHARMACOKINETICSBZs are lipophilic.Rapidly and completely absorbed after oral administration.Redistribution from CNS to skeletal muscles, adipose tissue.Cross placental barrier during pregnancy.Metabolized by the liver.Highly bound to plasma protein.Excreted in urine and milk (Fetal & neonatal depression).

Therapeutic usesANXIETY DISORDERS : alprazolam, lorazepam, lorazepam, diazepam and chlordiazepoxide.Alprazolam has anxiolytic-antidepressant effect.Diazepam is preferred in acute panic-anxiety.Chlordiazepoxide is preferred in chronic anxiety states.

Therapeutic usesINSOMNIA : in ability to sleep.

Triazolam, lorazepam is effective in treating individuals who have difficulty in going sleep.Flurazepam, temazepam & nitrazepam is useful for insomnia caused by inability to stay asleep.

Therapeutic usesTo control withdrawal symptoms of alcohols diazepam- chlordiazepoxide.

Anticonvulsants:Diazepam Lorazepam: Status epilepticusClonazepam-Clorazepate: in chronic treatment of epilepsy.

Muscle relaxation: in spastic states (Diazepam) .

Therapeutic usesIn Anesthesia : Preanesthetic medication diazepam Induction of balanced anesthesia (Midazolam)

ADVERSE EFFECTSAtaxia (motor incoordination), cognitive impairment.Hangover, drowsiness, confusion (especially in long acting drugs)Tolerance Physical and Psychological dependence (in high doses)Withdrawal symptoms (Abrupt discontinuation of BZs)Insomnia, anorexia, anxiety, agitation, tremors and convulsion.(Abrupt discontinuation of BZs)

DOSE RESPONSE CURVE OF DRUGS

Drug-A = Barbiturates , Drug-B = Benzodiazepines.

MISCELLANEOUS AGENTS

ZOLPIDEM

A hypnotic.Rapid onset and a short duration of action (about 4 hours)Its efficacy is similar to benzodiazepines. Minor effect on sleep pattern, but high doses suppress REM.

MECHANISM OF ACTIONZolpidem binds selectively to a subset of the BZs receptor family and facilitates GABA-mediated neuronal inhibition.

Advantages. Rapid onset . No withdrawal effects. . Minimal insomnia. . Little or no tolerance with prolonged use. . Minimal muscle relaxing effect. . Respiratory depression occurs only if large doses of zolpidem are ingested. . Antagonized by flumazenil

THERAPEUTIC USES AND ADVERSE EFFECTSa hypnotic drug for short term treatment of insomnia

Dose should be reduced in hepatic or old patients.

Adverse Effects GIT upsetDrowsiness Dizziness

BUSPIRONE

Buspirone is a non-sedating.Alternative to BZs but It may take up to four weeks to act. (Useful in chronic anxiety states)

AdvantagesNo hypnotic, anticonvulsant, or muscle relaxant properties. It has minimal abuse liability. Buspirone causes less psychomotor impairment than BZs and does not affect driving skills. The drug does not potentiate the CNS depressant effects of other sedative-hypnotics, ethanol or tricyclic antidepressants.

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