Sedative-Hypnotic Drugs

A sedative drug decreases activity, moderates excitement and calms the recipient A hypnotic drug produces drowsiness and facilitates the onset and maintenance of a state of sleep

Sedative (Anxiolytic) Exert a calming effect, Reduce tension, nervousness, fear, and apprehension, little or no effect on motor or mental function.

Hypnotics Produce state of drowsiness, promote onset and maintenance of sleep, Patient can be awakened readily.

Drug Classification Barbiturates Benzodiazepines Miscellaneous agents

Barbiturates (duration of action) Ultra Short action (8-10 h) Thiopental Short action (10-40 h) Amobarbital, Secobarbital, pentobarbital Intermediate action (35-50 h) Butabarbital Long action (80-120 h) Phenobarbital,

Benzodiazepines (duration of action) Ultra Short action (4-6 h) Triazolam, Midazolam Short action (12-18 h) Lorazepam, Oxazepam, Temazepam, Lormetazepam Intermediate action (24h) Alperazolam, Nitrazepam Long action (24-48 h) Diazepam, Chlordiazepoxide, Florazepam, Clonazepam

Pharmacodynamics Both enhance action of GABA by binding to different site of GABAA receptor/chloride channel Barbiturates are less specific than Benzodiazepines. Barbiturates increase the duration but Benzodiazepines increase the frequency of GABA- mediated chloride ion channel opening.

Pharmacodynamics Barbiturates Block the excitatory transmitter glutamic acid. Barbiturates At high concentration block the sodium channels.

GABAA receptors

Pharmacokinetics Absorption Oral absorption of Benzodiazepines depend on lipophilicity (Triazolam extremely rapid and Diazepam more rapid than others) Barbiturates are usually absorbed very rapidly Distribution The more lipid solubility the more entrance the CNS (Benzodiazepines: Diazepam & Teriazolam) (Barbiturates: Thiopental) Redistribution (Barbiturates: Thiopental) Protein binding (Benzodiazepines: 60-95%)

Pharmacokinetics Biotransformation -Benzodiazepines: Next slide -Barbiturates: Oxidation & Glucuronide conjugation Excretion - Both of them are excreted via the kidney, - 20-30% of Phenobarbital and trace amount of benzodiazepines is excreted unchanged, - Elimination of barbiturates can be increased by alkalinization of urine

Pharmacokinetic of BZD

Pharmacokinetic of BZD

Pharmacokinetics Barbiturates: Potent inducer (cytochrome p450), cause drug interactions & acute porphyria

Pharmacological effects and uses Sedation Hypnosis (decrease in REM duration) Anesthesia (Benzodiazepines: midazolam, Barbiturates: thiopental) Anticonvulsant action (Benzodiazepines: clonazepam, diazepam, Barbiturates: phenobarbital)

Pharmacological effects and uses Muscle relaxation (Diazepam) Tolerance & dependence CNS depression Hepatic metabolic uses (Phenobarbital in hyperbilirubinemia & kernicterus in neonates)

Tolerance to sleep facilitation Barbiturates 2 weeks Benzodiazepines 4-6 weeks Discontinuation rebound REM Sleep, Psychological Dependence

Benzodiazepines Replaced Barbiturates Benzodiazepine Advantages -Safer- higher therapeutic index -Tolerance- lower -Addictive liability- lower -Less drug interactions

Adverse Effects Unwanted daytime sedation (especially with triazolam) (especially with Diazepam, flurazepam) Daytime anxiety and amnesia (especially with triazolam) Respiratory and cardiovascular depression (especially with Barbiturates overdosage)

Miscellaneous agents 5-HT1A partial agonists (Buspirone, Ipsapirone, gepirone) Alcohols (Chloral hydrate, glutetimide) Other BZ receptor agonists (Zaleplon, Zolpidem) Others

5-HT1A partial agonists Atypical Anxiolytic No hypnotic,anticonvulsant or muscle relaxant Acts at 5-HT1A (partial agonist) and Dopamine receptors Does not produce tolerance and physical dependence Side effect: nausea, dizziness, headache, tachicardia,…

Alcohols Chloral Hydrate: Metabolized to trichloroethanol Short duration No enzyme induction Tolerance/Dependence Withdrawal can be severe

BZ receptor agonists Not a benzodiazepine but binds to BZ receptor (Zolpidem…) Not a benzodiazepine but binds to BZ receptor Minimal muscle relaxing & anticonvulsant effect Good hypnotic, with less effects on stages of sleep Can suppress REM in higher doses Low incidence of rebound insomnia, daytime sedation

BZ receptor agonists Side effects: -Respiratory depression -Tolerance less than Benzodiazepines

Others Meprobamate RARELY if ever used, Similar to Barbs. Beta- Blockers useful in alleviating performance anxiety.

Flumazenil Benzodiazepine competitive Antagonist, no activity in its own right It reverse CNS depressant effect of Benzodiazepines, Zolpidem and Zaleplone Ineffective for most other sedatives

Side effects of Flumazenil Agitation Confusion Dizziness Nausea Seizure & cardiac arrhytmia (patient treated with TCA) Transient improvement in mental status has been reported in patient with hepatic encephalopathy