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sedative_hypnotics

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									Sedative-Hypnotics

Sedative: a drug that subdues excitement and calms the individual without inducing sleep Hypnotic: a drug that induces /maintain sleep similar to normal sleep
Dose dependent CNS depression

Dose Response Relationships
Coma

Barbiturates

Medullary depression Benzodiazepines CNS Effects
Anesthesia

Hypnosis
Sedation, disinhibition, anxiolysis

Increasing dose

1.Barbiturates
Long acting : Phenobarbital Short acting: Pentobarbital Secobarbital Ultra Short acting: Thiopentone

2.Benzodiazepines (BZDs)
Hypnotic • Diazepam • Flurazepam • Midazolam Anticonvulsant • Diazepam • Clonazepam Antianxiety • Diazepam • Alprazolam • Chlordiazepoxide

3.Nonbenzodiazepine hypnotics
• Zopiclone • Zolpidem

MOA

GABA A receptor: Pentameric membrane protein containing an ion channel selective for chloride ions

β2
Extracellular part
Transmembrane part

α1 β2 α1

2

Cl-

Benzodiazepine Barbiturates GABA -GABA receptor complex β2 α1 β2 BZ1

2

α1

Act on GABA-BZD receptor Cl channel complex  Prolong duration of GABA-mediated chloride channel openings  CNS depression Inhibitory effects on glutamate receptors

MOA of Barbiturates

MOA of BZDs
Bind to BZ1() receptor, on GABABZD receptor Cl channel complex  increased frequency of GABAmediated chloride channel openings  CNS depression

MOA of Zolpidem and Zaleplon
Selective 1 Agonists – Stimulation of specific (1) benzodiazepine receptors – Bind to GABAA receptors isoforms that contain α1 subunits

Following agents facilitate or mimic the action of GABA
• alcohol; alphaxolone, etomidate, and propofol (intravenous anesthetics) • volatile anesthetics (eg, halothane) • several anticonvulsants (eg, gabapentin,vigabatrin) • ivermectin (an anthelmintic agent)

• Drugs block the channel directly (picrotoxin) or • interfere with GABA binding bicuculline -convulsions

Pharmacokinetics
Absorption and distribution
CNS entry depend on lipid solubility Thiopentone- high lipid soluble Rapid entry – used for induction of general anesthesia Rapid redistribution from brain to highly perfused tissues

Table 13-3.

Metabolism of benzodiazepines

Metabolism of BZDs
Long-acting metabolites 3-Hydroxy compounds Glucuronide conjugates

 -Hydroxy 

metabolites

Chlordiazepoxide

• Microsomal stimulation: multiple Desmethylchlordiazepoxide drug interactions, Clorazepate Diazepam porphyria Halazepam
Prazepam N-Hydroxyethylflurazepam

Lorazepam Demoxepam Temazepam

Nordazepam

Oxazepam

N-desalkylflurazepam 3-Hydroxy derivatives 2-Oxo-quazepam

Flurazepam Quazepam Estazolam Alprazolam Midazolam Triazolam -Hydroxy derivatives

Zolpidem and Zaleplon rapid metabolism by liver enzymes Short duration of action half-life 2.5 hr (zolpidem) and 1 hr (zaleplon)
Metabolism of Barbiturates

undergo oxidation in liver

Excretion BZD excreted via kidney Phenobarbital -elimination is increased by alkalanizing the urine

Actions
CNS: Dose dependent effects Sedation(anxiolysis)  sleep(hypnosis) anaesthesia coma Pentobarbital – Sedation (50-100 mg) – Hypnosis (100-200 mg) – Anesthesia (300-400 mg) – Death (>600 mg)

Steep dose response curve Not safe

Barbiturates

BZDs
Flat dose response curve Safer

CNS Actions
1. Sedative dose (smaller dose) • Drowsiness • Reduction in anxiety • Impair motor coordination • Impair learning and memory

2.Effect on sleep pattern • Shortens time taken for onset of sleep(sleep latency) •  Sleep duration • REM sleep is decreased • On discontinuation (barbiturates) rebound  in REM sleep hangover (irritability, dizziness, mood upset)

CNS Actions

• Zolpidem decreases REM sleep but has minimal effect on slow-wave sleep • Zaleplon decreases the latency of sleep onset with little effect on total sleep time, NREM, or REM sleep. • The use of sedative-hypnotics for more than 1–2 weeks leads to some tolerance to their effects on sleep patterns.

Selective 1 Agonists • Pharmacologic characteristics

(2)

– Rapid onset: 10-20 min – Short duration: half-life 2.5 (zolpidem) and 1 zaleplon) hr – Less amnesia; reduced anticonvulsant and muscle relaxant effects – Less selective antianxiety effect – Pregnancy category B (zolpidem), C (zaleplon) – May preserve normal sleep architecture – Reversible with flumazenil

CNS Actions
3. Anaesthesia high doses • Depress the CNS - general anaesthesia Thiopental, methohexital- inducing anaesthesia Diazepam i.v anaesthesia, along with other agents

CNS Actions cont.. 4. Anticonvulsant clonazepam, nitrazepam, diazepam Phenobarbital 5. Skeletal muscle relaxation BZDs inhibit Polysynaptic reflexes

Other Actions
Effect on RS High doses- respiratory depression Effect on CVS High doses- fall in BP

Tolerance repeated use- a decrease in responsiveness Psychological dependence compulsive use of the drug to relieve anxiety Physiologic dependence altered physiological state leading to withdrawal syndrome when drug is discontinued

Clinical Uses
• The perceived desirable properties of relief of anxiety, euphoria, disinhibition, and promotion of sleep have led to the compulsive misuse of virtually all sedativehypnotics. • For this reason, most sedative-hypnotic drugs are classified as Schedule III or Schedule IV drugs for prescribing purposes.

Clinical Uses
Insomnia • barbiturates not preferred • Estazolam, flurazepam, triazolam • Zolpidem and zaleplon Less cognitive impairment Anxiety • Alprazolam and clonazepam more efficacy – Buspirone • No sedation/ cognitive impairment • Slow onset time (1-3 weeks) • 5-HT1A receptor partial agonist

Uses cont…
Epilepsy Phenobarbitone- Generalized tonic clonic seizures BZDs -Status epilepticus Tetanus Febrile convulsions Induction of GA • Thiopentone

Uses cont…
Acute muscle spasms-BZDs As a muscle relaxant Before ECT, cardiac catheterization, endoscopies- BZDs reduce anxiety, muscle relaxant Alcohol withdrawal- BZDs

• Acute and chronic anxiety relief: Therapeuticlorazepam uses alprazolam, diazepam, • Perioperative sedation: diazepam, lorazepam, midazolam, triazolam • Acute insomnia: temazepam, triazolam • Alcohol withdrawal: diazepam, lorazepam • Muscle relaxation: diazepam • Seizures: clonazepam, clorazepate, diazepam, lorazepam, midazolam • Panic disorders and depression: alprazolam
Benzodiazepines

Toxicity
• Psychomotor dysfunction Hangover BZDs metabolites which have long half life • Dependence • Overdosage Acute barbiturate poisoining Shallow respiration, fall in BP, coma, renal failure

Gastric lavage Oxygen supportive measures Forced alkaline diuresis: i.v sodium bicarbonate Hemodialysis No specific antidote

Treatment of barbiturate poisoning

BZDs overdosage • Is not as fatal as barbiturates Specific antidote Flumazenil- BZD antagonist ,with a high affinity for the benzodiazepine binding site on the GABAA receptor flumazenil acts rapidly but has a short half-life (0.7–1.3 hours) due to rapid hepatic clearance. Because all benzodiazepines have a longer duration of action than flumazenil, sedation commonly recurs, requiring repeated administration of the antagonist.


								
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