Sedative and Hypnotics PDF

# Sedative Hypnotics ## What are Sedative Hypnotics? * **Sedatives** are drugs that decrease activity, moderate excitement, calm the recipient, decrease responsiveness to stimulation, and decrease motor activity. * **Hypnotics** are drugs that produce drowsiness and facilitate the onset and maint...

# Sedative Hypnotics ## What are Sedative Hypnotics? * **Sedatives** are drugs that decrease activity, moderate excitement, calm the recipient, decrease responsiveness to stimulation, and decrease motor activity. * **Hypnotics** are drugs that produce drowsiness and facilitate the onset and maintenance of sleep that resembles natural sleep. * Sedatives and hypnotics are CNS depressants that differ in time and action. * Hypnotics at low doses act as sedatives. * Hypnotics at high doses act as general anesthetics. ## Increasing Grades of CNS Depression: **Sedation** → **Hypnosis** → **General Anaesthesia** ## Classification of Sedative Hypnotics ### 1. **Barbiturates** * **Long acting:** Phenobarbitone * **Short acting:** Butobarbitone, Pentobarbitone * **Ultrashort acting:** Thiopentone, Methohexitone ### 2. **Benzodiazepines** * **Hypnotics:** Diazepam, Alprazolam, Nitrazepam * **Antianxiety:** Diazepam, Chlordiazepoxide, Lorazepam * **Anticonvulsant:** Diazepam, Clonazepam, Clobazam ### 3. **Newer non-benzodiazepine hypnotics** * Zopiclone, Zolpidem, Zaleplon A diagram showing the classification of Sedative-Hypnotics: * **Benzodiazepines** * Short Action * Intermediate Action * Long Action * **Barbiturates** * Ultra Action * Short Action * Long Action * **Miscellaneous agents** * Buspirone * Chloral hydrate * Zaleplon * Zolpidem ## Mechanism of Action of Sedative Hypnotics Barbiturates and benzodiazepines bind to the GABAA receptor at different allosteric sites. * At higher doses, barbiturates can act as GABA mimetics. * This binding facilitates GABA action * Barbiturates increase the duration and benzodiazepines increase the frequency of opening of the Cl- channel. * This leads to membrane hyperpolarization, which causes CNS depression. ## Barbiturates * Barbiturates are sedative and hypnotic drugs that depress CNS and excitable cells. * They were the most popular sedatives until the 1960s, until benzodiazepines were discovered. * More lipid-soluble barbiturates are potent and short-acting ### Mechanism of Action of Barbiturates * Barbiturates act on the GABA receptor, Cl channel complex, and increase inhibition by prolonging the duration of Cl- channel opening. * At high concentrations, barbiturates depress voltage-sensitive Na+ and K+ channels. ## Pharmacological Actions of Barbiturates ### CNS * The effects of barbiturates are dose-dependent. * **Sedation** → **Hypnosis** → **General Anaesthesia** → **Coma** * Barbiturates decrease the time to fall asleep and increase the duration of sleep. * They disrupt the REM-NREM sleep cycle. ### Respiration * Barbiturates depress the respiratory center. ### CVS * Barbiturates decrease heart rate and blood pressure. ## Skeletal Muscle * Anesthetic doses of barbiturates reduce muscle control. ### Smooth Muscle * Barbiturates decrease the tone and motility of the bowels. ### Kidney * Barbiturates decrease urine flow by decreasing blood pressure and increasing ADH release. ### Enzyme Induction * Barbiturates induce microsomal enzymes in the liver. ## Adverse Effects of Barbiturates * Hangover * Dizziness * Precipitation of Porphyria * Hypersensitivity * Tolerance * Dependence ## Contraindications of Barbiturates * Obstructive sleep apnea * Liver disease * Kidney disease * Severe pulmonary insufficiency ## Uses of Barbiturates * **Epilepsy:** * Phenobarbitone 30-60mg OD-TDS/100-200mg i.m./i.v.) * **Anesthesia:** * Thiopentone sodium (1-2mg/kg iv) ## Benzodiazepines * Benzodiazepines are the most widely used sedative hypnotics. * They have replaced barbiturates. * They are highly effective and safer than barbiturates, with a high therapeutic index. ### Mechanism of Action of Benzodiazepines * Benzodiazepines act on the GABA receptor and increase the frequency of Cl- channel opening. * The influx of chloride ions causes hyperpolarization and inhibits the formation of action potentials. ## Pharmacological Actions and Uses of Benzodiazepines 1. Sedative 2. Hypnotic 3. Anti-anxiety 4. Anticonvulsant 5. Muscle relaxant ## Adverse Effects of Benzodiazepines * Dizziness * Vertigo * Ataxia * Amnesia * Weakness * Blurring of vision * Withdrawal ## Duration of Action of Benzodiazepines * **Short acting:** Oxazepam, Triazolam (3-8 hours) * **Intermediate acting:** Alprazolam, Lorazepam, Temazepam (10-20 hours) * **Long acting:** Chlordiazepoxide, Diazepam, Flurazepam ## Benzodiazepines vs. Barbiturates | Feature | Benzodiazepines | Barbiturates | |:--------------------------------------:|:---------------------------------------:|:----------------------------------------:| | 1. Anesthesia | Do not produce anesthesia at high doses | Produce loss of consciousness | | | and patients can be aroused | and have a low margin of safety | | 2. Enzyme Induction | Not enzyme inducers | Enzyme inducers | | | | More drug interactions | | 3. Abuse Liability | Very low abuse liability | High abuse liability | | 4. Sleep | Lesser distortion of normal hypnogram | Marked suppression of REM sleep | | 5. Hyperalgesia | No hyperalgesia | Hyperalgesic action | | 6. Specific Antagonist | Flumazenil | No specific antagonist | ## Why are Benzodiazepines Preferred over Barbiturates? 1. High therapeutic index 2. Do not affect respiration or cardiovascular function 3. Do not impair sleep architecture 4. No microsomal enzyme induction: Less drug interaction 5. Low abuse liability: Low tolerance 6. Specific Antagonist \ Antidote: Flumazenil available ## Benzodiazepine Antagonist * Flumazenil is a GABAreceptor antagonist that can rapidly reverse the effects of benzodiazepines. * It works by competitively occupying the GABA receptor without causing a functional change in the Cl- channel. * The drug is available for intravenous administration only. * Onset is rapid but duration is short, with a half-life of about 1 hour. * Frequent administration may be necessary to maintain reversal of a long-acting benzodiazepine. ## The Ideal Anxiolytic Drug * Should calm the patient without causing too much daytime sedation and drowsiness. * Should not interact with other medications in such a way as to produce unwanted or dangerous effects. * Without producing physical or psychological dependence. * Should have very low toxicity ## The Ideal Hypnotic Drug * Should allow the patient to fall asleep quickly. * Should maintain sleep of sufficient quality and duration so that the patient awakes refreshed without a drug hangover (feeling of tiredness well after the patient wakes. This may lead to impaired ability to function normally for many hours after waking. Occasionally, nausea and dizziness occur.