Sedatives & Hypnotics PDF: Drug Classification & Mechanisms

Sedative & Hypnotics Dr AMBER  Sedative & Hypnotics  Anxiolytics : Drugs that clam the patient and reduce anxiety without inducing normal sleep.  Hypnotics : Drugs that initiate and maintain the normal sleep. Classification of hypnotic drugs 1. Benzodiazepines ( BD...

Sedative & Hypnotics Dr AMBER  Sedative & Hypnotics  Anxiolytics : Drugs that clam the patient and reduce anxiety without inducing normal sleep.  Hypnotics : Drugs that initiate and maintain the normal sleep. Classification of hypnotic drugs 1. Benzodiazepines ( BDZ ) 2. Barbiturates 3. Miscellaneous ( non BDZ non barbiturate drugs).  Zolpidem  Zaleplon Benzodiazepines Nomenclature End with suffix azolam or azepam Alprazolam Estazolam Triazolam Lorazepam Diazepam Oxazepam Temazepam Nitrazepam Classification of benzodiazepines According to duration of action : - Short acting: (3-5 hours). Triazolam - Intermediate: (6-24 hours) (LEOTAN). Lorazepam Estazolam Oxazepam Temazepam Alprazolam Nitrazepam - Long acting: ( 24-72 hours) Chlorazepate Chlordiazepoxide Diazepam Flurazepam Quazepam Prazepam Mechanism of Action By binding to BZ receptors (BZ1 or BZ2). Bzs facilitate GABA-induced chloride channels hyperpolarization = GABA- mediated inhibitory neurotansmission Mechanism of Action Benzodiazepines combine with BZ receptors increase GABA action on GABA receptors chloride channels opening  chloride influx to the cell cell membrane hyperpolarization inhibition of propagation of action potential inhibitory effect on different sites of the brain especially motor cortex & Pharmacological Actions  Anxiolytic action.  Depression of cognitive and psychomotor function.  Sedative & hypnotic actions: At higher dose, benzodiazepines change sleep pattern  Induction of normal sleep ( reduce latency of sleep).  Increase non REM sleep (stage II).  Decrease REM sleep & slow waves sleep (3,4 stages).  Anterograde amnesia  Some have anticonvulsant effect: diazepam, lorazepam, clonazepam, clorazepate.  Some have central skeletal muscle relaxant effect e. g. Diazepam (relax muscle spasticity by increasing presynaptic inhibition in the spinal cord).  CVS and respiratory system: Minimal depressant effects in therapeutic doses & in normal patients. Therapeutic Uses Anxiety disorders: short term relief of severe anxiety General anxiety disorder major depressive disorders Obsessive compulsive disorder Panic attack with depression Alprazolam since it has (antidepressant effect). In anesthesia  Preanesthetic medication e.g. diazepam  Induction of balanced anesthesia (Midazolam)  Adjunct therapy during minor surgery (endoscopy, bronchoscopy, dental surgery).  ADVERSE EFFECTS Ataxia (motor incoordination), Cognitive impairment. Hangover: Sleep tendency, drowsiness, confusion especially in long acting drugs. Tolerance Dependence: Physical and Psychological Skin rash and teratogenic effect. Respiratory & cardiovascular depression (Toxic effects). Dose should be reduced in o Liver disease o Old people. Precautions Not for pregnant women or breast-feeding. Not for people over 65. Used for limited time (2 weeks)  FLUMAZENIL  a selective competitive antagonist of BZD receptors.  Blocks action of benzodiazepines, zolpidem, & zaleplon but not other sedative/hypnotics.  Blocks psychomotor, cognitive and memory impairment of BZs.  Zolpidem (Ambien)  Imidazopyridine derivative.  Acts on benzodiazepine receptors (BZ 1) & facilitate GABA mediated neuronal inhibition.  Its action is antagonized by flumazenil.  Rapidly absorbed from GIT and metabolized to inactive metabolites via liver CYT P450.  Short duration of action ( 2- 4 h).  has no muscle relaxant effect.  has no anticonvulsant effect.  Minimal psychomotor dysfunction  Minimal tolerance & dependence.  Minimal rebound insomnia.  Its efficacy is similar to benzodiazepines.  Minor effect on sleep pattern, but high doses suppress REM.  Respiratory depression occur at high doses in combination with other CNS depressant as ethanol.  Zaleplon  Binds to BZs receptors and facilitate GABA actions.  Rapid absorption  Short onset of action Short duration of action (1 hr)  Metabolized by liver microsomal enzymes CYP3A4  Metabolism is inhibited by cimetidine.  Decreases sleep latency  Little effect on sleep pattern  Potentiates action of other CNS depressants (alcohol).  Dose reduction as before.  Used as hypnotic drug  Advantages Less impairment of pyschomotor and cognitive functions than BZs or zolpidem.  Barbiturates are second choice as sedative - hypnotic Mechanism of Action  are less selective in action than BZD.  Facilitation of GABA action on the brain. increase the duration of the GABA gated channel opening but in large dose, they can directly activating chloride channels. (not through BZD receptors).  depress excitatory neurotransmitters action.  Interfere with Na & K transport across cell membranes (reticular activating system inhibition). Classification of barbiturates:  Long acting( 24-28 h): Phenobarbitone  Intermediate (8-24h): Amylobarbitone  Short-acting(3-8h): Pentobarbitone Secobarbitone Amobarbital  Ultrashort acting (25 minutes): thiopental Pharmacological actions 1. CNS depression : a dose-dependent fashion. Sedative & hypnotic anesthesia in large dose Anticonvulsant action Coma and death. 2. Respiratory depression: is dose –related.  suppress hypoxic and chemoreceptor response to CO2  Large doses respiratory depression & death. 3. CVS depressions  Healthy patient: at low doses, they have insignificant effects.  Hypovolemic states, CHF, normal doses may cause cardiovascular collapse.  Large dose circulatory collapse due to medullary vasomotor depression direct vasodilatation. Advantages of BZD over barbiturates 1. Selective: minimal respiratory and cardiovascular depression. 2. High therapeutic index. 3. Less hangover. 4. Not enzyme inducer. 5. Less dependence with minimal withdrawal symptoms. 6. Has specific antagonist.