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Description : Sedative and Hypnotic Drugs are agents that are used in the treatment of organic or emotional disorders in order to produce a calming effect (sedation) or to induce sleep (Hypnosis)

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Published on : Nov 06, 2020 | Views : 5319 | Downloads : 64

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Sedative & Hypnotic Drugs Dr. Mohammed Samir Hussein BCs of Pharmaceutical Science MDs of Clinical Pharmacology
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Overview they are agents that is use in the treatment of organic or emotional disorders in order to produce a calming effect (sedation) or to induce sleep (Hypnosis) Insomnia: is difficulty in falling asleep, frequent nocturnal awakenings, and early-morning awakenings. Daytime impairments in concentration at school or work performance. Sedative: drug that reduces excitement and calms individual without inducing sleep. Hypnotic: a drug that induces /maintain sleep similar to normal sleep. Dose dependent CNS depression: in higher dose sedative acts as hypnotics. - CNS equilibrium is determined by a balance between excitatory and inhibitory neurotransmission. Excitation: Glutamate is prototypical neurotransmitter. (Aspartate). Inhibition: GABA is prototypical neurotransmitter (Glycine).
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CLASSIFICATION OF SEDATIVE HYPNOTICS Buspirone Clonidine Trazodone H1-antihistamines Β-blockers Ethanol
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BARBITURATES  Are classified on the basis of their onset and duration of action. A. Ultra -Short Acting: Have high lipid solubility which allows rapid transport across the blood – brain barrier. They are used principally as intravenous adjuvant to anesthesia. Ex. Thiopentone, Methohexitone, Hexobarbitone B. Short – Acting: Have a duration of action of about 2 hours; use principally as hypnotics Ex.Butobarbitone, Secobarbitone, Pentobarbitone C. Intermediate Acting: Have an effect lasting 3 to 5 hours, they have a “Hangover” liability if use as hypnotics, the result of residual depression of the CNS. Ex. Amobarbital D. Long – Acting: Have a duration of action greater than 6 hours; the least lipid soluble. They are dose effective hypnotics and sedatives and at a low dose are use as an antiepileptic agents; but they are ikely to cause hangover. Ex. Phenobarbitone, Mephobarbitone
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BARBITURATES MECHANISM OF ACTION - Stimulate GABAA receptors, which enhances GABAergic transmission. - Barbiturates potentiate GABA action on chloride entry into the neuron by prolonging the duration of the chloride channel openings. - In addition, barbiturates can block excitatory glutamate receptors. - Anesthetic concentrations of pentobarbital also block high-frequency sodium channels.
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BARBITURATES Pharmacologic Effects: Barbiturates generally inhibit the CNS gradually: • At low doses, the barbiturates produce sedation (calming effect, reducing excitement). • At higher doses, the drugs cause hypnosis. • Followed by anesthesia • Still higher dose coma and death. • Barbiturates do not raise the pain threshold and have no analgesic properties. They may even exacerbate pain.
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BARBITURATES A. CNS Depress all levels in a dose dependent fashion. REM sleep (Rapid Eye Movement) paradoxical sleep is reduced, “Hangover” may result. B. Anesthesia Producing anesthesia but only the ultra- short acting are useful as intravenous anesthetics. C. Convulsion activity The long acting is use as anti-convulsant. D. Respiration At therapeutic doses respiratory depression is similar to that in normal sleep. But in Larger doses causes hypoxic drive. Death from acute barbiturate poisoning is usually due to Respiratory failure. E. Liver Most barbiturates, but especially phenobarbital is capable of inducing the hepatic microsomal enzyme this result in: 1. Increased degradation of the barbiturate ultimately leading to barbiturate tolerance. 2. It also cause increase inactivation of other compounds
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BARBITURATES Therapeutic uses 1. Anesthesia: The ultra-short-acting barbiturates, such as thiopental, are used intravenous anesthesia. 2. Anticonvulsant: Phenobarbital is used in long-term management of tonic-clonic seizures and status epilepticus, and as the drug of choice for treatment of children with recurrent febrile seizures. 3. Anxiety: Barbiturates have been used as mild sedatives to relieve anxiety, nervous tension, and insomnia. 4. Treatment of Hyperbilirubinemia and Neonate
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BARBITURATES PHARMACOKINTICS  Absorbed orally and distributed widely throughout the body.  Movement between different tissues is important in causing the short duration of action of thiopental and similar short-acting derivatives.  They readily cross the placenta and can depress the fetus. Barbiturates are metabolized in the liver (enzyme induction), and inactive metabolites are excreted in the urine
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BARBITURATES Adverse effects 1. Tolerance 2. Physical dependence 3. Withdrawal symptoms: tremors, anxiety, weakness, restlessness, nausea and vomiting, seizures, delirium, and cardiac arrest 4. Coma in toxic doses 5. CNS: Drowsiness, impaired concentration, and mental and physical sluggishness. Synergize with those of ethanol 6. Drug hangover: hypnotic doses produce a feeling of tiredness well after the patient wakes. Drug Interactions: Drugs that increases the actions of barbiturates : Other sedative – hypnotics General anesthetics, Neuromuscular blocking agents Alcohol, Anti-anxiety drugs Barbiturates Reduce the Effect of many drugs: barbiturates induce the P450 system
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BARBITURATES Poisoning: - Leading cause of death (overdoses). - Severe depression of respiration is coupled with central cardiovascular depression. Treatment: - includes artificial respiration and purging the stomach of its contents if the drug has been recently taken. - No specific barbiturate antagonist is available. - Hemodialysis. - Alkalization of the urine: Sodium bicarbonate.
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Benzodiazepines They are preferred than barbiturates due to: Little or no hangover Not significantly enzyme inducers (so little interactions) Slow development of tolerance BDZs have a wide margin of safety if used for short periods. Prolonged use may cause mild dependence. BDZs have little effect on respiratory or cardiovascular function. BDZs depress the turnover rates of (NE), (DA) and (5-HT) in various brain nuclei, Minimal effect on sleep rhythm.
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Classification of Benzodiazepines Nitrazepam, Lorazepam, Flurazepam, clinical use Duration of Action Chlordiazepoxide, Quazepam Intermediate (6-24 hours) Ex. Alprazolam, Estazolam, Temazepam Long acting (24-72 hours) Ex. Chlorazepate, Diazepam, Hypnotic BDZ Ex. Diazepam, Flurazepam, Temazepam, Midazolam Antianxiety BDZ Ex. Diazepam, Chlordiazepoxide, Lorazepam Anticonvulsant BDZ Ex. Daizepam Clonazepam Clobazam Short acting (3-8 hours) Ex. Oxazepam, Triazolam, Midazolam
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Mechanism of action The targets for benzodiazepine actions are the γ-aminobutyric acid (GABAA) receptors. These binding sites are sometimes labelled benzodiazepine receptors as BZ1 and BZ2. Benzodiazepines increase the frequency of channel openings produced by GABA.  GABA binds to GABAA receptor β subunit and open Cl channel  Binding of BZ to GABAA receptor at a single site between α and γ subunits cannot open Cl channel directly, But it can cause more frequent opening. Benzodiazepines
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• At low doses, BDZs are anxiolytic. • Reduce anxiety by selectively enhancing gabaergic transmission subunit in their GABAA receptors. PHARMACOLOGICAL ACTIONS OF BDZS Reduction of anxiety At higher doses can produce hypnosis, mediated by the α1-GABAA Decrease the time to fall in sleep Non rapid eye movement (NREM) sleep increased Rapid eye movement (REM) sleep decreased Sedative and hypnotic actions
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Used for status epileptics and other seizure disorders. This effect is partially mediated by α1-GABAA receptors. Onazepam, Nitrazepam, Lorazepam, and Diazepam are seizures. PHARMACOLOGICAL ACTIONS OF BDZS Anticonvulsant At high doses, the benzodiazepines relax the spasticity of skeletal muscle Increasing presynaptic inhibition in spinal cord, where α2-GABAA R are located. Muscle relaxation is not an action with zolpidem, zaleplon, and eszopiclone. Muscle relaxant
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Temporary impairment of memory with BDZ is also mediated by the α1-GABAA. PHARMACOLOGICAL ACTIONS OF BDZS Anterograde amnesia: • High doses of certain sedative-hypnotics depress CNS to stage III of anesthesia. • Diazepam, Lorazepam, and Midazolam are used intravenously in Anesthesia. Anaesthesia
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Respiratory depression in patients with pulmonary disease Effect on respiratory depression is dose related , over dose can leads to repertory paralysis and death Respiratory effects are more when BZDz are given IV route PHARMACOLOGICAL ACTIONS OF BDZS At toxic doses, myocardial contractility and vascular tone may both be depressed by central and peripheral effects. Cardiovascular effects are more when BZDz are given IV route. Cardiovascular system Respiratory system
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PHARMACOKINETICS OF BDZS Most BDZs are metabolized by the hepatic microsomal system. The drugs' effects are terminated not only by excretion but also by redistribution. BDZs are excreted in the urine as glucuronides or oxidized metabolites. BDZs cross the placental barrier and may depress the CNS of the newborn. Nursing infants may also become exposed to the drugs in breast milk. The BDZs are lipophilic, rapidly and completely absorbed after oral administration distributed throughout the body
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They should be reserved for continued severe anxiety, and then should only be used for short periods. Benzodiazepines are effective for the treatment of the anxiety symptoms: Secondary to panic disorder Generalized anxiety disorder Social anxiety disorder Performance anxiety Posttraumatic stress disorder Extreme anxiety encountered with specific phobias, such as fear of flying Drugs: Diazepam (long acting). Tolerance: tolerance occurs within 1-2 weeks of treatment. For panic disorder: Alprazolam. Because of their addiction liability, used for severe anxiety and for short period. THERAPEUTIC USES OF BDZS Anxiety disorders:
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Tend to decrease the latency to sleep onset and increase Stage II of non-rapid eye movement (NREM) sleep. Both REM sleep and slow-wave sleep are decreased Examples: Long-acting: flurazepam Intermediate-acting: temazepam Short-acting: Triazolam THERAPEUTIC USES OF BDZS Sleep disorders:
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THERAPEUTIC USES OF BDZS Diazepam and Lorazepam are the drugs of choice in terminating grand mal epileptic seizures and status epilepticus. Clonazepam is occasionally used in the treatment of certain types of epilepsy, Chlordiazepoxide, Clorazepate, Diazepam, and Oxazepam are used in the treatment of alcohol withdrawal and reducing the risk of withdrawal-related seizures. Seizures:
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THERAPEUTIC USES OF BDZS Inhibitory effects on multi-synaptic reflexes, and at the NMJ For muscle strain, and in treating multiple sclerosis and cerebral palsy. Diazepam is used in treatment of skeletal muscle spasms, muscle strain, and spasticity Muscular disorders: Short-acting BZs used as premedication for Anterograde amnesia and unpleasant procedures, like endoscopic, bronchoscopy, certain dental procedures, Angioplasty. Drugs: Oxazepam – Triozolam (short-acting drugs) Amnesia:
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DEPENDANCE OF BDZs Psychological and physical dependence when taking high doses for prolonged period. Withdrawal symptoms: Confusion Anxiety Agitation Restlessness Insomnia Tension Seizures (rare).
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ADVERSE EFFECTS OF BDZS Sedation, Drowsiness and confusion (most common). Ataxia at high doses. Cognitive And memory impairment. Precautions: In patients with liver disease. Alcohol and other CNS depressants enhance the sedative-hypnotic effects of the benzodiazepines. Flumazenil: it is a BDZ analogue competes with BDZ agonist for the BDZ receptor and reverse their depressant effects. BENZODIAZEPINE ANTAGONIST
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OTHER HYPNOTIC AGENTS Newer Sedative & Hypnotics Structurally unrelated but as effective as BDZs. Minimal muscle relaxing and anticonvulsant effect. Mechanism of Action: • Binds selectively to BZ1 receptors. • Facilitates GABA-mediated neuronal inhibition. • Actions are antagonized by flumazenil Zolpidem Zolpidem has no anticonvulsant or muscle-relaxing properties. Minimal rebound insomnia. Little or no tolerance occurs with prolonged use. it has a rapid onset of action and short elimination half-life. Adverse effects of zolpidem include: nightmares, agitation, headache, gastrointestinal upset, dizziness, and daytime drowsiness.
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OTHER HYPNOTIC AGENTS Newer Sedative & Hypnotics Eszopiclone Non-benzodiazepine hypnotic. Utilizing the BZ1 receptor similar to zolpidem and zaleplon. Uses: for treating insomnia. Adverse events : anxiety, dry mouth, headache, peripheral edema, somnolence, and unpleasant taste. Zaleplon Zaleplon is very similar to zolpidem in its hypnotic actions with less adverse effects on psychomotor and cognitive functions.
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OTHER HYPNOTIC AGENTS Ramelteon & Tasimelteon Selective agonist at the MT1 and MT2subtypes of melatonin receptors. Induce and promote sleep and is indicated for the treatment of insomnia. Adverse effects dizziness, fatigue, and somnolence. Ramelteon may also increase prolactin levels. Antihistamines: Diphenhydramine – Doxylamine Uses: mild types of insomnia. Adverse effects: anticholinergic effects.
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OTHER HYPNOTIC AGENTS Chloral hydrate An aldehyde hydrate which has a pungent odor & causes unusual, unpleasant taste sensation caustic taste. Trichlorinated derivative of acetaldehyde that is converted to the active metabolite, trichloroethanol, in the body. The drug is an effective sedative and hypnotic that induces sleep in about 30 minutes and the duration of sleep is about 6 hours. Chloral hydrate is irritating to the gastrointestinal tract and causes epigastric distress. Ethanol: Has anxiolytic and sedative effects Ethanol is a CNS depressant, producing sedation and, ultimately, hypnosis with increasing dosage.
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OTHER HYPNOTIC AGENTS Buspirone Partial agonist at the serotonin 1a receptor. (5HT1A), it has not action on GABA receptor. Uses: Relieves anxiety without producing sedation, impairment of motor skills, or memory loss. Does not induce withdrawal symptoms upon discontinuation. Does not act immediately. Can take up to 1 week to become effective. Used for chronic anxiety states. It has some affinity to D2 receprors.
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