Sedative - Hypnotics - Anxiolytics PDF

Sedative – Hypnotics - Anxiolytics Prepared By: Dr. Ahmed Mohammed Saaduddin BDS, MDS, PhD Assistant Professor and Consultant of Oral Surgery Monday March. 24. 2024 Introduction Introduction Anxiolytic NORMAL CNS ACTIVITY Sedative Hypnotic General Anesthetic Coma CLASSIFICATION Classification Non-Be...

Sedative – Hypnotics - Anxiolytics Prepared By: Dr. Ahmed Mohammed Saaduddin BDS, MDS, PhD Assistant Professor and Consultant of Oral Surgery Monday March. 24. 2024 Introduction Introduction Anxiolytic NORMAL CNS ACTIVITY Sedative Hypnotic General Anesthetic Coma CLASSIFICATION Classification Non-Benzodiazepines Barbiturates Ultrashort Acting o Thiopental Short Acting Benzodiazepines Ultrashort Acting o Remimazolam Secobarbital “Seconal” o Midazolam o Pentobarbital o Triazolam o Amobarbital Long Acting o Zaleplon, o Zopiclone. o Eszopiclon Short Acting o Intermediate Acting o Zolpidem, Intermediate Acting o Temazepam Melatonin & Congeners o Melatonin, o Ramelteon Long Acting o Phenobarbital (Prototype) o Chlordiazepoxide (Prototype) o Methylphenobarbital o Diazepam o Clonazepam Others o Buspirone o Chloral hydrate Barbiturates vs Benzodiazepines Barbs vs Benzos Chemistry Barbiturates Benzodiazepines Benzine All members are derivatives of barbituric acid. All members contain fusion of benzine and diazepine rings Classification Barbiturates Category Ultrashort Acting: Thiopental Short Acting: Secobarbital “Seconal” Intermediate Acting: Benzodiazepines Onset Duration Immediate 20 mins. 10 – 15 mins. 6 – 8 hrs. Category Ultrashort Acting: Remimazolam Short Acting: Duration Immediate 30 mins. Rapid 8 hrs. Fast 16 hrs. Slow > 24 hrs. Midazolam - Triazolam 45 – 60 mins. 10 – 12 hrs. Amobarbital Intermediate Acting: Temazepam Long Acting: Long Acting: Phenobarbital > 60 mins. Methylphenobarbital > 10 hrs. Chlordiazepoxide Diazepam / Clonazepam -zolam / -zepam -bital Prototype Onset Prototype Pharmacokinetics Barbiturates Benzodiazepines Absorption: Absorption: - All are absorbed well from GIT. - Thiopental is given as IV only. - All are absorbed well from GIT. - Remimazolam is given as IV only. Distribution: Distribution: - - They are distributed into all tissues of the body. They cross blood brain barrier (BBB) They cross the placenta They are secreted in milk Redistribution to peripheral tissue occurs to highly lipid soluble drugs e.g. Thiopental. They are distributed into all tissues of the body. They cross blood brain barrier (BBB) They cross the placenta They are secreted in milk Redistribution to peripheral tissue occurs to highly lipid soluble drugs e.g. Diazepam. Metabolism: Distribution: - Oxidized in liver into inactive metabolites. - Phenobarbitone are microsomal enzyme inducer. - Oxidized in liver into active metabolites. - Temazepam is metabolized in liver to inactive metabolites. Excretion: Excretion: - Renal - Renal Drug Distribution and Redistribution Distribution Redistribution Mechanism of Action Barbiturates Benzodiazepines They All Have a GABA-Like Action They all have an ALLOSTERIC EFFECT that facilitates the GABA action on GABA receptors in the brain with subsequent enhancement for chloride ions conductance that result in hyperpolarization for the brain cells and accentuate the GABA inhibitory effect on the brain. They bind to β-subunits of GABA receptors They increase the duration of chloride ion channel opening They bind to α-subunits of GABA receptors β α They increase the frequency of chloride ion channel opening Mechanism of Action Pharmacologic Effects: Barbiturates Benzodiazepines 1) Anxiolytic effect in small doses. 1) Anxiolytic effect in small doses 2) Hypnotic effect in larger doses 2) Hypnotic effect in larger doses 3) Anesthetic effects (Thiopental) is used as IV 3) Anesthetic effects (Midazolam) is used as IV ultrashort acting anesthetic short acting anesthetic 4) Skeletal muscle relaxation 4) Skeletal muscle relaxation 5) Anticonvulsant effect 5) Anticonvulsant effect 6) Generalized CNS inhibition including the medullary centers in high doses with subsequent depression of respiratory and vasomotor centers leading to respiratory depression - Hypotension & myocardial collapse and coma) 7) Induction of hepatic microsomal enzymes 6) Anterograde amnesia (inability to remember events during the drug’s action) DOSE DEPENDENT CNS DEPRESSION THERAPEUTIC USES: Barbiturates 1) Anxiety: Methylphenobarbital Benzodiazepines 1) Anxiety: “Mephobarbital” is commonly used in Alprazolam “Xanax” is commonly used in management of management of anxiety disorders such as [Generalized anxiety disorders such as [Generalized anxiety disorder anxiety disorder (GAD) - Panic attacks - Social phobia]. (GAD) - Panic attacks - Social phobia]. 2) Insomnia: 2) Insomnia: Short acting (Secobarbital) and Intermediate acting BZD that have a rapid onset and sufficient duration are (Amobarbital) barbiturates are used to treat insomnia. widely used (e.g., Temazepam). 3) Anticonvulsant: - Phenobarbital for Grand mal “tonic-clonic” seizures. 3) Anticonvulsant: - Clonazepam for Petit mal “absence” seizures - Diazepam “Valium” IV in status epilepticus. 4) IV Anesthesia: 4) IV Sedation / Anesthesia in dental clinic: Thiopental “Ultrashort acting barbiturates are commonly Short acting BZD ”Midazolam” is commonly used in dental used for IV anesthesia. clinic for IV sedation/anesthesia in apprehensive patients. 5) Centrally Acting Muscle Relaxant: Diazepam is used for myofascial pain dysfunction syndrome THERAPEUTIC USES: Barbiturates Thiopental “Ultrashort acting anesthesia” Benzodiazepines Anxiolytic (e.g., Alprazolam “Xanax ) Insomnia: (e.g.,Temazepam). IV Sedation (Midazolam) Phenobarbital: Anticonvulsant (Clonazepam) Anticonvulsant (Diazepam) ADVERSE EFFECT: Barbiturates Benzodiazepines 1) Tolerance is a person's diminished response to a drug, which occurs when the drug is used repeatedly and the body adapts to the continued presence of the drug due to decreased sensitivity of GABA receptors. 2) Physical Dependence is a condition in which a person takes a drug over time, and unpleasant physical symptoms occur if the drug is suddenly stopped or taken in smaller doses due to decreased sensitivity of GABA receptors 3) Rebound Insomnia after discontinuation. 4) Hangover: state of psychomotor depression in the day following the use of long acting drugs “i.e. residual effect”) 5) Respiratory and Myocardial Depression. 5) Memory Disturbance CONTRAINDICATIONS Barbiturates Benzodiazepines 1) Severe respiratory insufficiency 2) Sleep apnea syndrome 3) Acute narrow angle glaucoma 4) Pregnant and lactating females 5) Severe CNS depression in alcoholics TREATMENT OF TOXICITY (OVERDOSE): Barbiturates 1) Mechanical “artificial” ventilation: Benzodiazepines 1) Flumazenil is the specific antagonist 2) IV fluids 3) Renal dialysis to remove the medicine from the blood Its molecular structure is similar to that of all Benzos. It has a more strong affinity to binding sites in BZDs receptors. It reverses all the effects of BZDs but it does not reverse the amnesia induced by benzodiazepines (so; the loss of memory of unpleasant events which took place before reversal is retained). It is useful for both elective and emergency reversal of sedation. Z - Hypnotics Zolpidem - Zaleplon – Zopiclone Eszopiclone Z - Hypnotics Mechanism of Action ▪ They are structurally different from BZDs but act by the same mechanism by binding to GABA receptors at a sites close to those occupied by BZDs Pharmacologic Effects ▪ They are SPECIFIC HYPNOTTICS WITHOUT anticonvulsant, antianxiety or muscle relaxant effects. ▪ They have a RAPID and SHORT DURATION of action. Uses ▪ They are used to TREAT INSOMNIA especially in patient with Narrow Angle Glaucoma. Adverse Effects ▪ The risk of Tolerance and Dependance is less than BZDs and withdrawal symptoms are milder. Treatment of Overdose ▪ Flumazenil Melatonin and Its Congeners Melatonin Mechanism of Action ▪ It acts on two types of receptors: - MT1: mediate sleep - MT2: regulate circadian rhythm Pharmacologic Effects ▪ Melatonin is a hormone secreted by the pineal gland. ▪ It is secreted at night and plays an important role in circadian rhythm ▪ It regulates the sleep. Uses ▪ Natural Hypnotic which is used to overcome Jet lag problems. Melatonin Congeners: Ramelteon A melatonin congeners that has a selective agonist at melatonin MT1 & MT2 receptors that are involved in sleep promotion and maintain normal circadian rhythm Chloral Hydrate Chloral Hydrate ▪ It is an alcohol derivative. ▪ It produces sedative and hypnotic effect within 30 minutes and last for 6 hours. ▪ It is used mainly as a hypnotic in children before a short procedures (e.g., dental procedures). Buspirone Buspirone Mechanism of Action ▪ It is an agonist of 5-HT1A (subtype of the serotonin receptors in midbrain). Pharmacologic Effects ▪ It suppress anxiety after a long delay (10 - 14) days. Uses ▪ It is selective ANXIOLYTIC without any hypnotic or muscle relaxant effects. ▪ It is the anxiolytic of choice in geriatrics. ▪ It has no liability for drug dependence Precaution ▪ Avoid combined use of buspirone with Selective serotonin reuptake inhibitors (SSRIs) to avoid the precipitation of Dangerous Serotonin Syndrome Serotonin, 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter between nerve cells in the brain. Thank You