Sedative-Hypnotics Chapter 22 PDF

Chapter 22 Sedative-Hypnotics 3P19 Hui Di Wang  References 1. Basic and Clinical Pharmacology Bertram G. Katzung 2. The Pharmacological basis of Therapeutics. Alfred Goodman Gilman  Objectives (1) You should be able to: Describe the Pharmacokinetics and ph...

Chapter 22 Sedative-Hypnotics 3P19 Hui Di Wang  References 1. Basic and Clinical Pharmacology Bertram G. Katzung 2. The Pharmacological basis of Therapeutics. Alfred Goodman Gilman  Objectives (1) You should be able to: Describe the Pharmacokinetics and pharmacodynamics of benzodiazepines and barbiturates, including their mechanisms of action. Describe the therapeutics uses and the adverse effects of sedative-hypnotics.  Objectives (2) Describe the major signs and symptoms of overdose with, and withdrawal from sedative-hypnotics. Describe the general principles of the management of overdose or withdrawal of sedative-hypnotics. Identify the most likely causes of death from commonly abused agents.  Objectives (3) Learn the following definitions: –Hypnosis –REM sleep –Tolerance –Physiologic dependence –Psychologic dependence –Withdrawal syndrome  Objectives (2) Learn the following definitions psychological dependence physiological dependence tolerance withdrawal syndrome  Key Drugs --Benzodiazepine - Diazepam, Chlordiazepoxide, Flurazepam,Triazolam(allergic reaction) Alprazolam and Desmethyldiazepam --Benzodiazepine antagonist – Flumazenil --Barbiturates-Phenobarbital and Sleep Disorders and Sedative-Hypnotics  Sleep disorder: Insomnia Less sleep than needed for daily activities Characterized by excessive daytime sleepiness Insomnia due to medical conditions whose symptoms interfere with sleep may be effectively treated with benzodiazepines or other hypnotic drugs.  Sleep disorder (cont’d) Chemically induced sleep is not normal sleep Many drugs suppress REM sleep During withdrawal, get REM rebound Hypnosis: induction of sleep Hypnotics: sleeping pills  Ideal Sleeping Pill Short half life, drug eliminated by morning Rapid onset Little effect on brain activity during sleep Classification of hypnotic drugs Benzodiazepines Barbiturates Antihistomines Others: Zolpidem Benzodiazepines and Barbiturates Benzodiazepines & Barbiturates Diazepam Pentobarbital Chlordiazepoxide Secobarbital Flurazepam Phenobarbital Oxazepam Chloral Hydrate Lorazepam Meprobamate Nitrazepam Glutethimide Triazolam Alprazolam Desmethyldiazepam Benzodiazepines Pharmacokinetics Absorption and Distribution (1) Lipid-soluble. Absorbed well from GI tract. Good distribution to the brain. As the plasma concentration of a benzodiazepine declines, the drug is redistribution from brain to the blood. This mechanism contributes significantly to the termination of its CNS effects. Absorption and Distribution (2) Sedative hypnotic drugs cross placental barrier during pregnancy Affects include depression of neonatal vital functions Sedative hypnotic drugs are detectable in breast milk and can affect CNS function of nursing infant Metabolism and Excretion (1) Most hypnotics are metabolized prior to elimination from the body, mainly by hepatic enzymes the type of metabolism & rates depend on the individual drug Metabolism and Excretion (2) Many benzodiazepines are converted initially to active metabolites with long half-lives in phase I oxidative reactions (e.g. diazepam t1/2 =20-80 hrs). Each of these active metabolites is eventually conjugated with glucuronate to form an inactive metabolite.  Major Drug Interaction Ethanol CNS depressants -increase depressant effects Mechanisms of actions  Benzodiazepines Specific binding site (BZ receptors) associated with GABAA receptor- chloride ion channel Enhance GABA effects, increase the frequency of Cl- channel opening. It is a GABA modulator not agonist! Flumazenil is an antagonist of BZ receptor Pharmacodynamics Hypnosis Sedation Anesthesia Therapeutic Uses of Sedatives CV Anti- & Convulsant Respiratory Muscle Relaxation  Pharmacodynamics A- Sedation; B-Hypnosis C-Anesthesia; D-Anticonvulsant action E-Muscle relaxation F-Medullary depression, (especially with barbiturates). What will it lead to? G-Tolerance and dependence  Side Effects -drowsiness, -fatigue, -amnesia, refers to a specific, acquired difficulty in learning new information and/or remembering information from the past. -ataxia, a broader sense to indicate lack of coordination in some physiological process. -confusion, impaired mental ability and is unable to think clearly -thrombosis/phlebitis (inflammation of a vein ) at site of injection if given i.v.  Not a complete list of side effects and others may occur. Treatment for acute overdose Flumazenil (floo MAZ e nil) Drug Dependence and Withdrawal  Use during pregnancy -generally NOT recommended -Risk Category D: justify their use during pregnancy. --i.e. Diazepam, Chlordiazepoxide, Alprazolam -Risk Category X: contraindicated for use in pregnancy – --i.e Flurazepam, Barbiturates Pharmacokinetics  Absorption and Distribution Lipid-soluble. Absorbed well from GI tract. Good distribution to the brain. As the plasma concentration of a benzodiazepine or barbiturate declines, the drug is redistribution from brain to the blood. This mechanism contributes significantly to the termination of its CNS effects.  -induce cyt P450 Synergistic CNS depression when taken with ethanol or benzodiazepine  Metabolism and Excretion With the exception of Phenobarbital, which is excreted partly unchanged in the urine, the barbiturates are extensively metabolized in liver.  pharmacology of anxiolytic/sedative-hypnotics Barbiturates Specific binding site associated with GABAA receptor-chloride ion channel Potentiate GABA, prolong the duration of Cl- channel opening. At high therapeutic concentration, it also inhibit Na+ and Ca2+ channels and block glutamate receptors Mechanisms of actions  Pharmacodynamics Hypnosis Lost effectiveness after 2 weeks Sedation Anesthesia Therapeutic Uses of Sedatives CV Anti- & Convulsant Respiratory Muscle Relaxation  Pharmacodynamics A- Sedation; B-Hypnosis C-Anesthesia; D-Anticonvulsant action E-Muscle relaxation F-Medullary depression, (especially with barbiturates). What will it lead to? G-Tolerance and dependence  Contraindications – Pregnancy:  Side Effects -sedation in adults -hyperactivity in children -cognitive impairment ataxia  Barbiturates Versus Benzodiazepines Bioavailability Bioavailability – rapid and reliable – rapid but Long half-lives unreliable due to their narrow Short half-lives margin of safety and Active metabolites their abuse liability, they were replaced by benzodiazepines  Barbiturates Versus Benzodiazepines The newer form of Coma Drug A sedative-hypnotics, the benzodiazepines Anesthesia are much more Hypnosis specific and require Drug B constant dose Sedation increments to achiever higher effects. Due to the specificity they are Increasing Dose much safer and less likely to cause an overdose. Drug A: Is a common Barbiturate with an infinitive effect on CNS depression Drug B: Is a newer form of benzodiazepine with a maximum affect  pharmacology of anxiolytic/sedative-hypnotics GABA Function and Distribution Inhibitory neurotransmitter Widely distributed throughout CNS Local inhibitory action, therefore rapidly alters neuronal output Desensitization to inhibitory effects with chronic stimulation of GABA Withdrawal syndrome: A term used to describe the signs and symptoms that occur on withdrawal of a drug in a physiological dependent person. Shorter half-lives, more pronounced withdrawal syndromes.  Sedative-Hypnotics The drugs are CNS depressants Their depressant effects enhanced by concomitant use of opioid analgesics, antipsychotic agents, marijuana, and any other drug with sedative properties. Sedative-Hypnotics Tolerance may develop to the sedative effect, but not to the respiratory depressant effect.  Overdose of Sedative- Hypnotics Acute overdoses commonly result in death through depression of the medullary respiratory and cardiovascular centers.  Management of Sedative- Hypnotics Overdose Maintenance a patent airway plus ventilatory support. Flumazenil: a BZ receptor antagonist, reverses the CNS depressant effects of benzodiazepines No antidote for barbiturates Withdrawal syndromes of Sedative-Hypnotics anxiety, tremor, nausea and vomiting, delirium, hallucination, seizures, death.  Treatment of Sedative- Hypnotic Withdrawal administration of a long-acting sedative-hypnotic (eg, chlordiazepoxide or diazepam) Gradual reduction of the dose Suppression of sympathetic overactivity (clonidine or propranolol).  Zolpidem (Ambien) Specific binding site Zolpidem produces relatively little tolerance and dependence. Its short duration of action leads to little daytime sedation and hangover. It is become the most widely used prescription drug for treating insomnia. Short term treatment of insomnia. Tolerance and dependence A- Tolerance and B-Psychological dependence C-Physiological dependence D-Withdrawal state or abstinent syndrome Tolerance: A decreased response to a drug. Need larger doses to achieve the same effect. Results from compensatory changes in receptors or effector systems involved in drug actions (functional tolerance). Drug dependence: Repeated psychoactive drug uses Learned behavior pleasurable effects Withdrawal effects Psychological dependence: Compulsive drug-using behavior in which the individual uses the drug for personal satisfaction, often despite known health risks. Physiological dependence: A state in which continued drug use is required to prevent an unpleasant withdrawal syndrome (frequently the opposite of those caused by a drug).