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Sedative-Hypnotics and Benzodiazepines Joan Heller Brown BIOM 255 April 12, 2011 1 CNS Depressants • Ethanol • Barbiturates • Benzodiazepines • Non-benzodiazepine hypnotics 2 Stages of CNS Depression • Sedation • Hypnosis • Loss of consciousness • Surgical anesthesia • Coma • Respiratory and cardiovascular shutdown 3 4 Other Pharmacological Responses to CNS Depressants • Varying degrees of CNS depression (above) • Anti-seizure activity • Psychomotor impairment • Drowsiness, confusion, amnesia 5 Common Properties of CNS Depressants • Tolerance • Cross-tolerance • Additivity • Physical dependence • Abuse potential 6 Causes of Insomnia not primarily treated with Sedative Hypnotics • Depression • Abuse of stimulants or depressants • Physical disorders 7 Causes of Insomnia appropriate for Treatment with Sedative Hypnotics • Body clock disturbances • External / environmental • Stress-associated 8 What Makes an Ideal Hypnotic? • Decrease time to fall asleep • Increase duration of sleep • Not disrupt normal sleep pattern • Not cause daytime sedation • Not cause rebound insomnia • Safe on overdose • Minimal drug interactions • Not cause physical dependence • Low abuse potential 9 Figure 22. 10 Barbiturates • Enhance inhibitory GABA-ergic transmission through allosteric effect on GABAA receptor • Tolerance, physical dependence, abuse potential are high • Pronounced induction of cytochrome P450s (and UDP glucuronosyltransferases) • Therapeutic index is low 11 Heaven's Gate revisited by the time he watched them, the By J. Harry Jones group would have moved on. STAFF WRITER Rio DiAngelo, whose real name was en years ago next week, Richard Ford, drove with his boss one of the strangest events from Los Angeles to the mansion. Af- in county history exploded ter looking inside, he placed an anony- into the public's conscious- mous phone call to 911 that dispatch- ness. For several days, ers initially found inconceivable. it was the biggest news story in the “I don't think anybody really be- world. lieved what the person was saying,” It began unfolding the afternoon of said Robert Brunk, a sheriff's deputy Wednesday, March 26, 1997, during a who had just started his shift at the En- period when the Hale-Bopp comet Heaven's Gate leader Marshall cinitas station. “It was an anonymous could be seen in the night sky. Applewhite, shown in this video call to the communications center stat- ing that 40 people had committed sui- Inside a mansion in Rancho Santa image, was known as "Do.“ APTV cide and they were cult members. It Fe, 39 members of the Heaven's Gate came out as a 'welfare check,' and they cult lay dead. Convinced that a space- and other drugs – the largest mass had held the call for a while because it ship was traveling behind the comet suicide on U.S. soil. was busy.” and that they would be transported to All went willingly under the guid- Brunk went to the address, 18241 the vessel to begin a new life “be- ance of their leader, Marshall Apple- Colina Norte, which turned out to be a yond human,” they had poisoned white, also known as “Do.” themselves. Twenty-one women and 9,000-square-foot, two-story home up 18 men died by eating pudding and Their bodies were discovered by a applesauce laced with phenobarbital former cult member who had received videotapes in the mail telling him that SEE Heaven’s Gate, A16 12 Other Drugs Used as Sedative Hypnotics • Chloral hydrate • Meprobamate • Diphenhydramine • Trazodone • Nutriceuticals – melatonin, kava, valerian 13 Benzodiazepines (Selected) • Diazepam (Valium®) • Flurazepam (Dalmane®) • Oxazepam (Serax®) • Alprazolam (Xanax®) • Temazepam (Restoril®) • Midazolam (Versed®) • Triazolam (Halcion®) 14 Benzodiazepines vs. Barbiturates • Tolerance, physical dependence, abuse potential are diminished • No induction of drug metabolizing enzymes • Safety on overdose (therapeutic index) greatly improved 15 16 Table 1. General Comparison of Barbiturates and Benzodiazepines Characteristic Barbiturates Benzodiazepines Induction of sleep Rapid Rapid Daytime sedation Yes Not necessarily Effect on sleep cycle Yes Yes, but less than barbiturates Additivity with other Yes Yes sedative-hypnotics Tolerance Yes (pharmacokinetic and Yes (pharmacodynamic) pharmacodynamic) Physical dependence Yes Yes Abuse potential High Moderate Drug interactions Many (induce cytochrome P450 and Few UDP glucuronosyltransferase) Safety on overdose No (low therapeutic index) Yes (when used alone) 17 Benzodiazepines • Structural similarities (see Table 2) • Mechanistic similarities: enhance GABA- ergic inhibitory transmission through allosteric effects on GABAA receptor • Mechanistic distinctions: not all GABAA receptors are the same; potential for selectivity for pharmacological effects 18 Table 2. Structures of Benzodiazepines 19 Benzodiazepines • Structural similarities (see Table 2) • Mechanistic similarities: enhance GABA- ergic inhibitory transmission through allosteric effects on GABAA receptor • Mechanistic distinctions: not all GABAA receptors are the same; potential for selectivity for pharmacological effects 20 Table 14-2 Pharmacological Effects of Benzodiazepines • Anxiolytic • Sedative hypnotic • Anticonvulsant • Muscle relaxant 22 Side Effects of Benzodiazepines • Drowsiness • Confusion • Amnesia (anterograde) • Psychomotor impairment 23 Principles of BDZ treatment • Insomnia, anxiety ( even seizures) could be treated with the same drug • Action is immediate, use can be intermittent • Withdraw gradually if used for extended times • Inform patients about additivity with other CNS depressants • Choice of drug is based on pharmacokinetic properties 24 Pharmacokinetic Properties Determine Choice of Benzodiazepines • Rates of absorption • Routes of metabolism • Biological half lives 25 Rate of Absorption • All are well absorbed orally • Most are poorly absorbed IM • Rapid absorption desirable for rapid sleep induction • Rapid absorption desirable for euphoria 26 Routes of Metabolism • Microsomal oxidation to biologically active N-desalkyl and a-hydroxylated metabolites • Glucuronidation to inactive conjugated metabolites excreted in urine • Some benzodiazepines are only metabolized by glucuronidation • Glucuronidation is less affected by age, liver function, other drugs than is microsomal oxidation 27 Figure 2. Major Routes of Metabolism for Selected Benzodiazepines (from Goodman and Gilman ). 28 Figure 3. Metabolism and Elimination of Selected Benzodiazepines. Compounds in bold represent drugs available for clinical use; asterisks designate active metabolites (from Katzung). 29 7 Routes of Metabolism: So What? • In patients with impaired hepatic function, BDZ half life is prolonged • In patients taking other drugs that inhibit microsomal metabolism, BDZ half life is prolonged • In elderly, impaired metabolism, other drugs and increased sensitivity contribute to exaggerated BDZ response 30 Biological half-life varies widely and is not necessarily related to route of metabolism 31 Table 3. Pharmacokinetic Properties of Benzodiazepines in Humans Drug Biological t1/2 Metabolites Comments (hours) Alprazolam 8-15 Active: α-hydroxyalprazolam Rapid oral absorption Diazepam 20-70 Active: desmethyldiazepam Poor intramuscular (aka nordazepam), oxazepam bioavailability Flurazepam 48-120 Active: desalkyl derivative Long elimination half-lives of and others active metabolites Oxazepam 5-15 Inactive: glucuronides Slow oral absorption Temazepam 8-20 Inactive: glucuronides Slow oral absorption Triazolam 2-6 Active: α-hydroxytriazolam Rapid oral absorption Midazolam 2-4 Active: α-hydroxymidazolam IV in anesthesia 32 Biological half-life is used in marketing 33 Table 4. Duration of Action of Common Benzodiazepines FDA-Approved Short Intermediate Long Indication Duration of Action Duration of Action Duration of Action Anxiolytic Midazolama [Versed®] Oxazepam [Serax®] Diazepam [Valium®] Alprazolam [Xanax®] Hypnotic Triazolam [Halcion®] Temazepam [Restoril®] Flurazepam [Dalmane®] a Typically used for the acute anxiety associated with surgical or diagnostic procedures. 34 Biological Half-lives and Hypnotic Choices • Psychomotor impairment, daytime sedation – Long biological half-life contributes to this (drug A) – Short biological half-lives do not (drug B) 35 Drug A Drug B 36 Biological Half-lives and Hypnotic Choices • Rebound insomnia – Short biological half-life allows this (drug B) – Long biological half-life limits this problem (drug A) 37 38 39 40 The Halcion Controversy 41 Non Benzodiazepine Hypnotics • Zaleplon (Sonata®)-ultrashort • Zolpidem (Ambien®)-short • Eszopiclone (Lunesta®)-intermed 42 Figure 22. 43 Table 5. Important FDA-Approved Hypnotics Class Medication Onset Biological t1/2 Comments (min) (hr)a BDZsb Triazolam [Halcion®] 15-30 2-6 Mainly for sleep-onset insomnia Temazepam [Restoril®] 45-60 8-20 Mainly for sleep-maintenance insomnia Flurazepam [Dalmane®] 60-120 48-120 Not generally recommended as a hypnotic because of its long t1/2 Non-BDZs Zolpidem [Ambien®] 30 3 Effective for sleep-onset and sleep- that bind to maintenance insomnia the BDZ Ambien CR® approved for long-term use binding site on the Zaleplon [Sonata®] 20 1 Mainly for sleep-onset insomnia, but GABAA because of ultrashort t1/2, can be taken receptor during the night to improve sleep maintenance Eszopiclone [Lunesta®] 30 6 Mainly for sleep-maintenance insomnia Approved for long-term use Melatonin Ramelteon [Rozerem®] 30 1-2 Mainly for sleep-onset insomnia agonist Approved for long-term use Not a controlled (scheduled) drug a 44 Includes drug and active metabolites. b Other FDA-approved BDZ hypnotics are quazepam [Doral®] and estazolam [ProSom®]. Non BDZ vs BDZ hypnotics • Although both classes of drugs bind to and enhance inhibitory transmission through GABAA receptors, the non BDZ hypnotics cause: – Less changes in sleep cycle, psychomotor impairment – Purportedly less physical dependence, tolerance, and rebound insomnia – Limited anxiolytic, muscle relaxant or anticonvulsant response at hypnotic doses – Zolpidem and eszopiclone tested and approved for long term use 45 Non Benzodiazepine Hypnotics • Ramelteon (Rozerem®) – An agonist at melatonin receptors – Rapid onset, short half life, so particularly useful for treating sleep onset insomnia – Only approved hypnotic that is not a scheduled (controlled) substance 46 Anxiolytics • Benzodiazepines- all can be used but in practice – diazepam, oxazepam, alprazolam – midazolam- acute, surgery – clonazepam- although not approved • Buspirone (Buspar®) • SSRIs • β-adrenergic antagonists 47
"BIOM 255 BDZ and Sedative Hypnotics 2011"