Sedative-Hypnotic Drugs Marina Bergman PharmD PhD Lecturer  Clinical Generalist – Pharmacist The Ohio State University Wexner Medical Center

Little Yellow Pill What a drag it is getting old "Kids are different today" I hear ev'ry mother say Mother needs something today to calm her down And though she's not really ill There's a little yellow pill She goes running for the shelter of a mother's little helper And it helps her on her way, gets her through her busy day

Objectives Identify the major chemical classes of sedative-hypnotics. Describe the pharmacodynamic of benzodiazepines and barbiturates, including their mechanisms of action. Compare the pharmacokinetics of commonly used benzodiazepines and barbiturates and discuss how differences among them affect clinical use. Describe the clinical uses and the adverse effects of sedative hypnotics. Identify the distinctive properties of buspirone, zolpidem eszopiclone , ramelteon and zaleplon.

Overview Anxiety – a state of tension, apprehension uneasiness. Sedative (anxiolytic) - agent that reduces anxiety Hypnotic - drug that induces sleep Benzodiazepines (BZs)- widely used sedative-hypnotics Barbiturates- anxiolytics at low doses, hypnotics at high doses

Learning Resource Trevor AJ and Way WL, Sedative-Hypnotic Drugs, in Basic and Clinical Pharmacology, Katzung BG, Master SB, McGraw-Hill Lange, New York 2012.

Benzodiazepines (BZs) Sedative (anxiolytics) – alprazolam, clorazepate chlordiazepoxide, diazepam, halazepam, lorazepam, oxazepam Hypnotics – estezolam, lorazepam, quazepam, temazepam, triazolam

Safety

Chemical Structures of Benzodiazepines Chemical structures of BZs- all members contain the 1,4 –benzodiazepines and most contain a halogen in the 7 position or a nitro group. Carboxamide group is present in most of the 7 member heterocyclic ring structure.

Mechanism of Action Receptor for BZs are found in many Brain regions Binding of BZs to the GABAA receptor promotes the inhibitory action of GABA BZs increase the frequency of GABA mediated chloride ion channel opening

gamma–Aminobutyric Acid GABA-alpha Receptor

Fig 1A Mechanism of action of GABA and benzodiazepines GABAA receptors are composed of , ,  subunit families of which a combination of five or more span the postsynaptic membrane and surround a chloride channel. Empty receptor is inactive, and the coupled chloride channel is closed. Receptor Empty (No Agonists) Cl- + + + + + + + + GABA receptor - - - - - - - - Chloride Channel closed Benzodiazepine site

Fig 1B Mechanism of action of GABA and benzodiazepines Binding of GABA causes chloride channel to open Cl- GABA + + + + + + + + GABA receptor - - - - - - - - Benzodiazepine site Cl-

Fig 1C Mechanism of action of GABA and benzodiazepines Benzodiazepines modulate the GABA effects by binding to their receptors near  and 2 subunits of GABAA receptor, thus increasing further the chloride influx. Binding of GABA is enhanced by benzodiazepine, resulting in a greater entry of chloride ion Cl- Benzodiazepine GABA +++++++ +++++++ GABA receptor -------------- -------------- Entry of chloride ions hyperpolarizes cell, making it difficult to depolarize and thus reducing neural excitability Cl- Cl- Cl- Cl- Cl-

Pharmacological Action of BZs Sedation (antianxiety) Hypnosis Anticonvulsant Muscle relaxant Amnesia

Duration of Action of Benzodiazepines

Therapeutic Uses Anxiety disorders Sleep disorders Muscular disorders Seizures Anesthesia

Anxiety Disorders BZ’s are effective for the treatment of the anxiety symptoms due to depression schizophrenia, panic disorders, social anxiety disorder, GAD, performance anxiety, post traumatic stress disorder, OCD, phobias The anti-anxiety effect of BZ’s is less subjective to tolerance Long acting agents are preferred, (e.g. lorazepam, diazepam, alprazolam)

Sleep disorders Flurazepam – reduces sleep-induction time and awakening Temazepam – used for pt w/ inability to stay asleep Triazolam – recurring insomnia, tolerance, rebound insomnia

Muscular disorders Diazepam - muscle spasms, spasticity in multiple sclerosis and cerebral palsy Clonazepam - chronic epilepsy Diazepam or Lorazepam - status epilepticus Chlordiazepoxide, Clorazepate, Diazepam, Oxazepam - alcohol withdraw related seizures

Anesthesia Conscious sedation – Midazolam Induction of anesthesia- Midazolam, Lorazepam Anxiety provoking and unpleasant procedures- Midazolam

Pharmacokinetics Absorption – rapid and complete (lipophilic properties) Distribution – throughout the body Duration of action – determines use Drug fate – metabolized to active compounds

Relationship of Half Life and Indication

Pharmacokinetics - Continued BZ’s are lipophilic and they completely absorbed after oral administration. Half life's of BZs is very important because the duration of action will determine the therapeutic use. Many BZ’s are converted to active metabolites in the body Lorazepam and Oxazepam do not form active metabolites. They undergo extrahepatic conjugation

Metabolism Most BZs are metabolized by the liver. They undergo microsomal oxidation (phase 1 reaction), the metabolites are subsequently conjugated (phase II reaction) and excreted in the urine. Many phase I metabolites are pharmacologically active. The formation of active metabolites makes pharmacokinetic of the Bzs in humans complicated because the elimination half life of the parent drugs have little relationship to the time course of the pharmacological effects.

Benzodiazepines Half Life and Age

Dependence Psychological and physical – high doses, prolonged periods Abrupt discontinuation- withdrawal Long half-life – delayed withdrawal Short half-life – abrupt, severe withdrawal Withdrawal Signs- anxiety, confusion, insomnia, agitation, tremors, hyperreflexia and seizures

Tolerance A decrease in responsiveness to repeated dose of the drug when used for more the 1-2 weeks Cross tolerance may occur among the different BZs agents.

Rebound

Adverse effects Drowsiness and confusion Ataxia Cognitive impairment Decreased long-term recall Decreased learning

Flumazenil Benzodiazepine antagonist Administered i.v. Rapid onset, short duration Withdrawal in dependent patients May cause seizures Side effects

Other hypnotic Agents

Other hypnotic agents All are hypnotic, selective GABAA agonists Zolpidem - not an anticonvulsant or muscle relaxant, fewer adverse effects Zaleplon - metabolized in liver, 1hr half-life, reduced dosage in elderly and liver damage Eszopiclone – metabolized in liver, 6hr half-life

Ramelteon Novel hypnotic for sleep induction Agonist for MT1 and MT2 receptors Acts via suprachiasmatic nuclei No effect on GABAergic system No rebound insomnia or withdrawal Rapid absorption, extensive metabolism Dizziness, somnolence, fatigue Testosterone decrease, prolactin increase

Other Anxiolytic Agents Hydroxyzine- an antihistamine, has low tendency for habituation and thus is useful in patients with anxiety who have history of drug abuse. Also Used in dental procedures Antidepressants- SSRI, TCAs MAOI duloxetine venlafaxine all have proven efficacy in managing symptoms of anxiety

Buspirone Selective anxiolytic effects, slow onset (weeks) Serotonin 5-HT1A and dopamine D2 agonist No direct effect on GABAergic system No anticonvulsant or muscle relaxant properties. Low sedative, hypnotic, euphoric effects. Low abuse potential No rebound insomnia or withdrawal Low frequency of side effects

Comparison between Buspirone and Alprazolam

Barbiturates Phenobarbital Pentobarbital Secobarbital Amobarbital Thiopental

Chemical Structures of Barbiturates and Other Hypnotic Drugs

Mechanism of Action Barbiturates: Interfere with Na+/K+ transport Inhibit reticular activating system Inhibit polysynaptic transmission Potentiate GABA action on Cl- flux Bind to subunits other than a and b

Barbiturate classification Duration of action: Thiopental – fast action, duration ~ 30 min, induction of anesthesia Phenobarbital – duration > 1 day, seizure treatment Pentobarbital, secobarbital, amobarbital- short acting hypnotics, not anxiolytic

Sedative Hypnotic Dose and CNS Effects

Drug Action Depression of CNS – dose dependent sedation, hypnosis, anesthesia, coma and death Respiratory depression - suppressed CO2 response Porphyria - Barbiturates can increase porphyrin synthesis and are contraindicated in patient with acute intermittent porphyria

Barbiturates and the P-450 Enzyme System Barbiturates induce the formation of the liver microsomal enzymes that metabolize drugs. The p-450 enzyme induction can lead to multiple drug interactions (e.g. birth control, warfarin, corticosteroids, anti epileptics) Barbiturates will decrease the serum level of drugs that are metabolized by P-450 enzymes.

Therapeutic Uses Anesthesia – induction of anesthesia selected for duration of action thiopental, ultra short-acting Seizures – tonic-clonic, status epilepticus eclampsia, febrile seizures Anxiety - sedation, tension, insomnia, mostly replaced by BZ’s

Pharmacokinetics Absorbed orally Distributed throughout body Sequential redistribution Short duration of action (thiopental) Metabolized in liver Excreted in urine

Adverse effects CNS- confusion, sedation, irritability Hypotension Drug hangover Respiratory depression Addiction Poisoning

Non-barbiturate Hypnotics Chloral hydrate – acetaldehyde derivative sedative and hypnotic,fast sleep induction, Can displaced warfarin from plasma proteins leading to increase anticoagulant effects Antihistamines – diphenhydramine, doxylamine can be used for mild insomnia. Both have undesirable side effects. Can be purchase over-the-counter. Ethanol - toxic potential

Drug Interaction with Alcohol Alcohol when used with benzodiazepines, antihistamines or barbiturates can produced sever CNS depression Alcohol should be avoided when a patient is using a sedative hypnotic agent from the classes above.

Special Populations Elderly patients are more sensitive to the effect of sedative-hypnotics Doses half of those used in young adults are considered safe and effective for the elderly. Increase sensitivity to sedative-hypnotics is also more common in patients with cardiovascular disease, respiratory disease or hepatic impairment

Sedative and Hypnotic Drugs Quiz

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