Lecture 2 sedative hypnotic and anxiolytic drugs

DRUGS USED IN DISORDERS OF THE CENTRAL NERVOUS SYSTEM AND TREATMENT OF PAIN Lecture 2:

Sedative-Hypnotic and Anxiolytic Drugs Marc Imhotep Cray, M.D.

Learning Objectives:

CNS Pharmacology Lecture 2

1. The structural aspects of the GABAA receptor and the receptor components (i.e. binding sites) mediating the effects of drugs that modulate GABAA receptor activity.

2. The differences between benzodiazepines with respect to Phase I only versus Phase I & II pharmacokinetics.

3. The similarities and differences among the benzodiazepines with respect to: a) time of onset, b) potency, c) metabolism and d) elimination half-lives.

4. The similarities and differences between the benzodiazepines and the barbiturates in producing sedativehypnotic effects.

Marc Imhotep Cray, M.D.

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Learning Objectives: cont.

CNS Pharmacology Lecture 2

5. The factors to consider in choosing the most appropriate drug for specific clinical situations and/or individuals.

6. The characteristics of benzodiazepines and other sedativehypnotics that contribute to different degrees of abuse liability and withdrawal symptoms.

7. The target sites or putative mechanisms of nonbenzodiazepine drugs that can be used to treat sleep disorders.

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Classification Schema: Sedative-Hypnotic and Anxiolytic Drugs

Marc Imhotep Cray, M.D.

BENZODIAZEPINES Alprazolam XANAX Chlordiazepoxide LIBRIUM Clonazepam KLONOPIN Clorazepate TRANXENE Diazepam VALIUM Estazolam Flurazepam DALMANE Lorazepam ATIVAN Midazolam VERSED Oxazepam Quazepam DORAL Temazepam RESTORIL Triazolam HALCION BENZODIAZEPINE ANTAGONIST Flumazenil ROMAZICON

CNS Pharmacology Lecture 2

OTHER ANXIOLYTIC DRUGS Antidepressants (Various) Buspirone BUSPAR BARBITURATES Amobarbital AMYTAL Pentobarbital NEMBUTAL Phenobarbital LUMINAL Secobarbital SECONAL Thiopental PENTOTHAL OTHER HYPNOTIC AGENTS Antihistamines (Various) Doxepin SILENOR Eszopiclone LUNESTA Ramelteon ROZEREM Zaleplon SONATA Zolpidem AMBIEN 4

CNS Pharmacology Lecture 2

Sedative-Hypnotic and Antianxiety Drugs Hypnotics are medications that induce sleep, and antianxiety drugs are medications that reduce anxiety  Many of these drugs have both hypnotic and antianxiety activity The common MOA (mechanism of action) is to enhance the inhibitory effects of GABA in the CNS  This hyperpolarizes neurons by increasing the entry of chloride ions Marc Imhotep Cray, M.D.

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Side Effects

CNS Pharmacology Lecture 2

Side Effects common to these drugs include: 1. Decreased REM sleep with a rebound increase in REM sleep upon withdrawal 2. Drowsiness 3. Hangover 4. Tolerance with prolonged administration due to  Increased metabolism from activation of mixed function oxidases (MFOs)  Reduced effects on the CNS

Marc Imhotep Cray, M.D.

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Side Effects cont.

CNS Pharmacology Lecture 2

5. Respiratory depression  These drugs reduce the sensitivity of the medullary respiratory centers to CO2  Respiratory depression is increased when these drugs are combined with any other sedating drug (alcohol, opiates)  This is the cause of death from an overdose  Tolerance does not develop to the depressant action on respiration  Respiratory depression is very marked with barbiturates and very weak with benzodiazepines 6. Abuse potential  Physical dependence occurs with all these drugs and results in an abstinence syndrome upon withdrawal

Marc Imhotep Cray, M.D.

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Clinical Uses

CNS Pharmacology Lecture 2

Clinical Uses of sedative–hypnotic and antianxiety drugs include: 1. Treatment of anxiety 2. Treatment of insomnia 3. Muscle relaxation 4. Treatment of seizures 5 Replacement therapy during withdrawal from sedative– hypnotics (e.g., ethanol) 6. IV anesthesia or sedation before surgical procedures

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Anxiety

CNS Pharmacology Lecture 2

 Anxiety is an unpleasant state of tension, apprehension, or uneasiness  Episodes of mild anxiety are common life experiences and do not warrant treatment  Disorders involving anxiety are among the most common mental disorders  Physical symptoms of severe anxiety are similar to those of fear (tachycardia, sweating, trembling, and palpitations) and involve sympathetic activation Marc Imhotep Cray, M.D.

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Clinical Anxiety

CNS Pharmacology Lecture 2

 Clinical anxiety, whether chronic or in the form of a panic attack, often impedes normal functioning and adversely affects the quality of life

 Clinical anxiety is approximately twice as common (possibly more often reported) in women than in men  The age at onset is usually between 20 and 30 years Marc Imhotep Cray, M.D.

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Clinical Anxiety (2)

CNS Pharmacology Lecture 2

 Common adult anxiety disorders include:  generalized anxiety disorder  social phobia  obsessive-compulsive disorder (OCD)  panic disorder  posttraumatic stress syndrome

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CNS Pharmacology Lecture 2

Marc Imhotep Cray, M.D.

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Clinical Anxiety (3)

CNS Pharmacology Lecture 2

 Severe, chronic, debilitating anxiety may be treated with antianxiety drugs (also called anxiolytics) and/or some form of psychotherapy

 Drugs for treating anxiety disorders, or anxiolytics, include benzodiazepines, non-benzodiazepines GABAergics, SSRI and buspirone  Because many antianxiety drugs also cause some sedation, they may be used clinically as both anxiolytic and hypnotic (sleep inducing) agents (to treat insomnia) Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 2

Anxiolytics ď ąTwo main categories of anxiolytics are benzodiazepines and miscellaneous (e.g., buspirone, zolpidem, zaleplon) ď ą Subclassification of benzodiazepines is based on speed of onset or duration of action, metabolism, and adverse effects

Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 2

Non-benzodiazepines Anxiolytics  Zolpidem and zaleplon resemble BZD in pharmacology (MOA) but differ chemically

 Buspirone (an azapirone) acts on 5-HT1A receptors  Not an effective hypnotic agent All 3 of these drugs have fewer adverse effects and less abuse potential

Marc Imhotep Cray, M.D.

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Benzodiazepines (BDZs) Alprazolam Chlordiazepoxide Clonazepam Clorazepate Diazepam Estazolam

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 2

Flurazepam Miscellaneous Agents Lorazepam Buspirone Midazolam Zaleplon Oxazepam Zolpidem Quazepam Temazepam Triazolam Benzodiazepine Antagonist Flumazenil

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Benzodiazepines (2)

CNS Pharmacology Lecture 2

Benzodiazepines preparations differ primarily in their duration of action 1. Antianxiety preparations usually have long durations of action ranging from 12 hours to several days. They include:  Chlordiazepoxide (Librium), also used for alcohol withdrawal  Diazepam (Valium), also used for skeletal muscle spasms and seizures  Alprazolam (Xanax), used to treat panic disorders

2. Hypnotic preparations (sleeping pills) have shorter durations of action than the antianxiety drugs  Flurazepam (Dalmane) has a short half-life, however, its active metabolites give it a long clinical effect (up to 100 hours) and result in daytime drowsiness  Temazepam (Restoril) has a t1/2 of 10 hours with no active metabolites  Triazolam (Halcion) has a short t1/2 of 2.5 hours, which can result in early morning awakening Marc Imhotep Cray, M.D.

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Benzodiazepines (3)

CNS Pharmacology Lecture 2

 BDZs bind to benzodiazepine site on GABAA receptors, which leads to an enhancement of GABA inhibition

 Effects include: 1.

2.

3.

4.

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Calming of behavior Reduction of anxiety Induction of sleep Anticonvulsant actions Muscle relaxation

 There are no autonomic effects (Why?)  Side effects include:  Drowsiness and confusion  Dependence, especially with quick onset agents (e.g., alprazolam, diazepam), thus long-term use should be avoided  A prolonged withdrawal syndrome Marc Imhotep Cray, M.D.

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BZD (4)

CNS Pharmacology Lecture 2

ď ą Contraindications:  Benzodiazepines should not be given to people with bronchopulmonary disease, and  they have additive or synergistic effects with other central depressants such as alcohol, barbiturates and antihistamines

Marc Imhotep Cray, M.D.

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Benzodiazepines(4)

CNS Pharmacology Lecture 2

BZDs have many advantages over barbiturates, including:  They are less likely to be abused, although abuse still occurs  Suicide potential is lower due to the high therapeutic index (TI)  Less reduction of REM sleep occurs  Induction of MFOs is less pronounced  Flumazenil, a benzodiazepine antagonist, will reverse the sedation effects of the benzodiazepines

Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 2

BZD GABAA Receptor ď ą Benzodiazepines cross the bloodbrain barrier and bind to specific receptors on the GABAA complex; these receptors occur in many brain regions ď ąThe BZDs do not bind to the same sites as does GABA but potentiate GABA action Marc Imhotep Cray, M.D.

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Distribution of Benzodiazepine Receptors in the Brain

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 2

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CNS Pharmacology Lecture 2

Schematic diagram of BDZ– GABA–Cl ion channel complex.

GABA = γ-aminobutyric acid.

Lippincott Illustrated Reviews-Pharmacology 6 Ed. 2014

Marc Imhotep Cray, M.D.

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Metabolism of Benzodiazepines

CNS Pharmacology Lecture 2

ď ą Diazepam, chlordiazepoxide, prazepam, and the prodrug clorazepate undergo hepatic metabolism to the intermediate Oxazepam ď ą Alprazolam, flurazepam, lorazepam, and triazolam directly undergo conjugation before excretion

Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 2

Barbiturates Amobarbital AMYTAL Pentobarbital NEMBUTAL Phenobarbital LUMINAL Secobarbital SECONAL Thiopental PENTOTHAL

Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 2

Barbiturates (2) Barbiturates are derived from barbituric acid, a combination of urea and malonic acid They are frequently provided as Na salts (e.g., Na pentobarbital) because the salt is more water soluble; however, it is very alkaline  The barbiturates are classified by duration of action:  Ultrashort-acting barbiturates (e.g., thiopental [Pentothal]) have very high lipid solubilities due to sulfur in the structure. They are used as IV anesthetics.  Short- and intermediate-acting barbiturates (e.g., pentobarbital [Nembutal]) have lower lipid solubilities and longer durations of action than are appropriate for sleeping pills  Long-acting barbiturates (e.g., phenobarbital [Luminal]) have the lowest lipid solubilities and the longest durations of action

Clinical Use: They can be used as sedatives, anticonvulsants, or antianxiety drugs

Marc Imhotep Cray, M.D.

Note: Barbiturates are largely obsolete as sedativehypnotics due to there adverse effects profile, include dependence, ataxia, and drowsiness.

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Barbiturates (3)

CNS Pharmacology Lecture 2

PPB and Metabolism: Binding to plasma proteins is highest for the highly lipid-soluble barbiturates Metabolism by side chain oxidation accounts for the clearance of all barbiturates from the body  Only phenobarbital has some clearance (30%) by the kidney, and this can be increased by increasing the urinary pH (urinary alkalization)  Barbiturates greatly induce the cytochrome P450 enzymes in the liver, which decreases the activities of other drugs that are metabolized by these enzymes Marc Imhotep Cray, M.D.

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Barbiturates (4)

CNS Pharmacology Lecture 2

Adverse Effects: There are multiple adverse effects:  Drowsiness and impaired concentration  Hangovers  Dependence and severe withdrawal that can be lethal  Overdoses due to the narrow therapeutic index (e.g., patients who overdose on barbiturates develop respiratory depression, which is managed symptomatically by assisting respiration and stabilizing blood pressure)  Due to an increase in porphyrin synthesis, acute intermittent porphyria is an absolute contraindication for the use of barbiturates Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 2

Zolpidem Zolpidem (Ambien), eszopiclone (Lunesta), and zaleplon (Sonata) are hypnotics with little effect on the stages of sleep  Although they are not benzodiazepines, they bind to a subgroup of benzodiazepine receptors (BZ1)  They are antagonized by flumazenil  They have little anxiolytic, anticonvulsant, or muscle relaxant activity

Marc Imhotep Cray, M.D.

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Eszopiclone

CNS Pharmacology Lecture 2

 An oral non-benzodiazepine hypnotic that also acts on the BZ1 receptor  Effective for insomnia for up to 6 months  Rapidly absorbed (time to peak, 1 hour), extensively metabolized by oxidation and demethylation via the CYP450 system, and mainly  Excreted in urine  Elimination half-life is approximately 6 hours  Adverse events with eszopiclone include anxiety, dry mouth, headache, peripheral edema, somnolence, and unpleasant taste

Marc Imhotep Cray, M.D.

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Ramelteon

CNS Pharmacology Lecture 2

 Ramelteon is a selective agonist at the MT1 and MT2 subtypes of melatonin receptors  Melatonin is a hormone secreted by the pineal gland that helps to maintain the circadian rhythm underlying the normal sleep–wake cycle  Stimulation of MT1 and MT2 receptors by ramelteon is thought to induce and promote sleep  Indication-treatment of insomnia characterized by difficulty falling asleep (increased sleep latency)  It has minimal potential for abuse, and no evidence of dependence or withdrawal effects has been observed  Can be administered long term  Common adverse effects include dizziness, fatigue, may also increase prolactin levels Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 2

Buspirone Buspirone (BuSpar) is an antianxiety drug that 1. Is not a benzodiazepine 2. Is a partial agonist at 5HT1A receptors 3. Does not have abuse potential 4. Has few CNS side effects (e.g., drowsiness is minimal) 5. Mildly increases respiratory drive

Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 2

Antihistamines and Ethanol ď ą Antihistamines and Ethanol also have sedating properties: 1. Hydroxyzine (Atarax, Vistaril) is an antihistamine with antianxiety activity, low abuse potential, and marked sedative and anticholinergic effects.

Other antihistamines (e.g., diphenhydramine) are found in many over-the-counter sleep preparations

2. Ethanol has both antianxiety and sedating effects However, it is not a therapeutically useful drug due to the high potential for abuse and dependence

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THE END

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 2

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Further study (SDL):

CNS Pharmacology Lecture 2

MedPharm Digital Guidebook: Unit 3-Drugs Used for CNS Disorders Companion eNotes: CNS- Central Nervous System Pharmacology Textbook Reading: Trevor AJ & Walter LW Ch. 22 Sedative-Hypnotic Drugs In: Katzung BG, ed. Basic & Clinical Pharmacology. 12th ed. Pgs. 373-88 Online resource center: Medical Pharmacology Cloud Folder

Lectures/discussions to follow: 3. Antiepileptic Agents 4. Antidepressants 5. Antipsychotic Agents 6. Drugs Affecting Bipolar Disorder 7. Drugs Affecting Movement Disorders and Other Neurodegenerative Disorders 8. CNS Skeletal Muscle Relaxants 9. Analgesics 10. Anesthetics Marc Imhotep Cray, M.D.

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