Sedative-Hypnotic-Anxiolytics:Benzodiazepines & others

Tracy A. Womble, Ph.D

Florida A&M University

College of Pharmacy and Pharmaceutical Sciences

SEDATIVE-HYPNOTICS

History of Sedatives

• Alcohol, the oldest known sedative– “When Noah left the Ark he planted a

vineyard, drank the wine, and was drunken, and he was uncovered within his tent.” Genesis 9:21

• 1900 Barbiturates: narrow TI • 1960’s Chlordiazepoxide (Librium)

SEDATIVE-HYPNOTIC DRUGSSEDATIVE-HYPNOTIC DRUGS

SEDATION• Reduction of anxiety• Calming effectANXIOLYTIC• Drug that reduces anxiety• SedativeHYPNOSIS• Induce sleep

– go to sleep fast, feel refreshed tomorrow !!!

What is Anxiety ?

• an unpleasant state of tension, apprehension, or uneasiness; a fear that seems to arise from a sometimes unknown source.

Classification of Anxiety Disorders

• Generalized Anxiety Disorder (GAD)• Panic Disorder• Social Phobia• Simple Phobia • Obsessive Compulsive Disorder (OCD)

Classification of Anxiety Disorders

Generalized Anxiety Disorder (GAD) exaggerated autonomic response, irritability, difficulty in concentrating and swallowing, and insomnia.

Panic Disorder - autonomic symptoms, hot flashes, and fear of dying or going crazy.

Social Phobia - fear of eating, writing or speaking in public.

Simple Phobia - Phobias of heights, animals, driving, or air travel.

Obsessive Compulsive Disorder (OCD) :• Obsessions are persistent ideas

– e.g., recurrent thoughts of contamination.• Compulsions are repetitive behaviors

– e.g., repetitive hand-washing.

• Significantly interfere with the patient’s social and practical life.

Classification of Anxiety Disorders (Cont)

Anxiolytics

• Benzodiazepines• Buspirone• SSRIs (Those FDA approved for

Anxiety)• SNRIs (Those approved for Anxiety)• Hydroxyzine• Clomipramine

Sedative/Hypnotic/Anxiolytic

• Because many of the antianxiety drugs also cause some sedation, the same drugs often function clinically as both anxiolytic and hypnotic (sleep-inducing) agents.

• In addition, some have anticonvulsant activity.

Dose Response Curve for Sedative/Hypnotics

EFFECTIVE SEDATIVE-HYPNOTIC DRUGS

EFFECTIVE SEDATIVE-HYPNOTIC DRUGS

• Lipid soluble• Absorbed well from the GIT• Good distribution to the brain• Metabolized before elimination from the

body

SEDATIVE-HYPNOTIC DRUGSSEDATIVE-HYPNOTIC DRUGS

Benzodiazepines Barbiturates Miscellaneous agents

Short Ultra short

acting acting

Intermediate Short Buspirone

acting acting Chloral hydrate

Long Long Zaleplon

acting acting Zolpidem

Actions of Sedative Hypnotics• Sedation / Anxiolytics

– Amnesia during surgical procedure

• Hypnosis (insomnia)• Adjunct to Anesthesia • Anticonvulsant effects (i.v.)• Muscle Relaxation• Respiration and Cardiovascular• Control of ethanol, sedative-hypnotic

withdrawal

Action Potential of a Neuron

SEDATIVE-HYPNOTIC DRUGSSEDATIVE-HYPNOTIC DRUGS

BENZODIAZEPINES• receptors

Form part of GABAA receptor-chloride ion channel macromolecular structure

Binding facilitates the inhibitory actions of GABA

Increased GABA mediated chloride ion conductance

Benzodiazepine Receptor• Located on the GABAA receptor

– Divided into 3 main types (A,B and C)• GABA A,B,C

– GABA A - ligand-gated Cl- ion channel (ionotropic)• GABA,B,C are metabotropic

• Hippocampus, striatum, spinal cord, mediate anxiolysis– Most common throughout CNS, mediate

sedation

Benzodiazepine Indications• Sedation/Hypnotic

• Anxiety

• Anesthesia

• Alcohol withdrawal syndrome

• Anticonvulsant

• Muscular disorders

Benzodiazepine Receptor

• Ionotropic receptor – (GABAA) form ion channels– Metabotropic receptor – (GABAB ) BZP’s have very

low affinity for GABAB

• GABAA receptor- contains 5 subunits found in many regions of brain, different regions of CNS

• contain different combinations– (6) α, (3) β, (3) γ and (2) δ

Benzodiazepines (BZP) Mechanism of Action

• BZP receptor linked to GABAA receptor complex (bound to Cl- channels). – BZP enhance GABAA effect.

– GABA: an inhibitory neurotransmitter

• Open Cl- channels in response to GABA activation, hyperpolarization, decrease neuronal firing

• Effects: Sedative, Hypnotic, Anticonvulsant, Muscle-Relaxant, Anxiolytic

Pharmacokinetics of Benzodiazepines

• Lipid-soluble: fast cross blood-brain-barrier: rapid onset of action. – obese, elderly

• Biotransformation & Half-Life: – Hepatic oxidation: long-t½, active

metabolites– Glucuronidation: short-t½, no active metab.

Pharmacokinetics of Benzodiazepines Pharmacokinetics of Benzodiazepines

• Diazepam, Chlordiazepoxide, Clorazepate

and Flurazepam – Converted initially to active metabolites with long

half-lives

After several days of therapy accumulation of active metabolites can lead to excessive sedation

Pharmacokinetics of Benzodiazepines Pharmacokinetics of Benzodiazepines

BENZODIAZEPINES

• Diazepam, Chlordiazepoxide, Clorazepate*desmethyldiazepam active

oxazepam metabolites

conjugation

* Prodrug

SEDATIVE-HYPNOTIC DRUGSSEDATIVE-HYPNOTIC DRUGS

BENZODIAZEPINES• Lorazepam and oxazepam

Undergo extrahepatic conjugation and do not form active metabolites

Biotransformation of BZPs

Benzodiazepine Classification Half Life (t½) (hrs.) Therapeutic Use

Midazolam(Versed)

Short Acting 2-6 Preanesthetic, intraoperative

Triazolam(Halicon)

Short Acting 2-3 Insomnia

Alprazolam(Xanax)

Intermediate Acting 12-15 Anxiolytic, agoraphobia

Estazolam(Prosom)

Intermediate Acting 10-24 Insomnia

Lorazepam(Ativan)

Intermediate Acting 10-20 Anxiolytic, preanesthetic

Temazepam(Restoril)

Intermediate Acting 10-40 Insomnia

Clonazepam(Klonipin)

Long Acting 18-50 Anticonvulsant

Clorazepate(Tranxene)

Long Acting 40-50 Anxiolytic, anticonvulsant

Diazepam(Valium)

Long Acting 20-80 Anxiolytic, status epilepticus, muscle relaxant, anesthetic

premed

Flurazepam(Dalmane)

Long Acting 40-100 Insomnia

BZD: Adverse Effects• BZD few SE • Sedation, CNS Depression

– Worse if combined with EtOH• Behavioral disinhibition

– Irritab, excitement, aggression • Psychomotor & Cognitive Impairment

– coordination, attention (driving)– poor visual-spatial ability (not aware of it)– Ataxia, confusion

BZD: Adverse Effects• Overdose: Rare fatalities if BZD

alone

• Hypnotic dose of BZP may worsen snoring/OSA

• Severe CNS & Respiratory Depression if combined –alcohol, barbiturates, narcotics,TCA’s

Benzodiazepine AntagonistBenzodiazepine Antagonist• Flumazenil (Romazicon)

Reverses the CNS effects of benzodiazepines, Eszopiclone, Zaleplon and Zolpidem

Antagonist at the BZP receptor, no effect on barbiturates.

Management of BZP overdose

t½ 0.7-1.3 hr – sedation commonly recurs, requires repeated admin.

Barbiturates• Not used for anxiety or insomnia

– Used for induction of anesthesia

• Potentially Fatal Respiratory Depression– narrow TI

• Induce P450 system: interactions

Barbiturates• Gen Anesthesia (induction) - thiopental• Sedative - Amobarbital, pentobarbital• Anticonvulsant – Phenobarbital

• Abrupt withdrawal after physical dependence may result in death

• Increase porphyrin synthesis, contraindicated in pts. w/ acute intermittent porphyria

Action of Barbiturates• CNS–

– Low dose, sedation. High dose, hypnosis, anesthesia, finally coma and death. CNS depression dependent on dose. No analgesic properties.

• Respiratory Depression– Suppress hypoxic and chemoreceptor response to CO2

• Enzyme Induction – induce P450 microsomal enzymes.

Barbiturate Poisoning• Lethal dose >10x hypnotic dose • Tx of acute barbiturate poisoning is

supportive– Hemodialysis or hemoperfusion– Purging of stomach– Diuresis/alkalinization of urine– Airway ventilation– Gastric lavage if < 24hr since ingestion

• Admin. Activated charcoal to shorten t½

• CNS stimulants contraindicated, increases mortality

Non-Benzodiazepine Sedative Hypnotics

• Zolpidem (Ambien)• Zaleplon (Sonata)• Eszopiclone (Lunesta• Buspirone (Buspar)• Chloral Hydrate

(Aquachloral)• Propofol (Diprivan)

Benzodiazepine-Receptor Agonists

• Zolpidem (Ambien), Zaleplon (Sonata), Eszopiclone (Lunesta)

• Structurally similar to BZPs

• Sedation and hypnosis

• Effects reversed by Flumazenil

Zolpidem (Ambien)• Ambien, Ambien CR, Zolpimist• Acts at subset of BZP receptors• no anticonvulsant or muscle relaxation

properties• no withdrawal effect, Minimal rebound

insomnia, t½ 2-3 hrs,• Little to no tolerance with prolonged use• Adverse effects - nightmares, agitation, h/a,

GI upset, dizziness and daytime drowsiness

Zaleplon (Sonata)• Similar to Zolpidem hypnotic action

• Less residual s/e on psychomotor and cognitive than zolpidem and BZPs

• Causes fewer cognitive side effects

• t½ < 1 hr.

Eszopiclone (Lunesta)• Used in tx of insomnia• Effective up to 6 months • Rapidly absorbed (1 hour)• metabolized by oxidation /demethylation• t½ ~ 6 hrs• Adverse effects – anxiety, dry mouth, chest

pain, h/a, migraine, peripheral edema, somnolence, unpleasant taste

Buspirone (Buspar)• mediated by serotonin ((5-HT1A)

• minimal sedation, no physical dependence or tolerance, no withdrawal

• Not a BZP, not hypnotic, no CNS depression w/ alcohol

• no anticonvulsant or muscle relaxant, minimal sedation

Buspirone (Buspar)• tx of GAD, onset of action – 1 wk

• Effects not reversed by Flumazenil

• hypothermia, inc. prolactin, GH release

• < motor function interference (important in elderly)

• < nicotine cravings in tobacco users

Chloral Hydrate• Prodrug - active. metab. inc.

anticoagulant effect– (displace form protein binding site)

• Sedative / hypnotic–onset ~ 30 min. DOA 6 - 10 hrs.

• Irritating to GI tract– Produces unusual, unpleasant taste

sensation, synergizes w/ alcohol

Propofol (Diprivan)

• i.v. sedative/hypnotic

• induction/maintenance of anesthesis

• smooth onset ~ 40s, facilitates CNS depression

• no postaneshetic n/v