sedative-hypnotic-anxiolytics: benzodiazepines & others tracy a. womble, ph.d florida a&m...
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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
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