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7/29/2019 An Xy Olitics Hypnotics
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SEDATIVE/HYPNOTICS
ANXIOLYTICS
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Sedated
Optimal
Performance
Nervous
Breakdown
Anxiety
GOALwww.freelivedoctor.com
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Manifestations of anxiety:
Verbal complaints. The patient says he/she
is anxious, nervous, edgy.
Somatic and autonomic effects. The patientis restless and agitated, has tachycardia,
increased sweating, weeping and often
gastrointestinal disorders.
Social effects. Interference with normal
productive activities.
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Pathological Anxiety
Generalized anxiety disorder (GAD): People sufferingfrom GAD have general symptoms of motortension, autonomic hyperactivity, etc. for at leastone month.
Phobic anxiety:Simple phobias. Agoraphobia, fear of animals, etc.
Social phobias.
Panic disorders: Characterized by acute attacks of
fear as compared to the chronic presentation ofGAD.
Obsessive-compulsive behaviors: These patientsshow repetitive ideas (obsessions) and behaviors
(compulsions). www.freelivedoctor.com
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Causes of Anxiety
1). Medical:
a) Respiratory
b) Endocrinec) Cardiovascular
d) Metabolic
e) Neurologic.
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Causes of Anxiety2). Drug-Induced:
Stimulants
Amphetamines, cocaine, TCAs, caffeine.
Sympathomimetics
Ephedrine, epinephrine, pseudoephedrinephenylpropanolamine.
Anticholinergics\Antihistaminergics
Trihexyphenidyl, benztropine, meperidine
diphenhydramine, oxybutinin.
Dopaminergics
Amantadine, bromocriptine, L-Dopa,
carbid/levodopa.www.freelivedoctor.com
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Causes of Anxiety
Miscellaneous:
Baclofen, cycloserine, hallucinogens,
indomethacin.
3). Drug Withdrawal:
BDZs, narcotics, BARBs, othersedatives, alcohol.
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Anxiolytics
Strategy for treatmentReduce anxiety without causing sedation.
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Anxiolytics
1) Benzodiazepines (BZDs).2) Barbiturates (BARBs).
3) 5-HT1A receptor agonists.
4) 5-HT2A, 5-HT2C & 5-HT3 receptor
antagonists.
If ANS symptoms are prominent:
-Adrenoreceptor antagonists.
2-AR agonists (clonidine).www.freelivedoctor.com
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Anxiolytics
Other Drugs with anxiolytic activity. TCAs (Fluvoxamine). Used for Obsessive
compulsive Disorder.
MAOIs. Used in panic attacks.Antihistaminic agents. Present in over the
counter medications.
Antipsychotics (Ziprasidone).
Novel drugs. (Most of these are still on clinical trials).
CCKB (e.g. CCK4).
EAA's/NMDA (e.g. HA966).www.freelivedoctor.com
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Sedative/Hypnotics
A hypnotic should produce, as much aspossible, a state of sleep that resembles
normal sleep.
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Properties of Sedative/Hypnotics in
Sleep
1) The latency of sleep onset is decreased
(time to fall asleep).
2) The duration of stage 2 NREM sleep isincreased.
3) The duration of REM sleep is decreased.
4) The duration of slow-wave sleep (whensomnambulism and nightmares occur) is
decreased.
Tolerance occurs after 1-2 weeks.www.freelivedoctor.com
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Sedative/Hypnotics
1) Benzodiazepines (BZDs):
Alprazolam, diazepam, oxacepam, triazolam
2) Barbiturates:
Pentobarbital, phenobarbital
3) Alcohols:
Ethanol, chloral hydrate, paraldehyde,
trichloroethanol,
4) Imidazopyridine Derivatives:Zolpidem
5) Pyrazolopyrimidine
Zaleplon www.freelivedoctor.com
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Sedative/Hypnotics
6) Propanediol carbamates:Meprobamate
7) Piperidinediones
Glutethimide8) Azaspirodecanedione
Buspirone
9) -Blockers**Propranolol
10) 2-AR partial agonist**
Clonidine www.freelivedoctor.com
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Sedative/Hypnotics
Others:
11) Antyipsychotics **
Ziprasidone12) Antidepressants **
TCAs, SSRIs13) Antihistaminic drugs **
Dephenhydraminewww.freelivedoctor.com
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Sedative/Hypnotics
All of the anxiolytics/sedative/hypnoticsshould be used only for symptomatic relief.
*************
All the drugs used alter the normal sleepcycle and should be administered only fordays or weeks, never for months.
************
USE FOR
SHORT-TERM TREATMENT
ONLY!!www.freelivedoctor.com
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Sedative/Hypnotics
Relationship betweenOlder vs Newer Drugs
Barbiturates BenzodiazepinesGlutethimide Zolpidem
Meprobamate Zaleplon
**All others differ in their effects and therapeuticuses. They do not produce general anesthesia
and do not have abuse liability.www.freelivedoctor.com
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SEDATIVE/HYPNOTICS
ANXYOLITICS
BENZODIAZEPINES BARBITURATES
GABAergic SYSTEMwww.freelivedoctor.com
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Sedative/Hypnotics
The benzodiazepines are the most
important sedative hypnotics.
Developed to avoid undesirable
effects of barbiturates (abuseliability).
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Benzodiazepines
Diazepam
Chlordiazepoxide
Triazolam
Lorazepam
Alprazolam
Clorazepate => nordiazepam
Halazepam
Clonazepam
Oxazepam
Prazepamwww.freelivedoctor.com
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Barbiturates
Phenobarbital
Pentobarbital Amobarbital
Mephobarbital
Secobarbital
Aprobarbital
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NORMAL
ANXIETY
_________ _________________SEDATION
HYPNOSISConfusion, Delirium, Ataxia
Surgical Anesthesia
COMA
DEATH
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Respiratory
Depression
Coma/
Anesthesia
Ataxia
Sedation
Anxiolytic
Anticonvulsant
DOSE
BARBS BDZs
ETOH
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Respiratory
Depression
Coma/
Anesthesia
Ataxia
Sedation
Anxiolytic
Anticonvulsant
DOSE
BARBS
BDZs
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GABAergic SYNAPSE
GABA
glutamate
glucose
Cl-
GAD
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GABA-A Receptor
Oligomeric (dgepr)
glycoprotein.
Major player in
Inhibitory Synapses.
It is a Cl-
Channel. Binding of GABA
causes the channel
to open and Cl- to
flow into the cell with
the resultant
membrane
hyperpolarization.
GABA AGONISTS
BDZs
d
g
BARBs
e
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Mechanisms of Action
1) Enhance GABAergic Transmission
frequency of openings of GABAergic
channels. Benzodiazepines
opening time of GABAergic channels.
Barbiturates
receptor affinity for GABA. BDZs and BARBS
2) Stimulation of 5-HT1A receptors.
3) Inhibit 5-HT2A, 5-HT2C, and 5-HT3 receptors.
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Patch-Clamp Recording of Single
Channel GABA Evoked Currents
From Katzung et al., 1996www.freelivedoctor.com
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Benzodiazepines
PHARMACOLOGY
BDZs potentiate GABAergic inhibition at alllevels of the neuraxis.
BDZs cause more frequent openings of theGABA-Cl- channel via membranehyperpolarization, and increased receptoraffinity for GABA.
BDZs act on BZ1 (1 and 2 subunit-containing)and BZ2 (5 subunit-containing) receptors.
May cause euphoria, impaired judgement, lossof cell control and anterograde amnesic effects.
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Pharmacokinetics of Benzodiazepines
Although BDZs are highly protein bound
(60-95%), few clinically significant
interactions.* High lipid solubility high rate of entry
into CNS rapid onset.
*The only exception is chloral hydrate and warfarin
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Lipid solubilitywww.freelivedoctor.com
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Pharmacokinetics of Benzodiazepines
Hepatic metabolism. Almost all BDZsundergo microsomal oxidation (N-
dealkylation and aliphatic hydroxylation)
and conjugation (to glucoronides). Rapid tissue redistribution long acting
long half lives and elimination half lives
(from 10 to > 100 hrs). All BDZs cross the placenta detectable
in breast milk may exert depressant
effects on the CNS of the lactating infant.www.freelivedoctor.com
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Pharmacokinetics of Benzodiazepines
Many have active metabolites with half-lives greater than the parent drug.
Prototype drug is diazepam (Valium), which
has active metabolites (desmethyl-diazepam and oxazepam) and is long
acting (t = 20-80 hr).
Differing times of onset and eliminationhalf-lives (long half-life => daytime
sedation).
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Biotransformation of Benzodiazepines
From Katzung, 1998
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Biotransformation of
Benzodiazepines
Keep in mind that with formation of activemetabolites, the kinetics of the parent drugmay not reflect the time course of the
pharmacological effect. Estazolam, oxazepam, and lorazepam,
which are directly metabolized toglucoronides have the least residual(drowsiness) effects.
All of these drugs and their metabolites areexcreted in urine.
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Properties of Benzodiazepines
BDZs have a wide margin of safety if usedfor short periods. Prolonged use may cause
dependence.
BDZs have little effect on respiratory orcardiovascular function compared to BARBS
and other sedative-hypnotics.
BDZs depress the turnover rates ofnorepinephrine (NE), dopamine (DA) and
serotonin (5-HT) in various brain nuclei.
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Side Effects of Benzodiazepines
Related primarily to the CNS depression
and include: drowsiness, excess sedation,
impaired coordination, nausea, vomiting,
confusion and memory loss. Tolerancedevelops to most of these effects.
Dependence with these drugs may
develop.
Serious withdrawal syndrome can
include convulsions and death.www.freelivedoctor.com
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Sedative/Hypnotics
They produce a pronounce, graded,
dose-dependent depression of thecentral nervous system.
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Toxicity/Overdose with
Benzodiazepines
Drug overdose is treated with flumazenil (a BDZreceptor antagonist, short half-life), but respiratoryfunction should be adequately supported and
carefully monitored.
Seizures and cardiac arrhythmias may occurfollowing flumazenil administration when BDZ are
taken with TCAs.
Flumazenil is not effective against BARBs
overdose. www.freelivedoctor.com
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Drug-Drug Interactions with BDZs
BDZ's have additive effects with other CNS
depressants (narcotics), alcohol => have agreatly reduced margin of safety.
BDZs reduce the effect of antiepileptic
drugs. Combination of anxiolytic drugs should beavoided.
Concurrent use with ODC antihistaminic andanticholinergic drugs as well as theconsumption of alcohol should be avoided.
SSRIs and oral contraceptives decrease
metabolism of BDZs.www.freelivedoctor.com
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Pharmacokinetics of Barbiturates
Rapid absorption following oraladministration.
Rapid onset of central effects.
Extensively metabolized in liver (exceptphenobarbital), however, there are noactive metabolites.
Phenobarbital is excreted unchanged.Its excretion can be increased byalkalinization of the urine.
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Pharmacokinetics of Barbiturates
In the elderly and in those with limitedhepatic function, dosages should be
reduced.
Phenobarbital and meprobamate cause
autometabolism by induction of liver
enzymes.
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Properties of Barbiturates
Mechanism of Action. They increase the duration of GABA-gated
channel openings.
At high concentrations may be GABA-mimetic.
Less selective than BDZs, they also:
Depress actions of excitatoryneurotransmitters.
Exert nonsynaptic membrane effects.www.freelivedoctor.com
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Toxicity/Overdose
Strong physiological dependence maydevelop upon long-term use.
Depression of the medullary respiratory
centers is the usual cause of death of
sedative/hypnotic overdose. Also loss of
brainstem vasomotor control and
myocardial depression.
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Toxicity/Overdose
Withdrawal is characterized by increaseanxiety, insomnia, CNS excitability andconvulsions.
Drugs with long-half lives have mildestwithdrawal (.
Drugs with quick onset of action are mostabused.
No medication against overdose withBARBs.
Contraindicated in patients with porphyria.www.freelivedoctor.com
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Sedative/Hypnotics
Tolerance and excessive rebound occur inresponse to barbiturate hypnotics.
NIGTHS OF DRUG DOSING
SLEEP
PERNIGHT
(%)
CONTROL WITHDRAWAL
NREM III and IV
REM
1 2 3
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Miscellaneous Drugs
Buspirone
Chloral hydrate
Hydroxyzine Meprobamate (Similar to BARBS)
Zolpidem (BZ1
selective)
Zaleplon (BZ1 selective)
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BUSPIRONE
Most selective anxiolytic currently available. The anxiolytic effect of this drug takes
several weeks to develop => used for GAD.
Buspirone does not have sedative effectsand does not potentiate CNS depressants.
Has a relatively high margin of safety, few
side effects and does not appear to beassociated with drug dependence.
No rebound anxiety or signs of withdrawal
when discontinued.www.freelivedoctor.com
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BUSPIRONE
Side effects: Tachycardia, palpitations,
nervousness, GI distress and
paresthesias may occur. Causes a dose-dependent pupillary
constriction.
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BUSPIRONE
Mechanism of Action:Acts as a partial agonist at the 5-HT1A
receptor presynaptically inhibiting
serotonin release. The metabolite 1-PP has 2 -AR
blocking action.
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Pharmacokinetics of BUSPIRONE
Not effective in panic disorders. Rapidly absorbed orally.
Undergoes extensive hepatic metabolism
(hydroxylation and dealkylation) to formseveral active metabolites (e.g. 1-(2-
pyrimidyl-piperazine, 1-PP)
Well tolerated by elderly, but may have slowclearance.
Analogs: Ipsapirone, gepirone, tandospirone.www.freelivedoctor.com
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Zolpidem
Structurally unrelated but as effective asBDZs.
Minimal muscle relaxing and anticonvulsant
effect.
Rapidly metabolized by liver enzymes into
inactive metabolites.
Dosage should be reduced in patients withhepatic dysfunction, the elderly and patients
taking cimetidine.www.freelivedoctor.com
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Properties of Zolpidem
Mechanism of Action:
Binds selectively to BZ1 receptors.
Facilitates GABA-mediated neuronal
inhibition.
Actions are antagonized by flumazenil
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?
NEDA 5-HT
ACh
(-)
(-)
(-)
(-)
(-)
ANXIOLYTIC ?
SEDATION ?
ANTICONVULSANT/
MUSCLE RELAXANT ?
GABA
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Properties of Other drugs.
Chloral hydrate
Is used in institutionalized patients. It
displaces warfarin (anti-coagulant) fromplasma proteins.
Extensive biotransformation.
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Properties of Other Drugs
2-Adrenoreceptor Agonists(eg. Clonidine)
Antihypertensive.
Has been used for the treatment of panicattacks.
Has been useful in suppressing anxietyduring the management of withdrawal fromnicotine and opioid analgesics.
Withdrawal from clonidine, after protracteduse, may lead to a life-threateninghypertensive crisis.
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Properties of Other Drugs
-Adrenoreceptor Antagonists(eg. Propranolol)
Use to treat some forms of anxiety,
particularly when physical (autonomic)symptoms (sweating, tremor, tachycardia)
are severe.
Adverse effects of propranolol mayinclude: lethargy, vivid dreams,
hallucinations.www.freelivedoctor.com
OTHER USES
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OTHER USES1. Generalized Anxiety Disorder
Diazepam, lorazepam, alprazolam, buspirone2. Phobic Anxiety
a. Simple phobia. BDZs
b. Social phobia. BDZs3. Panic Disorders
TCAs and MAOIs, alprazolam
4. Obsessive-Compulsive BehaviorClomipramine (TCA), SSRIs
5. Posttraumatic Stress Disorder (?)
Antidepressants, buspironewww.freelivedoctor.com
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ANXYOLITICS
Alprazolam
Chlordiazepoxide
Buspirone
Diazepam
Lorazepam
Oxazepam
Triazolam
Phenobarbital
Halazepam
Prazepam
HYPNOTICS
Chloral hydrate
Estazolam
Flurazepam
Pentobarbital
Lorazepam
Quazepam
Triazolam
Secobarbital
Temazepam
Zolpidemf li d