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Transcript of SEDATIVE/HYPNOTICS ANXIOLYTICS Martha I. Dávila-García, Ph.D. Howard University Department of...
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SEDATIVE/HYPNOTICSANXIOLYTICS
Martha I. Dávila-García, Ph.D.
Howard University
Department of Pharmacology
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Sedated
Optimal
Performance
NervousBreakdown
Per
form
ance
AnxietyGOAL
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Manifestations of anxiety:
• Verbal complaints. The patient says he/she is anxious, nervous, edgy.
• Somatic and autonomic effects. The patient is 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 suffering from GAD have general symptoms of motor tension, autonomic hyperactivity, etc. for at least one 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 of GAD.
Obsessive-compulsive behaviors: These patients show repetitive ideas (obsessions) and behaviors (compulsions).
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Causes of Anxiety
1). Medical:
a) Respiratory
b) Endocrine
c) Cardiovascular
d) Metabolic
e) Neurologic.
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Causes of Anxiety2). Drug-Induced:
– Stimulants• Amphetamines, cocaine, TCAs, caffeine.
– Sympathomimetics• Ephedrine, epinephrine, pseudoephedrine
phenylpropanolamine.– Anticholinergics\Antihistaminergics
• Trihexyphenidyl, benztropine, meperidine diphenhydramine, oxybutinin.
– Dopaminergics• Amantadine, bromocriptine, L-Dopa,
carbid/levodopa.
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Causes of Anxiety
– Miscellaneous:
• Baclofen, cycloserine, hallucinogens, indomethacin.
3). Drug Withdrawal:• BDZs, narcotics, BARBs, other
sedatives, 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:• ß-Adrenoreceptor antagonists. 2-AR agonists (clonidine).
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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).
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Sedative/Hypnotics
• A hypnotic should produce, as much as possible, 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 is increased.
3) The duration of REM sleep is decreased.
4) The duration of slow-wave sleep (when somnambulism and nightmares occur) is decreased.
Tolerance occurs after 1-2 weeks.
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Sedative/Hypnotics1) Benzodiazepines (BZDs):
Alprazolam, diazepam, oxazepam, triazolam
2) Barbiturates:
Pentobarbital, phenobarbital
3) Alcohols:
Ethanol, chloral hydrate, paraldehyde, trichloroethanol,
4) Imidazopyridine Derivatives:
Zolpidem
5) Pyrazolopyrimidine
Zaleplon
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Sedative/Hypnotics6) Propanediol carbamates:
Meprobamate
7) PiperidinedionesGlutethimide
8) AzaspirodecanedioneBuspirone
9) -Blockers**Propranolol
10) 2-AR partial agonist**Clonidine
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Sedative/Hypnotics
Others:11) Antyipsychotics **
Ziprasidone
12) Antidepressants **
TCAs, SSRIs
13) Antihistaminic drugs **
Dephenhydramine
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Sedative/Hypnotics
All of the anxiolytics/sedative/hypnotics should be used only for symptomatic relief.
************* All the drugs used alter the normal sleep
cycle and should be administered only for days or weeks, never for months.
************
USE FORSHORT-TERM TREATMENT
ONLY!!
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Sedative/HypnoticsRelationship between Older vs Newer Drugs
Barbiturates BenzodiazepinesGlutethimide ZolpidemMeprobamate Zaleplon
**All others differ in their effects and therapeutic uses. They do not produce general anesthesia and do not have abuse liability.
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SEDATIVE/HYPNOTICSANXYOLITICS
BEN ZO D IAZEPIN ES BAR BITU R ATES
GABAergic SYSTEM
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Sedative/Hypnotics
The benzodiazepines are the most important sedative hypnotics.
Developed to avoid undesirable effects of barbiturates (abuse liability).
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Benzodiazepines• Diazepam• Chlordiazepoxide• Triazolam• Lorazepam• Alprazolam
• Clorazepate => nordiazepam• Halazepam
• Clonazepam• Oxazepam• Prazepam
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Barbiturates
• Phenobarbital
• Pentobarbital
• Amobarbital
• Mephobarbital
• Secobarbital
• Aprobarbital
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NORMAL ANXIETY
_________ _________________SEDATION
HYPNOSIS Confusion, Delirium,
Ataxia
Surgical
Anesthesia
COMA
DEATH
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Respiratory
Depression
Coma/
Anesthesia
Ataxia
Sedation
Anxiolytic
Anticonvulsant
DOSE
RE
SP
ON
SE
BARBSBDZs
ETOH
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Respiratory
Depression
Coma/
Anesthesia
Ataxia
Sedation
Anxiolytic
Anticonvulsant
DOSE
RE
SP
ON
SE
BARBS
BDZs
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GABAergic SYNAPSE
GABA
glutamate
glucose
Cl-
GAD
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GABA-A Receptor• Oligomeric
(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
BARBs
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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., 1996
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Benzodiazepines
PHARMACOLOGY• BDZs potentiate GABAergic inhibition at all
levels of the neuraxis.• BDZs cause more frequent openings of the
GABA-Cl- channel via membrane hyperpolarization, and increased receptor affinity for GABA.
• BDZs act on BZ1 (1 and 2 subunit-containing) and BZ2 (5 subunit-containing) receptors.
• May cause euphoria, impaired judgement, loss of 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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CN
S E
ffec
ts(R
ate
of O
nset
)
Lipid solubility
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Pharmacokinetics of Benzodiazepines
Hepatic metabolism. Almost all BDZs undergo 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.
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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 (t½ = 20-80 hr).
Differing times of onset and elimination half-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 active metabolites, the kinetics of the parent drug may not reflect the time course of the pharmacological effect.
• Estazolam, oxazepam, and lorazepam, which are directly metabolized to glucoronides have the least residual (drowsiness) effects.
• All of these drugs and their metabolites are excreted in urine.
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Properties of Benzodiazepines
• BDZs have a wide margin of safety if used for short periods. Prolonged use may cause dependence.
• BDZs have little effect on respiratory or cardiovascular function compared to BARBS and other sedative-hypnotics.
• BDZs depress the turnover rates of norepinephrine (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. Tolerance develops to most of these effects.
• Dependence with these drugs may develop.
• Serious withdrawal syndrome can include convulsions and death.
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Sedative/Hypnotics
• They produce a pronounce, graded, dose-dependent depression of the central nervous system.
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Toxicity/Overdose with Benzodiazepines
• Drug overdose is treated with flumazenil (a BDZ receptor antagonist, short half-life), but respiratory function should be adequately supported and carefully monitored.
• Seizures and cardiac arrhythmias may occur following flumazenil administration when BDZ are taken with TCAs.
• Flumazenil is not effective against BARBs overdose.
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Drug-Drug Interactions with BDZs• BDZ's have additive effects with other CNS
depressants (narcotics), alcohol => have a greatly reduced margin of safety.
• BDZs reduce the effect of antiepileptic drugs.
• Combination of anxiolytic drugs should be avoided.
• Concurrent use with ODC antihistaminic and anticholinergic drugs as well as the consumption of alcohol should be avoided.
• SSRI’s and oral contraceptives decrease metabolism of BDZs.
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Pharmacokinetics of Barbiturates
• Rapid absorption following oral administration.
• Rapid onset of central effects.• Extensively metabolized in liver (except
phenobarbital), however, there are no active metabolites.
• Phenobarbital is excreted unchanged. Its excretion can be increased by alkalinization of the urine.
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Pharmacokinetics of Barbiturates
• In the elderly and in those with limited hepatic 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 excitatory
neurotransmitters.• Exert nonsynaptic membrane effects.
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Toxicity/Overdose
• Strong physiological dependence may develop 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 increase anxiety, insomnia, CNS excitability and convulsions.
• Drugs with long-half lives have mildest withdrawal (.
• Drugs with quick onset of action are most abused.
• No medication against overdose with BARBs.
• Contraindicated in patients with porphyria.
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Sedative/Hypnotics
Tolerance and excessive rebound occur in response to barbiturate hypnotics.
NIGTHS OF DRUG DOSING
SL
EE
P P
ER
NIG
HT
(%)
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 effects and does not potentiate CNS depressants.
• Has a relatively high margin of safety, few side effects and does not appear to be associated with drug dependence.
• No rebound anxiety or signs of withdrawal when discontinued.
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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 form several active metabolites (e.g. 1-(2-pyrimidyl-piperazine, 1-PP)
• Well tolerated by elderly, but may have slow clearance.
• Analogs: Ipsapirone, gepirone, tandospirone.
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Zolpidem
• Structurally unrelated but as effective as BDZs.
• Minimal muscle relaxing and anticonvulsant effect.
• Rapidly metabolized by liver enzymes into inactive metabolites.
• Dosage should be reduced in patients with hepatic dysfunction, the elderly and patients taking cimetidine.
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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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?NE
DA 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) from plasma proteins.
• Extensive biotransformation.
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Properties of Other Drugs2-Adrenoreceptor Agonists (eg. Clonidine)
• Antihypertensive.• Has been used for the treatment of panic
attacks.• Has been useful in suppressing anxiety
during the management of withdrawal from nicotine and opioid analgesics.
• Withdrawal from clonidine, after protracted use, may lead to a life-threatening hypertensive 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 may include: lethargy, vivid dreams, hallucinations.
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OTHER USES1. Generalized Anxiety Disorder
Diazepam, lorazepam, alprazolam, buspirone 2. Phobic Anxiety
a. Simple phobia. BDZsb. Social phobia. BDZs
3. Panic DisordersTCAs and MAOIs, alprazolam
4. Obsessive-Compulsive BehaviorClomipramine (TCA), SSRI’s
5. Posttraumatic Stress Disorder (?)Antidepressants, buspirone
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ANXYOLITICSAlprazolam
Chlordiazepoxide
Buspirone
Diazepam
Lorazepam
Oxazepam
Triazolam
Phenobarbital
Halazepam
Prazepam
HYPNOTICSChloral hydrate
Estazolam
Flurazepam
Pentobarbital
Lorazepam
Quazepam
Triazolam
Secobarbital
Temazepam
Zolpidem
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References:• Katzung, B.G. (2001) Basic and Clinical
Pharmacology. 7th ed. Appleton and Lange. Stamford, CT.
• Brody, T.M., Larner,J., and Minneman, K.P. (1998) Human Pharmacology: Molecular to Clinical. 2nd ed. Mosby-Year Book Inc. St. Louis, Missouri.
• Rang, H.P. et al. (1995) Pharmacology . Churchill Livingston. NY., N.Y.
• Harman, J.G. et al. (1996) Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. McGraw Hill.