SEDATIVE/HYPNOTICSANXIOLYTICS
www.freelivedoctor.com
Sedated
Optimal
Performance
NervousBreakdown
Per
form
ance
AnxietyGOALwww.freelivedoctor.com
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.
www.freelivedoctor.com
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). www.freelivedoctor.com
Causes of Anxiety
1). Medical:
a) Respiratory
b) Endocrine
c) Cardiovascular
d) Metabolic
e) Neurologic.
www.freelivedoctor.com
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.www.freelivedoctor.com
Causes of Anxiety
– Miscellaneous:
• Baclofen, cycloserine, hallucinogens, indomethacin.
3). Drug Withdrawal:• BDZs, narcotics, BARBs, other
sedatives, alcohol.
www.freelivedoctor.com
Anxiolytics
Strategy for treatmentReduce anxiety without causing sedation.
www.freelivedoctor.com
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).www.freelivedoctor.com
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
Sedative/Hypnotics• A hypnotic should produce, as much as
possible, a state of sleep that resembles normal sleep.
www.freelivedoctor.com
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.www.freelivedoctor.com
Sedative/Hypnotics1) 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
Sedative/Hypnotics6) Propanediol carbamates:
Meprobamate
7) PiperidinedionesGlutethimide
8) AzaspirodecanedioneBuspirone
9) -Blockers**Propranolol
10) 2-AR partial agonist**Clonidine www.freelivedoctor.com
Sedative/Hypnotics
Others:11) Antyipsychotics **
Ziprasidone
12) Antidepressants **
TCAs, SSRIs
13) Antihistaminic drugs **
Dephenhydraminewww.freelivedoctor.com
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!! www.freelivedoctor.com
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.www.freelivedoctor.com
SEDATIVE/HYPNOTICSANXYOLITICS
BEN ZO D IAZEPIN ES BAR BITU R ATES
GABAergic SYSTEMwww.freelivedoctor.com
Sedative/Hypnotics
The benzodiazepines are the most important sedative hypnotics.
Developed to avoid undesirable effects of barbiturates (abuse liability).
www.freelivedoctor.com
Benzodiazepines• Diazepam• Chlordiazepoxide• Triazolam• Lorazepam• Alprazolam
• Clorazepate => nordiazepam• Halazepam
• Clonazepam• Oxazepam• Prazepam
www.freelivedoctor.com
Barbiturates
• Phenobarbital
• Pentobarbital
• Amobarbital
• Mephobarbital
• Secobarbital
• Aprobarbitalwww.freelivedoctor.com
NORMAL ANXIETY
_________ _________________SEDATION
HYPNOSIS Confusion, Delirium,
Ataxia
Surgical
Anesthesia
COMA
DEATH www.freelivedoctor.com
Respiratory
Depression
Coma/
Anesthesia
Ataxia
Sedation
Anxiolytic
Anticonvulsant
DOSE
RE
SP
ON
SE
BARBSBDZs
ETOH
www.freelivedoctor.com
Respiratory
Depression
Coma/
Anesthesia
Ataxia
Sedation
Anxiolytic
Anticonvulsant
DOSE
RE
SP
ON
SE
BARBS
BDZs
www.freelivedoctor.com
GABAergic SYNAPSE
GABA
glutamate
glucose
Cl-
GAD
www.freelivedoctor.com
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
www.freelivedoctor.com
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.
www.freelivedoctor.com
Patch-Clamp Recording of Single Channel GABA Evoked Currents
From Katzung et al., 1996www.freelivedoctor.com
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.www.freelivedoctor.com
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
www.freelivedoctor.com
CN
S E
ffec
ts(R
ate
of O
nset
)
Lipid solubilitywww.freelivedoctor.com
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.www.freelivedoctor.com
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).
www.freelivedoctor.com
Biotransformation of Benzodiazepines
From Katzung, 1998www.freelivedoctor.com
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.
www.freelivedoctor.com
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.
www.freelivedoctor.com
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.
www.freelivedoctor.com
Sedative/Hypnotics
• They produce a pronounce, graded, dose-dependent depression of the central nervous system.
www.freelivedoctor.com
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. www.freelivedoctor.com
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.www.freelivedoctor.com
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.
www.freelivedoctor.com
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.
www.freelivedoctor.com
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.
www.freelivedoctor.com
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.
www.freelivedoctor.com
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.www.freelivedoctor.com
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 3www.freelivedoctor.com
Miscellaneous Drugs
• Buspirone
• Chloral hydrate
• Hydroxyzine
• Meprobamate (Similar to BARBS)
• Zolpidem (BZ1 selective)
• Zaleplon (BZ1 selective)
www.freelivedoctor.com
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.www.freelivedoctor.com
BUSPIRONE
Side effects:
• Tachycardia, palpitations, nervousness, GI distress and paresthesias may occur.
• Causes a dose-dependent pupillary constriction.
www.freelivedoctor.com
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.
www.freelivedoctor.com
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.www.freelivedoctor.com
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.
www.freelivedoctor.com
Properties of Zolpidem
Mechanism of Action:• Binds selectively to BZ1 receptors.
• Facilitates GABA-mediated neuronal inhibition.
• Actions are antagonized by flumazenil
www.freelivedoctor.com
?NE
DA 5-HT
ACh
(-)
(-)
(-)
(-)
(-)
ANXIOLYTIC ?SEDATION ?
ANTICONVULSANT/
MUSCLE RELAXANT ?
GABA
www.freelivedoctor.com
Properties of Other drugs.
• Chloral hydrate
• Is used in institutionalized patients. It displaces warfarin (anti-coagulant) from plasma proteins.
• Extensive biotransformation.
www.freelivedoctor.com
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.
www.freelivedoctor.com
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.
www.freelivedoctor.com
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
www.freelivedoctor.com
ANXYOLITICSAlprazolam
Chlordiazepoxide
Buspirone
Diazepam
Lorazepam
Oxazepam
Triazolam
Phenobarbital
Halazepam
Prazepam
HYPNOTICSChloral hydrate
Estazolam
Flurazepam
Pentobarbital
Lorazepam
Quazepam
Triazolam
Secobarbital
Temazepam
Zolpidemwww.freelivedoctor.com
Top Related