Optimal Performance Sedated Nervous Breakdown
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.
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.
L-Dopa. oxybutinin. www. epinephrine. Drug-Induced:
– Stimulants • Amphetamines. carbid/levodopa. meperidine diphenhydramine. – Anticholinergics\Antihistaminergics • Trihexyphenidyl. cocaine. bromocriptine. TCAs. pseudoephedrine phenylpropanolamine. – Dopaminergics • Amantadine. benztropine.Causes of Anxiety
. – Sympathomimetics • Ephedrine. caffeine.
• BDZs. other sedatives.
www.freelivedoctor.Causes of Anxiety
– Miscellaneous: • Baclofen. hallucinogens. narcotics. alcohol.com
. BARBs. indomethacin. cycloserine.
Strategy for treatment
Reduce anxiety without causing sedation.freelivedoctor.
3) 5-HT1A receptor agonists. 5-HT2C & 5-HT3 receptor antagonists. 2) Barbiturates (BARBs).freelivedoctor. 4) 5-HT2A. www.
If ANS symptoms are prominent: • ß-Adrenoreceptor antagonists.Anxiolytics
1) Benzodiazepines (BZDs).com
. • 2-AR agonists (clonidine).
(Most of these are still on clinical trials). – CCKB (e.g. – Antihistaminic agents.com – EAA's/NMDA (e. Used for Obsessive compulsive Disorder. – Antipsychotics (Ziprasidone).freelivedoctor.Anxiolytics
• Other Drugs with anxiolytic activity.
.g. – MAOIs. www. • Novel drugs. CCK4). – TCAs (Fluvoxamine). Present in over the counter medications. HA966). Used in panic attacks.
as much as possible.freelivedoctor. a state of sleep that resembles normal sleep.
• A hypnotic should produce.
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. www. 4) The duration of slow-wave sleep (when somnambulism and nightmares occur) is decreased.com
.freelivedoctor. 3) The duration of REM sleep is decreased. Tolerance occurs after 1-2 weeks.
1) Benzodiazepines (BZDs): Alprazolam.com Zaleplon
. diazepam. oxacepam. triazolam 2) Barbiturates: Pentobarbital. 4) Imidazopyridine Derivatives: Zolpidem 5) Pyrazolopyrimidine www. chloral hydrate.freelivedoctor. trichloroethanol. phenobarbital 3) Alcohols: Ethanol. paraldehyde.
6) Propanediol carbamates:
10) 2-AR partial agonist**
13) Antihistaminic drugs **
11) Antyipsychotics ** Ziprasidone 12) Antidepressants **
USE FOR SHORT-TERM TREATMENT ONLY!!
All of the anxiolytics/sedative/hypnotics should be used only for symptomatic relief. never for months.freelivedoctor. ************* All the drugs used alter the normal sleep cycle and should be administered only for days or weeks.
They do not produce general anesthesia www.
Relationship between Older vs Newer Drugs
Barbiturates Glutethimide Meprobamate
Benzodiazepines Zolpidem Zaleplon
**All others differ in their effects and therapeutic
uses.freelivedoctor.com and do not have abuse liability.
The benzodiazepines are the most important sedative hypnotics.
Developed to avoid undesirable effects of barbiturates (abuse liability).
• Diazepam • Chlordiazepoxide • Triazolam • Lorazepam • Alprazolam • Clorazepate => nordiazepam • Halazepam • Clonazepam • Oxazepam • www.com Prazepam
• • • • • • Phenobarbital Pentobarbital Amobarbital Mephobarbital Secobarbital Aprobarbital
Respiratory Depression BARBS Coma/ Anesthesia Ataxia ETOH Sedation Anticonvulsant Anxiolytic BDZs
.Respiratory Depression Coma/ Anesthesia Ataxia Sedation Anticonvulsant Anxiolytic
glutamate GAD GABA
• Binding of GABA g causes the channel to open and Cl to d flow into the cell with e the resultant membrane www.Channel.freelivedoctor. GABA AGONISTS • It is a Cl. BDZs • Major player in BARBs Inhibitory Synapses.com hyperpolarization.
• Oligomeric (dgepr) glycoprotein.
BDZs and BARBS
2) Stimulation of 5-HT1A receptors. Barbiturates receptor affinity for GABA. 3) Inhibit 5-HT2A. Benzodiazepines opening time of GABAergic channels. and 5-HT3 receptors.freelivedoctor.Mechanisms of Action
1) Enhance GABAergic Transmission
frequency of openings of GABAergic channels.com
Patch-Clamp Recording of Single Channel GABA Evoked Currents
www.freelivedoctor.com From Katzung et al.. 1996
com anterograde amnesic effects. impaired judgement.freelivedoctor.Benzodiazepines
PHARMACOLOGY • BDZs potentiate GABAergic inhibition at all levels of the neuraxis. and increased receptor affinity for GABA. • BDZs act on BZ1 (1 and 2 subunit-containing) and BZ2 (5 subunit-containing) receptors.
. loss of cell control andwww. • May cause euphoria.channel via membrane hyperpolarization. • BDZs cause more frequent openings of the GABA-Cl.
few clinically significant interactions.freelivedoctor.com
*The only exception is chloral hydrate and warfarin
www.* High lipid solubility high rate of entry into CNS rapid onset.Pharmacokinetics of Benzodiazepines
Although BDZs are highly protein bound (60-95%).
Lipid solubility www.freelivedoctor.com
Rapid tissue redistribution long acting long half lives and elimination half lives (from 10 to > 100 hrs).com
. Almost all BDZs undergo microsomal oxidation (Ndealkylation and aliphatic hydroxylation) and conjugation (to glucoronides). www.Pharmacokinetics of Benzodiazepines
Hepatic metabolism.freelivedoctor. All BDZs cross the placenta detectable in breast milk may exert depressant effects on the CNS of the lactating infant.
. which has active metabolites (desmethyldiazepam and oxazepam) and is long acting (t½ = 20-80 hr). Prototype drug is diazepam (Valium). Differing times of onset and elimination half-lives (long half-life => daytime sedation).Pharmacokinetics of Benzodiazepines
Many have active metabolites with halflives greater than the parent drug.
Biotransformation of Benzodiazepines
From Katzung. 1998
the kinetics of the parent drug may not reflect the time course of the pharmacological effect. oxazepam.
www. and lorazepam. • All of these drugs and their metabolites are excreted in urine. • Estazolam. which are directly metabolized to glucoronides have the least residual (drowsiness) effects.com
.freelivedoctor.Biotransformation of Benzodiazepines
• Keep in mind that with formation of active metabolites.
Properties of Benzodiazepines
• BDZs have a wide margin of safety if used for short periods.
www. • BDZs depress the turnover rates of norepinephrine (NE).freelivedoctor. Prolonged use may cause dependence. dopamine (DA) and serotonin (5-HT) in various brain nuclei. • BDZs have little effect on respiratory or cardiovascular function compared to BARBS and other sedative-hypnotics.com
• Dependence with these drugs may develop. Tolerance develops to most of these effects. • Serious withdrawal syndrome can include convulsions and death.com
. excess sedation. nausea.freelivedoctor.Side Effects of Benzodiazepines
• Related primarily to the CNS depression and include: drowsiness. impaired coordination. confusion and memory loss. www. vomiting.
. dose-dependent depression of the central nervous system. graded.
• They produce a pronounce.
.Toxicity/Overdose with Benzodiazepines
• Drug overdose is treated with flumazenil (a BDZ receptor antagonist. but respiratory function should be adequately supported and carefully monitored. short half-life).
• Seizures and cardiac arrhythmias may occur following flumazenil administration when BDZ are taken with TCAs. • Flumazenil is not effective against BARBs overdose.
.Drug-Drug Interactions with BDZs
• BDZ's have additive effects with other CNS depressants (narcotics). • BDZs reduce the effect of antiepileptic drugs. • Combination of anxiolytic drugs should be avoided. • SSRI’s and oral contraceptives decrease www. • Concurrent use with ODC antihistaminic and anticholinergic drugs as well as the consumption of alcohol should be avoided. alcohol => have a greatly reduced margin of safety.com metabolism of BDZs.
• Rapid onset of central effects.
www.freelivedoctor. • Extensively metabolized in liver (except phenobarbital). however. there are no active metabolites. • Phenobarbital is excreted unchanged.com
.Pharmacokinetics of Barbiturates
• Rapid absorption following oral administration. Its excretion can be increased by alkalinization of the urine.
.Pharmacokinetics of Barbiturates
• In the elderly and in those with limited hepatic function. • Phenobarbital and meprobamate cause autometabolism by induction of liver enzymes. dosages should be reduced.
• They increase the duration of GABA-gated channel openings. • At high concentrations may be GABAmimetic. www.freelivedoctor.Properties of Barbiturates
Mechanism of Action. • Exert nonsynaptic membrane effects. Less selective than BDZs.com
. they also: • Depress actions of excitatory neurotransmitters.
www. • Depression of the medullary respiratory centers is the usual cause of death of sedative/hypnotic overdose.freelivedoctor. Also loss of brainstem vasomotor control and myocardial depression.Toxicity/Overdose
• Strong physiological dependence may develop upon long-term use.
• Withdrawal is characterized by increase anxiety.freelivedoctor. • Contraindicated in patients with porphyria. • No medication against overdose with BARBs.
www. • Drugs with long-half lives have mildest withdrawal (.com
. • Drugs with quick onset of action are most abused. insomnia. CNS excitability and convulsions.
Tolerance and excessive rebound occur in response to barbiturate hypnotics.freelivedoctor.com NIGTHS OF DRUG DOSING
SLEEP PER NIGHT (%)
REM NREM III and IV
1 2 3
• • • • • • Buspirone Chloral hydrate Hydroxyzine Meprobamate (Similar to BARBS) Zolpidem (BZ1 selective) Zaleplon (BZ1 selective)
• Most selective anxiolytic currently available. few side effects and does not appear to be associated with drug dependence. • The anxiolytic effect of this drug takes several weeks to develop => used for GAD. • Has a relatively high margin of safety. • Buspirone does not have sedative effects and does not potentiate CNS depressants.freelivedoctor. • No rebound anxiety or signs of withdrawal www.com when discontinued.
Side effects: • Tachycardia.com
. palpitations. • Causes a dose-dependent pupillary constriction.freelivedoctor. GI distress and paresthesias may occur. nervousness.
• The metabolite 1-PP has 2 -AR blocking action.freelivedoctor.
Mechanism of Action: • Acts as a partial agonist at the 5-HT1A receptor presynaptically inhibiting serotonin release.
.Pharmacokinetics of BUSPIRONE
• Not effective in panic disorders. gepirone.g.
• Analogs: Ipsapirone. tandospirone. but may have slow clearance. • Undergoes extensive hepatic metabolism (hydroxylation and dealkylation) to form several active metabolites (e. 1-(2pyrimidyl-piperazine. 1-PP) • Well tolerated by elderly. • Rapidly absorbed orally.
the elderly and patients taking cimetidine. • Rapidly metabolized by liver enzymes into inactive metabolites.Zolpidem
• Structurally unrelated but as effective as BDZs.
www. • Minimal muscle relaxing and anticonvulsant effect.freelivedoctor. • Dosage should be reduced in patients with hepatic dysfunction.com
Properties of Zolpidem
Mechanism of Action:
• Binds selectively to BZ1 receptors. • Facilitates GABA-mediated neuronal inhibition.
• Actions are antagonized by flumazenil
(-) (-) (-) (-) (-)
NE DA 5-HT ACh
ANTICONVULSANT/ MUSCLE RELAXANT ?
• Chloral hydrate • Is used in institutionalized patients.freelivedoctor.
www. It displaces warfarin (anti-coagulant) from plasma proteins.Properties of Other drugs. • Extensive biotransformation.
• Withdrawal from clonidine.com
. Clonidine) • Antihypertensive.Properties of Other Drugs
2-Adrenoreceptor Agonists (eg.
www. • Has been used for the treatment of panic attacks. after protracted use.freelivedoctor. • Has been useful in suppressing anxiety during the management of withdrawal from nicotine and opioid analgesics. may lead to a life-threatening hypertensive crisis.
vivid dreams. particularly when physical (autonomic) symptoms (sweating. hallucinations. tremor.Properties of Other Drugs
-Adrenoreceptor Antagonists (eg. tachycardia) are severe. • Adverse effects of propranolol may include: lethargy.freelivedoctor.
• Use to treat some forms of anxiety.com
Posttraumatic Stress Disorder (?)
Antidepressants. SSRI’s 5. lorazepam. alprazolam. Obsessive-Compulsive Behavior Clomipramine (TCA). Panic Disorders
TCAs and MAOIs.com
.freelivedoctor. Generalized Anxiety Disorder Diazepam. Phobic Anxiety
a. Simple phobia. BDZs
3. buspirone 2.OTHER USES
1. buspirone www. BDZs b. Social phobia. alprazolam
Alprazolam Chlordiazepoxide Buspirone Diazepam Lorazepam Oxazepam Triazolam Phenobarbital Halazepam Prazepam
Chloral hydrate Estazolam Flurazepam Pentobarbital Lorazepam Quazepam Triazolam Secobarbital Temazepam Zolpidem