Martha I. Dávila-García, Ph.D. Howard University Department of Pharmacology
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.
Agoraphobia. etc. Phobic anxiety: Simple phobias.
Generalized anxiety disorder (GAD): People suffering from GAD have general symptoms of motor tension. for at least one month. Panic disorders: Characterized by acute attacks of fear as compared to the chronic presentation of GAD. autonomic hyperactivity. Social phobias. etc. fear of animals. Obsessive-compulsive behaviors: These patients show repetitive ideas (obsessions) and behaviors (compulsions).
Medical: a) Respiratory b) Endocrine c) Cardiovascular d) Metabolic e) Neurologic.
.Causes of Anxiety
caffeine. L-Dopa.Causes of Anxiety
. TCAs. pseudoephedrine phenylpropanolamine. – Sympathomimetics • Ephedrine. oxybutinin. bromocriptine. epinephrine. cocaine. – Anticholinergics\Antihistaminergics • Trihexyphenidyl. meperidine diphenhydramine. benztropine. Drug-Induced:
– Stimulants • Amphetamines. – Dopaminergics • Amantadine. carbid/levodopa.
alcohol. BARBs. indomethacin. hallucinogens.
3). Drug Withdrawal:
• BDZs. cycloserine.
.Causes of Anxiety
– Miscellaneous: • Baclofen. other sedatives. narcotics.
Strategy for treatment
Reduce anxiety without causing sedation.
5-HT2C & 5-HT3 receptor antagonists. • 2-AR agonists (clonidine).
1) Benzodiazepines (BZDs). 3) 5-HT1A receptor agonists. 4) 5-HT2A.
If ANS symptoms are prominent: • ß-Adrenoreceptor antagonists. 2) Barbiturates (BARBs).
. – EAA's/NMDA (e. Present in over the counter medications.Anxiolytics
• Other Drugs with anxiolytic activity.g. – Antihistaminic agents.g. HA966). – TCAs (Fluvoxamine). Used for Obsessive compulsive Disorder. • Novel drugs. – Antipsychotics (Ziprasidone). (Most of these are still on clinical trials). CCK4). – CCKB (e. Used in panic attacks. – MAOIs.
• A hypnotic should produce. as much as possible.
. a state of sleep that resembles normal sleep.
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.
.Properties of Sedative/Hypnotics in Sleep
1) The latency of sleep onset is decreased (time to fall asleep). Tolerance occurs after 1-2 weeks.
1) Benzodiazepines (BZDs): Alprazolam. chloral hydrate. oxacepam. trichloroethanol. phenobarbital 3) Alcohols: Ethanol. 4) Imidazopyridine Derivatives: Zolpidem 5) Pyrazolopyrimidine Zaleplon
. triazolam 2) Barbiturates: Pentobarbital. paraldehyde. diazepam.
6) Propanediol carbamates:
10) 2-AR partial agonist**
13) Antihistaminic drugs **
11) Antyipsychotics ** Ziprasidone 12) Antidepressants **
never for months. ************* All the drugs used alter the normal sleep cycle and should be administered only for days or weeks. ************
USE FOR SHORT-TERM TREATMENT ONLY!!
All of the anxiolytics/sedative/hypnotics should be used only for symptomatic relief.
Relationship between Older vs Newer Drugs
Barbiturates Glutethimide Meprobamate
Benzodiazepines Zolpidem Zaleplon
**All others differ in their effects and therapeutic
uses. They do not produce general anesthesia 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 • Prazepam
• • • • • • Phenobarbital Pentobarbital Amobarbital Mephobarbital Secobarbital Aprobarbital
Confusion. Delirium. Ataxia
Respiratory Depression BARBS Coma/ Anesthesia Ataxia ETOH Sedation Anticonvulsant Anxiolytic BDZs
Respiratory Depression Coma/ Anesthesia Ataxia Sedation Anticonvulsant Anxiolytic
glutamate GAD GABA
• Oligomeric (dgepr) glycoprotein. • Binding of GABA causes the channel to open and Cl.to flow into the cell with the resultant membrane hyperpolarization.Channel. • It is a Cl.
. • Major player in Inhibitory Synapses.
and 5-HT3 receptors.
. BDZs and BARBS
2) Stimulation of 5-HT1A receptors. 3) Inhibit 5-HT2A. Barbiturates receptor affinity for GABA. 5-HT2C. Benzodiazepines opening time of GABAergic channels.Mechanisms of Action
1) Enhance GABAergic Transmission
frequency of openings of GABAergic channels.
..Patch-Clamp Recording of Single Channel GABA Evoked Currents
From Katzung et al.
and increased receptor affinity for GABA. loss of cell control and anterograde amnesic effects.channel via membrane hyperpolarization. impaired judgement. • BDZs act on BZ1 (1 and 2 subunit-containing) and BZ2 (5 subunit-containing) receptors. • May cause euphoria.
. • BDZs cause more frequent openings of the GABA-Cl.Benzodiazepines
PHARMACOLOGY • BDZs potentiate GABAergic inhibition at all levels of the neuraxis.
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
All BDZs cross the placenta detectable in breast milk may exert depressant effects on the CNS of the lactating infant. Rapid tissue redistribution long acting long half lives and elimination half lives (from 10 to > 100 hrs).Pharmacokinetics of Benzodiazepines
. Almost all BDZs undergo microsomal oxidation (Ndealkylation and aliphatic hydroxylation) and conjugation (to glucoronides).
Prototype drug is diazepam (Valium).
. Differing times of onset and elimination half-lives (long half-life => daytime sedation). which has active metabolites (desmethyldiazepam and oxazepam) and is long acting (t½ = 20-80 hr).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. which are directly metabolized to glucoronides have the least residual (drowsiness) effects. • Estazolam.
. oxazepam. and lorazepam.Biotransformation of Benzodiazepines
• Keep in mind that with formation of active metabolites. • All of these drugs and their metabolites are excreted in urine.
• BDZs depress the turnover rates of norepinephrine (NE).
. 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.Properties of Benzodiazepines
• BDZs have a wide margin of safety if used for short periods.
. confusion and memory loss. impaired coordination. vomiting. • Dependence with these drugs may develop.Side Effects of Benzodiazepines
• Related primarily to the CNS depression and include: drowsiness. nausea. excess sedation. Tolerance develops to most of these effects. • Serious withdrawal syndrome can include convulsions and death.
• They produce a pronounce.
. dose-dependent depression of the central nervous system.
. • Flumazenil is not effective against BARBs overdose. short half-life). but respiratory function should be adequately supported and carefully monitored.Toxicity/Overdose with Benzodiazepines
• Drug overdose is treated with flumazenil (a BDZ receptor antagonist.
• Seizures and cardiac arrhythmias may occur following flumazenil administration when BDZ are taken with TCAs.
• SSRI’s and oral contraceptives decrease metabolism of BDZs. alcohol => have a greatly reduced margin of safety.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. • Concurrent use with ODC antihistaminic and anticholinergic drugs as well as the consumption of alcohol should be avoided.
Pharmacokinetics of Barbiturates
• Rapid absorption following oral administration. Its excretion can be increased by alkalinization of the urine. • Extensively metabolized in liver (except phenobarbital). • Phenobarbital is excreted unchanged. however.
. there are no active metabolites. • Rapid onset of central effects.
dosages should be reduced. • Phenobarbital and meprobamate cause autometabolism by induction of liver enzymes.Pharmacokinetics of Barbiturates
• In the elderly and in those with limited hepatic function.
• At high concentrations may be GABAmimetic. • Exert nonsynaptic membrane effects. Less selective than BDZs.
. • They increase the duration of GABA-gated channel openings.Properties of Barbiturates
Mechanism of Action. they also: • Depress actions of excitatory neurotransmitters.
Also loss of brainstem vasomotor control and myocardial depression.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.
• Withdrawal is characterized by increase anxiety. • Drugs with quick onset of action are most abused. • Drugs with long-half lives have mildest withdrawal (.
. • Contraindicated in patients with porphyria. insomnia. • No medication against overdose with BARBs. CNS excitability and convulsions.
SLEEP PER NIGHT (%)
REM NREM III and IV
1 2 3
NIGTHS OF DRUG DOSING
Tolerance and excessive rebound occur in response to barbiturate hypnotics.
• • • • • • Buspirone Chloral hydrate Hydroxyzine Meprobamate (Similar to BARBS) Zolpidem (BZ1 selective) Zaleplon (BZ1 selective)
few side effects and does not appear to be associated with drug dependence. • Has a relatively high margin of safety. • Buspirone does not have sedative effects and does not potentiate CNS depressants.
• Most selective anxiolytic currently available. • The anxiolytic effect of this drug takes several weeks to develop => used for GAD. • No rebound anxiety or signs of withdrawal when discontinued.
• Causes a dose-dependent pupillary constriction. nervousness. GI distress and paresthesias may occur. palpitations.BUSPIRONE
Side effects: • Tachycardia.
• The metabolite 1-PP has 2 -AR blocking action.
Mechanism of Action: • Acts as a partial agonist at the 5-HT1A receptor presynaptically inhibiting serotonin release.
• Rapidly absorbed orally.
.Pharmacokinetics of BUSPIRONE
• Not effective in panic disorders. • Undergoes extensive hepatic metabolism (hydroxylation and dealkylation) to form several active metabolites (e. 1-(2pyrimidyl-piperazine.
• Analogs: Ipsapirone.g. but may have slow clearance. 1-PP) • Well tolerated by elderly. gepirone. tandospirone.
the elderly and patients taking cimetidine.
. • Rapidly metabolized by liver enzymes into inactive metabolites.Zolpidem
• Structurally unrelated but as effective as BDZs. • Dosage should be reduced in patients with hepatic dysfunction. • Minimal muscle relaxing and anticonvulsant effect.
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 ?
. • Extensive biotransformation.
• Chloral hydrate • Is used in institutionalized patients.Properties of Other drugs. It displaces warfarin (anti-coagulant) from plasma proteins.
after protracted use.
. Clonidine) • Antihypertensive. • Has been useful in suppressing anxiety during the management of withdrawal from nicotine and opioid analgesics.Properties of Other Drugs
2-Adrenoreceptor Agonists (eg. • Has been used for the treatment of panic attacks. • Withdrawal from clonidine. may lead to a life-threatening hypertensive crisis.
tachycardia) are severe. • Adverse effects of propranolol may include: lethargy. hallucinations. particularly when physical (autonomic) symptoms (sweating.
• Use to treat some forms of anxiety. vivid dreams. tremor.Properties of Other Drugs
-Adrenoreceptor Antagonists (eg.
Generalized Anxiety Disorder Diazepam. BDZs b. alprazolam. SSRI’s 5. buspirone
3. Simple phobia. Panic Disorders
TCAs and MAOIs. alprazolam
4. Posttraumatic Stress Disorder (?)
Antidepressants. Obsessive-Compulsive Behavior Clomipramine (TCA). Phobic Anxiety
a. buspirone 2. lorazepam. Social phobia.
Alprazolam Chlordiazepoxide Buspirone Diazepam Lorazepam Oxazepam Triazolam Phenobarbital Halazepam Prazepam
Chloral hydrate Estazolam Flurazepam Pentobarbital Lorazepam Quazepam Triazolam Secobarbital Temazepam Zolpidem
7th ed. (1995) Pharmacology . 2nd ed. Churchill Livingston. and Minneman. NY. Louis.
.M.Y. CT. et al.. B. (2001) Basic and Clinical Pharmacology.G. • Harman. Larner.J.G. (1996) Goodman and Gilman's The Pharmacological Basis of Therapeutics.P. K. et al. T. J..References:
• Katzung. Missouri. H. • Rang. Stamford. N. St. Appleton and Lange. 9th ed.. Mosby-Year Book Inc.P. • Brody. McGraw Hill. (1998) Human Pharmacology: Molecular to Clinical.