SEDATIVE/HYPNOTICSANXIOLYTICS

Martha I. Dávila-García, Ph.D.

Howard University

Department of Pharmacology

Sedated

Optimal

Performance

NervousBreakdown

Per

form

ance

AnxietyGOAL

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.

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).

Causes of Anxiety

1). Medical:

a) Respiratory

b) Endocrine

c) Cardiovascular

d) Metabolic

e) Neurologic.

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.

Causes of Anxiety

– Miscellaneous:

• Baclofen, cycloserine, hallucinogens, indomethacin.

3). Drug Withdrawal:• BDZs, narcotics, BARBs, other

sedatives, alcohol.

Anxiolytics

Strategy for treatmentReduce anxiety without causing sedation.

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).

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).

Sedative/Hypnotics

• A hypnotic should produce, as much as possible, a state of sleep that resembles normal sleep.

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.

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

Sedative/Hypnotics6) Propanediol carbamates:

Meprobamate

7) PiperidinedionesGlutethimide

8) AzaspirodecanedioneBuspirone

9) -Blockers**Propranolol

10) 2-AR partial agonist**Clonidine

Sedative/Hypnotics

Others:11) Antyipsychotics **

Ziprasidone

12) Antidepressants **

TCAs, SSRIs

13) Antihistaminic drugs **

Dephenhydramine

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!!

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.

SEDATIVE/HYPNOTICSANXYOLITICS

BEN ZO D IAZEPIN ES BAR BITU R ATES

GABAergic SYSTEM

Sedative/Hypnotics

The benzodiazepines are the most important sedative hypnotics.

Developed to avoid undesirable effects of barbiturates (abuse liability).

Benzodiazepines• Diazepam• Chlordiazepoxide• Triazolam• Lorazepam• Alprazolam

• Clorazepate => nordiazepam• Halazepam

• Clonazepam• Oxazepam• Prazepam

Barbiturates

• Phenobarbital

• Pentobarbital

• Amobarbital

• Mephobarbital

• Secobarbital

• Aprobarbital

NORMAL ANXIETY

_________ _________________SEDATION

HYPNOSIS Confusion, Delirium,

Ataxia

Surgical

Anesthesia

COMA

DEATH

Respiratory

Depression

Coma/

Anesthesia

Ataxia

Sedation

Anxiolytic

Anticonvulsant

DOSE

RE

SP

ON

SE

BARBSBDZs

ETOH

Respiratory

Depression

Coma/

Anesthesia

Ataxia

Sedation

Anxiolytic

Anticonvulsant

DOSE

RE

SP

ON

SE

BARBS

BDZs

GABAergic SYNAPSE

GABA

glutamate

glucose

Cl-

GAD

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

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.

Patch-Clamp Recording of Single Channel GABA Evoked Currents

From Katzung et al., 1996

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.

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

CN

S E

ffec

ts(R

ate

of O

nset

)

Lipid solubility

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.

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).

Biotransformation of Benzodiazepines

From Katzung, 1998

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.

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.

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.

Sedative/Hypnotics

• They produce a pronounce, graded, dose-dependent depression of the central nervous system.

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.

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.

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.

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.

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.

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.

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.

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

Miscellaneous Drugs

• Buspirone

• Chloral hydrate

• Hydroxyzine

• Meprobamate (Similar to BARBS)

• Zolpidem (BZ1 selective)

• Zaleplon (BZ1 selective)

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.

BUSPIRONE

Side effects:

• Tachycardia, palpitations, nervousness, GI distress and paresthesias may occur.

• Causes a dose-dependent pupillary constriction.

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.

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.

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.

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

(-)

(-)

(-)

(-)

(-)

ANXIOLYTIC ?SEDATION ?

ANTICONVULSANT/

MUSCLE RELAXANT ?

GABA

Properties of Other drugs.

• Chloral hydrate

• Is used in institutionalized patients. It displaces warfarin (anti-coagulant) from plasma proteins.

• Extensive biotransformation.

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.

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.

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

ANXYOLITICSAlprazolam

Chlordiazepoxide

Buspirone

Diazepam

Lorazepam

Oxazepam

Triazolam

Phenobarbital

Halazepam

Prazepam

HYPNOTICSChloral hydrate

Estazolam

Flurazepam

Pentobarbital

Lorazepam

Quazepam

Triazolam

Secobarbital

Temazepam

Zolpidem

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.