An Xy Olitics Hypnotics

7/29/2019 An Xy Olitics Hypnotics

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SEDATIVE/HYPNOTICS

ANXIOLYTICS

www.freelivedoctor.com


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Sedated

Optimal

Performance

Nervous

Breakdown

Anxiety

GOALwww.freelivedoctor.com


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Manifestations of anxiety:

Verbal complaints. The patient says he/she

is anxious, nervous, edgy.

Somatic and autonomic effects. The patientis 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 sufferingfrom GAD have general symptoms of motortension, autonomic hyperactivity, etc. for at leastone 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 ofGAD.

Obsessive-compulsive behaviors: These patientsshow repetitive ideas (obsessions) and behaviors

(compulsions). www.freelivedoctor.com


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Causes of Anxiety

1). Medical:

a) Respiratory

b) Endocrinec) Cardiovascular

d) Metabolic

e) Neurologic.



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Causes of Anxiety2). Drug-Induced:

Stimulants

Amphetamines, cocaine, TCAs, caffeine.

Sympathomimetics

Ephedrine, epinephrine, pseudoephedrinephenylpropanolamine.

Anticholinergics\Antihistaminergics

Trihexyphenidyl, benztropine, meperidine

diphenhydramine, oxybutinin.

Dopaminergics

Amantadine, bromocriptine, L-Dopa,

carbid/levodopa.www.freelivedoctor.com


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Causes of Anxiety

Miscellaneous:

Baclofen, cycloserine, hallucinogens,

indomethacin.

3). Drug Withdrawal:

BDZs, narcotics, BARBs, othersedatives, 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:

-Adrenoreceptor antagonists.

2-AR agonists (clonidine).www.freelivedoctor.com


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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).www.freelivedoctor.com


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Sedative/Hypnotics

A hypnotic should produce, as much aspossible, 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 isincreased.

3) The duration of REM sleep is decreased.

4) The duration of slow-wave sleep (whensomnambulism and nightmares occur) is

decreased.

Tolerance occurs after 1-2 weeks.www.freelivedoctor.com


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Sedative/Hypnotics

1) 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


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Sedative/Hypnotics

6) Propanediol carbamates:Meprobamate

7) Piperidinediones

Glutethimide8) Azaspirodecanedione

Buspirone

9) -Blockers**Propranolol

10) 2-AR partial agonist**

Clonidine www.freelivedoctor.com


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Sedative/Hypnotics

Others:

11) Antyipsychotics **

Ziprasidone12) Antidepressants **

TCAs, SSRIs13) Antihistaminic drugs **

Dephenhydraminewww.freelivedoctor.com


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Sedative/Hypnotics

All of the anxiolytics/sedative/hypnoticsshould be used only for symptomatic relief.

*************

All the drugs used alter the normal sleepcycle and should be administered only fordays or weeks, never for months.

************

USE FOR

SHORT-TERM TREATMENT

ONLY!!www.freelivedoctor.com


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Sedative/Hypnotics

Relationship betweenOlder vs Newer Drugs

Barbiturates BenzodiazepinesGlutethimide Zolpidem

Meprobamate Zaleplon

**All others differ in their effects and therapeuticuses. They do not produce general anesthesia

and do not have abuse liability.www.freelivedoctor.com


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SEDATIVE/HYPNOTICS

ANXYOLITICS

BENZODIAZEPINES BARBITURATES

GABAergic SYSTEMwww.freelivedoctor.com


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Sedative/Hypnotics

The benzodiazepines are the most

important sedative hypnotics.

Developed to avoid undesirable

effects of barbiturates (abuseliability).



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Benzodiazepines

Diazepam

Chlordiazepoxide

Triazolam

Lorazepam

Alprazolam

Clorazepate => nordiazepam

Halazepam

Clonazepam

Oxazepam

Prazepamwww.freelivedoctor.com


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Barbiturates

Phenobarbital

Pentobarbital Amobarbital

Mephobarbital

Secobarbital

Aprobarbital



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NORMAL

ANXIETY

_________ _________________SEDATION

HYPNOSISConfusion, Delirium, Ataxia

Surgical Anesthesia

COMA

DEATH



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Respiratory

Depression

Coma/

Anesthesia

Ataxia

Sedation

Anxiolytic

Anticonvulsant

DOSE

BARBS BDZs

ETOH



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Respiratory

Depression

Coma/

Anesthesia

Ataxia

Sedation

Anxiolytic

Anticonvulsant

DOSE

BARBS

BDZs



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GABAergic SYNAPSE

GABA

glutamate

glucose

Cl-

GAD



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GABA-A Receptor

Oligomeric (dgepr)

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

d

g

BARBs

e



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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., 1996www.freelivedoctor.com


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Benzodiazepines

PHARMACOLOGY

BDZs potentiate GABAergic inhibition at alllevels of the neuraxis.

BDZs cause more frequent openings of theGABA-Cl- channel via membranehyperpolarization, and increased receptoraffinity for GABA.

BDZs act on BZ1 (1 and 2 subunit-containing)and BZ2 (5 subunit-containing) receptors.

May cause euphoria, impaired judgement, lossof 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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Lipid solubilitywww.freelivedoctor.com


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Hepatic metabolism. Almost all BDZsundergo 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


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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 (t = 20-80 hr).

Differing times of onset and eliminationhalf-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 activemetabolites, the kinetics of the parent drugmay not reflect the time course of the

pharmacological effect. Estazolam, oxazepam, and lorazepam,

which are directly metabolized toglucoronides have the least residual(drowsiness) effects.

All of these drugs and their metabolites areexcreted in urine.



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Properties of Benzodiazepines

BDZs have a wide margin of safety if usedfor short periods. Prolonged use may cause

dependence.

BDZs have little effect on respiratory orcardiovascular function compared to BARBS

and other sedative-hypnotics.

BDZs depress the turnover rates ofnorepinephrine (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. Tolerancedevelops to most of these effects.

Dependence with these drugs may

develop.

Serious withdrawal syndrome can

include convulsions and death.www.freelivedoctor.com


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Sedative/Hypnotics

They produce a pronounce, graded,

dose-dependent depression of thecentral nervous system.



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Toxicity/Overdose with

Benzodiazepines

Drug overdose is treated with flumazenil (a BDZreceptor antagonist, short half-life), but respiratoryfunction should be adequately supported and

carefully monitored.

Seizures and cardiac arrhythmias may occurfollowing flumazenil administration when BDZ are

taken with TCAs.

Flumazenil is not effective against BARBs

overdose. www.freelivedoctor.com


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Drug-Drug Interactions with BDZs

BDZ's have additive effects with other CNS

depressants (narcotics), alcohol => have agreatly reduced margin of safety.

BDZs reduce the effect of antiepileptic

drugs. Combination of anxiolytic drugs should beavoided.

Concurrent use with ODC antihistaminic andanticholinergic drugs as well as theconsumption of alcohol should be avoided.

SSRIs and oral contraceptives decrease

metabolism of BDZs.www.freelivedoctor.com


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Pharmacokinetics of Barbiturates

Rapid absorption following oraladministration.

Rapid onset of central effects.

Extensively metabolized in liver (exceptphenobarbital), however, there are noactive metabolites.

Phenobarbital is excreted unchanged.Its excretion can be increased byalkalinization of the urine.



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Pharmacokinetics of Barbiturates

In the elderly and in those with limitedhepatic 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 excitatoryneurotransmitters.

Exert nonsynaptic membrane effects.www.freelivedoctor.com


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Toxicity/Overdose

Strong physiological dependence maydevelop 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 increaseanxiety, insomnia, CNS excitability andconvulsions.

Drugs with long-half lives have mildestwithdrawal (.

Drugs with quick onset of action are mostabused.

No medication against overdose withBARBs.

Contraindicated in patients with porphyria.www.freelivedoctor.com


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Sedative/Hypnotics

Tolerance and excessive rebound occur inresponse to barbiturate hypnotics.

NIGTHS OF DRUG DOSING

SLEEP

PERNIGHT

(%)

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 effectsand does not potentiate CNS depressants.

Has a relatively high margin of safety, few

side effects and does not appear to beassociated with drug dependence.

No rebound anxiety or signs of withdrawal

when discontinued.www.freelivedoctor.com


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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 formseveral active metabolites (e.g. 1-(2-

pyrimidyl-piperazine, 1-PP)

Well tolerated by elderly, but may have slowclearance.

Analogs: Ipsapirone, gepirone, tandospirone.www.freelivedoctor.com


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Zolpidem

Structurally unrelated but as effective asBDZs.

Minimal muscle relaxing and anticonvulsant

effect.

Rapidly metabolized by liver enzymes into

inactive metabolites.

Dosage should be reduced in patients withhepatic dysfunction, the elderly and patients

taking cimetidine.www.freelivedoctor.com


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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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?

NEDA 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) fromplasma proteins.

Extensive biotransformation.



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Properties of Other Drugs

2-Adrenoreceptor Agonists(eg. Clonidine)

Antihypertensive.

Has been used for the treatment of panicattacks.

Has been useful in suppressing anxietyduring the management of withdrawal fromnicotine and opioid analgesics.

Withdrawal from clonidine, after protracteduse, may lead to a life-threateninghypertensive 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 mayinclude: lethargy, vivid dreams,

hallucinations.www.freelivedoctor.com

OTHER USES


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OTHER USES1. Generalized Anxiety Disorder

Diazepam, lorazepam, alprazolam, buspirone2. Phobic Anxiety

a. Simple phobia. BDZs

b. Social phobia. BDZs3. Panic Disorders

TCAs and MAOIs, alprazolam

4. Obsessive-Compulsive BehaviorClomipramine (TCA), SSRIs

5. Posttraumatic Stress Disorder (?)

Antidepressants, buspironewww.freelivedoctor.com


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ANXYOLITICS

Alprazolam

Chlordiazepoxide

Buspirone

Diazepam

Lorazepam

Oxazepam

Triazolam

Phenobarbital

Halazepam

Prazepam

HYPNOTICS

Chloral hydrate

Estazolam

Flurazepam

Pentobarbital

Lorazepam

Quazepam

Triazolam

Secobarbital

Temazepam

Zolpidemf li d

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An Xy Olitics Hypnotics