SEDATIVES&

HYPNOTICS

-By Dr. Jayesh Vaghela

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Overview

Sleep cycle

Introduction about Drug groups

Classification : - BZDs

- Barbiturates

- Non-BZD hypnotics

- Atypical Anxiolytics

Recent advances

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Sedative :

A drug that ↓ excitement & calms the subject,

Without Inducing sleep.

↓ responsiveness to any level of stimulation & ↓ motor activity

Hypnotics :

A drug that induces and/or maintains sleep

Similar to normal arousable sleep

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History

Alcohol, laudanum, herbals ⇒ sleep

Bromide, Chloral hydrate, paraldehyde, urethane, sulfanol.

1903 - Barbital

1912 - Phenobarbital

1960s - BZDs07-Jul-14

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Dose Dependent Action

Sedation(Sedative)

Sleep(Hypnotic)

Anesthesia

(Anesthetic)

Coma

Death

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Sleep Cycle

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• Eyes open – β, Eyes are closed - α waves Awake

• Dozing, α + θ, disappearance of α – onset of sleep Stage I

• θ + sleep spindles and K complex• 40- 50% of total sleep timeStage II

• Appearance of δ wavesStage III

• δ wave predominatesStage IV

• Reappearance of α, low voltage high frequency (Saw tooth waves)

• 20-30% of total sleep time REM

NREM

70-80% Of Total sleep time

Slow wave sleep

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BENZODIAZEPINES ( BZDs )

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Benzodiazepinesa/c to Duration of Action

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Short acting

• Triazolam

• Oxazepam

• Midazolam

Intermediate acting Long acting

• Alprazolam

• Estazolam

• Temazepam

• Lorazepam

• Nitrazepam

• Diazepam

• Flurazepam

• Clonazepam

• Chlordiazepoxide

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Benzodiazepinesa/c to Indications

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Hypnotic Antianxiety Anticonvulsant

• Diazepam

• Flurazepam

• Nitrazepam

• Alprazolam

• Temazepam

• Triazolam

• Diazepam

• Chlordiazepoxide

• Oxazepam

• Lorazepam

• Alprazolam

• Diazepam

• Lorazepam

• Clonazepam

• Clobazam

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Site of Action

Midbrain ( RAS ) - Wakefulness

Limbic system - Thought & mental functions

Medulla - Muscle relaxation

Cerebellum - Ataxia

Effect : Limbic system > Midbrain RAS⇓

- Therapeutic dose ⇒ Anxiolytic > Sedative- Higher dose ⇒ Depress RAS → Sedative & hypnotic effect

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Mechanism of Action

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α γ

α

β

GABA

Bicuculline

Diazepam

Intra cellular side

Flumazenil

DMCM

Barbiturate

GABAA Receptor

Barbiturate receptor

BZD Receptor

Cl--Picrotoxin

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β

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BZDs Barbiturates

o Less neuronal depressiono High therapeutic index

o More neuronal depression

o No effect on respiration or cardiovascular functions at hypnotic doses

o Only i.v. injection causes ↓ BP, cardiac contractility

o Suppression is seen

o No effect on other body systems o Suppressive effects on other systems,

- Skeletal & smooth muscles, kidney

o Specific antagonist – Flumazenil o No antagonist available

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BZDs Barbiturateso No anaesthesia even at high

doses,o Patient can be aroused

o Loss of consciousness,o Low margin of safety

o Not enzyme inducers – - No metabolic tolerance- Less drug interactions

o Potent enzyme inducers – - Metabolic tolerance seen- More drug interactions

o No effect on REM sleepo Less distortion of normal

hypnogram

o ++ suppression of REM sleepo Withdrawal ⇒ rebound ↑ in sleepo Hangover

o Abuse liability very low o Toleranceo Dependence

o No hyperalgesia o Hyperalgesiao ↑ Sensitivity to pain

o Amnesia without automatism o Amnesia with automatismo Loss of short term memory

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Pharmacokinetics

Absorption : - All can be given orally ( Except, Midazolam )

Distribution : - Wide volume of distribution

- PPB variable, flurazepam 10% to diazepam 90%

Metabolism : - Phase 1 reactions ⇒ Phase 2 reactions

- Some phase 1 metabolites are active ⇒ ↑ T1/2 &

duration of action

- e.g. - Midazolam - Diazepam - Flurazepam

- Alprazolam - Chlordiazepoxide07-Jul-14

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Categorization a/c to Pharmacokinetic Profile

1) Slow elimination of parent drug / active metabolite

Flurazepam

2) Relatively slow elimination ; Marked Redistribution

Diazepam, Nitrazepam

3) Relatively Rapid elimination ; Marked Redistribution

Alprazolam, Temazepam

4) Ultra rapid elimination

Triazolam, Midazolam

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Therapeutic uses

1) Anxiety Neuroses :

• Alprazolam : - Anxiety with Depression ( 0.25-0.5 mg BD/TDS )

- Anxiety with Panic disorder ( max 6 mg/day )

• Lorazepam : - Suitable for parenteral use

- Short lived anxiety states, Compulsive-Obsessive

neuroses, tension-induced psychosomatic symptoms

- Dose : 1 – 6 mg / day

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• Oxazepam : - Elderly or liver dysfunction with Short-lived anxiety

states

- Dose : 30 – 60 mg in 3 divided doses

• Diazepam : - Acute panic-anxiety with organic disease

- Where sedation is also required

- Dose : 2 – 10 mg BD / TDS

• Chlordiazepoxide:- Chronic Anxiety states

- Dose : 20 – 50 mg / day in 3 divided doses07-Jul-14

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2) Insomnia :

Type Duration Cause Drug Dose Remarks

Transient < 7 days Jet-lagShift workOvernight journey

Triazolam 0.125 – 0.25 mg

Difficulty in going to sleep

Temazepam 15 – 30 mg Inability to stay asleep

Short term

1 – 3 week

BereavementOccupational problems

Flurazepam 15 – 30 mg Frequent nocturnal awakenings

Temazepam 15 – 30 mg Inability to stay asleep

Estazolam 1 – 2 mg --

Long term

> 3 weeks

Underlying diseasePersonality disorders

Flurazepam 15 – 30 mg Intermittent use( Break after every 3rd day )

Nitrazepam 5 – 10 mg

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3) Preanaesthetic medication & Induction of anaesthesia :

Midazolam - i.v.

- More amnesia, rapid onset, shorter duration

Others : Diazepam, Lorazepam

4) As skeletal muscle relaxant :

Diazepam

In muscle spasticity of central origin

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5) As anticonvulsant :

Status epilepticus - Diazepam & Clonazepam ( slow i.v. )

Myoclonic / petit mal - Clonazepam

6) Treatment of alcohol withdrawal :

Diazepam / Chlordiazepoxide

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Benzodiazepines as hypnotics

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Drug T1/2 ( hours )

Dose ( mg ) Indications

Long ActingFlurazepam 50 – 100 15 – 30 Chronic insomnia,

Short term insomnia with anxiety,Frequent nocturnal awakening,Night before operation

Diazepam 30 – 60 5 – 10

Nitrazepam 30 5 – 10

Short ActingAlprazolam 12 0.25 – 0.5 Sleep onset difficulties,

Patients who react unfavourably to unfamiliar surroundings or unusual timing of sleep

Temazepam 8 – 12 10 – 20

Triazolam 2 – 3 0.125 – 0.25

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Adverse effects

Higher safety margin ( 50 times dose )

Tolerance to sedative effects – “ self inducers ”

Dependence

Down regulation ⇒ ↓ functional GABA activity

↑ Age ⇒ ↓ phase 1 metabolism ⇒ confusion, forgetfulness

Paradoxical stimulation ( flurazepam )

Flunitrazepam – sedative-amnesic effects – “ date rapes ”

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Drug Interactions

CNS depressants - Potentiation (alcohol, hypnotics, neuroleptics)

Smoking - ↓ Activity of BZDs

Aminophylline - Antagonises sedative effects of BZDs

Enzyme inhibitors- ↑ Activity

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NON – BZD HYPNOTICS( THE “ Z ” COMPOUNDS )

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Zolpidem Zaleplon Zopiclone Eszopiclone

T1/2 2 hr 1 hr 5 – 6 hr

Use • Short term use in• Sleep onset insomnia,• Intermittent awakenings

Sleep onset insomnia

Short term insomnia< 2 weeks

Short term & chronic insomnia

Advantage

• No effect on sleep stages,

• Less day time sedation,• No rebound insomnia,• No tolerance,• No abuse,• Safety in overdose

• Late night,• No day

time anxiety,

• No rebound insomnia

-- --

Dose 5 – 10 mg HS 5 – 10 mg HS 7.5 mg HS --

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Flumazenil BZD analogue with little intrinsic activity

Competes with BZD agonist & antagonist

Uses :

To reverse BZD anaesthesia :

- Dose : 0.3 – 1 mg i.v.

- Allows early discharge of patient after diagnostic procedures

- Facilitates postanaesthetic management

BZD overdose :

- 0.2 mg / min i.v.

ADRs : Agitation, discomfort, withdrawal seizures.07-Jul-14

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BARBITURATES

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Barbiturates

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Long Acting Short Acting Ultra-short Acting

• Phenobarbitone • Butobarbitone

• Pentobarbitone

• Thiopentone

• Methohexitone

o Epilepsyo Neonatal jaundice

Anaesthesia

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Barbiturates

Binds to GABAA receptor (on α or β subunit)

Facilitates GABA action

Increase in duration of opening of Cl- channel

Membrane hyperpolarization

CNS depression

At higher dose it can act as GABA mimetics

Mechanism of Action

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Pharmacological Actions

CNS - Generalized depression, Dose dependent action

Sleep –

o ↓ Latency of sleep onseto ↑ Total duration of sleepo ↓ Night awakeningo Sleep cycle distortion - Hangovero Rebound increase in REM sleep on discontinuation

Anti - convulsant activity

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RS :

Depression of respiratory center

CVS :

Depression of VMC

↓ Myocardial contractility

↓ BP, HR

Smooth muscles :

↓ tone & motility of bowel

Kidney :

↓ Urine flow

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Adverse effects

Hangover

Hypersensitivity

Tolerance & Dependence ( Abuse potential )

Poisoning ⇒ No Antidote, Only Symptomatic Treatment

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Interactions

Enzyme inducers - ↑ Metabolism, ↓ Effectiveness

- Steroids, Warfarin

CNS depressants - Additive action

Sod. Valproate - ↑ Concentration of phenobarbitone

Phenytoin - Induction & Inhibition by phenobarbitone

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Atypical Anxiolytics

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Buspirone, Ipsapirone, Gepirone

M/A - Partial agonist at 5-HT1A receptors

Activation of presynaptic inhibitory 5-HT1A receptor

↓ 5-HT neurotransmission

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Use - Long term anxiety states ( effect take >2 weeks, not for acute )

Advantages- minimal abuse potential

- No withdrawal reactions

- less impairment of psychomotor skills

ADRs – Tachycardia, Nervousness, GI distress, Paresthesias

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Beta Adrenoceptor Antagonist

Worrying situations & Apprehensions ( job interview, exam, etc. )

Palpitation, tremors, GI upset.

Reinforce anxiety

Propranolol 20 mg TDS breaks the vicious cycle

CVS effects ⇒ Unlikely to be used as anxiolytic

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Melatonin

Pineal gland hormone

Affects sleep – wake cycle

Darkness ⇒ Melatonin ⇒ MT1 MT2 receptors in SCN ⇒ Circadian rhythm

Use - Jet-lag insomnia

Dose: 3 mg 2 hour before bed time

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Ramelteon

MT1 & MT2 receptor agonist

Use - Sleep onset insomnia- Speeds sleep onset- Longer duration of sleep

Adv. - No dependence- No rebound insomnia

Dose- 8 mg ½ hour before going to sleep

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Tasimelteon

MT 1 & MT 2 receptor agonist

Recently approved by USFDA in Jan – 2014

Use - Non 24-hour sleep wake disorder in totally blind

ADR - Headache, Nightmares.

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References

Catterall AW and Mackie K. Sedatives & Hypnotics. In : Bruton LL, editor. Goodman & Gilman’s – The Pharmacological basis of therapeutics. 12th edition. New York : Mc Graw Hill Publication; 2011. p. 566-82.

Schulman JM and Strichartz GR. Neurotransmission in central nervous system. In: Golan DE, editor. Principles of Pharmacology – The pathophysiological basis of drug therapy. 3rd edition. New Delhi: Walters Kluwer Publication; 2012. p. 147-62.

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Tripathi KD. Essentials of Medical Pharmacology. 6th ed. New Delhi : Jaypee brothers medical publishers; 2009. p. 360-71.

Sharma HL & Sharma KK. Principles of Pharmacology. 2nd ed. New Delhi: Paras publication; 2012. p. 212-22.

Shrivastava SK. A complete textbook of medical pharmacology. 1st ed. New Delhi: Avichal publication; 2012. p. 552-67.

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