sedatives & hypnotics dr jayesh vaghela
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sedative and hypnotic drugs in pharmacology by Dr Jayesh VaghelaTRANSCRIPT
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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