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INSOMNIA
Dr. Resu Neha Reddy
MD Pharmacology
Osmania Medical College
SEDATIVES AND HYPNOTICS
SEDATIVE:
Drug or dose of the drug that
produce calmness of the mind
without inducing sleep
 Drowsiness/Sleepiness
HYPNOTIC:
Drug that induce &/or
maintains sleep from which
a person can be aroused as
during natural sleep
 ANALGESIC: A drug that relieves pain without sedation/ drowsiness
 NARCOTIC: A drug that relieves pain together with drowsiness or sleep
 ANAESTHETIC: A drug that causes the loss of sensation; GA/LA
 ANTICONVULSANTS: A drug that prevents &/or suppresses convulsions
HISTORY
Alcoholic
beverages,
herbals were used
to induce sleep
BROMIDE
First agent introduced as a
sedative-Hypnotic in the
middle of 19th centuary
Chloral hydrate,
paraldehyde,
urethane
Were used before
barbiturates
Phenobarbital –
1912
Barbiturates were
used till 1960’s
Leo H Sternbach
He is credited with the discovery
of chlordiazepoxide, diazepam, flurazepam, nitrazepam, flunitrazepam
and clonazepam
SLEEP
• Transient physiological depression.
• Characterised- cyclical eye movements, muscular relaxation, EEG changes
• 2 categories : NREM and REM sleep.
• NREM further divided into 5 stages : Phases 0, 1, 2, 3, 4.
• NREM REM NREM REM
(1 hr ) (20-25 min) (80-100 min) (20-25 min)
NEUROTRANSMISSION
• Balance should be maintained between excitatory (glutaminergic) and
inhibitory (GABAergic) transmissions.
GABA
ACTIVITY
GABA
ACTIVITY
EEG EXAMINATION
Alpha waves – 8-14 Hz
Βeta waves – 15-35Hz
Theta waves – 4-7 Hz
Delta waves – 0.5-3 Hz
Kappa complex- deep negative wave
followed by a positive wave
Sleep spindles - sudden bursts of
oscillatory brain activity  reticular
nucleus of the thalamus
EEG WAVES
SLEEP
80% of sleep
Slow wave sleep
BP,HR,RR decreased
Relaxed muscles
EEG : low frequency and high
amplitude
For physical restoration
Somnabulism,Eneuresis,
Somnoloqui,Bruxism,
Pavor Nocturnus
20% of sleep
Fast wave sleep
BP,HR,RR fluctuating
Profoundly relaxed muscles
For consolidation of learning
Active dreaming, Night Mares,
Narcolepsy, Cataplexy,
Penile erection
PHARMACOLOGICAL THERAPY
• Ideal hypnotic :
Induce and maintain sleep with normal architecture
No rebound anxiety or sedation on next day
No rebound insomnia on discontinuation
No interaction with other drugs
No dependency on chronic usage
Sedatives
and
hypnotics
Benzodiazepines
Long
acting
Diazepam
Chlordiazepo
xide
Clonazepam
Flurazepam
Intermediate
acting
Alprazolam
Estazolam
Lorazepam
Short
acting
Triazolam
Oxazepam
Midazolam
Barbiturates
Long
acting
Phenobar
bitone
Intermediate
acting
Butobarb
itone
Pentobar
bitone
Short
acting
Thiopentone
Methohexiton
e
Non-
benzodiaz
epines
Zopiclone
Eszopiclon
e
Zoleplon
Zolpidem
Other
hypnotics
Triclofos
Melatonin
Ramelteon
Suvorexant
Epilepsy
Neonatal jaundice
Anaesthesia
MOLECULAR PHARMACOLOGY OF GABA RECEPTOR
GABA RECEPTOR
Mutation in α1 subunit
Resistance to sedative and amnestic
effects without any effect on anxiolytic
and muscle relaxant actions
Mutation in α2 subunit
Resistance in anxiolytic
actions
DOSE RESPONSE CURVE
MECHANISM OF ACTION
BENZODIAZEPINES/BARBITURATES
Bind to GABA-A receptor
Facilitatatory action by cl- channel opening
Hyperpolarisation of membrane
Depression of CNS
BENZODIAZEPINES
Facilitatory action
Increase frequency of
chloride channel opening
BARBITURATES
Facilitatory action by
increasing the duration of the
chloride channel
At higher doses, show GABA
mimetic action, directly
increase ion conductance
BARBITURATES
BARBITURATES
• Derivatives of barbituric acid - 2,4,6 – trioxohexahydropyrimidine
• Alkyl or aryl groups at 5th position confers sedative-hypnotic activity
• Thiobarbiturates : highly lipid soluble = C2 – Oxygen Sulphur/thio group
CLASSIFICATION
• THIOPENTAL , METHOHEXITAL
ULTRA SHORT ACTING
• PENTOBARBITAL
• SECOBARBITAL
• AMOBARBITAL
SHORT ACTING (3-8HRS)
• AMYLOBARBITONE
INTERMEDIATE ACTING (8-24H)
• PHENOBARBITONE
LONG ACTING (>24H)
MECHANISM OF ACTION
1. GABA facilitatory action : by prolonging the duration of chloride channel opening
and at higher doses directly activate and increase influx of chloride.
2. Decrease glutamate-induced depolarization
(by inhibiting AMPA receptors).
3. Inhibit voltage dependent Na⁺ and K⁺ conductances.
• Multiplicity of actions – surgical anaesthesia
profound CNS depression and
low margin of safety
PHARMACOKINETICS
• Absorption : - rapid oral absorption
- IM Injection : Necrosis
• Distribution : - wide distribution (high lipid solubility)
- redistribution into muscle and fat occurs- terminates the action
- readily crosses placenta
PHARMACOKINETICS
• Metabolism : - by liver microsomal enzymes
- oxidation conjugation excreted in urine
- oxidation at 5th carbon – terminates the action
- 25% of phenobarbital and aprobarbital are excreted
unchanged in urine
• Excretion : - t1/2 in elderly and cirrhotic patients
- drug accumulation occurs on repeated administration
- weak acids – ALKALINIZATION increases their excretion
PHARMACOLOGICAL ACTIONS
• Dose dependent action :
• Presence of even moderate pain – decreases sedative activity  HYPERALGESIC action.
• Higher doses : - suppress hypoxic and chemoreceptor drives  Respiratory depression.
- cardiodepressant
- circulatory collapse due to medullary vasomotor
depression
sedation hypnosis anaesthesia coma death
PHARMACOLOGICAL ACTIONS
• Hypnotic : total sleep time
sleep latency
REM sleep and Slow-wave sleep
number of awakenings
> 2 wks – tolerance
discontinuation : rebound increase of all parameters
• Enzyme induction : - potent enzyme inducer of CYP’S – drug interctions and tolerance.
- induces ALA synthetase, exacerbations in Acute Intermittent Porphyria.
THERAPEUTIC USES
• INSOMNIA : amobarbital, butabarbital, pentobarbital, secobarbital.
• PREOP-SEDATION : amobarbital, butabarbital, pentobarbital, secobarital, thiopental
• INDUCTION OF ANAESTHESIA : thiopental, methohexital
• ANTICONVULSANT : phenobarbital in status epilepticus
mephobarbital as second line anticonvulsant
• HYPERBILIRUBINEMIA OF NEONATES : due to increased activity of glucornyl transferase.
ADVERSE EFFECTS
• TOLERANCE : - mood, sedation, hypnosis >> anticonvulsant
• DEPENDENCE AND ABUSE
• WITHDRAWAL SYMPTOMS
• HANGOVER
• DRUG AUTOMATISM
ADVERSE EFFECTS :
• HYPERSENSITIVITY
• VITAMIN K AND D METABOLISM : increased by phenobarbital
– impairs bone mineralization and coagulation defects in newborns.
• UNWANTED PREGNANCY : due to increased metabolism of OCP’S.
CONTRAINDICATIONS : - Acute Intermittent Porphyria
- respiratory insufficieny
- liver diseases
- elderly
- pregnancy
BARBITURATE POISONING
• Suicidal >> Accidental - >> 10 times the hypnotic dose.
• With Alcohol or CNS depressants – occurs at low doses.
• Severe intoxication : - patient – comatose
- respiration : shallow and rapid
- cardiac depression and circulatory collapse
- renal failure
• Treatment : - supportive measures
- artificial respiration
- gastric lavage
- forced alkaline diuresis
- hemodialysis if necessary
BENZODIAZEPINES
STRUCTURE OF BENZODIAZEPINES
• Benzene ring
• Diazepine ring- 7 membered
• 5-aryl substituent
• Halogen or Nitro group at 7th position conferes
sedative-hypnotic activity.
• Triazolo ring at 1st and 2nd positions are substituted
in triazolam and alprazolam.
BENZODIAZEPINES - PHARMACOKINETICS
• Lipophilic
• Complete oral absorption except for CLORAZEPATE which is rapidly decarboxylated to N-
desmethyldiazepam (Nordazepam) by gastric juice.
• Rapid distribution into brain followed by redistribution into muscle and fat.
• Metabolism : by CYP’S 3A4 and 2C19.
• Cross placenta and excreted in milk - fetal and neonatal depression.
BENZODIAZEPINES METABOLISM
• Occurs in 3 phases
• PHASE 1 : modification or removal
of the substituent at 1st or 2nd
position.
products : N-desalkylated compounds,
biologically active.
• PHASE 2 : hydroxylation at 3rd
position yields 3-hydroxylated
compounds, also biologically active.
METABOLISM OF BENZODIAZEPINES
• PHASE 3 : conjugation with
glucuronic acid yeids inactive
metabolites which are
excreted.
EXCEPTIONS : no active
metabolites are formed in LEO-
lorazepam, estazolam, oxazepam.
• Triazolam, alprazolam, midazolam
undergo α-hydroxylation initially
and then conjugation.
PHARMACOLOGICAL ACTIONS
1. SEDATIVE AND HYPNOTIC :
latency of sleep
number of awakenings total sleep duration by increasing
REM sleep duration stage 2
stages 1, 3 , 4 of NREM sleep
> 2 WEEK USE : tolerance occurs.
Discontinuation : rebound increase in REM sleep.
2. ANXIOLYTIC : Mainly used for Acute Anxiety States.
3. PREANAESTHETIC MEDICATION : Eg: chlordiazepoxide, diazepam, lorazepam, midazolam.
PHARMACOLOGICAL ACTIONS
4. ANTICONVULSANT : diazepam , lorazepam – used in status epilepticus.
5. ANTEROGRADE AMNESIA : mediated by α1 subunit of GABA-A receptor.
6. MUSCLE-RELAXANT : at higher doses, mediated by α2 subunit of GABA-A receptor.
7. RESPIRATORY : higher doses- decreases hypoxic drive and depress alveolar ventilation,
hence not used in COPD patients.
Even hypnotic doses decrease muscle tone of upper airway in Obs.Sleep Apnea patients.
THERPEUTIC USES
• Longer t1/2 BZD’S : anticonvulsants and anti-anxiety agents
• Shorter t1/2 BZD’S : sedative-hypnotics.
• ANXIOLYTICS : Acute Anxiety States
Alprazolam – panic disorders, and agoraphobia.
Diazepam, Lorazepam, Oxazepam.
• INSOMNIA : short acting agents more preffered.
eg : estazolam, triazolam, temazepam.
• ALCOHOL WITHDRAWAL : Chlordiazepoxide, Clorazepate, Diazepam, Oxazepam.
THERAPEUTIC USES
• ANAESTHESIA : Preanaesthetic medication to produce amnesia – diazepam, lorazepam
Both introperative and preanaesthetic medication – midazolam
• STATUS EPILETICUS : Diazepam, Lorazepam.
• OTHER EPILEPSIES : Clonazepam – Myoclonic Seizures.
Clorazepate – Complex Partial Seizures.
• SKELETAL MUSCLE RELAXANT : Diazepam in Spastic disorders.
ADVERSE EFFECTS
• Common side effects : headache, blurred vision, nausea ,vomiting.
• Impaired cognition
• Residual day time sleepiness
• Tolerance
• Dependency and Abuse liability : eg : Flunitrazepam (ROHYPNOL)
• Withdrawal syndromes : rebound insomnia, anxiety, tremors, unpleasant dreams,
anorexia, dizziness.
BENZODIAZEPINES
• Drug interactions : seen with enzyme inhibitors (erythromycin, ketoconazole)
- CIMITIDINE and OCP’S : inhibit dealyklation and hydroxylation of BZD’S.
- ETHANOL – synergistic effect on CNS depression, hence should not be used along
ethanol and other CNS depressants.
- Neonatal depression and HYPOTONIA (FLOPPY BABY SYNDROME) when given in
pregnant female.
• Dose reduction : Elderly
Liver disease
ADVANTAGES OF BENZODIAZEPINES
BARBITURATES
• Narrow therapeutic index
• More suppression of REM sleep
• Enzyme inducer
• High abuse liability
• Produces non-specific CNS depression
• No antidote available
BENZODIAZEPINES
• High therapeutic index
• Less suppression of REM sleep
• Not an enzyme inducer
• Lesser abuse liability
• Do not produce
• Antidote – Flumazenil available
THANK YOU…

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Sedatives & hypnotics

  • 2.
  • 4. Dr. Resu Neha Reddy MD Pharmacology Osmania Medical College SEDATIVES AND HYPNOTICS
  • 5. SEDATIVE: Drug or dose of the drug that produce calmness of the mind without inducing sleep  Drowsiness/Sleepiness HYPNOTIC: Drug that induce &/or maintains sleep from which a person can be aroused as during natural sleep
  • 6.  ANALGESIC: A drug that relieves pain without sedation/ drowsiness  NARCOTIC: A drug that relieves pain together with drowsiness or sleep  ANAESTHETIC: A drug that causes the loss of sensation; GA/LA  ANTICONVULSANTS: A drug that prevents &/or suppresses convulsions
  • 7. HISTORY Alcoholic beverages, herbals were used to induce sleep BROMIDE First agent introduced as a sedative-Hypnotic in the middle of 19th centuary Chloral hydrate, paraldehyde, urethane Were used before barbiturates Phenobarbital – 1912 Barbiturates were used till 1960’s Leo H Sternbach He is credited with the discovery of chlordiazepoxide, diazepam, flurazepam, nitrazepam, flunitrazepam and clonazepam
  • 8. SLEEP • Transient physiological depression. • Characterised- cyclical eye movements, muscular relaxation, EEG changes • 2 categories : NREM and REM sleep. • NREM further divided into 5 stages : Phases 0, 1, 2, 3, 4. • NREM REM NREM REM (1 hr ) (20-25 min) (80-100 min) (20-25 min)
  • 9.
  • 10. NEUROTRANSMISSION • Balance should be maintained between excitatory (glutaminergic) and inhibitory (GABAergic) transmissions. GABA ACTIVITY GABA ACTIVITY
  • 12. Alpha waves – 8-14 Hz Βeta waves – 15-35Hz Theta waves – 4-7 Hz Delta waves – 0.5-3 Hz Kappa complex- deep negative wave followed by a positive wave Sleep spindles - sudden bursts of oscillatory brain activity  reticular nucleus of the thalamus EEG WAVES
  • 13.
  • 14. SLEEP 80% of sleep Slow wave sleep BP,HR,RR decreased Relaxed muscles EEG : low frequency and high amplitude For physical restoration Somnabulism,Eneuresis, Somnoloqui,Bruxism, Pavor Nocturnus 20% of sleep Fast wave sleep BP,HR,RR fluctuating Profoundly relaxed muscles For consolidation of learning Active dreaming, Night Mares, Narcolepsy, Cataplexy, Penile erection
  • 15.
  • 16. PHARMACOLOGICAL THERAPY • Ideal hypnotic : Induce and maintain sleep with normal architecture No rebound anxiety or sedation on next day No rebound insomnia on discontinuation No interaction with other drugs No dependency on chronic usage
  • 18.
  • 19. MOLECULAR PHARMACOLOGY OF GABA RECEPTOR
  • 20. GABA RECEPTOR Mutation in α1 subunit Resistance to sedative and amnestic effects without any effect on anxiolytic and muscle relaxant actions Mutation in α2 subunit Resistance in anxiolytic actions
  • 22. MECHANISM OF ACTION BENZODIAZEPINES/BARBITURATES Bind to GABA-A receptor Facilitatatory action by cl- channel opening Hyperpolarisation of membrane Depression of CNS BENZODIAZEPINES Facilitatory action Increase frequency of chloride channel opening BARBITURATES Facilitatory action by increasing the duration of the chloride channel At higher doses, show GABA mimetic action, directly increase ion conductance
  • 24. BARBITURATES • Derivatives of barbituric acid - 2,4,6 – trioxohexahydropyrimidine • Alkyl or aryl groups at 5th position confers sedative-hypnotic activity • Thiobarbiturates : highly lipid soluble = C2 – Oxygen Sulphur/thio group
  • 25. CLASSIFICATION • THIOPENTAL , METHOHEXITAL ULTRA SHORT ACTING • PENTOBARBITAL • SECOBARBITAL • AMOBARBITAL SHORT ACTING (3-8HRS) • AMYLOBARBITONE INTERMEDIATE ACTING (8-24H) • PHENOBARBITONE LONG ACTING (>24H)
  • 26. MECHANISM OF ACTION 1. GABA facilitatory action : by prolonging the duration of chloride channel opening and at higher doses directly activate and increase influx of chloride. 2. Decrease glutamate-induced depolarization (by inhibiting AMPA receptors). 3. Inhibit voltage dependent Na⁺ and K⁺ conductances. • Multiplicity of actions – surgical anaesthesia profound CNS depression and low margin of safety
  • 27. PHARMACOKINETICS • Absorption : - rapid oral absorption - IM Injection : Necrosis • Distribution : - wide distribution (high lipid solubility) - redistribution into muscle and fat occurs- terminates the action - readily crosses placenta
  • 28. PHARMACOKINETICS • Metabolism : - by liver microsomal enzymes - oxidation conjugation excreted in urine - oxidation at 5th carbon – terminates the action - 25% of phenobarbital and aprobarbital are excreted unchanged in urine • Excretion : - t1/2 in elderly and cirrhotic patients - drug accumulation occurs on repeated administration - weak acids – ALKALINIZATION increases their excretion
  • 29. PHARMACOLOGICAL ACTIONS • Dose dependent action : • Presence of even moderate pain – decreases sedative activity  HYPERALGESIC action. • Higher doses : - suppress hypoxic and chemoreceptor drives  Respiratory depression. - cardiodepressant - circulatory collapse due to medullary vasomotor depression sedation hypnosis anaesthesia coma death
  • 30. PHARMACOLOGICAL ACTIONS • Hypnotic : total sleep time sleep latency REM sleep and Slow-wave sleep number of awakenings > 2 wks – tolerance discontinuation : rebound increase of all parameters • Enzyme induction : - potent enzyme inducer of CYP’S – drug interctions and tolerance. - induces ALA synthetase, exacerbations in Acute Intermittent Porphyria.
  • 31. THERAPEUTIC USES • INSOMNIA : amobarbital, butabarbital, pentobarbital, secobarbital. • PREOP-SEDATION : amobarbital, butabarbital, pentobarbital, secobarital, thiopental • INDUCTION OF ANAESTHESIA : thiopental, methohexital • ANTICONVULSANT : phenobarbital in status epilepticus mephobarbital as second line anticonvulsant • HYPERBILIRUBINEMIA OF NEONATES : due to increased activity of glucornyl transferase.
  • 32. ADVERSE EFFECTS • TOLERANCE : - mood, sedation, hypnosis >> anticonvulsant • DEPENDENCE AND ABUSE • WITHDRAWAL SYMPTOMS • HANGOVER • DRUG AUTOMATISM
  • 33. ADVERSE EFFECTS : • HYPERSENSITIVITY • VITAMIN K AND D METABOLISM : increased by phenobarbital – impairs bone mineralization and coagulation defects in newborns. • UNWANTED PREGNANCY : due to increased metabolism of OCP’S. CONTRAINDICATIONS : - Acute Intermittent Porphyria - respiratory insufficieny - liver diseases - elderly - pregnancy
  • 34. BARBITURATE POISONING • Suicidal >> Accidental - >> 10 times the hypnotic dose. • With Alcohol or CNS depressants – occurs at low doses. • Severe intoxication : - patient – comatose - respiration : shallow and rapid - cardiac depression and circulatory collapse - renal failure • Treatment : - supportive measures - artificial respiration - gastric lavage - forced alkaline diuresis - hemodialysis if necessary
  • 36. STRUCTURE OF BENZODIAZEPINES • Benzene ring • Diazepine ring- 7 membered • 5-aryl substituent • Halogen or Nitro group at 7th position conferes sedative-hypnotic activity. • Triazolo ring at 1st and 2nd positions are substituted in triazolam and alprazolam.
  • 37.
  • 38. BENZODIAZEPINES - PHARMACOKINETICS • Lipophilic • Complete oral absorption except for CLORAZEPATE which is rapidly decarboxylated to N- desmethyldiazepam (Nordazepam) by gastric juice. • Rapid distribution into brain followed by redistribution into muscle and fat. • Metabolism : by CYP’S 3A4 and 2C19. • Cross placenta and excreted in milk - fetal and neonatal depression.
  • 39. BENZODIAZEPINES METABOLISM • Occurs in 3 phases • PHASE 1 : modification or removal of the substituent at 1st or 2nd position. products : N-desalkylated compounds, biologically active. • PHASE 2 : hydroxylation at 3rd position yields 3-hydroxylated compounds, also biologically active.
  • 40. METABOLISM OF BENZODIAZEPINES • PHASE 3 : conjugation with glucuronic acid yeids inactive metabolites which are excreted. EXCEPTIONS : no active metabolites are formed in LEO- lorazepam, estazolam, oxazepam. • Triazolam, alprazolam, midazolam undergo α-hydroxylation initially and then conjugation.
  • 41. PHARMACOLOGICAL ACTIONS 1. SEDATIVE AND HYPNOTIC : latency of sleep number of awakenings total sleep duration by increasing REM sleep duration stage 2 stages 1, 3 , 4 of NREM sleep > 2 WEEK USE : tolerance occurs. Discontinuation : rebound increase in REM sleep. 2. ANXIOLYTIC : Mainly used for Acute Anxiety States. 3. PREANAESTHETIC MEDICATION : Eg: chlordiazepoxide, diazepam, lorazepam, midazolam.
  • 42. PHARMACOLOGICAL ACTIONS 4. ANTICONVULSANT : diazepam , lorazepam – used in status epilepticus. 5. ANTEROGRADE AMNESIA : mediated by α1 subunit of GABA-A receptor. 6. MUSCLE-RELAXANT : at higher doses, mediated by α2 subunit of GABA-A receptor. 7. RESPIRATORY : higher doses- decreases hypoxic drive and depress alveolar ventilation, hence not used in COPD patients. Even hypnotic doses decrease muscle tone of upper airway in Obs.Sleep Apnea patients.
  • 43. THERPEUTIC USES • Longer t1/2 BZD’S : anticonvulsants and anti-anxiety agents • Shorter t1/2 BZD’S : sedative-hypnotics. • ANXIOLYTICS : Acute Anxiety States Alprazolam – panic disorders, and agoraphobia. Diazepam, Lorazepam, Oxazepam. • INSOMNIA : short acting agents more preffered. eg : estazolam, triazolam, temazepam. • ALCOHOL WITHDRAWAL : Chlordiazepoxide, Clorazepate, Diazepam, Oxazepam.
  • 44. THERAPEUTIC USES • ANAESTHESIA : Preanaesthetic medication to produce amnesia – diazepam, lorazepam Both introperative and preanaesthetic medication – midazolam • STATUS EPILETICUS : Diazepam, Lorazepam. • OTHER EPILEPSIES : Clonazepam – Myoclonic Seizures. Clorazepate – Complex Partial Seizures. • SKELETAL MUSCLE RELAXANT : Diazepam in Spastic disorders.
  • 45. ADVERSE EFFECTS • Common side effects : headache, blurred vision, nausea ,vomiting. • Impaired cognition • Residual day time sleepiness • Tolerance • Dependency and Abuse liability : eg : Flunitrazepam (ROHYPNOL) • Withdrawal syndromes : rebound insomnia, anxiety, tremors, unpleasant dreams, anorexia, dizziness.
  • 46. BENZODIAZEPINES • Drug interactions : seen with enzyme inhibitors (erythromycin, ketoconazole) - CIMITIDINE and OCP’S : inhibit dealyklation and hydroxylation of BZD’S. - ETHANOL – synergistic effect on CNS depression, hence should not be used along ethanol and other CNS depressants. - Neonatal depression and HYPOTONIA (FLOPPY BABY SYNDROME) when given in pregnant female. • Dose reduction : Elderly Liver disease
  • 47. ADVANTAGES OF BENZODIAZEPINES BARBITURATES • Narrow therapeutic index • More suppression of REM sleep • Enzyme inducer • High abuse liability • Produces non-specific CNS depression • No antidote available BENZODIAZEPINES • High therapeutic index • Less suppression of REM sleep • Not an enzyme inducer • Lesser abuse liability • Do not produce • Antidote – Flumazenil available