1. Pharmacology Department
Sedative & Hypnotics
Prof. Hanan Hagar
Pharmacology Department
Medical College
King Saud University

2. Sedative & Hypnotics
Anxiolytics : Drugs that clam the patient and reduce anxiety without inducing normal sleep.
Hypnotics : Drugs that initiate and maintain
the normal sleep.

3. Classification of hypnotic drugs
1. Benzodiazepines ( BDZ )
2. Barbiturates
3. Miscellaneous ( non BDZ non barbiturate drugs).
Zolpidem
Zaleplon

4. Benzodiazepines Nomenclature
End with suffix azolam or azepam
Alprazolam
Estazolam
Triazolam
Lorazepam
Diazepam
Oxazepam
Temazepam
Nitrazepam

5. Classification of benzodiazepines
According to duration of action :
- Short acting: (3-5 hours).
Triazolam
-  Intermediate: (6-24 hours) (LEOTAN).
Lorazepam
Estazolam
Oxazepam
Temazepam
Alprazolam
Nitrazepam

6. - Long acting: ( 24-72 hours) Chlorazepate Chlordiazepoxide
Diazepam Flurazepam
Quazepam Prazepam
According to uses
Anxiolytics
Lorazepam Oxazepam Alprazolam
Chlordiazepoxide Diazepam Prazepam
Clonazepam

7. Long: Flurazepam, Quazepam
Hypnotics
short: Triazolam
Intermediate:
Lorazepam , Estazolam
Temazepam Nitrazepam
Long: Flurazepam, Quazepam
Preanesthetics
  Diazepam Midazolam
    

9. Mechanism of Action By binding to BZ receptors (BZ1 or BZ2).
Bzs facilitate GABA-induced chloride channels hyperpolarization = GABA-mediated inhibitory neurotansmission

10. Mechanism of Action
Benzodiazepines combine with BZ receptors  increase GABA action on GABA receptors  chloride channels opening 
 chloride influx to the cell  cell membrane hyperpolarization  inhibition of propagation of action potential  inhibitory effect on different sites of the brain especially motor cortex & limbic system.

12. Pharmacokinetics of benzodiazepines
Bzs are lipid soluble, well absorbed orally,
Rapid absorption
e.g. triazolam & diazepam & chlorazepate
(chlorazepate is prodrug converted by acid hydrolysis in stomach to form nordiazepam (desmethyldiazepam).
Slower absorption
e.g. lorazepam & oxazepam, temazepam (LOT)

13. Can be given parenterally
Chlordiazepoxide - Diazepam (IV only NOT IM)
Lorazepam - Midazolam (IV or IM)
Bzs are widely distributed.
Cross placental barrier during pregnancy
and are excreted in milk (Fetal & neonatal
depression).
Redistribution from CNS to skeletal muscles,
adipose tissue) (termination of action).

14. All benzodiazepines are metabolized in the
liver to active compounds
EXCEPT No active metabolites are formed for
(LEO) Lorazepam, Estazolam, Oxazepam

15. Metabolism occurs in two phases
Phase I: ( liver microsomal system)
Phase II: glucouronide conjugation excreted in the urine.
Many of Phase I metabolites are active
 elimination half life of the parent comp.
cumulative effect with multiple doses

18. Pharmacological Actions Anxiolytic action.
Depression of cognitive and psychomotor function.
Sedative & hypnotic actions:
At higher dose, benzodiazepines change sleep pattern
Induction of normal sleep ( reduce latency of sleep).
Increase non REM sleep (stage II).
Decrease REM sleep & slow waves sleep (3,4 stages). 

21. Anterograde amnesia
Some have anticonvulsant effect:
diazepam, lorazepam, clonazepam, clorazepate.
Some have central skeletal muscle relaxant effect e. g. Diazepam (relax muscle spasticity by increasing presynaptic inhibition in the spinal cord).
CVS and respiratory system: Minimal depressant effects in therapeutic doses & in normal patients.

22. Therapeutic Uses Anxiety disorders:
short term relief of severe anxiety
General anxiety disorder
major depressive disorders
Obsessive compulsive disorder
Panic attack with depression Alprazolam
since it has (antidepressant effect).

23. Sleep disorders (Insomnia)
Triazolam: initiate sleep
(tolerance & rebound insomnia)
Estazolam - Lorazepam - temazepam:
(sustain sleep)
Flurazepam – Quazepam (hangover).
Usage for 1-2 weeks  tolerance to their effect on sleep patterns
Drug withdrawal  anxiety, irritability, restlessness, increase in REM sleep, rebound insomnia

24. Treatment of epilepsy
Diazepam – Lorazepam
Clonazepam -Clorazepate
Muscle relaxation: in spastic states (Diazepam)
As cerebral palsy and multiple sclerosis.
To control withdrawal symptoms of alcohols
diazepam- chlordiazepoxide

25. In anesthesia
Preanesthetic medication e.g. diazepam
Induction of balanced anesthesia (Midazolam)
Adjunct therapy during minor surgery
(endoscopy, bronchoscopy, dental surgery).

27. Respiratory & cardiovascular depression
ADVERSE EFFECTS
Ataxia (motor incoordination),
Cognitive impairment.
Hangover: Sleep tendency, drowsiness,
confusion especially in long acting drugs.
Tolerance
Dependence: Physical and Psychological
Skin rash and teratogenic effect.
Respiratory & cardiovascular depression
(Toxic effects).

28. Withdrawal symptoms:
Rebound insomnia, anorexia, anxiety, agitation, tremors and convulsion.

29. t ½ of benzodiazepines Drug Interactions Examples CNS depressants
CNS depressants, alcohol & Antihistaminics of
effect of benzodiazepines
Cytochrome P450 (CYT P450) inhibitors
Cimetidine & Erythromycin
t ½ of benzodiazepines
CYT P450 inducers
Phenytoin & Rifampicin
t 1/2 of benzodiazepines

30. Dose should be reduced in
Liver disease
Old people.
Precautions
Not for pregnant women or breast-feeding.
Not for people over 65.
Used for limited time (2 weeks)

31. FLUMAZENIL a selective competitive antagonist of BZD receptors.
Blocks action of benzodiazepines, zolpidem, & zaleplon but not other sedative/hypnotics.
Blocks psychomotor, cognitive and memory
impairment of BZs.

32. PHARMACOKINETICS
Has short duration of action T 1 /2 = 1 hour
Absorbed orally
Undergoes extensive first pass metabolism
NO active metabolites
Should be used IV
(Repeated doses are necessary).

33. Therapeutic Uses 1. Acute BZD toxicity (comatose patients).
2. Reversal of BZD sedation after endoscopy,
dentistry.
Side Effects
  Nausea
Dizziness
Precipitate withdrawal symptoms.

34. Zolpidem (Ambien)
Imidazopyridine derivative.
Acts on benzodiazepine receptors (BZ 1) &
facilitate GABA mediated neuronal inhibition.
Its action is antagonized by flumazenil.
Rapidly absorbed from GIT and metabolized to inactive metabolites via liver CYT P450.
 Short duration of action ( 2- 4 h).

35. has no muscle relaxant effect.
 has no anticonvulsant effect.
  Minimal psychomotor dysfunction
Minimal tolerance & dependence.
 Minimal rebound insomnia.
 Its efficacy is similar to benzodiazepines.
Minor effect on sleep pattern, but high
doses suppress REM.
Respiratory depression occur at high doses in
combination with other CNS depressant as
ethanol.

36. Adverse Effects
Dizziness
GIT upset
Drowsiness
Uses
a hypnotic drug for short term treatment of insomnia.

37. Drug Interactions
Inducers
Rifampicin, phenytoin, carbamazepine
Inhibitors
Cimetidine, erythromycin

38. Short duration of action (1 hr)
Zaleplon
Binds to BZs receptors and facilitate GABA
actions.
Rapid absorption
Short onset of action
Short duration of action (1 hr)
Metabolized by liver microsomal enzymes CYP3A4
Metabolism is inhibited by cimetidine.

39. Decreases sleep latency
Little effect on sleep pattern
Potentiates action of other CNS depressants (alcohol).
Dose reduction as before.
Used as hypnotic drug
Advantages
Less impairment of pyschomotor and cognitive functions than BZs or zolpidem.

40. Barbiturates are second choice as sedative - hypnotic
Mechanism of Action
are less selective in action than BZD.
Facilitation of GABA action on the brain. increase the duration of the GABA gated channel opening but in large dose, they can directly activating chloride channels. (not through BZD receptors).
depress excitatory neurotransmitters action.
Interfere with Na & K transport across cell membranes (reticular activating system inhibition).

41. Classification of barbiturates:
Long acting( h): Phenobarbitone
Intermediate (8-24h): Amylobarbitone
Short-acting(3-8h):
Pentobarbitone
Secobarbitone
Amobarbital
Ultrashort acting (25 minutes): thiopental

42. Pharmacokinetics
All barbiturates are weak acids
Are absorbed orally.
Distribute throughout the body depending on lipid solubility e.g. thiobarbiturates are very lipid soluble with high rate of entry into CNS.
Redistribute in the body from the brain to
skeletal muscles - adipose tissues.

43. Metabolized in the liver to inactive metabolites
Excreted in the urine. Alkalinization increases
excretion ( NaHCO3 ).
Cross the placenta ( # pregnancy).

44. Pharmacological actions
1. CNS depression : a dose-dependent fashion.
Sedative & hypnotic
anesthesia in large dose
Anticonvulsant action
Coma and death.
2. Respiratory depression: is dose –related.
suppress hypoxic and chemoreceptor response to CO2
Large doses respiratory depression & death.

45. 3. CVS depressions
Healthy patient: at low doses, they have
insignificant effects.
Hypovolemic states, CHF, normal doses
may cause cardiovascular collapse.
Large dose  circulatory collapse due to
medullary vasomotor depression  direct
vasodilatation.

46. 4. Enzyme induction.
CYT P-450 microsomal enzymes inducers (Tolerance - drug interaction).
      
Increase activity of hepatic gamma amino
levulinic acid synthetase (ALA)  synthesis of
porphyrin (# porphyria).

47. Uses : Anticonvulsants: (Phenobarbitone)
Phenobarbital is indicated in the treatment of all types of seizures except absence seizures.
Tonic-clonic seizures, status epilepticus
Eclampsia and febrile convulsion.
Induction of anesthesia (thiopental, methohexital).
Hypnotic (pentobarbital)
Hyperbilirubinemia and kernicterus in the neonates (increase glucouronyl transferase activity).

48. Adverse effects:
1.  Respiratory depression.
2. Hangover: residual sedation after awakening.
3. Tolerance
4. Withdrawal symptoms
5. Precipitation of acute attack of porphyria.
6. Many drug interactions.
7. Allergic reaction: urticaria and skin rash.

49. Toxicity
Respiratory depression, cardiovascular collapse, coma and death.
Contraindications
1.  Acute intermittent porphria.
2.  Respiratory obstruction.
3.  Liver & kidney diseases.
4.  Shock.
5.  Old people (mental confusion).
6.  Pregnancy.
7.  Hypersensitivity to barbiturates.

50. Drug interactions
1. Other CNS depressants: Ethanol
2. MAOI: potentiate CNS depression
3. Phenytoin, warfarin, and dicumarol: their
metabolism is increased.

51. Advantages of BZD over barbiturates
1. Selective: minimal respiratory and cardiovascular depression.
2. High therapeutic index.
3. Less hangover.
4. Not enzyme inducer.
5. Less dependence with minimal withdrawal symptoms.
6. Has specific antagonist.