1. Sedative & Hypnotics By
Prof. Dr. Hanan Hagar

2. Sedative & Hypnotics
Sedative : Drugs that clam the patient and reduce anxiety without inducing normal sleep.
Hypnotic : 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 (BDZ)

6. Classifications According to Duration of Action :
- Short acting: (3-5 hours).
Triazolam
-  Intermediate: (6-24 hours).
Alprazolam
Lorazepam (ALEOT)
Estazolam
Oxazepam
Temazepam

7. Long acting: ( 24-72 hours) Chlorazepate Chlordiazepoxide
Diazepam Flurazepam.
Quazepam Prazepam
Nitrazepam

8. According to uses Sedative (Anxiolytics) Alprazolam Chlordiazepoxide
Diazepam Prazepam
Hypnotics
Triazolam
Lorazepam Estazolam Temazepam
Flurazepam Nitrazepam Quazepam
Preanesthetics
  Diazepam - Midazolam

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

10. Bzs  facilitation of 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, and limbic system.

12. 1. most of them are well absorbed orally, Rapid absorption
PHARMACOKINETICS
1. most of them are well absorbed orally,
Rapid absorption
e.g. triazolam & Alprazolam
diazepam & chlorazepate
Slow absorption
e.g. lorazepam & oxazepam, temazepam (LOT)

13. Diazepam-Chlordiazepoxide (IV only NOT IM)
2. Chlorazepate is a prodrug converted by acid hydrolysis in stomach to form nordiazepam (desmethyldiazepam).
3. Can be given parenterally
Diazepam-Chlordiazepoxide (IV
only NOT IM)
Midazolam – Lorazepam (IV or IM)

14. 4. Bzs are lipid soluble and widely distributed
5. Redistribution from CNS to skeletal muscles, adipose tissue) (termination of action).
6. Cross placental barrier during pregnancy and are excreted in milk (Fetal & neonatal depression).

15. 7. Highly bound to plasma protein.
8.  ALL Bzs are metabolized in the liver
Phase I: ( liver microsomal system)
Phase II: glucouronide conjugation and excreted in the urine.

16. 9. Many of Phase I metabolites are active
 elimination half life of the parent comp.  cumulative effect with multiple doses
EXCEPT No active metabolites are formed for (LEO) Lorazepam, Estazolam, Oxazepam

19. Pharmacological Actions
1. Anxiolytic action.
2. Depression of cognitive and psychomotor
function.
3.Anterograde amnesia.

20. 4. Hypnotic actions
at higher dose, BDZs change sleep pattern
Induction of normal sleep (latency of
sleep is reduced).
Increase non REM sleep (stage II).
Decrease REM sleep & slow waves sleep (3,4 stages). 
Usage for more than 2 weeks  tolerance to their effect on sleep patterns

22. 4. Anticonvulsant effect: especially
diazepam, lorazepam, clorazepate,
clonazepam, nitrazepam.
5. Central skeletal muscle relaxant effect
e.g. Diazepam relaxes muscle spasticity by presynaptic inhibition in the spinal cord.

23. 6. CVS and respiratory system: Minimal
depressant effects in therapeutic doses & in
normal patients.

24. Therapeutic Uses
Anxiety disorders:   alprazolam
General anxiety disorders
Panic attack - major depressive disorders

25. Sleep disorders (Insomnia).
Triazolam: initiate sleep ????
Estazolam - Lorazepam - temazepam: sustain sleep????
Flurazepam - Quazepam
Long acting drugs can cause hangover.

26. To control withdrawal symptoms of alcohols
diazepam- chlordiazepoxide.
Treatment of epilepsy
Diazepam – Lorazepam: Status epilepticus
Clonazepam-Clorazepate: absence , myoclonic seizures.
Muscle relaxation: in spastic states (Diazepam)

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

29. ADVERSE EFFECTS
Ataxia (motor incoordination), cognitive impairment.
2.Hangover Sleep tendency, drowsiness, confusion especially in long acting drugs.
3.  Tolerance
4. Physical and Psychological dependence
5.  withdrawal symptoms
Rebound Insomnia, anorexia, anxiety, agitation, tremors and convulsion.

30. 6. Drug Interaction
Synergistic effect with other CNS depressants
Enzyme Modulators. 
Rifampicin (decreases half life)
Cimetidine (increases half life)
7. Skin rash
8. Teratogenic effect.

31. Dose reduction in
Liver disease
Old people.
Contraindication
to be combined with Alcohol and other CNS depressants, antihistaminics. 

32. FLUMAZENIL
a selective competitive antagonist of BZD
receptors (Bz1).
Blocks action of benzodiazepines, zaleplon and zolpidem but not other sedative /hypnotics.
Blocks psychomotor, cognitive and memory
impairment of BZs.

33. 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).

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

35. Barbiturates are derivatives of barbituric acid
second choice as sedative – hypnotic
Its members end with the suffix (barbital or barbitone)
Thiobarbiturates are highly lipid soluble.

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

37. Mechanism of Action
1. 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).

38. 2. depress excitatory neurotransmitter actions
3. Interfere with Na & K transport across cell membranes (reticular activating system inhibition).
4. are less selective in action than BZD.

39. Pharmacokinetics
1.  All barbiturates are weak acids
2. are lipid soluble
4. absorbed orally.
3. distribute throughout the body
5. Thiobarbiturates are very lipid soluble (high rate of entry into CNS- very brief onset of action).

40. 6. Redistribute in the body from the brain to skeletal muscles- adipose tissues.
7. metabolized in the liver to inactive metabolites
8. Excreted in the urine.
Alkalinization increases excretion (NaHCO3)
9. Cross the placenta ( # pregnancy).

41. Pharmacological actions
CNS depression:
In a dose-dependent fashion.
Sedative
Hypnotic
Anesthesia in large dose
Anticonvulsant action
Coma and death.

42. 2. Respiratory depression:
is dose –related.
suppress hypoxic and chemoreceptor response to CO2
Large doses respiratory depression & death.

43. 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.

44. 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).

45. Uses :
Anticonvulsants: (Phenobarbitone)
tonic-clonic seizures, status epilepticus and febrile convulsion.
Induction of anesthesia
(thiopental, methohexital).

46. Hypnotic (pentobarbital)
Hyperbilirubinemia and kernicterus in the
neonates (increase glucouronyl transferase
activity).

47. 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.

48. 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.

49. 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.

52. Zolpidem (Ambien) imidazopyridine derivative.

53. 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).

54.   Only hypnotic effect
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.

55. has no muscle relaxant effect.
 has no anticonvulsant effect.
 Minimal psychomotor dysfunction
Minimal tolerance & dependence.
 Minimal rebound insomnia.

56. Uses
a hypnotic drug for short term treatment of insomnia
Dose should be reduced in hepatic or old patients.

57. Adverse Effects
GIT upset
Drowsiness
Dizziness
Drug interactions
Rifampicin (decreases half life)
Cimetidine (increases half life)

58. Zaleplon
Binds to BZs receptors and facilitate GABA
actions.

59. Zaleplon
Rapid absorption
rapid onset of action
Short duration of action (1 hr)
Metabolized by liver microsomal enzymes
metabolism is inhibited by cimetidine.

60. Only hypnotic effect
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 performance than BZs or zolpidem.