1. Anxiolytic, Sedative-Hypnotic Drugs Department of pharmacology

2. Contents
Overview
History
Benzodiazepines
Barbiturates
Other drugs

3. Physiology of sleep Sleep： NREMS （non-rapid-eye movement sleep ） REMS
SWS
（slow wave sleep ）
Stage 3,4 of NREMS are called SWS

4. Definitions
Anxiolytic
Sedation
Hypnosis

5. Anxiety Feeling of helplessness Difficulty in concentrating
Irritability & insomnia
GI disturbances
Excessive perspiration
Dread(terror)

6. Anxiety (Edvard Munch, 1894) The Scream (Edvard Munch, 1893)

7. Sedation
decreases activity, moderates excitement and calms the recipient

8. Sedation Character: Decreased anxiety Decreased motor activity
Decreased mental acuity

9. Hypnosis
produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep

10. Hypnosis Character: Increased tendency to sleep
Induce the soporific state( Sleep)

11. History
In the latter part of 19th century, bromide and chloral hydrate were developed.
by 1912 Phenobarbital (barbiturate) and within the next 25 years, 50 similar drugs were discovered.
In the1950’s meprobamate was discovered

12. History
In 1960, the first receptor-specific drugs, the benzodiazepines was discovered

13. History
By the mid 1990’s, non-benzodiazepines, with hopefully fewer side effects and a lower risk for dependence
such as buspirone (Buspar), an anxiolytic and zolpidem (Ambien) a hypnotic were developed.

14. History
Presently, the search continues for more effective and safer agents.

15. Classification
1.Benzodiazepines
2.Barbiturates
3.Other drugs

16. Benzodiazepines Pharmacological effects Mechanism of action
Therapeutic uses
Pharmacokinetics
Adverse effects
Precautions

17. Benzodiazepines 【classification】 1.short-acting triazolam (t1/2 2~4h)
2.intermediate-acting
chlordiazepoxide (t1/2 5~10h)
oxazepam (t1/2 5~10h)
3.long-acting
diazepam (t1/2 30~60h)
flurazepam (t1/2 50~100h)

18. Pharmacokinetics
Benzodiazepines are lipophilic and are rapidly and completely absorbed after oral administration
distributed throughout body.

19. Most benzodiazepines are metabolized by hepatic microsomal metabolizing system to compounds that are also active.
The benzodiazepines are excreted in urine.

20. Diazepam

21. Pharmacologic effects and uses antianxiety small dose sedation hypnosis anticonvulsion respiratory depression large dose DOSE, ADMINISTRATION

22. Pharmacological effects
1) Reduction of anxiety
-At low doses, the drugs cause little sedation
-Inhibiting neuronal circuits in the limbic system of the brain selectively

23. Pharmacological effects
2) Sedative
- Decreased anxiety leads to calming effect - No effects on motor or mental functions - Minimal CNS depression

24. Pharmacological effect
3) Hypnotic action
-at high doses, produce drowsiness & sleep
- higher CNS depression by increased dose

25. Characteristics of hypnosis
3) Hypnotic action
High selectivity, wide margin of safety, no anesthetic effect;
Respiratory depression is small, not easily stop breathing
The low incidence of tolerance and dependence after long-term use
Characteristics of hypnosis

26. Pharmacological effects
4) Anticonvulsant
-exert anticonvulsant effects without marked central nervous system depression
so that mental and physiologic activity are relatively unaffected.

27. - Increasing presynaptic inhibition in the spinal cord
5)Muscle relaxant
- Increasing presynaptic inhibition in the spinal cord

28. 5)Muscle relaxant
-exert inhibitory effects on polysynaptic reflexes and internuncial transmission

29. 5)Muscle relaxant
at high doses may also depress transmission at the skeletal neuromuscular junction

30. 5 transmembrane polypeptide subunits per receptor/channel complex
Mechanism of Action
“Most” sedative-hypnotics exert effects on GABA A receptor
GABA - the major inhibitory NT in the CNS
GABAa receptors -
5 transmembrane polypeptide subunits per receptor/channel complex

31. GABAA－R ß subunite ß subunite BDZR steroid α subunite Picrotoxin
barbiturate
benzodiazepine
ß subunite
α subunite
GABAR
BDZR
GABAR
γ subunite

32. Mechanism of Action
GABA binding stimulates Cl- current hyperpolarizing effect inhibitory effect on neuronal excitability

33. Mechanism of Action
GABAA receptor composition varies in different regions
BNZs bind to receptors with alpha & gamma subunits.
BNZ binding “enhances” the effect of GABA on the Cl-channel
BNZs exert no effect in the absence of GABA

34. Mechanism of action opens Cl— channel Cl— influx to neurons
Benzodiazepines activate BZR
promote GABA binding to GABAA receptors
opens Cl— channel
Cl— influx to neurons
causes a small hyperpolarization
inhibits formation of action potentials
inhibitory effect on neuronal conduction.*

37. capable of relieving anxiety at sedative doses,
【Therapeutic uses】
1. antianxiety
(1) effect
capable of relieving anxiety at sedative doses,
but benzodiazepines exert antianxiety action at the lowest effective doses that do not cause sedation.

38. 1. antianxiety
(2) use
anxiety states: restlessness
worry
stress
phobia states
common drug: chlordiazepoxide, diazepam
P.O./small dose

39. tracheoscopy examination electric defibrillation
2. sedation(calming effect)
use:
general anaesthesis
tracheoscopy examination
electric defibrillation
(temporary loss of memory, i.v.)
common drug: diazepam
P.O. / i.v. /small dose

40. 3. hypnosis (1) effect to reduce awaking times, to prolong sleep time to shorten sleep latency.

41. 3. hypnosis (2) use insomnia, especially insomnia with anxiety
common drug: flurazepam, temazepam,
triazolam,
P.O./middle dose

42. 4. anticonvulsant effect (1) effect to inhibit development and spread of epileptiform activity in CNS. (2)use: convulsion and status epilepticus, injection/large dose.

43. 4. anticonvulsant effect
(3) common drug:
①clonazepam for chronic treatment of epilepsy;
②diazepam for terminating grand mal epileptic seizures and status epilepticus;
③chlordiazepoxide, clorazepate, diazepam and oxazepam for alcohol withdrawal.

44. 5. muscle relaxation (1) effect
inhibitory effects on polysynaptic reflexes and internuncial transmission in CNS, leading to muscle relaxation
(2) use
relaxing muscle spasm induced by cerebral palsy
common drug: diazepam
injection/large dose

45. Action
Clinical use
Anxiolytic - relief of anxiety
-Anxiety and panic disorders, phobias
Hypnotic - promotion of sleep
- Insomnia
Myorelaxant - muscle relaxation
- Muscle spasms
Anticonvulsant - stop Convulsions
- some forms of epilepsy
Amnesia - impair short-term memory
Premedication for operations

46. Pharmacokinetics A. Absorption: orally.
Benzodiazepines Diazepam
A. Absorption: orally.
crosses the placental barrier and blood-brain barrier
B. Distribution: extensively
is highly binding to plasma protein

47. Pharmacokinetics C. Biotransformation:
Benzodiazepines Diazepam
C. Biotransformation:
-Hepatic oxidation: long-t1/2, active metabolites
Glucuronidation: short-t1/2, no active metab.
D. Excretion: The water-soluble metabolites of benzodiazepines are excreted mainly via the kidney.
Pharmacokinetics

48. 【adverse effects】 Benzodiazepines have a low toxicity and wide margin of safety (therapeutic index). 1. central inhibitory effect dizziness, asthenia, drowsiness. 2. tolerance, dependence and addiction. 3. acute toxication flumazenil--competitively BZR blocker.

49. Adverse effects
A Depression of central nervous system: drowsiness, a significant impact on driving ability
B Tolerance; Psychologic & Physiologic dependence,

50. Tolerance
-Decreased responsiveness to a drug following repeated exposure is a common feature of sedative-hypnotic use.
-Result in an increase in the dose needed to maintain symptomatic improvement or to promote sleep.

51. The reason of tolerance
-The mechanisms responsible for tolerance to sedative-hypnotics are not well understood.
-is associated with down regulation of brain benzodiazepine receptors.

52. Precautions Enhance the effect of alcohol and other CNS depressants
Be care for patients of liver diseases
(why?)

53. Barbiturates
Overview
The typical sedative-hypnotic for treatment of anxiety and insomnia from 1912 to 1960.

54. Barbiturates associated with suicides, death by accidental ingestion.
Overview
associated with suicides, death by accidental ingestion.
dependency and abuse, along with serious interactions with other drugs and alcohol.

55. Barbiturates less commonly used due to undesirable side-effects.
-induces psychologic & physical dependence.
–  Dose-dependent sedation, hypnosis, general anesthesia,coma,death.

56. Barbiturates 【classification】 1. ultra-short-acting
thiopental (action of duration：0.25h)
2. short-acting
secobarbital (action of duration：2~3h)
3.intermediate-acting
pentobarbital and amobarbital
(action of duration：3~6h)
4. long-acting
phenobarbital (action of duration：6~8h)

57. Pharmacokinetics
Duration of action depends on
rate of metabolic degradation,
degree of lipid solubility,
extent of binding to serum proteins.

58. Pharmacokinetics
Ultra-short-acting barbiturates are highly lipid-soluble, whereas long- acting barbiturates are lowly lipid-soluble.

59. Pharmacokinetics redistribution: e.g. thiopental.
excretion via kidney. Alkalinization of urine profoundly promotes excretion of barbiturates.

60. Mechanism of action ①to enhance effects of GABA
Mechanism of action ①to enhance effects of GABA. ②to interfere with sodium and potassium transport across cell membrane that leads to inhibition of mesencephalic reticular activating system.

61. Mechanism of action ③to directly activate chloride channel,
to prolong opening time of chloride channel,
to increase influx of Cl- to enlarge membrane potential in large dose.

62. Pharmacologic effects and clinical uses
1. Sedation: barbiturates depress the CNS at all levels in a dose-dependent fashion.
2. Hypnotics: they decrease the amount of time spent in REM sleep.

63. Pharmacologic effects and clinical uses
3.Anesthesia and administration before anesthetic.
4.Anticonvulsant: Phenobarbital.

64. Benzodiazepines Barbiturates
CNS Effects
Increasing dose
Coma
Barbiturates
Medullary depression
Anesthesia
Hypnosis
Sedation, Anxiolytics
Benzodiazepines
Possible selective anticonvulsant & muscle-relaxing activity

65. 【pharmacologic effects】 to depress CNS at all levels sedation small dose hypnosis anticonvulsion anesthesia respiratory depression depression of vasomotor center large dose

66. Pharmacologic effects and clinical uses
5. Muscle relaxation
6. Effects on respiration and Cardiovascular system
7. Most barbiturates, but especially Phenobarbital, are capable of inducing the hepatic microsomal P-450.

67. physiologic and psychological dependence.
Untoward effects
1.Depressant effects include over-sedation and decrease in REM sleep.
2. Barbiturate dependence.
physiologic and psychological dependence.

68. 3. Addiction, withdrawal syndrome.
Withdrawal of barbiturates may result in
grand mal seizures,
severe tremors,
vivid hallucinations,
psychoses.
Abrupt withdrawal should be avoided.

69. (1) clinical menifestations coma, diminished reflexes,
4. acute barbiturate overdosage
(1) clinical menifestations
coma,
diminished reflexes,
severe respiratory depression,
cardiovascular collapse,
renal failure.

70. 4. acute barbiturate overdosage
(2) treatments
① supporting respiration and circulation;
② alkalizing gastric juice, body fluids and
urine(sodium bicarbonate),
③ diuresis.

71. Differentiation of barbiturates with benzodiazepines benzodiazepines barbiturates 1. antianxiety: dose lower than same dose as one for sedation. for sedation. 2. shortening REMS : weak obvious 3. central muscular have no 4. anaesthesis: no have 5. hepatic micro- no have some induction: 6. margin of safety: wide narrow 7. depression of weak strong respiration:

72. Other drugs Buspirone 5-HT-1A mixed agonist-antagonist, weak DA block
Not a benzo, not hypnotic, no tolerance, no dependence, no withdrawal symptoms Anxiolytic, possible efficacy
No anticonvulsant

73. Another sedative hypnotic drug
Melatonin (MT)
It's secreted by the pineal gland, a pea-size structure at the center of the brain.
At night melatonin is produced to help our bodies regulate our sleep-wake cycles.

74. Another sedative hypnotic drug Melatonin (MT)
The amount of it produced by our body seems to lessen as we get older.
This may be can explain why young people have less problem sleeping than older people.

75. Melatonin (MT)
hasten sleep and ease jet lag, without the hazards or side effects of prescription sleeping pills.
to make people feel better, strengthen the immune system,

76. Melatonin (MT)
it's effect as an immuno-modulator in cancer, delayed sleep-phase disorders, and jet lag.

77. Another sedative hypnotic drug
Chloral hydrate
1. a relatively safe hypnotic drug, inducing sleep in a half hour and lasting about 6 hours.
2. relatvely small reduction in REM sleep.
3. use: children and the elderly with
insomania, most effective for 1-3 nights.

78. Another sedative hypnotic drug Chloral hydrate
4. bad-tasting and irritating to the gastrointestinal tract, administered by enema in children.
5. addiction can occur.

79. Paraldehyde 1. CNS depressant activity of paraldehyde resembles that of alcohol, chloral hydrate and barbiturates. 2. use exclusively for patients undergoing withdrawal from alcohol and for patients with hepatic or renal failure.

80. Summary for this chapter 1. main effects 2. main uses 3
Summary for this chapter 1. main effects 2. main uses 3.main adverse reactions central inhibition dependence toxic effects 4.common drugs 5.dose and administration

81. sedative-hypnotic drugs
Barbiturates
Barbiturates both enhance GABA responses and mimic GABA by opening the chloride channel in the absence of GABA

82. Barbiturates depress the CNS in a dose dependent fashion, producing sedation, sleep, anesthesia, coma, and, ultimately, fatal depression of respiration and cardiovascular regulation

83. Barbiturates will induce the liver P-450 system.
other drug that is metabolized by the P-450 system will be altered by the presence of barbiturates.

84. The barbiturates as older sedative-hypnotic drugs have a low degree of selectivity and therapeutic index.
Thiopental and methohexital, the ultra-short-acting barbiturates, are used in anesthesia
The long-duration barbiturate phenobarbital is used to treat epilepsy

85. BENZODIAZEPINES
Binding of benzodiazepines to a specific site enhances the affinity of GABA receptors for GABA, resulting in more frequent opening of the chloride channels.

86. BENZODIAZEPINES
The increased influx of chloride cause hyperpolarization and increased inhibition.

87. The effects of benzodiazepines are decreasing anxiety, sedation, hypnosis, neural muscle relaxation, and anticonvulsant activity
The benzodiazepines reduce anxiety at doses that do not produce sedation

88. Most benzodiazepine are metabolized in the liver to active metabolites
Most benzodiazepine are metabolized in the liver to active metabolites. In general the metabolites have slower elimination rates than the parent compound.
FLUMAZENIL is a benzodiazepine antagonist

89. Q1: What is the cellular mechanism of action and pharmacological agent of BENZODIAZEPINES?

90. Q2. Description of different point for Benzodiazepines and Barbiturates