1. Sedative Hypnotics and anxiolytics
Dr. Yieldez Bassiouni

2. Terminology
Anxiolytics: Minor Tranquilizers treat excitment and anxiety
Sedative-Hypnotics: Sedation and sleep

3. Sedative hypnotics are drugs used for the treatment of anxiety and sleep disorders.
A sedative Sometimes called anxiolytic, or minor tranquilizer, reduces anxiety and exerts a calming effect
A hypnotic drug produces drowsiness and encourage the onset and maintenance of sleep

4. Anxiety disorders
Generalized anxiety disorder (GAD)= excessive anxiety lacking any clear reason
Panic disorder (sudden attacks of severe fear accompanied by sweating, tachycardia, chest pains,….)
Phobias (strong fears of snakes, open spaces, flying)
Post-traumatic stress disorder (anxiety triggered by recall of past stressful experiences)
Obsessive compulsive disorder (OCD) e.g. fear of contamination

5. Examples of Sedative-Hypnotic drugs:
1- Benzodiazepines
2- Buspirone
3- Zolpidem
4- Barbiturates
5- Ethyl alcohol
NB: BZs and barbiturates share very similar properties but BZs have a much safer pharmacological profile
All have the same
Mechanism of action
(acting on GABA)
except Buspirone

6. Graded dose-dependent depression of the CNS function
is a characteristic of sedative-hypnotics
Individual drugs differ in the relationship between the dose and the degree of CNS depression

7. BENZODIAZEPINES

8. Benzodiazepines (BZs) are the most widely used sedative-hypnotic drugs
They have replaced barbiturates for most uses, particularly for treatment of anxiety and sleep disorders

9. How Do BZs Work?

10. A model of the GABAA receptor-chloride ion channel
The receptor consists of five or more membrane-spanning subunits. GABA interact with alpha or beta subunits triggering chloride channel opening with resultant membrane hyperpolarization.
Binding of BZs to gamma subunits potentiates effects of GABA, (facilitates the process of channel opening).

11. BZs increases the frequency of channel opening by a given concentration of GABA, but no change in the mean open time

12. 1-BZs bind to specific BZ receptors
3- Opens chloride (Cl) channels, causing an
influx of Cl ions
4- hyperpolarization of the neuron and inhibition of neuronal firing
1-BZs bind to specific BZ receptors
2-GABA binds with the GABA A-receptor

13. Pharmacokinetics
BZS are well absorbed orally, giving a peak plasma concentration in about 1 hour
They bind strongly to plasma proteins, and their high lipid solubility causes many to accumulate in body fat
given by mouth or i.v. (e.g. diazepam in status epilepticus, midazolam in anesthesia)
BZs are all metabolized and excreted in the urine

14. Classificaion of BZs According to duration of action:
Very = ultra -short (< 6 h): Triazolam
Short (12-18 h): Lorazepam (Ativan)
Medium (24 h): Alprazolam (Xanax),
Long (24-48 h): Diazepam (Valium)
The longer acting agents form active metabolites with long half-lives

15. Pharmacological Actions

16. The main effects of BZs are:
1- Reduction of anxiety and aggression 2- Sedation & induction of sleep
3- Reduction of skeletal muscle tone and coordination
4- Anticonvulsant (antiepileptic) effect 5- Anterograde amnesia ., they obliterate memory of events experienced while under their influence

17. Therapeutic uses

18. 1) as anxiolytic Short-term treatment of acute anxiety states
Alprazolam for panic disorders. With the possible exception of alprazolam , benzodiazepines do not have antidepressant effects

19. 2) for insomnia
BZs decrease rapid eye movement (REM) sleep, which is associated with dreaming
For short-term courses, as tolerance , dependence, hangover may
occur
Temazepam, nitrazepam

20. 3) Reduction of muscle tone and coordination
Increased muscle tone is a common feature of anxiety states in humans and may contribute to the aches, pains and headache
The relaxant effect of BZs may therefore be clinically useful

21. 4) As anticonvulsants Through effects on GABAA receptors
Clonazepam has selective anticonvulsant action ( epilepsy)
Diazepam i.v. in status epilepticus to control life-threatening seizures

22. 5) Muscular disorders Strong muscle-relaxing properties In cases of :
- muscle spasm
- spastic disorders (MS, cerebral palsy)

23. 6) Treatment of alcohol withdrawal symptoms
By ameliorating the alcohol withdrawal syndrome
The commonly used drug is Diazepam

24. 7) as a pre-ansthetic medication
for : i) Anxiolytic effects
ii) Amnesia
(impair short-term memory)
8) To control extreme
mania (diazepam)

25. BZ antagonist “Flumazenil”
Mechanism of action
Flumazenil acts as a competitive antagonist to the binding of BZs to their receptors
Flumazenil is a short-acting drug while, most BZs have longer half-lives, therefore, repeated i.v. administration of flumazenil is required to avoid relapse into the sedative state

26. Therapeutic uses
1- To reverse the sedative effect of BZs used during anesthesia
2- For diagnosis of self-poisoning and also for treatment of acute BZs overdose
3- Hepatic encephalopathy as flumazenil may improve the mental status of these patients
4- Flumazenil can antagonize the hypnotic effect of zolpidem

27. Advantages

28. Why BZ have replaced barbiturates ??
1- Less tolerance & physical dependence
2- They cause less disturbance in sleep patterns
3- Barbiturates causes drug interaction because they are enzyme inducers
e.g. They increase metabolism of warfarin
due to induction of cytochrome P450
thus making it less effective

29. 4- BZ are Safe in overdose while Barbiturates have lower therapeutic index (easily overdosed)
They don’t produce marked and fatal CNS depression
Symptoms of overdose of BZ are less than of barbiturates and can be treated with Flumazenil
5- BZs produce minimal sedation and motor impairment
6- A Benzodiazepine antagonist is available (Flumazenil)

30. Advanges as Hypnotics
REM sleep ( rapid eye movement) is less affected if compared with the same effect of other hypnotics ( barbiturates)
Artificial interruption of REM sleep causes irritability and anxiety even if the total amount of sleep is not reduced

31. Side Effects of BZ

32. Drowsiness and confusion, amnesia
BZ may paradoxically produce an increase in irritability and aggression in some individuals (particularly if short- acting drugs are given (triazolam)
Hypotension in old patients
Ataxia occurs at high doses and interfere with motor coordination (e.g. driving a car)
BZs enhance the depressant effect of other drugs ; alcohol, in a more than additive way

34. Tolerance and dependence
If high doses of BZs are given over a prolonged period, weight gain as well as physical dependence may develop
Abrupt discontinuation of BZs causes withdrawal symptoms, including confusion, anxiety, restlessness, tremor and dizziness
Short-acting BZs (triazolam) cause more withdrawal effects
Less than Barbiturates

35. Contraindications

36. 1.Pregnancy, labour and lactation:
During pregnancy
Late in pregnancy or around the time of labour and delivery
During the period of breast feeding
2. In patients with myasthenia gravis: due to the muscle relaxing effect of BZs
3.Pre-existing CNS depression

37. II. BUSPIRONE (Buspar) Mechanism of action: Advantages of buspirone:
Buspirone is a partial agonist at 5HT1A receptor with anxiolytic activity but little sedation. It is this action that is thought to mediate its anxiolytic and antidepressant effects
It is primarily used to treat generalized anxiety disorder (GAD)
Advantages of buspirone:
1.Unlike BZs, buspirone has no sedative hypnotic, anticonvulsant, or muscle relaxant properties
2. It has minimal abuse liability

38. Disadvantages of buspirone:
3.Buspirone causes less psychomotor impairment than BZs and does not affect driving skills
4. The drug does not potentiate the CNS depressant effects of other sedative-hypnotics e.g. ethyl alcohol
Disadvantages of buspirone:
Its anxiolytic effect takes several weeks to develop . (useful in chronic anxiety states)
Buspirone is ineffective in controlling panic attacks or severe anxiety states

39. Side effects
Buspirone has side effects quite different from those of BZs.
Main side effects are nausea, dizziness, headache , restlessness, sleepiness
Less troublesome than the side effects of BZs

40. Drug interactions Drugs which increase plasma level of buspirone
Haloperidol
Itraconazole ( anti-fungal)
Drugs which decrease plasma level of buspirone
Rifampicin
Carbamazepine

41. IV. BARBITURATES
Barbiturates are non-selective CNS depressants. They can produce varying degrees of CNS depression ranging from mild sedation to general anesthesia

42. Barbiturates have been largely replaced by BZs, because of the following:
High incidence of tolerance and physical dependence following chronic use
Barbiturates have a low therapeutic index (they are dangerous in overdose)
Barbiturates are enzyme inducers especially cytochrome P450 system, they increase the rate of metabolic degradation of many other drugs, so liable to cause drug interactions
They don’t have an antagonist

43. Mechanism of Action:
Barbiturates like BZs, cause activation of GABAA receptor and opening of the Cl- channel associated with the receptor
The neuronal membrane is hyperpolarized and less likely to fire
They bind to a different site on the GABAA receptor/chloride channel, and their action is less specific.

44. Actions : At low doses, barbiturates produce sedation
At higher doses, they cause hypnosis followed by anesthesia
Overdosage may cause respiratory depression and death

45. CNS depression death ★ anesthesia ★ hypnosis ★ BZDs sedation ★
medullary depression★ Barbiturates
anesthesia ★
hypnosis ★ BZDs
sedation ★
antianxiety★
Relative concentration
CNS depression

46. Classification
Ultra-short acting: Thiopental Na is an i.v. anesthetic that acts within seconds with short duration of action
Short-acting: Pentobarbital and secobarbital act for 3-8 hours
Long-acting: Phenobarbital (> than 24 h)

47. Therapeutic Uses:
1- Anesthesia: Thiopental Na is used iv to induce anesthesia
2- As sedative-hypnotic agents: Barbiturates have been replaced by BZs
3-Anticonvulsants: Emergency treatment
of convulsions in status epilepticus by thiopental as the last approach

48. 4-Phenobarbital is used in long-term
management of tonic-clonic seizures and
eclampsia
5- To lower serum bilirubin in Neonatal jaundice (kernicterus)
Barbiturates such as phenobarbital can increase the conjugation of bilirubin and reduces this risk by inducing the activity of glucuronyl transferase enzyme

49. Side effects
1-CNS effects: drowsiness can interfere with motor & mental performance; hangover. In large doses, barbiturates cause marked depression of CNS (may be fatal) 2- Induction of P450 thus the rate at which they are metabolized increases over the first few days of administration. Also, it leads to increased metabolism of other drugs e.g. estrogen and warfarin ( oral contraceptives and oral anticoagulants) 3-Tolerance and physical dependence with prolonged use 4-Teratogenicity

50. Contraindications:
Because of enzyme induction, barbiturates are also dangerous to patients suffering from the metabolic disease known as acute intermittent porphyria
During labour
Old age
Severe respiratory diseases

51. III. ZOLPIDEM, Z drugs Mechanism of action:
Zolpidem is a non-benzodiazepine hypnotic that binds selectively to a subset of the BZs receptor family and facilitates GABA-mediated neuronal inhibition
Zolpidem has a rapid onset and a short duration of action (about 4 hours)
Its action is antagonized by flumazenil
Zopiclone is similar to zolpidem
ultrashort

52. Advantages Disadvantages
Rapid onset
less daytime sleepiness
Less tolerance or dependence with prolonged use
It has no effect on psychomotor skills
Antagonized by flumazenil
Least effect on REM
Short duration of action
Nightmares
GIT upset
Safe, however, respiratory depression occurs only if large doses of zolpidem are ingested together with other central depressants

53. Hypnotic drugs
On the basis of electroencephalography measurements, several levels of sleep can be recognized. Of particular psychological importance are rapid eye movement (REM) sleep, which is associated with dreaming, and slow-wave sleep, which corresponds to the deepest level of sleep when the metabolic rate and adrenal steroid secretion are at their lowest and the secretion of growth hormone is at its highest.
Most hypnotic drugs reduce the proportion of REM sleep, although BZs affect it less than other hypnotics, and zolpidem least of all. Artificial interruption of REM sleep causes irritability and anxiety

54. Hypnotic drugs Benzodiazepines (e.g. Temazepam , nitrazepam)
Related drugs working on the BZ receptor (e.g. zolpidem, zopiclone)
Sedating antihistamines (e.g. Diphenhydramine promethazine), which cause drowsiness and are used for occasional insomnia. They can impair performance the day after

55. V. ETHYL ALCOHOL (Ethanol)
Ethyl alcohol (ethanol) is the most
abused drug in the world. Ethyl alcohol in low to moderate amounts relieves anxiety and causes euphoria
Large dose causes hypnosis and respiratory depression which may be fatal

56. Mechanism of action
Ethanol enhances GABA- mediated synaptic inhibition
Ethanol inhibits excitatory NMDA glutamate receptors

57. Treatment of Chronic Alcoholism
Hospitalization, psychotherapy and nutritional therapy may be needed.
Drug therapy includes:
BZs (e.g. diazepam) are used to prevent alcohol withdrawal symptoms. They are preferred over barbiturates because of their wide margin of safety. The dose must be tapered slowly over several weeks

58. Disulfiram
The drug given by itself to nondrinkers has little effects however, it causes extreme discomfort to patients who drink alcohol (Flushing, throbbing headache, nausea, vomiting, sweating, hypotension and confusion)

59. Mechanism of action
Disulfiram acts by inhibiting aldehyde dehydrogenase thus, alcohol is metabolized as usual but acetaldehyde accumulates. Acetaldehyde will form the toxic intermediates; methanol and formaldehyde

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