1. Sedative Hypnotics and anxiolytics

2. Terminology Tranquilizers (anxiolytics): Treat excitment and anxiety
Sedative-Hypnotics (sleeping pills): 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 BZ 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. Pharmacokinetics:
absorption: well absorbed if given orally , Cmax reached in about 1 h
strongly bound to plasma proteins
distribution: high lipid solubility
metabolism: hydroxylation &conjugation with glucuronic acid

13. Pharmacological Actions

14. 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

15. Therapeutic uses

16. 1) as anxiolytic
Short-term treatment of acute anxiety states

17. 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

18. 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 and pains, headache
The relaxant effect of BZs may therefore be clinically useful

19. 4) As anticonvulsants
Clonazepam has selective anticonvulsant action ( epilepsy)
Diazepam i.v. in status epilepticus

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

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

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

23. Pharmacokinetics
BZS are well absorbed orally, giving a peak plasma concentration in about 1 hour
They bind strongly to plasma protein, 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 anaesthesia)
BZs are all metabolized and excreted in the urine

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

25. Classificaion of BZs According to therapeutic uses:
  Hypnotic- Temazepam, Nitrazepam Anti-anxiety- Diazepam, Oxazepam
For panic attacks; Alprazolam Anticonvulsant- Diazepam, Lorazepam,

26. Advantages

27. 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

28. 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
5- BZs produce minimal sedation and motor impairment
6- A Benzodiazepine antagonist is available (Flumazenil)

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

30. 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
The term inverse agonist (Ch. 2) is applied to drugs that bind to benzodiazepine receptors and exert the opposite effect to that of conventional benzodiazepines, producing signs of increased anxiety and convulsions.

31. Side Effects

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

33. 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

34. Contraindications

35. 1.Pregnancy, labour and lactation:
During pregnancy
Late in pregnancy or around the time of labor 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

36. II. BUSPIRONE Mechanism of action: Advantages of buspirone:
Buspirone is a 5HT1A receptor agonist
with anxiolytic activity but little sedation
5-HT1A receptors are inhibitory receptors that reduce the release of 5-HT and other mediators
Advantages of buspirone:
1.Unlike BZs, buspirone has no sedative hypnotic, anticonvulsant, or muscle relaxant properties (anxiolytic only)
2. It has minimal abuse liability
II. BUSPIRONE

37. 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 days or weeks to develop . (useful in chronic anxiety states)
Buspirone is ineffective in controlling panic attacks or severe anxiety states

38. Side effects
Buspirone has side effects quite different from those of BZs. It does not cause sedation or motor incoordination, nor have withdrawal effects been reported.
Main side effects are nausea, dizziness, headache and restlessness
Less troublesome than the side effects of BZs

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

40. 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

41. 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

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

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

44. 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)

45. 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

46. 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

47. 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

48. 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

49. 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
Respiratory depression occurs only if large doses of zolpidem are ingested together with other central depressants

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

51. 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

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

53. 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

54. 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)

55. 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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