1. Sedative-Hypnotic Drugs
Marina Bergman PharmD PhD
Lecturer 
Clinical Generalist – Pharmacist
The Ohio State University
Wexner Medical Center

2. Little Yellow Pill What a drag it is getting old
"Kids are different today" I hear ev'ry mother say
Mother needs something today to calm her down
And though she's not really ill
There's a little yellow pill
She goes running for the shelter of a mother's little helper
And it helps her on her way, gets her through her busy day

3. Objectives Identify the major chemical classes of sedative-hypnotics.
Describe the pharmacodynamic of benzodiazepines and barbiturates, including their mechanisms of action.
Compare the pharmacokinetics of commonly used benzodiazepines and barbiturates and discuss how differences among them affect clinical use.
Describe the clinical uses and the adverse effects of sedative hypnotics. Identify the distinctive properties of buspirone, zolpidem eszopiclone , ramelteon and zaleplon.

4. Overview Anxiety – a state of tension, apprehension uneasiness.
Sedative (anxiolytic) - agent that reduces anxiety
Hypnotic - drug that induces sleep
Benzodiazepines (BZs)- widely used sedative-hypnotics
Barbiturates- anxiolytics at low doses, hypnotics at high doses

5. Learning Resource
Trevor AJ and Way WL, Sedative-Hypnotic Drugs, in Basic and Clinical Pharmacology, Katzung BG, Master SB, McGraw-Hill Lange, New York 2012.

6. Benzodiazepines (BZs)
Sedative (anxiolytics) – alprazolam, clorazepate chlordiazepoxide, diazepam, halazepam, lorazepam, oxazepam
Hypnotics – estezolam, lorazepam, quazepam, temazepam, triazolam

7. Safety

8. Chemical Structures of Benzodiazepines
Chemical structures of BZs- all members contain the 1,4 –benzodiazepines and most contain a halogen in the 7 position or a nitro group. Carboxamide group is present in most of the 7 member heterocyclic ring structure.

9. Mechanism of Action Receptor for BZs are found in many Brain regions
Binding of BZs to the GABAA receptor promotes the inhibitory action of GABA
BZs increase the frequency of GABA mediated chloride ion channel opening

10. gamma–Aminobutyric Acid GABA-alpha Receptor

11. Fig 1A Mechanism of action of GABA and benzodiazepines
GABAA receptors are composed of , ,  subunit families of which a combination of five or more span the postsynaptic membrane and surround a chloride channel.
Empty receptor is inactive, and the coupled chloride channel is closed.
Receptor Empty (No Agonists)
Cl-
GABA receptor
Chloride Channel closed
Benzodiazepine site

12. Fig 1B Mechanism of action of GABA and benzodiazepines
Binding of GABA causes chloride channel to open
Cl-
GABA
GABA receptor
Benzodiazepine site
Cl-

13. Fig 1C Mechanism of action of GABA and benzodiazepines
Benzodiazepines modulate the GABA effects by binding to their receptors near  and 2 subunits of GABAA receptor, thus increasing further the chloride influx.
Binding of GABA is enhanced by benzodiazepine, resulting in a greater entry of chloride ion
Cl-
Benzodiazepine
GABA
GABA receptor
Entry of chloride ions hyperpolarizes cell, making it difficult to depolarize and thus reducing neural excitability
Cl-
Cl-
Cl-
Cl-
Cl-

14. Pharmacological Action of BZs
Sedation (antianxiety)
Hypnosis
Anticonvulsant
Muscle relaxant
Amnesia

15. Duration of Action of Benzodiazepines

16. Therapeutic Uses Anxiety disorders Sleep disorders Muscular disorders
Seizures
Anesthesia

17. Anxiety Disorders
BZ’s are effective for the treatment of the anxiety symptoms due to depression schizophrenia, panic disorders, social anxiety disorder, GAD, performance anxiety, post traumatic stress disorder, OCD, phobias
The anti-anxiety effect of BZ’s is less subjective to tolerance
Long acting agents are preferred, (e.g. lorazepam, diazepam, alprazolam)

18. Sleep disorders
Flurazepam – reduces sleep-induction time and awakening
Temazepam – used for pt w/ inability to stay asleep
Triazolam – recurring insomnia, tolerance, rebound insomnia

19. Muscular disorders
Diazepam - muscle spasms, spasticity in multiple sclerosis and cerebral palsy
Clonazepam - chronic epilepsy
Diazepam or Lorazepam - status epilepticus
Chlordiazepoxide, Clorazepate, Diazepam, Oxazepam - alcohol withdraw related seizures

20. Anesthesia Conscious sedation – Midazolam
Induction of anesthesia- Midazolam, Lorazepam
Anxiety provoking and unpleasant procedures- Midazolam

21. Pharmacokinetics
Absorption – rapid and complete (lipophilic properties)
Distribution – throughout the body
Duration of action – determines use
Drug fate – metabolized to active compounds

22. Relationship of Half Life and Indication

23. Pharmacokinetics - Continued
BZ’s are lipophilic and they completely absorbed after oral administration.
Half life's of BZs is very important because the duration of action will determine the therapeutic use.
Many BZ’s are converted to active metabolites in the body
Lorazepam and Oxazepam do not form active metabolites. They undergo extrahepatic conjugation

24. Metabolism
Most BZs are metabolized by the liver. They undergo microsomal oxidation (phase 1 reaction), the metabolites are subsequently conjugated (phase II reaction) and excreted in the urine. Many phase I metabolites are pharmacologically active. The formation of active metabolites makes pharmacokinetic of the Bzs in humans complicated because the elimination half life of the parent drugs have little relationship to the time course of the pharmacological effects.

25. Benzodiazepines Half Life and Age

26. Dependence Psychological and physical – high doses, prolonged periods
Abrupt discontinuation- withdrawal
Long half-life – delayed withdrawal
Short half-life – abrupt, severe withdrawal
Withdrawal Signs- anxiety, confusion, insomnia, agitation, tremors, hyperreflexia and seizures

27. Tolerance
A decrease in responsiveness to repeated dose of the drug when used for more the 1-2 weeks
Cross tolerance may occur among the different BZs agents.

28. Rebound

29. Adverse effects Drowsiness and confusion Ataxia Cognitive impairment
Decreased long-term recall
Decreased learning

30. Flumazenil Benzodiazepine antagonist Administered i.v.
Rapid onset, short duration
Withdrawal in dependent patients
May cause seizures
Side effects

31. Other hypnotic Agents

32. Other hypnotic agents All are hypnotic, selective GABAA agonists
Zolpidem - not an anticonvulsant or muscle relaxant, fewer adverse effects
Zaleplon - metabolized in liver, 1hr half-life, reduced dosage in elderly and liver damage
Eszopiclone – metabolized in liver, 6hr half-life

33. Ramelteon Novel hypnotic for sleep induction
Agonist for MT1 and MT2 receptors
Acts via suprachiasmatic nuclei
No effect on GABAergic system
No rebound insomnia or withdrawal
Rapid absorption, extensive metabolism
Dizziness, somnolence, fatigue
Testosterone decrease, prolactin increase

34. Other Anxiolytic Agents
Hydroxyzine- an antihistamine, has low tendency for habituation and thus is useful in patients with anxiety who have history of drug abuse. Also Used in dental procedures
Antidepressants- SSRI, TCAs MAOI duloxetine venlafaxine all have proven efficacy in managing symptoms of anxiety

35. Buspirone Selective anxiolytic effects, slow onset (weeks)
Serotonin 5-HT1A and dopamine D2 agonist
No direct effect on GABAergic system
No anticonvulsant or muscle relaxant properties.
Low sedative, hypnotic, euphoric effects. Low abuse potential
No rebound insomnia or withdrawal
Low frequency of side effects

36. Comparison between Buspirone and Alprazolam

37. Barbiturates Phenobarbital Pentobarbital Secobarbital Amobarbital
Thiopental

38. Chemical Structures of Barbiturates and Other Hypnotic Drugs

39. Mechanism of Action Barbiturates: Interfere with Na+/K+ transport
Inhibit reticular activating system
Inhibit polysynaptic transmission
Potentiate GABA action on Cl- flux
Bind to subunits other than a and b

40. Barbiturate classification
Duration of action:
Thiopental – fast action, duration ~ 30 min, induction of anesthesia
Phenobarbital – duration > 1 day, seizure treatment
Pentobarbital, secobarbital, amobarbital short acting hypnotics, not anxiolytic

41. Sedative Hypnotic Dose and CNS Effects

42. Drug Action
Depression of CNS – dose dependent sedation, hypnosis, anesthesia, coma and death
Respiratory depression - suppressed CO2 response
Porphyria - Barbiturates can increase porphyrin synthesis and are contraindicated in patient with acute intermittent porphyria

43. Barbiturates and the P-450 Enzyme System
Barbiturates induce the formation of the liver microsomal enzymes that metabolize drugs.
The p-450 enzyme induction can lead to multiple drug interactions (e.g. birth control, warfarin, corticosteroids, anti epileptics)
Barbiturates will decrease the serum level of drugs that are metabolized by P-450 enzymes.

44. Therapeutic Uses
Anesthesia – induction of anesthesia selected for duration of action thiopental, ultra short-acting
Seizures – tonic-clonic, status epilepticus eclampsia, febrile seizures
Anxiety - sedation, tension, insomnia, mostly replaced by BZ’s

45. Pharmacokinetics Absorbed orally Distributed throughout body
Sequential redistribution
Short duration of action (thiopental)
Metabolized in liver
Excreted in urine

46. Adverse effects CNS- confusion, sedation, irritability Hypotension
Drug hangover
Respiratory depression
Addiction
Poisoning

47. Non-barbiturate Hypnotics
Chloral hydrate – acetaldehyde derivative sedative and hypnotic,fast sleep induction,
Can displaced warfarin from plasma proteins leading to increase anticoagulant effects
Antihistamines – diphenhydramine, doxylamine can be used for mild insomnia. Both have undesirable side effects. Can be purchase over-the-counter.
Ethanol - toxic potential

48. Drug Interaction with Alcohol
Alcohol when used with benzodiazepines, antihistamines or barbiturates can produced sever CNS depression
Alcohol should be avoided when a patient is using a sedative hypnotic agent from the classes above.

49. Special Populations
Elderly patients are more sensitive to the effect of sedative-hypnotics
Doses half of those used in young adults are considered safe and effective for the elderly.
Increase sensitivity to sedative-hypnotics is also more common in patients with cardiovascular disease, respiratory disease or hepatic impairment

50. Sedative and Hypnotic Drugs Quiz

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