Sedative/Hypnotics

Question 1

Sedative vs Hypnotic effect?

Answer 1

Hypnotic - major depression of CNS to produce drowsiness

Sedation - reduce anxiety and exert a calming effect - increasing dose can induce drowsiness

Elevated doses of barbiturates (sedative-hypnotics) you get hypnosis, then anesthesia, then respiratory depression and ultimately death. [Benzodiazepines are safer where you cannot get respiratory depression or death]

Question 2

Benzodiazepines MOA?

Answer 2

Mot widely used anxiolytic drugs that have replaced barbiturates due to being safer and more effective.

MOA - 2 benzo molecules bind bind to benzodiazepine binding site (BZ1, BZ2 - these are the subtypes within the CNS)on GABAa receptor [b/t alpha and gamma subunit] in neuronal membranes in the CNS increasing frequency of chloride channel opening [barbiturates cause increased duration of channel opening]
GABAa receptor - 2 alpha, 2 beta, 1 gamma subunit - these 5 subunits span the membrane and create a chloride channel
*Benzos enhance GABAs effect/action by allosterically enhancing the frequency of the channel – shift EC50 to the left (decreases) – benzos do not do anything on their own

Question 3

What are the different benzodiazepine-receptor interactions?

Answer 3

1. agonist - positive allosteric modulators as they enhance the GABA effect
2. antagonists - ex. Flumazenil - blocks benzodiazepine receptors preventing other benzo binding
3. inverse agonist - negative allosteric moedulators of GABA receptor functions that oppose GABA and close the channel [they cause anxiety and seizures]

Question 4

Flumazenil?

Answer 4

Benzodiazepine-receptor antagonist. Approved for reversing CNS depressant effects of benzo overdose and to hasten recovery post benzo use in anesthetic and diagnostic procedures.

• rapid onset
• short duration
• precipitates withdrawal in dependent pts
• may cause seizures if benzos are used to control seizures

Question 5

Actions of benzodiazepines?

Answer 5

1. reduce anxiety
2. sedative and hypnotic action
3. anticonvulsants
4. muscle relaxant
5. anesthesia

Question 6

Pharmacokinetics/metabolism of Benzodiazepines?

Answer 6

• lipophilic
• distributed throughout the body
• half lives vary and determine therapeutic use - short-, intermediate- and long-acting groups
• metabolism involves conjugation and urinary excretion [phase I rxn to form glucuronide via CYP3A4]
• Desmethyldiazepam - long-acting and has activemetabolite
• Oxazepam, lorazepam and temazepam do not need P450 metabolism [no phase I rxn] but they do undergo phase II rxn in the liver - they go straight to glucuronidation
• Flurazepam is oxidized by liver enzymes to active metabolites hat have longer half lives than the parent compound

Question 7

Long, intermediate and short acting benzodiazepines?

Answer 7

Long-acting [1-3 days] - diazepam, flurazepam

Intermediate-acting [10-20 hrs] - alprazolam, lorazepam, temazepam

Short-acting [3-8 hrs] - oxazepam, Triazolam

Question 8

Uses of benzodiazepines?

Answer 8

1. anxiety disorders - short-term use only [SSRIs are the long-term DOC management]
2. Muscle spasm - benzos relax muscles and tx muscular disorders [ex. diazepam]
3. tx seizures - Clonazepam (epileptic seizures) and Lorazepam and diazepam [status epilepticus]
4. Tx drug withdrawal - diazepam and oxazepam (esp withdrawal fro ethanol)
5. anesthesia
6. sleep disorders [long-acting flurazepam, intermediate-acting temazepam, short-acting triazolam]

Question 9

AE of benzodiazepines?

Answer 9

1. drowsiness and confusion
2. ataxia
3. cognitive impairment
4. psychological effects - paradoxical effects (rare)
5. dependence - if high doses are given over prolonged periods - abrupt discontinuation leads to withdrawal symptoms

Question 10

MOA barbiturates?

Answer 10

Replaced by benzodiazepines. These medications induce tolerance, physical dependence and lead to severe withdrawal symptoms. A coma ca occur at high doses.

Binds to different site from GABA and benzos increasing duration of GABA gated chloride channel opening.

Barbs can also block glutamate receptors and sodium channels.

• depress CNS [sedation, hypnosis, anesthesia, coma, death – with increase dosage]
• respiratory depression - suppress hypoxic and chemoreceptor response to CO2
• enzyme induction - barbs induce P450 enzymes
• anesthesia - ultra short acting barbs (ex. thiopental) are used IV to induce anesthesia
• anticonvulsant - phenobarbital used in long-term management of tonic-clonic seizures, status epilepticus and eclampsia

Question 11

AE of barbiturates?

Answer 11

• Drowsiness, impaired concentration
• Paradoxical excitement
• Hypersensitivity
• Hangover
• Respiratory: In the presence of pulmonary insufficiency they may cause serious respiratory depression.
• Pain: May worsen perception of pain.
• Dependence: Severe withdrawal syndrome.
• Poisoning: severe respiratory depression and central CV depression.

Question 12

Non-benzo benzodiazepine receptor agonist?

Answer 12

1. zolpidem
2. zaleplon
3. eszopiclone

**act at BZ1 subtype of benzodiazepine receptors acting as hypnotics with minimal muscle relaxing/anticonvulsant activity, lack of tolerance and low AE incidence

Question 13

Zolpidem?

Answer 13

• Short duration of action.
• Short half life = 1.5 - 3.5 h.
• Indicated for the short-term treatment of
insomnia characterized by difficulties with sleep
initiation.

Question 14

Zaleplon?

Answer 14

• Rapid onset and very short duration of action.
• Elimination half life = 1 h.
• Indicated for the short-term treatment of
insomnia.

Question 15

Eszopiclone?

Answer 15

• (S)-Entantiomer of zopiclone.
• Pharmacologically active enantiomer of
zopiclone.
• Approved for treatment of insomnia.
• Decreases sleep latency and improves sleep
maintenance.
• Half-life = 6 hours.

Question 16

Buspirone?

Answer 16

5-HT1A partial agonist

• There is no hypnotic, anticonvulsant or muscle relaxant properties – solely ANXIOLYTIC action and indicated for management of anxiety disorders
• takes 2-3 weeks for onset requiring some sort of gene expression [therefore use for chronic NOT acute management]

Advantages..
• Less psychomotor impairment than BZ.
• No drug interactions with EtOH
• No drug interactions with benzodiazepines and
other sedative-hypnotics
• No rebound anxiety or withdrawal signs on
abrupt discontinuance
• No dependence

**not that effective for tx of anxiety b/c it is very random and unpredictable – second line when other things fail

Question 17

Ramelteon?

Answer 17

Melatonin receptor agonist - MT1 and MT2 melatonin receptors indicated for tx of insomnia

*short half life and used for people who have problems of sleep onset

Question 18

Hydroxyzine?

Answer 18

Antihistamine with antiemetic activity that is also approved for symptomatic relief of anxiety.

Question 19

Propranolol?

Answer 19

Used to control performance anxiety [clonidine may also modify autonomic expression of anxiety]

Question 20

Dephenhydramine and doxylamine?

Answer 20

Nonprescription antihistamines with sedating properties used over the counter to treat anxiety and insomnia.