4.2 | Sedative-Hypnotic Drugs

Sedative

- anxiolytic (reduce anxiety)

- WITHOUT drowsiness

Hypnotic

- with drowsiness

- maintain state of sleep

Sedative-Hypnotic: Absorption

depends on several factors

- primarily on lipophilicity

- site of action: CNS

Degree of lipophilicity

- determines the rate a drug can enter the CNS

- responsible for its rapid onset of action

Degree of lipophilicity: Absorption & Distribution

easy absorption

rapid distribution

can also cross placental barrier: ADR

may contribute to depression of neonatal vital sign when taken pre delivery period

detectable in breast milk: ADR

cause depressant effect in the nursing infant

Sedative-Hypnotic: Drug Classes (6)

1. Benzodiazepines

2. Barbiturates

3. Newer Hypnotics

4. Melatonin-Receptor Agonists

5. Orexin Antagonists

6. 5-HT Receptor Agonist

Sedative-Hypnotic Drug Classes: Older Generations (2)

1. Benzodiazepines

2. Barbiturates

Benzodiazepines

Widely used class with their effects attributed to the presence of halogen or nitro group at C7

Benzodiazepines: Metabolism is dependent on

3-OH group (easily metabolized)

Without 3-OH group

- long-acting

- not easily metabolized

Benzodiazepines: Primarily carried out by (3)

1. CYP3A4 metabolism

2. Glucoronidation

3. Urinary excretion

Benzodiazepines: Phase 1 Metabolites

1. many stay active - Desmethyldiazepam

2. some have long half-lives: ~40 hours

Short half-life BZDs

- rapidly conjugated

- more useful as HYPNOTIC than a sedative

Short half-life BZD: Drug

Midazolam

Benzodiazepines: Drugs (13)

1. Alprazolam

2. Chlordiazepoxide

3. Clonazepam

4. Clorazepate

5. Diazepam

6. Estazolam

7. Flurazepam

8. Lorazepam

9. Midazolam

10. Oxazepam

11. Quazepam

12. Temazepam

13. Triazolam

Barbiturates

Effects attributed to the 5,5-substitution of the barbituric acid structure

Barbiturates: Use

less as anxiolytics

more as anticonvulsants

Barbiturates are used LESS as anxiolytics due to (4)

1. numerous ADRs

2. drug effects

3. drug interactions

4. high degree of tolerance noted

Barbiturates: Primarily carried out by (3)

1. Hepatic metabolism

2. Glucoronidation

3. Urinary excretion

Barbiturates: Primary Metabolism

Hepatic metabolism through oxidative reactions leading to

1. alcohols

2. acids

3. ketone metabolites

Barbiturates: True or False: All barbiturates undergo urinary excretion.

FALSE. Thiobarbital does not undergo excretion.

Barbiturates: Urinary excretion

- slow

- except thiobarbital

Barbiturates: % Excreted Unchanged

20-30%

Barbiturates: Increased Elimination via?

Urinary Alkalinization

Urinary Alkalinization via?

NaHCO3

Hence, treatment for Barbiturates toxicity/overdose is?

NaHCO3 ionizes WAs like barbiturates

What ionizes weak bases?

Ascorbic acid ionizes WBs (prohibited/regulated drugs) like Amphetamine

Barbiturates: Drugs (6)

1. Amobarbital

2. Butabarbital

3. Mephobarbital

4. Pentobarbital

5. Phentobarbital

6. Secobarbital

Barbiturates: Pharmacophore

Barbituric acid

Newer Hypnotics

- with novel chemical structure that are not related to BZDs

- exhibit similar MOA as Barbiturates and BZDs

Newer Hypnotics: AKA

Gen Z or Z-drugs

Newer Hypnotics: Drugs (3)

1. Zolpidem

2. Zalepion

3. Eszopiclone

Zolpidem

imidazopyridine

Zaleplon

pyrazolopyrimidine

Eszopiclone

cyclopyrrolone

Newer Hypnotics: Primarily carried out by (3)

1. CYP3A4 metabolism (like BZDs)

2. Glucoronidation

3. Urinary excretion

Newer Hypnotics: CYP3A4 metabolism (2)

1. Oxidation (like Barbis)

2. Hydroxylation

Melatonin-Receptor Agonists

acts on melatonin receptors

Melatonin receptors

- in the suprachiasmatic nuclei (SCN) in the anterior part of the hypothalamus

- activates their receptors to inhibit arousal signaling & promote sleep

Suprachiasmatic nuclei (SCN)

regulates circadian rhythm of the body

Melatonin-Receptor Agonists: Drugs (2)

1. Ramelteon

2. Tasimelteon

(mel: melatonin)

Orexin Antagonists

blocks orexin and other neuropeptides that are responsible for promoting wakefulness

Orexin Antagonists: Drugs (2)

1. Suvorexant

2. Lemoborexant

(-OREXANT

orex: orexin | ant: antagonist)

Orexin Antagonists: Primarily carried out by (2)

1. CYP3A4 Metabolism

2. Excretion

True or False: All sedative-hypnotics undergo urinary excretion.

FALSE. Suvorexant is mainly excreted in the feces and less in the urine

Suvorexant: Excretion

fecal, less in the urine

5-HT Receptor Agonists

- action: uncertain

- partial agonist of 5-HT receptors

- possible affinity of D3 receptors; centrally inhibitory

5-HT Receptor Agonists: Pharmacophore

Azaspirodecanediones

Azaspirodecanediones

Aza = N

Spiro = cyclic structure

decane = 10 C

diones = 2 ketoness

5-HT Receptor Agonists: Drugs (4)

1. Buspirone

2. Gepirone

3. Isapirone

4. Tiospirone

BZDs, Barbiturates, Newer Hypnotics: MOA

acts on the GABA receptor-chloride ion channel

GABA receptor-chloride ion channel

- hetero-oligomeric glycoprotein complex

- consists of 5+ membrane-spanning subunits.

- functions as Cl-channel

- activated by GABA NTs

GABAₐ receptors: Molecular Heterogeneity

Multiple forms of α, β, and γ subunits

- arranged in different penta-meric combinations

- so that GABA, receptors exhibit molecular heterogeneity.

GABAₐ receptors: triggers chloride channel opening

GABA interacts at two sites between α & β subunits

- triggering chloride channel opening with resulting membrane hyperpolarization.

BZDs & Newer Hypnotics: MOA

Binding occurs at a single site between α and γ subunits

- facilitating the process of chloride ion channel opening.

BZD Flumanezil

- binds at the site between α and γ subunits

- can reverse Zolpidem's hypnotic effects

GABAₐ receptors: Barbiturates

These binding sites are distinct from those of the barbiturates.

(3) Drugs that bind SELECTIVELY to GABAₐ

1. Zolpidem

2. Zaleplon

2. Eszopiclone

_ and other Sedative-Hypnotics have low affinity for GABA B

BZDs

_ potentiate GABAergic inhibition at all CNS levels

BZDs

BZDs potentiate GABAergic inhibition at all CNS levels

↑ efficacy of GABAergic synaptic inhibition

❌ substitute GABA

- enhance Cl-ion conductance by ↑ frequency of channel-opening events

GABA: Barbiturates similar to BZDs

interact with GABA at multiple sites

GABA: Barbiturates unlike BZDs

↑ duration of GABA-gated Cl-channel openings

↓ selective than BZDs

GABA: Barbiturates

- depress the action of excitatory NT glutamic acid

- less selective than BZDs

- more pronounced CNS depressant effects

- induced full surgical anesthesia

Sedative-Hypnotics: Drug Effects (6)

1. Sedation

2. Hypnosis

3. Anesthesia

4. Anticonvulsant

5. Muscle Relaxation

6. Respiratory & CV Function

Sedation: BZDs, Barbiturates, older agents

low dose: calming/anxiolytic effect

Sedation: BZDs only

dose-dependent anterograde amneasia

Hypnosis

- Varying effects on the latency

- onset of non-REM and REM sleep

Anesthesia: Good Agents (2)

1. Thiopental

2. Methohexital

Anesthesia: Thiopental & Methohexital

fast onset & tissue distribution

Anesthesia: BZDs (3)

1. Diazepam

2. Lorazepam

3. Midazolam

Anesthesia: BZDs: Indication

IV agents; adjuncts

Anesthesia: Newer agents

LACK anesthetic activity

Anticonvulsant: BZDs (4)

1. Clonazepam

2. Nitrazepam

3. Lorazepam

4. Diazepam

Anticonvulsant: Barbiturates (2)

1. Phenobarbital

2. Metharbital

Anticonvulsant: Barbiturates: Indication

generalized tonic-clonic seizures

Anticonvulsant: Drugs Lacking This (3)

1. Zolpidem

2. Zaleplon

3. Eszopiclone

Muscle Relaxation: Drugs (2)

1. High-dose meprobamate

2. BZDs

Muscle Relaxation: BZDs

inhibit transmission skeletal neuromuscular junction

Respiratory & CV Function: SEs (2)

1. Respiratory depression

2. Orthostatic hypotension

Respiratory & CV Function: IV drug

more significant effectts

Sedative-Hypnotics: Clinical Uses (8)

1. Anxiety relief

2. Insomnia

3. Surgical sedation / amnesia

4. Epilepsy & Seizure states

5. Balanced anesthesia

6. Alcohol / sedative-hypnotic withdrawal states

7. Muscle relaxation

8. Diagnostic aid in psychiatric condition

Anxiety relief

calming effect

Anxiety relief: Indications (2)

1. Secondary &

2. Generalized Anxiety Disorder (GAD)

Surgical sedation / amnesia: Agents

short-acting agents (preferred)

- like BZDs

BZDs: Adverse Effects (9)

1. CNS depression

2. Drowsiness

3. Ataxia

4. Confusion

5. Dysarthria

6. Nausea

7. Vomiting

8. Diarrhea

9. Potential for abuse & dependence

Antidote for BZD toxicity

Flumanezil

- GABA receptor antagonist

Barbiturates: Adverse Effects (10)

1. CNS effects

2. Respiratory depression

3. Bradycardia

4. Orthostatic hypotension

5. Steven-Johnson syndrome

6. Exfoliative dermatitis

7. Headache

8. Fever

9. Hepatotoxicity

10. Megaloblastic anemia

Megaloblastic anemia is specific to which Barbiturate?

Phenobarbital

Buspirone: Adverse Effects (5)

1. Restlessness

2. Dizziness

3. Headache

4. Diarrhea

5. Paresthesia

Sedative-Hypnotics: Other Effects

Teratogenicity

- different category

- caution for pregnant Px

Steven-Johnsons Syndrome & Toxic Epidermal Necrolysis

- rare

- immune-mediated

- mucocutaneous

- exact cause: not understood

- Type 4 Hypersensitivity

- Barbiturates > BZDs

- may also occur with 5-HT Agonists

SJS & TEN are ADRs associated with what drug classes?

- Barbiturates > BZDs

- may also occur with 5-HT Agonists