Sedative-Hypnotic Drugs

Sedatives or anxiolytics

Agents that reduce anxiety and exerts a calming effect

Hypnotics

Agents that produce drowsiness and encourage the onset and maintenance of a state of sleep

Absorption depends on several factors, primarily on degree of lipophilicity (determines the rate a drug can enter the CNS and is responsible for its rapid onset of action)

lipophilicity

Absorption depends on several factors, primarily on degree of ____________ (determines the rate a drug can enter the CNS and is responsible for its rapid onset of action)

placental barrie

Sedatives can cross ________________ and may contribute to depression of neonatal vital sign when taken predelivery period.

breast milk

Sedatives are detectable in ______________ which may also cause depressant effect in the nursing infant.

Diazepam, Midazolam, Lorazepam

DRUGS INCLUDED IN THE SEDATIVES:

• examples of Benzodiazepines

Phenobarbital, Amobarbital, Thiopenta

DRUGS INCLUDED IN THE SEDATIVES:

• examples of Barbiturates

Zolpidem, Zaleplon, Eszopiclone

DRUGS INCLUDED IN THE SEDATIVES:

• examples of Newer Hypnotics

Ramelteon and Tasimelteon

DRUGS INCLUDED IN THE SEDATIVES:

• examples of Melatonin-Receptor Agonists

Suvorexant, Lemoborexant

DRUGS INCLUDED IN THE SEDATIVES:

• examples of Orexin Antagonists

Buspirone

DRUGS INCLUDED IN THE SEDATIVES:

• examples of 5-HT Receptor Agonist

level of anesthesia with slight medullary depression

DRUGS INCLUDED IN THE SEDATIVES:

• Benzodiazepines can produce effects up to the a.________________________, while increasing doses of barbiturates may progress to b.____________.

a = ?

coma

DRUGS INCLUDED IN THE SEDATIVES:

• Benzodiazepines can produce effects up to the a.________________________, while increasing doses of barbiturates may progress to b.____________.

b = ?

Benzodiazepines

DOSE-RESPONSE CURVE

Sedation

1. ______________ are used more frequently.

2. Newer, unclassified agents have a __________________.

1 = ?

flatter curve

DOSE-RESPONSE CURVE

Sedation

1. ______________ are used more frequently.

2. Newer, unclassified agents have a __________________.

2 = ?

Benzodiazepines

DOSE-RESPONSE CURVE

Hypnosis

1. ______________ can induce sleep which results to reduced REM

2. Rebound effect results to ________________________

3. _______________ for newer agents

1 = ?

Hyper-REM sleep

DOSE-RESPONSE CURVE

Hypnosis

1. ______________ can induce sleep which results to reduced REM

2. Rebound effect results to ________________________

3. _______________ for newer agents

2 = ?

Fewer side effects

DOSE-RESPONSE CURVE

Hypnosis

1. ______________ can induce sleep which results to reduced REM

2. Rebound effect results to ________________________

3. _______________ for newer agents

3 = ?

Phenobarbital

DOSE-RESPONSE CURVE

Antiseizure

1. Low doses of ___________________

2. High doses of _________________________

1 = ?

Lorazepam and Midazolam

DOSE-RESPONSE CURVE

Antiseizure

1. Low doses of ___________________

2. High doses of _________________________

2 = ?

Benzodiazepine

DOSE-RESPONSE CURVE

Anesthesia

1. can cause anterograde amnesia

2. commonly used with anesthesia

3. usual side effects

1 = ?

Thiopental

DOSE-RESPONSE CURVE

Anesthesia

1. can cause anterograde amnesia

2. commonly used with anesthesia

3. usual side effects

2 = ?

amnesia and suppressed reflex

DOSE-RESPONSE CURVE

Anesthesia

1. can cause anterograde amnesia

2. commonly used with anesthesia

3. usual side effects

3 = ?

Respiratory arrest, hypotension, cardiovascular collapse, Death

DOSE-RESPONSE CURVE

Medullary Suppression, Coma

• ADRs

halogen or nitro group

Benzodiazepines

• widely used class with their effects attributed to the presence of a._________________ at b.___________

a = ?

C7

Benzodiazepines

• widely used class with their effects attributed to the presence of a._________________ at b.___________

b = ?

3-hydroxyl group

Benzodiazepines

1. Metabolism is highly dependent on presence of the _________________

2. _____________ = easily metabolized

3. _________________ = long-acting, not readily metabolized

1 = ?

with the -OH group

Benzodiazepines

1. Metabolism is highly dependent on presence of the _________________

2. _____________ = easily metabolized

3. _________________ = long-acting, not readily metabolized

2 = ?

without -OH group

Benzodiazepines

1. Metabolism is highly dependent on presence of the _________________

2. _____________ = easily metabolized

3. _________________ = long-acting, not readily metabolized

3 = ?

CYP3A4

Benzodiazepines

• Primarily carried out by a.________________, followed by b.____________, then c.____________________

a = ?

glucoronidation

Benzodiazepines

• Primarily carried out by a.________________, followed by b.____________, then c.____________________

b = ?

urinary excretion

Benzodiazepines

• Primarily carried out by a.________________, followed by b.____________, then c.____________________

c = ?

desmethyldiazepam

Benzodiazepines

• Many Phase I metabolites such as ___________________________ stay active and some have long half-lives (~40 hours).

half-life

Benzodiazepines

• Short a.____________ BZDs are rapidly conjugated and are more useful as b.__________________.

a = ?

hypnotic

Benzodiazepines

• Short a.____________ BZDs are rapidly conjugated and are more useful as b.__________________.

b = ?

Short-Acting (less than 12 hours)

Benzodiazepines Classification

• Midazolam

• Triazolam

Intermediate-Acting (12 to 24 hours)

Benzodiazepines Classification

• Alprazolam

• Estazolam

• Lorazepam

• Oxazepam

• Temazepam

Long-Acting (more than 24 hours)

Benzodiazepines Classification

• Chlordiazepoxide

• Clonazepam

• Clorazepate

• Diazepam

• Flurazepam

• Quazepam

5,5-substitution

Barbiturates’ effects are attributed to the a.___________________ of the b.______________________ structure.

a = ?

barbituric acid

Barbiturates’ effects are attributed to the a.___________________ of the b.______________________ structure.

b = ?

anxiolytics

Barbiturates are used less as a._____________ due to the b.__________________________________________ noted.

a = ?

numerous ADRs, drug interactions, and high degree of tolerance

Barbiturates are used less as a._____________ due to the b.__________________________________________ noted.

b = ?

hepatic metabolism

Barbiturates

• primarily metabolized via a.________________________ through b._________________ leading to c.___________________ metabolites.

• d.__________________ takes place in Phase II

• Then, slow urinary excretion takes place except e.__________________

• 20-30% f._________________ is excreted unchanged

• elimination is increased g.____________________ as barbiturates are h.______________________.

a = ?

oxidative reactions

Barbiturates

• primarily metabolized via a.________________________ through b._________________ leading to c.___________________ metabolites.

• d.__________________ takes place in Phase II

• Then, slow urinary excretion takes place except e.__________________

• 20-30% f._________________ is excreted unchanged

• elimination is increased g.____________________ as barbiturates are h.______________________.

b = ?

alcohols, acids, and ketone

Barbiturates

• primarily metabolized via a.________________________ through b._________________ leading to c.___________________ metabolites.

• d.__________________ takes place in Phase II

• Then, slow urinary excretion takes place except e.__________________

• 20-30% f._________________ is excreted unchanged

• elimination is increased g.____________________ as barbiturates are h.______________________.

c = ?

glucuronidation

Barbiturates

• primarily metabolized via a.________________________ through b._________________ leading to c.___________________ metabolites.

• d.__________________ takes place in Phase II

• Then, slow urinary excretion takes place except e.__________________

• 20-30% f._________________ is excreted unchanged

• elimination is increased g.____________________ as barbiturates are h.______________________.

d = ?

thiobarbital

Barbiturates

• primarily metabolized via a.________________________ through b._________________ leading to c.___________________ metabolites.

• d.__________________ takes place in Phase II

• Then, slow urinary excretion takes place except e.__________________

• 20-30% f._________________ is excreted unchanged

• elimination is increased g.____________________ as barbiturates are h.______________________.

e = ?

phenobarbital

Barbiturates

• primarily metabolized via a.________________________ through b._________________ leading to c.___________________ metabolites.

• d.__________________ takes place in Phase II

• Then, slow urinary excretion takes place except e.__________________

• 20-30% f._________________ is excreted unchanged

• elimination is increased g.____________________ as barbiturates are h.______________________.

f = ?

urinary alkalinization

Barbiturates

• primarily metabolized via a.________________________ through b._________________ leading to c.___________________ metabolites.

• d.__________________ takes place in Phase II

• Then, slow urinary excretion takes place except e.__________________

• 20-30% f._________________ is excreted unchanged

• elimination is increased g.____________________ as barbiturates are h.______________________.

g = ?

weak acids

Barbiturates

• primarily metabolized via a.________________________ through b._________________ leading to c.___________________ metabolites.

• d.__________________ takes place in Phase II

• Then, slow urinary excretion takes place except e.__________________

• 20-30% f._________________ is excreted unchanged

• elimination is increased g.____________________ as barbiturates are h.______________________.

h = ?

Ultra-short Acting (5 to 30 minutes)

Barbiturates Classification:

• Thiopental, Methohexital

Short-Acting (3 to 8 hours)

Barbiturates Classification:

• Secobarbital, Pentobarbital

Intermediate-Acting (4 to 10 hours)

Barbiturates Classification:

• Amobarbital, Butabarbital

Long-Acting (more than 12 hours)

Barbiturates Classification:

• Phenobarbital. Mephobarbital

Newer Hypnotics

• Agents with novel chemical structure that are not related to BZDs but exhibit similar mechanism of action

• CYP3A4 is primarily involved in the metabolism via oxidation and hydroxylation reactions; glucuronidation takes place in Phase II and then urinary excretion; physical dependence is rare

Zolpidem

Newer Hypnotics

• imidazopyridine

Zalepleon

Newer Hypnotics

• contains pyrazolopyrimidine

Eszopiclone

Newer Hypnotics

• contains cyclopyrrolone

GABA receptor-chloride

Newer Hypnotics MOA:

• It acts on the ______________________ ion channel

Benzodiazepines

MOA:

• Higher frequency of channel opening. Open the channel more often when GABA is present.

• They have halogens like Fluorine, which increase the drug’s lipid solubility = stronger relaxation = higher GABA

• GABA Mechanism: relaxation is caused by the influx of Chloride ions. When GABA binds, the channel opens, Cl enters the neuron, causes hyperpolarization, and makes the neuron less likely to fire. This is what leads to CNS depression/relaxation.

Barbiturates

MOA:

• Longer duration.

• Open the chlorine channel longer. At high doses, they act as GABA mimetics (open the channel even in the absence of GABA), whereas BZDs require GABA to work.

• Flumazenil – Competitive antagonist for B

Flumazenil

MOA:

• Competitive antagonist for BZDs; binds to the BZ binding site, not the barbiturate site.

GABA A

MOA:

• BZDs, Barbiturates and newer hypnotics bind to components of _________ receptor which functions as Cl-channel and is activated by GABA NTs

Zolpidem, Zaleplon, Eszopiclone

MOA:

1. low affinity for GABA A

2. low affinity for GABA B

1 = ?

BZDs and other sedative-hypnotics

MOA:

1. low affinity for GABA A

2. low affinity for GABA B

2 = ?

potentiate GABAergic inhibition

MOA:

1. BZDs ________________________ at all levels of the CNS

2. Increases the efficacy of GABAergic synaptic inhibition but do not substitute GAB, only enhancing Cl-ion conductance by increasing _____________ of channel-opening events

1 = ?

frequency

MOA:

1. BZDs ________________________ at all levels of the CNS

2. Increases the efficacy of GABAergic synaptic inhibition but do not substitute GAB, only enhancing Cl-ion conductance by increasing _____________ of channel-opening events

2 = ?

multiple site

MOA:

1. Barbiturates interact with GABA at ________________ similar to BZDs

2. Increases the _____________ of GABA-gated Cl-channel openings

3. Barbiturates depress the action of excitatory NT glutamic acid making it __________________ than BZDs

4. lead to more pronounced CNS depressant effects and even induced ____________________________

5. Also antagonize ____________________

1 = ?

duration

MOA:

1. Barbiturates interact with GABA at ________________ similar to BZDs

2. Increases the _____________ of GABA-gated Cl-channel openings

3. Barbiturates depress the action of excitatory NT glutamic acid making it __________________ than BZDs

4. lead to more pronounced CNS depressant effects and even induced ____________________________

5. Also antagonize ____________________

2 = ?

less selective

MOA:

1. Barbiturates interact with GABA at ________________ similar to BZDs

2. Increases the _____________ of GABA-gated Cl-channel openings

3. Barbiturates depress the action of excitatory NT glutamic acid making it __________________ than BZDs

4. lead to more pronounced CNS depressant effects and even induced ____________________________

5. Also antagonize ____________________

3 = ?

full surgical anesthesia

MOA:

1. Barbiturates interact with GABA at ________________ similar to BZDs

2. Increases the _____________ of GABA-gated Cl-channel openings

3. Barbiturates depress the action of excitatory NT glutamic acid making it __________________ than BZDs

4. lead to more pronounced CNS depressant effects and even induced ____________________________

5. Also antagonize ____________________

4 = ?

glutamic acid

MOA:

1. Barbiturates interact with GABA at ________________ similar to BZDs

2. Increases the _____________ of GABA-gated Cl-channel openings

3. Barbiturates depress the action of excitatory NT glutamic acid making it __________________ than BZDs

4. lead to more pronounced CNS depressant effects and even induced ____________________________

5. Also antagonize ____________________

5 = ?

Melatonin-Receptor Agonists

Acts on melatonin receptors (MT1 and MT2) found in the suprachiasmatic nuclei (SCN) in the anterior part of the hypothalamus

suprachiasmatic nuclei (SCN)

Melatonin-Receptor Agonists

• responsible of regulating the circadian rhythm of the body

arousal signaling

Melatonin-Receptor Agonists

• Activates the SCN receptors to inhibit a.____________________ and promote b.______________.

a = ?

sleep

Melatonin-Receptor Agonists

• Activates the SCN receptors to inhibit a.____________________ and promote b.______________.

b = ?

CYP1A2 and CYP2C9

Melatonin-Receptor Agonists

• Metabolized to an active metabolite by ____________________________

Tasimelteon

Melatonin-Receptor Agonists

• Initially for non-24-hour sleep-wake disorder (N24SWD)

Orexin Antagonists

Blocks orexin and other neuropeptides that are responsible for promoting wakefulness

CYP3A4

Orexin Antagonists

• Primarily metabolized by _________________

Suvorexant

Orexin Antagonists

• mainly excreted in the feces and less in the urine

5-HT Receptor Agonists

Action is uncertain but hypothesized as partial agonist of 5-HT receptors with possible affinity of D3 receptors (centrally inhibitory)

Azaspirodecanedione

5-HT Receptor Agonists

• structure

BZDs, Barbiturates and older agents

DRUG EFFECTS — Sedation:

1. exert calming/anxiolytic effect at low doses

2. exhibit dose-dependent anterograde amnesia

1 = ?

Benzodiazepine

DRUG EFFECTS — Sedation:

1. exert calming/anxiolytic effect at low doses

2. exhibit dose-dependent anterograde amnesia

1 = ?

non-REM and REM sleep

DRUG EFFECTS — Hypnosis:

• Varying effects on the latency and onset of _____________________

Thiopental and Methohexital

DRUG EFFECTS — Anesthesia:

1. good agents due to fast onset and tissue distribution

2. IV agents used as adjuncts

3. lack anesthetic activity

1 = ?

diazepam, lorazepam, midazolam

DRUG EFFECTS — Anesthesia:

1. good agents due to fast onset and tissue distribution

2. IV agents used as adjuncts

3. lack anesthetic activity

2 = ?

Newer agents

DRUG EFFECTS — Anesthesia:

1. good agents due to fast onset and tissue distribution

2. IV agents used as adjuncts

3. lack anesthetic activity

3 = ?

clonazepam, nitrazepam, lorazepam, diazepam

DRUG EFFECTS — Anticonvulsant

1. benzodiazepines used

2. for generalized tonic-clonic seizures

3. lack anticonvulsant activity

1 = ?

phenobarbital, metharbital

DRUG EFFECTS — Anticonvulsant

1. benzodiazepines used

2. for generalized tonic-clonic seizures

3. lack anticonvulsant activity

2 = ?

newer agents

DRUG EFFECTS — Anticonvulsant

1. benzodiazepines used

2. for generalized tonic-clonic seizures

3. lack anticonvulsant activity

3 = ?

meprobamate, BZDs

DRUG EFFECTS — Muscle Relaxation:

1. high doses inhibit transmission skeletal neuromuscular junction

respiratory depression and orthostatic hypotension

DRUG EFFECTS — Respiratory and CV Function

1. May cause _______________________________

2. Effects are more significant when agents are given as ___________

1 = ?

IV drug

DRUG EFFECTS — Respiratory and CV Function

1. May cause _______________________________

2. Effects are more significant when agents are given as ___________

2 = ?

secondary and generalized anxiety disorder (GAD)

CLINICAL USES OF SEDATIVE-HYPNOTICS:

1. Anxiety relief for _______________________

2. short-acting agents are preferred

3. _______________ and seizure states

4. ______________________ induction

5. ____________________________ withdrawal states

6. __________________ and seizure disorders

7. Diagnostic aid in ___________________________

1 = ?

Surgical Sedation/Amnesia

CLINICAL USES OF SEDATIVE-HYPNOTICS:

1. Anxiety relief for _______________________

2. short-acting agents are preferred

3. _______________ and seizure states

4. ______________________ induction

5. ____________________________ withdrawal states

6. __________________ and seizure disorders

7. Diagnostic aid in ___________________________

2 = ?

Epilepsy

CLINICAL USES OF SEDATIVE-HYPNOTICS:

1. Anxiety relief for _______________________

2. short-acting agents are preferred

3. _______________ and seizure states

4. ______________________ induction

5. ____________________________ withdrawal states

6. __________________ and seizure disorders

7. Diagnostic aid in ___________________________

3 = ?

Balanced anesthesia

CLINICAL USES OF SEDATIVE-HYPNOTICS:

1. Anxiety relief for _______________________

2. short-acting agents are preferred

3. _______________ and seizure states

4. ______________________ induction

5. ____________________________ withdrawal states

6. __________________ and seizure disorders

7. Diagnostic aid in ___________________________

4 = ?