Living Textbook MC 417

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Sedative Hypnotics and Anxiolytics II


These are drugs that do not belong to the BZD family, but bind to the BZD receptor.  The “Z-drugs” are the most important of these agents.  They show a similar efficacy to BZD, but are only useful as sleep aids and not effective as anxiolytics since they specifically bind to the α1-subunit.

These agents are less likely than BZDs to change sleep patterns, have less day-after psychomotor depression and less amnesic effects. They shorten sleep latency and prolong sleep time.  They cause fewer withdrawal effects and show no tolerance.
They are generally very lipophillic with a rapid rate of absorption.

Adverse Effects:
There is a risk of abuse (schedule IV) and may still cause amnesia. 

Individual Agents:
Zolpidem (Ambien®) - Top 200
An Imidazopyridine hypnotic agent with a fast onset and short duration of action.  It shortens sleep latency and prolongs sleep time.  It has a half-life around two hours.  An extended biphasic release form (Ambien CR®) is available with a longer duration of action.  It forms a number of inactive metabolites through hydroxylation.

Zaleplon (Sonata®)
A pyrazolopyrimidine with a short half-life around one hour, metabolized by aldehyde oxidase and CYP450.   It is well absorbed, but its bioavailability is only 30% due to first pass metabolism).  Metabolism via N-dealkylation or aromatic hydroxylation followed by glucuronidation

Eszopiclone (Lunesta®) - Top 200
A cyclopyrrolone with a higher half-life (around 6 hr), thus has a longer duration of action, thus shows a better profile in maintaining sleep and can be used in chronic insomnia.  It is also metabolized by CYP450. 

These agents bind to their own receptor on the GABAA receptor, and increase the duration of the chloride channel opening.  They were very popular as hypnotics, but have been supplanted by BZDs and Z-drugs.

Characteristics of Barbiturates
They induce CYP450’s in liver, leading to various DDIs as they can increase metabolism of other drugs
Tolerance develops to these CYP450 effect and to both the behavioral and anticonvulsant effects.  It can also result in physical dependence with rapid withdrawal effects that can lead to overexcitement: seizures, fever and death.
Barbiturates share many of the effects of BZD, but do not cause anterograde amnesia.  It does show the risk of respiratory depression at higher doses.

Structure Activity Relationship

Increasing lipophilicity will lead to faster onset, but a shorter duration of action.
1-position, must have the nitrogen, may be substituted if N3 is unsubstituted.   Alkyl substitutions will have faster onset of action and a shorter duration of actions.

2-position, replacing the carbonyl oxygen with sulfur will lead to a quicker onset and shorter duration of action.

3-position, must have the nitrogen, may be substituted if N1 is unsubstituted.   Alkyl substitutions will have faster onset of action and a shorter duration of actions.

4-position, must be a carbonyl.

Substitution on the 5-position is allowed.  Lipophilic groups are essential for entry into CNS, but must have some hydrophilicity to allow solubility.

6-position, must be a carbonyl.

Multiple substitutions:


Individual Agents:
Phenobarbital - Top 200

Relatively low lipid solubility, leading to a longer onset of action.  It is excreted in the urine with around 25% unchanged.

Pentobarbital (Nembutal®)
Intermediate lipid solubility, leading to a faster onset of action compared to Phenobarbital.  It undergoes extensive metabolism.

Thiopental (Pentothal®)
High lipid solubility, leading to a very fast onset of action.  Mostly used as an anesthetic (not widely used anymore)

Miscellaneous Agents:
Ramelteon (Rozerem®) is a melatonin receptor agonist at both the MT1 and MT2 receptors.  It reduces latency of persistent sleep with no effects on sleep architecture and shows no rebound insomnia or withdrawal symptoms.
Ramelton is rapidly absorbed, but suffers from significant first pass metabolism, leading to a very low oral bioavailability.
It is metabolized by CYP450s, mostly CYP1A2, with some active metabolite.
Drug-drug interactions with CYP1A2 and CYP2C9 inhibitors.

Buspirone (Buspar®) is used to treat generalized anxiety with limited severity, by acting as a partial agonist at 5-HT1A receptors.  It has the advantage of lacking CNS depressant properties, but has a slow onset of action.

Meprobamate is an anti-anxiety agent that is rarely used today.  It causes drowsiness and can induce sine CYP450s.

Chloral Hydrate (Somnote®) has a quick onset of action, with no analgesic, tranquilizing or respiratory effects.  It is rapidly degrades to trichloroethanol, which itself is a hypnotic.  It is useful for sedation in children or elderly.