Sedative Hypnotic Agents

Sedative Hypnotic Agents

Sedative Hypnotic Agents

Cause drowsiness and facilitates the initiation and maintenance of sleep

Grouped with anti-anxiety agents Effects of these drugs are dose related Ideal hypnotic should meet the following criteria

Transient decrease in the level of consciousness for the purpose of sleep without lingering effects

Have no potential for decreasing or arresting respirations even at high doses

Produce no abuse, addiction, tolerance or dependence

Classification of Hypnotics

An arbitrary classification is as follows Benzodiazepines Barbiturates Others

Sedative Hypnotics

Benzodiazepines Used as daytime anxiolytics, sleep inducers, anesthetics,

anticonvulsants and muscle relaxants Depending on the dose any benzodiazepine may be used

as a hypnotic The benzodiazepines were shown to bind to the GABAA

receptors involved in the regulation of the chloride channel. Studies suggest two subclasses of receptors BZ1 and BZ2

It has been proposed that compounds specific for the BZ1 subclass would be “nonsedative” and the BZ2 subclass is responsible for the sedative-hypnotic character of the benzodiazepines.

Sedative Hypnotics - Benzodiazepines Major advantage in that they are relatively

safe Fatalities from overdose is rare Their tendency to interact with other drugs is

less than that seen with other hypnotics

Sedative Hypnotics

Benzodiazepine N at position 1 optimal for activity

R2 – various alkyl substitutions

R3 – O, S, N (2-carbonyl is optimal)

Fuzed triazoloring at positions 1 &2 or an imidazolo ring may be present. In these compounds

position 7 electron withdrawing groups are not required.

Sedative Hypnotics

Benzodiazepine Alkyl group at 3 decreases activity, -OH retains activity

Saturation of the 4,5 double bond or bond shift to 3,4 decreases activity

Phenyl group at 5 enhances activity

Electron withdrawing groups are required at position 7 (R1)

Positions 6,8 & 9 should not be substituted

Sedative Hypnotics

Benzodiazepine Substitution at 2’ or 6’ or both with electron withdrawing groups increase activity. Para substitution decreases activity tremendously

Sedative Hypnotics - Benzodiazepines Estazolam (Prosom) Used as a sedative and

hypnotic in the treatment of insomnia

Increase total sleep Decrease nocturnal

wakefullness, body movements, number of awakenings and sleep latency

No active metabolite

Sedative Hypnotics - Benzodiazepines Triazolam (Halcion) Used as a sedative and

hypnotic in the treatment of insomnia

No active metabolite Oral benzodiazepine and has

an intermediate rate of absorption

High receptor binding affinity Ultra-short half life Hydroxylation of triazole methyl

group makes an inactive metabolite

Sedative Hypnotics - Benzodiazepines Temazepam (Restoril)

Has an inactive metabolite

Absorbed slowly Rapidly metabolized

Sedative Hypnotics - Benzodiazepines Flurazepam (Dalmane) Induces impairment of

motor function and has hypnotic properties

Used to treat insomnia Has active metabolites Metabolized by N-

dealkylation and hydroxylation to the imine

Oral benzodiazepine and is absorbed most rapidly

Sedative Hypnotics - Benzodiazepines Quazepam (Doral) Induces impairment of

motor function and has hypnotic properties

Used to treat insomnia Has active metabolites Metabolized by

oxidation to the 2-oxo compound and then N-dealkylation

Sedative Hypnotics - Benzodiazepines Oxazepam(Serax) Prototype for the 3-

hydroxy compounds Short duration of action

Sedative Hypnotics - Benzodiazepines Alprazolam (Xanax) Oxidative metabolism

of the methyl group to the methyl alcohol followed by conjugation is rapid

Short duration of action Highly potent on

milligram basis

Sedative Hypnotics - Benzodiazepines Chlordiazepoxide (Librium) N-demethylation and

hydrolysis of the condensed amidino group produces demoxepam an active metabolite with anticonvulsant properties. It is converted to nordazepam which is converted to oxepam which undergoes conjugation and then is excreted.Demoxepam

Sedative Hypnotics - Benzodiazepines Nordiazepam It is converted to

norda1zepam which is converted to oxazepam which undergoes conjugation and then is excreted.

Oxazepam

Sedative Hypnotics - Benzodiazepines Clorazepate (Tranxene)

Prodrug Undergoes rapid loss of

water then carboxylation to nordiazepam which is converted to oxazepam

Sedative Hypnotics - Benzodiazepines Diazepam (Valium)

Metabolized by N-demethylation to nordazepam which is then metabolized ot oxazepam

Sedative Hypnotics - Benzodiazepines Lorazepam (Ativan) Recognized as the 2’

chloro substituted analog of oxazepam

This substitution increases activity

Sedative Hypnotics - Benzodiazepines Midazolam

Also an anesthetic

Sedative Hypnotics - Benzodiazepines Clonazepam (Klonopin)

Also used in some seizures Treatment of panic disorder extensively metabolised by

reduction to 7-amino-clonazepam and by N-acetylation to 7-acetamino-clonazepam. Hydroxylation at the C-3 position also occurs.

Sedative Hypnotics - Barbiturates

Minimal use as sedative hypnotics due to toxicity

Cause greater CNS depression

Induces liver drug metabolizing enzymes

Cause tolerance and dependence

Some use as sedative hypnotics

Primarily used as anesthetics and antiseizure drugs

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Act postsynaptically to promote GABA binding and prolong the mean open time of Cl ion channels by binding to a site other than the BD binding site or the GABA binding site

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A good hypnotic must be a weak acid

5,5-disubstituted barbituric acids, 5,5-disubstituted thiobarbituric acids and 1,5,5-trisubstituted barbituric acids possess acceptable hypnotic activity

Other substitutiona are inactive or produce convulsions

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What would be the product of barbituric acid (structure shown) reacting with NaOH twice? Show the intermediate product as well.

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Sedative Hypnotics – Barbiturates

As you increase the # of carbons, lipophilicity increases

Branching, unsaturation, replacement of alicyclic or aromatic substituents for alkyl substituents, halogens onn the alkyl substituents all increase lipid solubility

As lipophilicity increases, hydrophilicity decreases

Polar groups decreases lipid solubility

HN NH

R1 R2

OO

O

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5,5-Disubstitution

Sedative Hypnotics – Barbiturates Substitution on one imide

hydrogen by an alkyl group increases lipid solubility

Quicker onset and shorter duration of action

As the size of the N-alkyl substituent increases the lipid solubility increases and hydrophilic character decreases

Attachment of large alkyl groups imparts convulsant properties

Alkyl substituents to both nigrogens makes the drug nonacidic and inactive

Substitution on Nitrogen

HN NH

R1 R2

OO

O

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Sedative Hypnotics – Barbiturates

Replacement of C-2 oxygen by sulfur increases lipid solubility

Onset of activity is rapid Used as iv anesthetics

Modification of Oxygen

HN NH

R1 R2

OO

O

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Barbiturates – Long Duration of Action (6+ hours) Phenobarbital

(Luminal) 5-ethyl, 5-phenyl subst. Also anticonvulsant

Mephobarbital (Metharbital) 3-methyl, 5-phenyl and 5-ethyl

substituents N-dealklyated to phenobarbital Also anticonvulsant

Barbiturates – Intermediate Duration of Action (3-6 hours) Amobarbital (Amytal) 5-ethyl and 5-isopentyl

substituents Sedative-hypnotic Has a water-soluble sodium

salt Amobarbital Sodium (Alurate)

Butabarbital Sodium (Butisol Sodium)

Water-soluble salt of 5-sec-butyl-5-ethylbarbituric acid

Sedative-hypnotic

Barbiturates – Short Duration of Action (less than 3 hours) Pentobarbital Sodium

(Nembutal) 5-ethyl, 5-(1methylbutyl)

substituents More rapid metabolism

Secobarbital (Seconal) 5-allyl, 5-(1-methylbutyl)

substituents More rapid metabolism

MiscellaneousSedative Hypnotic Agents

Sedative Hypnotics - Nonbenzodiazepines Zolpidem (Ambien) Short acting hypnotic

Acts at the GABAA receptor Imidazolpyridine Binds with higher affinity at

the BZR1 receptor Drug dependence Rapid onset and short

elimination half life Metabolized to inactive

metabolites

Sedative Hypnotics - Pyrazolopyrimidine Zaleplon (Sonata) Oyrazolopyrimidine

derivative Short half-life Interacts with the

GABAA receptor at the BZR1 receptor

Inactive metabolites

Sedative Hypnotics Cyclopyrrolone Eszopiclone (Lunesta) Used for insomnia

single chiral center with an (S)-configuration

very slightly soluble in water, slightly soluble in ethanol, and soluble in phosphate buffer

pyrrolopyrazine extensively

metabolized by oxidation and demethylation

Melatonin Receptor Agonist Activates MT1 and MT2 receptors Rapid onset of sleep with minimal

rebound insomnia or withdrawal symptoms

(S)-enantiomer freely soluble in organic solvents,

slightly soluble in water oxidation to hydroxyl and carbonyl

derivatives, with secondary metabolism producing glucuronide conjugates

Ramelteon (Roxerem)

Sedative Hypnotics Benzodiazepine Antagonist

Flumazenil Antagonist at benzodiazepine binding sites on the GABAA receptor

Blocks actions of benzodiazepines and zolpidem but not other sedative hypnotics

Management of benzodiazepine overdose

5-HT Receptor Agonist Partial agonist at 5-HT

receptors Slow onset (1-2 weeks) Minimal psychomotor

impairment No additive CNS

depression with sedative-hypnotic drugs

Buspirone (Buspar)

Chloral Hydrate (Noctec) A diol Metabolized to an active

metabolite (trichloroethanol)

Metabolite responsible for prolonged hypnotic effect

Sedative in non operating room procedures for pediatrics

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Sedative Hypnotic Agents