Download - 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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Sedative Hypnotics - Barbiturates
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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Sedative Hypnotics - Barbiturates
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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Sedative Hypnotics - Barbiturates
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