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 GABA A receptors involved in the regulation of the chloride channel.  Studies suggest two subclasses of receptors BZ 1 and BZ 2  It has been proposed that compounds specific for the BZ 1 subclass would be “nonsedative” and the BZ 2 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 (R 1 ) 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

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

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

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

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 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

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

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

Miscellaneous Sedative Hypnotic Agents

Sedative Hypnotics - Nonbenzodiazepines Zolpidem (Ambien) Short acting hypnotic Acts at the GABA A receptor Imidazolpyridine Binds with higher affinity at the BZR 1 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 GABA A receptor at the BZR 1 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 MT 1 and MT 2 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 GABA A 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