Midazolam Log P 367 t12 2 h


Zolpidem (Ambien, an imidazopyridine) and eszopiclone (Lunesta, a cyclopyrrolone) are nonben-zodiazepines and have been introduced as short- and moderate-acting hypnotics, respectively. Zolpidem exhibits a high selectivity for the ai subunit of benzodiazepine-binding site on GABAA receptor complex, whereas es-zopiclone is a "superagonist" at BzRs with the subunit composition a1p2j2 and a1j2y3. Zolpidem has a rapid onset of action of 1.6 hours and good bioavailability (72%), mainly because it is lipophilic and has no ionizable groups at physiological pH. Food can prolong the time to peak concentration without affecting the half-life probably for the same reason. It has short elimination half-life, because its aryl methyl groups is extensively a-hydroxylated to inactive metabolites by CYP3A4 followed by further oxidation by aldehyde dehydrogenase to the ionic car-boxylic acid. The metabolites are inactive, short-lived, and eliminated in the urine. Its half-life in the elderly or the patients with liver disease is increased. Therefore, dosing should be modified in patients with hepatic insufficiency and the elderly. Because it has longer elimination half-life than zaleplon, it may be preferred for sleep maintenance. It was the most commonly prescribed drug for insomnia in 2001.

Zopiclone was originally marketed as a racemic mixture. Because its ^-isomer is a primary active hypnotic, it is now marketed as eszopiclone in the United States. It is less selective for the a1 subunit of GABAA receptor, and it has relatively longer elimination half-life (~6 hours) than zolpidem and zaleplon. Consequently, it may be used for patients who tend to awaken during the night.

Zaleplon. Zaleplon (Sonata, a pyrazolopyrimidine) is another short-acting nonbenzodiazepine hypnotic. Pharmacologically and pharmacokinetically, zaleplon is similar to zolpidem; both are hypnotic agents with short half-lives. It also has selective high affinity for a1-subunit containing BzRs but produces effects at other BzR/GABAA subtypes as well. Zaleplon is well absorbed following oral administration with an absolute bioavailability of approximately 30% because of significant presystemic metabolism. It exhibits a mean half-life of approximately 1 hour, with less than 1% of the dose excreted unchanged in urine. It is primarily metabolized by aldehyde oxidase to 5-oxo-zaleplon and is also metabolized to a lesser extent by CYP3A4. n-demethylation yields desethylzaleplon, which is quickly converted, presumably by aldehyde oxidase, to 5-oxo-de-sethylzaleplon. These oxidative metabolites are then converted to glucuronides and eliminated in urine. All of zal-eplon's metabolites are pharmacologically inactive. It may have a more rapid onset (about 1 hour) and termination of action than zolpidem, and therefore, it is good to initiate sleep instead of keeping sleep.

Melatonin Receptor Agonist: Ramelteon

In the brain, three melatonin receptors (MT1, MT2, and MT3) have been characterized. Activation of the MT1 receptor results in sleepiness, whereas the MT2 receptor may be related to the circadian rhythm. MT3 receptors may be related to intraocular pressure. Their endogenous ligand, melatonin (n-acetyl-5-methoxytryptamine), at times referred to as "the hormone of darkness," is n-acetylated and o-methylated product of serotonin found in the pineal gland and is biosynthesized and released at night and may play a role in the circadian rhythm of humans. It is promoted commercially as a sleep aid by the food supplement industry. However, it is a poor hypnotic drug because of its poor potency, poor absorption, poor oral bioavailability, rapid metabolism, and nonselective effects.

Mt3 ReceptoresMt3 Receptores

Ramelteon (Rozerem). The melatonin molecule was modified mainly by replacing the nitrogen of the indole ring with a carbon to give an indane ring and by incorporating 5-methoxyl group in the indole ring into a more rigid furan ring. The selectivity of the resulting ramelteon for MTi receptor is eight times more than that of MT2 receptor. Unlike melatonin, it is more effective in initiating sleep (MT1 activity) rather than to readjust the circadian rhythm (MT2 activity). It appears to be distinctly more efficacious than melatonin but less efficacious than benzodiazepines as a hypnotic. Importantly, this drug has no addiction liability (it is not a controlled substance). As a result, it has recently been approved for the treatment of insomnia.


The barbiturates were used extensively as sedative-hypnotic drugs. Except for a few specialized uses, they have been replaced largely by the much safer benzodiazepine. Barbiturates act throughout the CNS. However, they exert most of their characteristic CNS effects mainly by binding to an allosteric recognition site on GABAa receptors that positively modulates the effect of the GABAA receptor— GABA binding. Unlike benzodiazepines, they bind at different binding sites and appear to increase the duration of the GABA-gated chloride channel openings. In addition, by binding to the barbiturate modulatory site, barbiturates can also increase chloride ion flux without GABA attaching to its receptor site on GABAA. This has been termed a GABA mimetic effect. It is thought to be related to the profound CNS depression that barbiturates can produce.

The barbiturates are 5,5-disubstituted barbituric acids. Consideration of the structure of 5,5-disubstituted barbituric acids reveals their acidic character. Those without methyl substituents on the nitrogen have pKa's of about 7.6; those with a methyl substituent have pKa's of about 8.4. The free acids have poor water solubility and good lipid solubility (the latter largely a function of the two hydrocarbon sub-stituents on the 5-position, although in the 2-thiobarbiturates, the sulfur atom increases lipid solubility).

Sodium salts of the barbiturates are readily prepared and are water soluble. Their aqueous solutions generate an alkaline pH. A classic incompatibility is the addition of an agent with an acidic pH in solution, which results in

Components Pharmaceutical Chemistry

must be a weak acid Figure 12.3 • Structure-activity relationship of barbiturates.

formation and precipitation of the free water-insoluble disubstituted barbituric acid. Sodium salts of barbiturates in aqueous solution decompose at varying rates by base-catalyzed hydrolysis, generating ring-opened salts of car-boxylic acids.

Structure-Activity Relationships

Extensive synthesis and testing of the barbiturates over a long time span have produced well-defined SARs (see Fig. 12.3), which have been summarized.18 The barbituric acid is 2,4,6-trioxohexahydropyrimidine, which lacks CNS depressant activity. However, the replacement of both hydrogens at position 5 with alkyl or aryl groups confers the activity. Both hydrogen atoms at the 5-position of barbituric acid must be replaced. This may be because if one hydrogen is available at position 5, tautomerization to a highly acidic tri-hydroxypyrimidine (pKa ~4) can occur. Consequently, the compound is largely in the anionic form at physiological pH, with little nonionic lipid-soluble compound available to cross the blood-brain barrier.

In general, increasing lipophilicity increases hypnotic potency and the onset of action and decreases the duration of action. Thus, beginning with lower alkyls, there is an increase in onset and a decrease in duration of action with increasing hydrocarbon content up to about seven to nine total carbon atoms substituted on the 5-position. It is because that lipophilicity and an ability to penetrate the brain in the first case and an ability to penetrate liver microsomes in the second may be involved. In addition for more lipophilic compounds, partitioning out of the brain to other sites can be involved in the second instance. There is an inverse correlation between the total number of carbon atoms substituted on the 5-position and the duration of action, which is even better when the character of these sub-stituents is taken into account, for example, the relatively polar character of a phenyl substituent (approximates a three- to four-carbon aliphatic chain), branching of alkyls, presence of an isolated double or triple bond, and so on. Additionally, these groups can influence the ease of oxida-tive metabolism by effects on bond strengths as well as by influencing partitioning.

Absorption from the GI tract is good. Binding to blood proteins is substantial. Compounds with low lipophilicity may be excreted intact in the urine, whereas highly lipophilic compounds are excreted after metabolism to polar metabolites. Increasing the lipophilicity generally increases the rate of metabolism, except for compounds with an extremely high lipophilicity (e.g., thiopental), which tend to depotize and are thus relatively unavailable for metabolism. Metabolism generally follows an ultimate (w) or penultimate (w-1) oxidation pattern. Ring-opening reactions are usually minor. N-methylation decreases duration of action, in large part, probably, by increasing the concentration of the lipid-soluble free barbituric acid. 2-Thiobarbiturates have a very short duration of action because its lipophilicity is extremely high, promoting depotization. Barbiturates find use as sedatives, as hypnotics, for induction of anesthesia, and as anticonvulsants.

Some of the more frequently used barbiturates are described briefly in the following sections. For the structures, the usual dosages required to produce sedation and hypnosis, the times of onset, and the duration of action, see Table 12.1.


Mephobarbital, USP. Mephobarbital, 3-methyl-5-ethyl-5-phenylbarbituric acid (metharbital), is metabolically N-demethylated to phenobarbital, which many consider to account for almost all of the activity. Its principal use is as an anticonvulsant.

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