Lecture Notes on Central Nervous System Depressants PDF

Central Nervous System Depressants Central nervous system (CNS) depressants are drugs that can be used to slow down or “depress” the functions of the CNS. ANXIOLYTIC, SEDATIVE, AND HYPNOTIC AGENTS GABAA Receptors, Benzodiazepines, and Related Compounds γ-aminobutyric acid (GABA) is the most common a...

Central Nervous System Depressants Central nervous system (CNS) depressants are drugs that can be used to slow down or “depress” the functions of the CNS. ANXIOLYTIC, SEDATIVE, AND HYPNOTIC AGENTS GABAA Receptors, Benzodiazepines, and Related Compounds γ-aminobutyric acid (GABA) is the most common and major inhibitory neurotransmitter (NT) in the brain and it exerts its rapid inhibitory action mostly through GABA receptors. GABAA receptor is the target for many anxiolytics and sedative–hypnotic agents including benzodiazepines, barbiturates, zaleplon, steroids, anticonvulsive agents. Most benzodiazepines are 5-aryl-1,4- benzodiazepines and contain a carboxamide group in the seven membered diazepine ring structure. Aromatic or heteroaromatic ring A is required for the activity. An electronegative substituent at position 7 is required for activity, and the more electronegative it is, the higher the activity. Positions 6, 8, and 9 should not be substituted. A phenyl ring C at position 5 promotes activity. If this phenyl group is ortho (2ʹ) or diortho (2ʹ,6ʹ) substituted with electron-withdrawing groups, activity is increased. On the other hand, para substitution decreases activity greatly. In diazepine ring B, saturation of the 4,5-double bond or a shift of it to the 3,4-position decreases activity. Alkyl substitution at the 3-position decreases activity; substitution with a 3-hydroxyl does not. The presence or absence of the 3-hydroxyl group is important pharmacokinetically. Compounds without the 3-hydroxyl group are nonpolar, 3-hydroxylated in liver slowly to active 3-hydroxyl metabolites, and have long overall half-lives. In contrast, 3-hydroxyl compounds are much more polar, rapidly converted to inactive 3-glucuronides, which are excreted in urine and thus are short-lived. The 2-carbonyl function is important for activity, as is the nitrogen atom at position 1. A proton- accepting group at C2 is required and may interact with a proton donor in benzodiazepine binding site of GABAA receptor. Other triazole or imidazole rings capable of H-bonding can be fused on positions 1 and 2 and increase the activity. BENZODIAZEPINES Chlordiazepoxide Hydrochloride It is converted principally to its active metabolite nordazepam, which is also a major active metabolite of diazepam. Nordazepam, in turn, is converted principally to active oxazepam, which conjugated to the excreted glucuronide.  Diazepam Is prototypical and was the first member of the benzodiazepine-2-one group to be introduced. As with chlordiazepoxide, diazepam is metabolized by N-demethylation to active nordazepam, which is 3- hydroxylated to active oxazepam. It is widely used for several anxiety states.  Flurazepam It is marketed almost exclusively for use in insomnia. Metabolism of the dialkylaminoalkyl side chain gives a major metabolite which is N1-dealkyl flurazepam. Lorazepam Is the 2ʹ-chloro derivative of oxazepam. Metabolism is the same as oxazepam.  Quazepam. Quazepam (hypnotic agent) is metabolized by oxidation to the 2- oxo compound and then N-dealkylation. Both metabolites are active; the first is the more potent. Then a 3-hydroxylation and glucuronidation occur. Alprazolam (TRIAZOLOBENZODIAZEPINES) α-Hydroxylation of the methyl group to the methyl alcohol followed by conjugation is rapid; consequently, the duration of action is short. The drug is a highly potent anxiolytic on a milligram basis. Midazolam. Is imidazolobenzodiazepine used intravenously as a short acting sedative–hypnotic and as an induction anesthetic due to its short half-life because it is rapidly α-hydroxylated to the 1-methyl alcohol, which is then rapidly conjugated and excreted. NONBENZODIAZEPINE Zaleplon. Zaleplon (a pyrazolopyrimidine) is a short-acting nonbenzodiazepine hypnotic. It is primarily metabolized by aldehyde oxidase to 5-oxo-zaleplon. N-deethylation yields desethylzaleplon, which is quickly converted to 5-oxo- desethylzaleplon. Melatonin Receptor Agonist: In the brain, three melatonin receptors (MT1, MT2, and MT3) have been characterized. Activation of the MT1 receptor results in sleepiness. Their endogenous ligand, melatonin (N-acetyl-5-methoxytryptamine) “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. Ramelteon 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. It is more efficacious than melatonin but less efficacious than benzodiazepines as a hypnotic. Barbiturates The barbiturates were used extensively as sedative–hypnotic drugs. The barbiturates are 5,5-disubstituted barbituric acids. The barbituric acid is 2,4,6-trioxohexahydropyrimidine, which lacks CNS depressant activity. The replacement of both hydrogens at position 5 with alkyl or aryl groups gives the activity. This is because if one hydrogen is available at position 5, tautomerization to a highly acidic trihydroxypyrimidine (pKa 4̴ ) can occur. Then the compound is largely in the anionic form at physiological pH, with little nonionic lipid-soluble compound available to cross the blood-brain barrier. Beginning with lower alkyls, there is an increase in onset and a decrease in duration of action with increasing hydrocarbon content on the 5-position. N-methylation decreases duration of action 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. BARBITURATES WITH A LONG DURATION OF ACTION (MORE THAN 6 HOURS) Mephobarbital. Mephobarbital is metabolically N-demethylated to phenobarbital, which accounts for all of the activity. Its principal use is as an anticonvulsant. BARBITURATES WITH AN INTERMEDIATE DURATION OF ACTION (3–6 HOURS) They are used principally as sedative–hypnotics. They include amobarbital and Butabarbital. BARBITURATES WITH A SHORT DURATION OF ACTION (LESS THAN 3 HOURS) Pentobarbital and secobarbital. Miscellaneous Sedative–Hypnotics AMIDES AND IMIDES Glutethimide is one of the most active nonbarbiturate hypnotics that is structurally similar to the barbiturates, especially phenobarbital. Alcohols and Their Carbamate Derivatives Chlorphenesin Carbamate. Chlorphenesin carbamate is the p-chloro substituted and 1- carbamate derivative of the lead compound in the development of this group of agents, mephenesin. Mephenesin is weakly active and short lived because of metabolism of the primary hydroxyl group. Carbamylation of this group increases activity. p- Chlorination increases the lipophilicity and protects the para position from hydroxylation. ALDEHYDES AND THEIR DERIVATIVES Chloral Hydrate Trichloroacetaldehyde monohydrate. chloral hydrate is very quickly converted to trichloroethanol, which is generally assumed to account for almost all of the hypnotic effect. The trichloroethanol is metabolized by oxidation to chloral and then to the inactive metabolite, trichloracetic acid, which is also extensively metabolized to acylglucuronides via conjugation with glucuronic acid. ANTIPSYCHOTICS Antipsychotic drugs are used in the symptomatic treatment of thought disorders (psychoses), mostly the schizophrenias. Antipsychotics are grouped into typical and atypical categories. Both categories share a common feature, a dopamine (DA)-like structure. This feature can be related to the competitive antagonism of DA at D2 receptors. The fundamental differences between typical and atypical antipsychotics are that the atypical agents are (a) less prone to produce extrapyramidal symptoms (EPS). (b) more active against negative symptoms. Phenothiazines Phenothiazines have a tricyclic structure (6-6-6 system) in which two benzene rings are linked by a sulfur and a nitrogen atom. The best position for substitution is the 2-position. Activity increases as electron- withdrawing ability of the 2-substituent increases. Another important structural feature in the more potent compounds is the presence of an unshared electron pair on an atom or atoms of the 2-substituent. Substitution at the 3-position can improve activity over nonsubstituted compounds but not as significantly as substitution at the 2-position. Substitution at position 1 has an undesirable effect on antipsychotic activity, as does substitution at the 4-position. The significance of these substituent effects could be that the hydrogen atom of the protonated amino group of the side chain H- bonds with an electron pair of an atom of the 2-substituent to develop a DA-like arrangement. X-ray crystallography, proposed that the chlorine-substituted ring of chlorpromazine base could be superimposed on the aromatic ring of DA base, with the sulfur atom aligned with the p-hydroxyl group of DA. The three-carbon chain between position 10 and the aliphatic amino nitrogen is critical for neuroleptic activity. Shortening or lengthening the chain at this position decreases the activity. The amine is always tertiary. N-dealkylation of the side chain or increasing the size of amino N- alkyl substituents reduces antidopaminergic and antipsychotic activity. Branching with large groups (e.g., phenyl) decreases activity, as does branching with polar groups. PRODUCTS Chlorpromazine Beside antipsychotic effect, other uses are in nausea, vomiting, and hiccough. Triflupromazine The drug has uses analogous to those of chlorpromazine. Prochlorperazine Is in the piperazine subgroup of the phenothiazines. Because of the high EPS, it is used mainly for its antiemetic effect, not for its antipsychotic effect.  Thioridazine Is a member of the piperidine subgroup of the phenothiazines. Thioridazine is converted to the active metabolite mesoridazine, which contributes to the antipsychotic activity of thioridazine. Trifluoperazine Trifluoperazine is indicated for the management of schizophrenia and short- term treatment of nonpsychotic anxiety. Fluphenazine Is a member of the piperazine subgroup with a trifluoromethyl group at the 2- position of the phenothiazine system and is most potent antipsychotic phenothiazine. It is also available as two lipid-soluble esters for depot intramuscular injection, the enanthate (heptanoic acid ester) and the decanoate ester.  Ring Analogs of Phenothiazines: Dibenzoxazepines, and Dibenzodiazepines Additional tricyclic antipsychotic agents are the benzazepines, containing a seven-membered central ring (6-7-6 system). They have some important differences, notably low production of EPS and reduction of negative symptoms. PRODUCTS Clozapine. Is a dibenzodiazepine derivative. It is effective against both positive and negative symptoms of schizophrenia and has a low tendency to produce EPS.  Loxapine. A dibenzoxazepine derivative. Loxapine is an effective antipsychotic. It is N-demethylated to yield amoxapine (an antidepressant drug). Fluorobutyrophenones Attachment of a tertiary amino group to the fourth carbon of the butyrophenone skeleton is essential for neuroleptic activity; lengthening, shortening, or branching of the three carbons propyl chain decreases neuroleptic potency. This aliphatic amino nitrogen is required, and highest activity is seen when it is incorporated into a cyclic form. A p-fluoro substituent aids activity. The C=O group gives optimal activity, although other groups, C(H)OH and C(H)aryl, also give good activity. The Y group can vary and assist activity, and an example is the hydroxyl group of haloperidol.  Haloperidol A potent antipsychotic useful in schizophrenia. Haloperidol-induced dyskinesias may involve neurotoxicological metabolite similar to dopaminergic toxicant MPP+ (1- methyl-4-phenylpyridinium). MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Haloperidol tetrahydropyridine (HPTP). (HPP+) Haloperidol pyridinium.  Ziprasidone. Is a benzisothiazol-piprazinylindolone derivative has the structural features of a trazodone-like antidepressant. Aripiprazole. An arylpiperazine quinolinone derivative. Pimozide A diphenylbutylpiperidine derivative which is a modification of the fluorobutyrophenone class.  β-AMINOKETONES Several β-aminoketones have been examined as antipsychotics. In addition to the β-aminoketone group, there must be an aryl group positioned as in molindone. It might be concluded that the proton on the protonated amino group in these compounds H-bonds with the electrons of the carbonyl oxygen atom. This would produce a cationic center, two-atom distance, and an aryl group that could be superimposed on the analogous features of protonated DA.  BENZAMIDES The benzamides evolved from observations that the gastro- prokinetic and antiemetic agent, metoclopramide, has antipsychotic activity related to D2 receptor block. An H-bond between the amido H and the unshared electrons of the methoxyl group to generate a pseudo ring is considered important for antipsychotic activity in these compounds. These features can be seen in sulpiride.