UNIVERSITY OF SANTO TOMAS FACULTY OF PHARMACY Submitted by: JUACALLA, Patrick Angelo D. KALALO, Katherine Joy C.

LEDESMA, Donna Marie S. 3F-Pharmacy

SEDATIVE-HYPNOTICS
I. Definition The brain has two opposing forces: excitation and inhibition (depression). CNS drugs or depressants slow down the functions of the nervous system. They are further classified as sedatives, hypnotics and anti-psychotics. Most sedative-hypnotics are in non-ionized form at physiological pH, well absorbed in the GI tract, metabolized before elimination from the body by hepatic enzymes, and possess high lipophilic character in order to cross the blood-brain barrier to exhibit desired effect. The difference between the two drugs is that sedatives or anxiolytics calm the patients and reduce anxiety without inducing normal sleep, as hypnotic drugs initiate and maintain the normal sleep of the patients.

A. Benzodiazepines
Benzodiazepines (BZDs) are the chemicals having the versatile medicinal values as tranquillizers and were used therapeutically as anxiolytics and anticonvulsants in epilepsy. They bind with specific receptors in the nervous system that are part of GABA (gamma-aminobutyric acid) neurotransmitter system. The mechanism of action of these drugs is that they bind tightly to a specific part of the GABA receptor, called the benzodiazepine site, which is different from the GABAA binding site. Its binding enhances the effect of GABA to shut down activity more effectively. It opens the receptors which results to the influx of chloride ions, promoting hyperpolarization, increasing the activity.

Structure-Activity Relationship Ring A Aromatic (benzene) or heteroaromatic ring that participates in pi-pi C6, C8, C9 must not be substituted C7 must have an electronegative constituent

stacking with aromatic amino acid residues of the receptor

Ring B The diazepine ring 1 Nitrogen component is important for activity; side chains are tolerated Other imidazole or triazole rings capable of hydrogen bondings can be fused on C1 and C2, which increases the activity. C2 ketone is important for activity C2 requires proton-accepting group (e.g. carboxylate group, carbonyl) which interacts with histidine residue in BZD-binding sites of GABAA receptor. C3 alkyl substitution here decreases activity o o o OH substitution does not affect activity, but making it much more polar, making it slowly absorbed and excreted in urine rapidly (short-lived) OH substituted metabolites have long overall half-lives Without OH makes drug non-polar

C5 phenyl increases activity 2 (ortho) or diortho (2, 6) increases activity 4 (para) decreases activity greatly Chlordiazepoxide

RING C

Long-acting benzodiazepines (lasts 24-72 hours) include the following: 1.) CHLORDIAZEPOXIDE IUPAC: 7-chloro-2-(methylamino)-5-phenyl-3H-1,4-benzodiazepine-4-oxide Relieves fear before surgery; anxiolytic/ sedative 7-Chloro increases activity

2.) DIAZEPAM IUPAC: 7-chloro-1,3-dihydro-1-methyl-5-phenyl-1,4-benzodiazepine-2-one Used as anti-convulsant and pre-anesthetic Methyl substitution at N1 marks optimal activity Diazepam 2

7-Chloro increases electronegativity and activity

3.) CLORAZEPATE DIPOTASSIUM IUPAC: 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3carboxylic acid dipotassium salt monohydrate Prodrug, used for anxiety problems for children 7-Chloro increases electronegativity and activity CO2K or COOH makes it more polar, decreasing activity

Clorazepate Dipotassium

4.) FLURAZEPAM IUPAC: 7-Chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro1,4-benzodiazepin-2-one Anxiolytic, anti-convulsant and used for insomnia 2-Fluorophenyl increases activity (ortho position) Metabolism of diaminoalkyl is extensive

Difference of the four drugs: 1.) Chlordiazepoxide has 2-methylamino and 4-oxide without 2-fluoro 2.) Diazepam has 1-methyl and no 2-fluoro 3.) Clorazepate Dipotassium has 3-carboxyl and no 2-fluoro 4.) Flurazepam has 2-diethylaminoethyl and 2 fluoro Flurazepam

TRIAZOLOBENZODIAZEPINES
These are characterized for having an addition of azole rings such as imidazole or triazole rings, which are known to increase activity and shortens the duration of action. 1.) ALPRAZOLAM IUPAC: 8-chloro-1-methyl-6-phenyl-4H-triazolo[4,3-a][1,4] benzodiazepine Intermediate sedative (lasts 6 to 24 hours) Used for panic attacks and anxiety disorders Triazole ring increases activity Alprazolam

Triazolam 3

2.) TRIAZOLAM IUPAC: 8-chloro-6-(2-chlorophenyl)-1-methyl-4Htriazolo[4,3-a][1,4] benzodiazepine Used for jet lag and insomnia 2-chloro increases activity and triazole makes it a short-acting drug

3.) MIDAZOLAM IUPAC: 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo(1,5-a) (1,4)benzodiazepine Has imidazole ring that makes it a short-acting drug Pre-anesthetic for endoscopy and surgery Midazolam

Difference of the three drugs: 1.) Alprazolam is intermediate-acting, similar to triazolam, but with no 2-substitution 2.) Triazolam is short-acting (3-8 hours), similar to alprazolam, but with 2-chloro 3.) Midazolam is short-acting (3-8 hours), with imidazole ring, with 2-fluoro

B. Barbiturates
These are drugs derived from barbituric acid. They are often called downers, and they are depressants of the central nervous system (CNS) that impair or reduce the activity of the brain by acting as a Gamma Amino Butyric Acid (GABA) potentiator. It has a similar mechanism of action with benzodiazepines, but acting on a different site (barbiturate acting site) on the GABAA receptor. They are mostly used for treating most seizures, including neonatal seizures.

Synthesis of barbituric acid Barbituric acid is synthesized by a condensation reaction that results in the release of water (dehydration) and the heterocyclic pyrimidine. There is further substitution of side chains on the ring that produce the pharmacologically active barbiturates.

Structure Activity Relationship

Substitution at carbon 5 - Sedative-hypnotic properties * Branched chain --> greater hypnotic activity than straight chain * Phenol group (like phneobarbital) --> Greater anticonvulsant activity

Carbon 2 * No substitution (oxygen) = oxybarbiturates * Substitution with sulfur = thiobarbiturates

Sulfuration at carbon 2 increases lipid solubility --> Greater hypnotic potency --> More rapid onset, but shorter duration of action

Addition of a methyl group to nitrogen (e.g. methohexitone) --> Short duration of action 1.) PHENOBARBITAL IUPAC: 5-ethyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione Treatment of all types of seizures except absence seizures. It is no less effective at seizure control than more modern drugs such as phenytoin and carbamazepine. It is, however, significantly less well tolerated. The first-line drugs for treatment of status epilepticus are fast-acting benzodiazepines, such as diazepam or lorazepam. First-line choice for the treatment of neonatal seizures Phenobarbital 5-Phenyl and 5-ethyl increases lipophilicity 5-Phenyl increases anti-convulsant activity

2.) AMOBARBITAL IUPAC: 5-ethyl-5-(3-methylbutyl)-1,3-diazinane-2,4,6-trione Used to treat insomnia and anxiety

3.) SECOBARBITAL IUPAC: 5-allyl-5-(1-methylbutyl) barbituric acid Treatment of epilepsy Temporary treatment of insomnia Use as a preoperative medication to produce anaesthesia and anxiolysis in short surgical, diagnostic, or therapeutic procedures which are minimally painful.

Amobarbital

4.) THIOPENTAL IUPAC: 5-ethyl-5-(2-methylpentyl)-4,6-dioxo-1,4,5,6-tetrahydropyrimidine2-thiolate Thiopental is an ultra-short-acting barbiturate and has been used commonly in the induction phase of general anesthesia. C2 is substituted with sulfur = thiobarbiturate, making it more lipid soluble than the others

Secobarbital

Thiopental

C. Miscellaneous group
i. Piperidinediones GLUTETHIMIDE IUPAC: 2-ethyl-2-phenyl-glutarimide

One of the most active non-barbiturate hypnotics Structure similar to barbiturates, especially phenobarbital Low aqueous solubility so dissolution and absorption from GIT somewhat erratic High lipophilicity so undergoes extensive oxidative metabolism in the liver; half-life approx. 10 hours Used as a racemic mixture with the (+) enantiomer primarily metabolized on the glutarimide ring and the (-) enantiomer on the phenyl ring. Product of metabolic detoxification is excreted after conjugation with glucorinic acid at the hydroxyl group

Enzyme inducer 6

Adverse effects infrequent at therapeutic dose; toxic effects in overdose as severe as barbiturates (or more)

ii.

Aldehydes: CHLORAL HYDRATE IUPAC: Tricholoroacetaldehyde monohydrate, CCl3CH(OH)2

Barbiturate-like binding to GABAA receptors Stability is because of the dipole-dipole repulsion between tricholoromethyl carbon and the carbonyl carbon Unstable in alkaline solutions: undergoing haloform reaction to yield chloroform and formate ion In hydroalcoholic solutions, forms hemiacetal with ethanol A weak acid because CCl3 group is very strong electron-withdrawing 10% aqueous solution has pH 3.5 to 4.4 thus irritating to mucus membrane of stomach Synergism between two different CNS depressants The Mickey Finn Available: capsule, syrup, suppository Sedative in non-operating procedure for pediatric patients 1. Ethanol (by increasing the concentration of NADH nicotinamide adenine dinucleotide) enhances the reduction of chloral to trichloroethanol, the more active metabolite; while chloral can inhibit the metabolism of alcohol because it inhibits alcohol dehydrogenase. 2. Chloral hydrate is very quickly converted to trichlorethanol, which accounts for almost all hypnotic effect. 3. Trichloroethanol is metabolized by oxidation to chloral and then to inactive metabolite, trichloroacetic acid which is metabolized further to acylglucuronides via conjugation 7 with glucuronic acid.

Reaction and metabolism of chloral

iii.

Alcohols

e.g., Ethanol: has a long history of use as sedative and hypnotic; anesthetic; selfmedication as sedative-hypnotic; seldom preferred medically - CNS depressant potency increases to 8 carbon atoms, with activity decreasing thereafter - Branching of alkyl chain increases depressant activity - In isometric series, potency is tertiary > secondary > primary, because tertiary and secondary alcohols are not oxidized to corresponding carboxylic acids - Replacement of hydrogen atom in the alkyl group by a halogen increases the alkyl portion, and accordingly, for the lower molecular weight compounds, increases potency Alcohols: ETHCHLORVYNOL IUPAC: 1-chloro-3-ethyl-1-penten-4-yn-3-ol

Mild sedative-hypnotic Quick onset, short duration of action (t1/2= 5.6h) Highly lipophilic, so extensively metabolized to secondary alcohol (~90%) prior to excretion Induces microsomal hepatic enzymes Acute overdoes similar to barbiturate overdose

DISULFIRAM IUPAC: Diethylcarbamothioylsulfanyl N,N-diethylcarbamodithioate

Treatment for chronic alcoholism/alcohol dependency by producing an acute sensitivity to alcohol Exerts its effect by inhibiting the enzyme aldehyde dehydrogenase (ALDH).

SODIUM BROMIDE NaBr; white, crystalline solid that resembles NaCl Bromide Frequently used as sedatives in the 19th and early 20th century. Their use in over-the-counter sedatives and headache remedies extended to 1975, when bromides were withdrawn as ingredients, due to chronic toxicity Antiepileptic, particularly in veterinary medicine.

Potassium bromide is equally effective (bromide salts)

HYDROXYZINE IUPAC: 2-(2-{4-[(4-chlorophenyl)-phenylmethyl]piperazin-1-yl}ethoxy)ethanol

antihistamine with anticholinergic (drying) and sedative properties used to treat allergic reactions; may also be antiemetic, anxiolytic, antipruritic After ingestion, it is converted to its active form called cetirizine. Although both hydroxyzine and cetirizine act as antihistamines, hydroxyzine causes more sedation than cetirizine.

synergism: adds to (exaggerates) the sedating effects of alcohol and other drugs that can cause sedation; also adds to anticholinergic properties of other medications