Sedative -Hypnotics 4th Year Pharmacy 2015- 2016

Major Uses A. Anxiety state B. Insomnia C. Epilepsy D. Muscle spasticity E. Induction of amnesia F. Adjunct in alcohol withdrawal G. For differential psychiatric diagnosis. I-General Anesthesia

Classification According to their chemical structure, Sedatives agents can be divided into three classes: benzodiazepines- - GABA receptor modulators: Diazepam, Alprazolam. Barbiturates Non- barbiturates

1. Benzodiazepines

In 1990 diazepam and lorazepam were in the top 20 most frequently used generic drugs. Benzodiazepines are not general depressants of the CNS like barbiturates and other sedatives and hypnotics. They don’t induce true anaesthetic effect, since awareness is still present and total muscular relaxation is not obtained even in with large doses. It is believed that they exert at least some of their action via GABA- mediated inhibitory neurotransmission by binding to a specific site on GABAA receptor. Benzodiazepines are orally absorbed.

1,4-benzodiazpine 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2-on 1960 by Hoffman –La Roche  - which, since 1963, has also marketed the benzodiazepine Diazepam  (Valium). In 1977 benzodiazepines were globally the most prescribed medications

1) 3H-1,4-benzodiazepines Chlordiazepoxide (librium) The first drug discover Indications: anxiety, parenteral for preanesthetic use, status epilepticus, chemotherapy induced N/V, acute alcohol withdrawl, psychogenic catatonia, chronic insomnia 0.5, 1.2 mg tablets, oral solution concentrate, injection 7-Chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide

Synthesis

Structure Activity Relationship In ring A an electron – withdrawing group such as Cl, Br, NO2, NO2, or CN at position 7. A methyl Group is attached to the nitrogen atom in position 1 in ring B. However, substituents at position 1 that are metabolically are still clinically useful e.g. Flurazepam. Replacement of the carbonyl function with two hydrogens in position 2 gives medazepam, less potent than diazepam.

Replacement of one of the hydrogen with a OH group on position 3 lower the activity on the one hand and aids elimination on the other. Introduction of a carbonyl function in the 3 position increases the duration of action and also favours formation of water soluble salts.

A phenyl substituent at the 5, position. α-pyridyl derivative and cycloalkyl substituent at 5 position give potent compounds. Electronegative substituents such as Cl or F at the ortho and disubstituted in both ortho positions in ring C. Derivatives with additional rings joining the diazepine nucleus at the 1 and 2 positions are generally more active than the corresponding 1-methylbenzodiazepines. Replacement of the benzene ring by heteroaromatic (e.g. pyrazole) resulted in compounds with interesting anxiolytic properties ( e.g. ripazepam). Saturation of the 4,5- double bond reduces potency, as does a shift of the unsaturation into the 3,4-position.

Benzodiazepines 3/2/11 CHEM E-120 12

7- Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one Diazepam (valium) 7- Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

Assay: A sample (0.5) is dissolved in glacial acetic acid (80ml). Uses: It is used for the control of anxiety and tension state, the relief of muscle spasm. It is also helpful in combating withdrawal symptoms in chronic alcoholics. It has shown effectiveness in certain types of epilepsy and in labour it has many advantages over other drugs. It is metabolized to nordiazepam which is also active with half – life of 60 hrs. Assay: A sample (0.5) is dissolved in glacial acetic acid (80ml). The solution is titrated with 0.1 N perchloric acid and the end point is determined potentiometrically. Dose: 5 to 30mg daily in divided doses.

Metabolism Biotransformation of benzodiazepines takes place in the liver by microsomal – metabolizing system. N-demethyation gives active metabolite with longer life than the parent drug. Diazepam and Chlorzepate to active metabolite such as N-desmethyl diazepam (nordiazepam). Hydroxylation at position 3 followed by glucuronidation is the main metabolic pathway.