Benzodiazepines drm

benzodiazepines drugs with their uses

1. Benzodiazepines By Mrs. Dhanashri R Mali

2. Benzodiazepines The term benzodiazepine refers to the portion of the structure composed of a benzene ring (A) fused to a seven- membered diazepine ring (B). Approved for use ~ 50 years ago Chlodiazepoxide - 1960 Diazepam - 1961

3. MODE OF ACTION Benzodiazepines binds to GABA A receptor Facilitate GABA- GABA A receptor activity allosterically  Frequency of the channel opening &  affinity of GABA for the receptor  Chloride ion conductance  Hyperpolarization of the neuronal cell membrane

4. P h a rmac o l ogi c a l E f f ec ts Reduction of anxiety and aggression Sedation and induction of sleep: T he latency of sleep onset is decreased; T he duration of stage 2 NREM sleep is i ncreased; T he duration of slow-wave sleep is d ecreased. Anticonvulsant and antiseizure The can enhance GABA-mediated synaptic systems and inhibit excitatory transmission. Muscle relaxation relax contracted muscle in joint disease or muscle spasm. Other effects lead to temporary amnesia decrease the dosage of anesthetic; depress respiratory and cardiovascular function .

5. Structure Activity Relationship Ring A: It is believed to participate in π- π bonding with aromatic residue of aromatic amino acids of the receptor. 1-4 diazepine derivative having ring-A replaced with hetrocyclic ring have weak activity and affinity as compared to phenyl derivatives Presence of an electron withdrawing group in position 7 is required for activity. More the electron-withdrawing more will be the activity. Position 6,8 and 9 should not be substituted. A B C

6. Ring B A proton acceptingA proton accepting group (carbonyl oxygen) at 2- position of ring B is necessary to interact with receptor histidine residue that act as proton donor and help in ligand binding. Substitution 3-position methylene or imine nitrogen is sterically unfavorable. Derivatives having 3-hydroxy moiety have comparable potency to non- hydroxylated analogue but are excreted faster. Saturation of the N4-C5 double bond or its shifting to other positions decreases activity. The nitrogen atom at position 1, the N-substituent should be small.

7. Ring C A phenyl ring in position 5 promotes activity. Activity is increased when the phenyl is ortho or diortho substituted with electron withdrawing groups. Substitution in para position brings about decrease in activity. This aromatic ring contribute favorable hydrphobic or steric interactions to receptor binding and its relationship to ring A Annelating the 1,2 bond of ring B with an additional electron rich ring such as triazole ( alprazolam ) or imidazole ( midazolam ) results in pharmacologically active benzodiazepine derivatives with high affinity to BZR

8. Pharmacokinetic Aspects Well absorbed when given orally; Distribution volumes is big. Metabolic transformation in the microsomal drug-metabolizing enzyme systems of the liver, eventually excreted as glucuronide conjugates in the urine . Rapid tissue redistribution  long acting  long half lives and elimination half lives (from 10 to > 100 hrs). · All BDZs cross the placenta  detectable in breast milk  may exert depressant effects on the CNS of the lactating infant.

9. Metabolism Hepatic metabolism. Almost all BDZs undergo microsomal oxidation (N- dealkylation and aliphatic hydroxylation) and conjugation (to glucoronides ). Metabolites of some benzodiazepines are not only active but also have long half-lives, thus these drugs are long acting. Estazolam , oxazepam , and lorazepam , which are directly metabolized to glucoronides have the least residual (drowsiness) effects. Cytochrome inhibitors (erythromycin, clarithromycin , ritonavir , itraconazole , ketoconazole , nefazodone , and grapefruit juice) can affect their metabolism. They have lower abuse potential and a much greater margin of safety than the barbiturates.

10. * Wilson and Gisvold’s Textbook of Organic Medicinal And Pharmaceutical Chemistry,446

11. Comparison of Benzodiazepines Drug Peak Blood Level (Hours) E li m i n a ti o n Half-Life 1 (Hours) Comments Alprazolam 1-2 12-15 Rapid Oral A bs o r p tion Chlordiazepoxide 2-4 15-40 Active metabolites; erratic bioavailability from IM injection Diazepam 1-2 20-80 Active metabolites; erratic bioavailability from IM injection Lorazepam 1-6 10-20 No active metabolites Temazepam 2-3 10-40 Slow oral absorption; no active metabolites Triazolam 1 2-3 Rapid onset; short duration of action Oxazepam 2-4 10-20 No active metabolites 1 Includes half-lives of major metabolites

12. ADVERSE EFFECTS Light-headedness Fatigue Increased reaction time Motor incoordination Impairment of mental and motor functions Confusion Antero-grade amnesia Cognition appears to be affected less than motor performance. All of these effects can greatly impair driving and other psychomotor skills, especially if combined with ethanol.

13. Uses: Antianxiety drugs: Diazepam, Chlordiazepoxide , Oxazepam , Lorazepam , Alprazolam , Clonazepam , Flurazepam Sedative and hypnotics Anticonvulsant: Nitrazepam , Clonazepam Muscle relaxant properties General Anesthetics: Midazepam

14. Benzodiazepines

15. Chlordiazepoxide 7- chloro-2-( methylamino )-5-phenyl-3 H-1,4-benzodiazepine- 4-oxide Well absorbed after oral administration. Peak plasma levels are reached in 2 to 4 hours. The half-life is 6 to 30 hours. Because of the long half-life of parent drug and its active metabolites, this drug is long acting and self-tapering. Repeated administration of chlordiazepoxide can result in accumulation of parent drug and its active metabolites, and thus cause excessive sedation.

16. Diazepam 7-chloro-1,3-dihydro-1- methyl-5-phenyl-2 H-1,4-benzodiazepine-2-one prototypical and was the first member of the benzodiazepine-2-one group to be introduced. It is very lipophilic It is rapidly and completely absorbed after oral administration. Max peak blood conc. occurs in 2 hours Elimination is slow, with a half-life : 46 hours. Log P: 3.86, Protein Binding: 99%

17. Repeated administration of diazepam leads to accumulation of an active nordazepam . Diazepam clearance is decreased in the elderly and in patients with hepatic insufficiency, a dosage reduction may be warranted. Uses: Short-term management of anxiety: Insomnia associated with Sleepwalking; night terrors— Children and adolescents (up to 18 years) Anesthetic premedication Adjunct in the management of seizures Muscle spasms

18. Name of drug Structure IUPAC Name Onset of action Peak Blood Level ( Hrs ) Elimination Half-Life (Hrs ) Active metabolite Uses Long Acting Chlordiazepoxide  7-chloro-2-( methylamino ) -5-phenyl-3 H -1,4-benzodiazepine 4-oxide 15-30 min 2-4(po) 5-30 3-100 Sedative and Hypnotics Diazepam 7-chloro-1,3-dihydro-1- methyl-5-phenyl-2 H -1,4-benzodiazepine-2-one Within 15 min 1(po) 20-50 3-100 Sedative and Hypnotics skeletal muscle relaxant, anticonvulsant and antianxiety agent. Flurazepam 7-chloro-1-[2-( diethylamino )ethyl]-5-( 2-fluorophenyl) - 1, 3-dihydro-2 H -1, 4-benzodiazepine-2-one dihydrochloride Within 15 min 0.5-2 inactive 47-100 Sedative and Hypnotics Quazepam 7-chloro-5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-3 H -1,4-benzodiazepine-2-thione 15-30 min 1-2 39 -- Sedative and Hypnotics

19. Prazepam 7-chloro-1-( cyclopropylmethyl )- 1,3-dihydro -5 - phenyl-2H-1,4-benzodiazepine-2-one Within 15 min 1(po) 20-50 3-100 Sedative and Hypnotics Halazepam 7-chloro-1,3-dihydro-5- phenyl-1(2,2,2-trifluoroethyl)-2 H -1,4-benzodiazepine-2-one 30-60 min 1-3 6-20 47-100 Anxiolytics , anticonvulsant, sedative, muscle relaxing effects Intermediate acting Nitrazepam 7-Nitro-5-phenyl-1,4-benzodiazepin-2-one Within 15 min 1( po ) 6-20 sedatives and hypnotics, and myoclonic seizures. Clorazepate Dipotassium 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1 H -1,4-benzodiazepine- 3-carboxylic acid dipotassium salt monohydrate 15-30 1 Inactive 40-50 Anxiolytics, Sedative and Hypnotics Oxazepam 7-chloro-1,3-dihydro-3- hydroxy-5-phenyl-2 H -1,4-benzodiazpin-2-one 30-60 min 2-3 4-8 - Sedative and Hypnotics

20. Lorazepam 7-chloro-5-(2-chlorophenyl)- 3-dihydro-3-hydroxy-2 H -1,4-benzodiazepine-2-one 15-30 min 1-1.5 (po) 2-6 - Sedative and Hypnotics Temazepam. 7-chloro-1,3-dihydro-3-hydroxy- 1-methyl-5-phenyl -2 H -1,4-benzodiazepine-2-one 30-60 min  0.75-1.5 10-20 Anxiolytics , Sedative and Hypnotics TRIAZOLOBENZODIAZEPINES Alprazolam 8-chloro-1-methyl-6- phenyl-4 H - s -triazolo[4,3- a ][1,4]benzodiazepine 15-30 min 0.7-1.6 6-20 -- Anxiolytics, Sedative and Hypnotics Triazolam 8-chloro-6-( o -chlorophenyl)- 1-methyl-4 H - s -triazolo[4,3-a][1,4] benzodiazepine 15-30 min 0.75-2 1.6-5.5 amnesic, anxiolytic , sedative , anticonvulsant, and muscle relaxant Midazolam. 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine  Most  Rapid IV 0.5-1 (IV 1-4 - General anesthetics, Anticonvulsant