THINGS TO KNOW Arthur G. Roberts

Benzodiazepine and benzodiazepine-like drugs

diazepine azepine benzo-di-azepine benzene 8 9

Benzodiazepines  GABA  GABA A receptor  Properties  Sedation/hypnosis  Decreased anxiety  Anterograde amnesia (negative)  Anticonvulsant  Muscle relaxation  -aminobutyric acid 4

Benzodiazepines  Therapeutic and Efficacy  half life  Anticonvulsants  long half-lives  CNS and Status epilepticus  Sleep  short half-lives  Anti-anxiety  long half-life, except aprazolam (Xanax) ~12 hours 5 alprazolam (Xanax)

(  site ) 6 Chloride Conductance A B C  -aminobutyric acid (GABA) D

K D ’s of GABA A agonists Compound 11 22 33 55 Diazepam16 nM Clonazepam Triazolam Ro Zolpidem >15000 L How to Use the Table

Rules     and  5 non-selective  1 -  3 anticonvulsant  1 sedation and hypnosis  2 and  5 anxiolytic 8

9 Benzodiazepines SAR 1 47 Know the SAR rules basic characteristics Know names of BZD from class

Flumazenil (Anexate)  GABA A receptor antagonist  BZD overdoses  hypersomnia  X Patent  Liver  Carboxylic Acid Metabolite + Glucuronidation  ADR: headache and insomnia 10 5

METABOLISM 11

12 diazepam (Valium) clorazepate prazepam halazepam NH 2

13 OH midazolam  hydroxymethyl midazolam

Non-benzodiazepines (Non- BZD)  imidazopyridines  pyrazolopyrimidine  cyclopyrrolones 14

 Insomnia  Melatonin receptor (MT 1 and MT 2 ) agonist (No GABA A )  sleep-wake cycle and circadian rhythm  Onset 30 mins  Bioavailable is 1.8%  Metabolized by CYP1A2, first pass converts to active metabolite M-II  Food delays absorption  82% protein bound  ADR: headache, depression, insomnia worsened Melatonin 15 Alternative: Ramelteon (Rozerem) 1/10 M-II

Bisphosphonates (BP)

Ionization AB C

Bisphosphonates (BP) Ca 2+ BP complexed with Ca 2+  History  1897 Von Baeyer and Hoffman  1960 Blazer and Worms- Ca 2+ and Mg 2+ complexation  late 1960s Fleisch- reduced bone resorption in rats (2 x Science) and first clinical trials  1970s and 1980s- clinical development of Bisphosphonates (Procter and Gamble)  Procter and Gamble prescription drug business sold to Warner Chilcott (formerly Galen)

Bone Remodeling Breakdown Formation

Bisphosphonates and Bone Remodeling  Promote Osteoclast Apoptosis  Stabilize Bone Matrix

Bisphosphonates and Bone Remodeling Bisphosponates FPP = Farnesyl Pyrophosphate Synthase; HMG-CoA = 3-hydroxy-3-methyl-CoA side effects ? FPP farnesyl pyrophosphate 2 x 3-isopentenyl pyrophosphate dimethylallyl pyrophosphate A B Osteoclast Formation Bone Breakdown mevalonate pathway General Understanding

Bisphosphonates and Bone Remodeling  localize at sites of bone resorption.  2 phosphonates chelate exposed Ca 2+ in the bone matrix

Bisphosphonates and Bone Remodeling  Normal bone is formed on top of the compounds by osteoblasts  Incorporated into the matrix, but no pharmacological action  Continuously administered to maintain positive bone formation balance

Bisphosphonates use and indications  Osteoporosis  Glucocorticoid-induced osteoporosis  Paget’s disease  Cancer  Hypercalcemia  Osteolytic bone metastases

Bisphosphonates

Pharmacophore N ~4 Å..

Bisphosphonates: General Considerations  Care needed  Side effects, Possible long half-life  Strong acids (pKa < 1)  will not chelate. Lose effectiveness.  Fairly high affinity for calcium and other di- and trivalent minerals ( Mg, Fe, Al, etc. )  Plain water  avoid water containing minerals (e.g. mineral, spring, tap and well water) because of chelation  Food affects absorption  empty stomach