Things TO KNoWArthur G. Roberts
Benzodiazepine and benzodiazepine-like drugs
1 2
3
45
6
7
2
8
9
3
1 2
345
67
diazepine
azepine
benzo-di-azepine
benzene8
9
Benzodiazepines GABA GABAA 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
KD’s of GABAA agonists
Compound 1 2 3 5
Diazepam 16 nM 16 17 15
Clonazepam 1.3 1.7 2 -
Triazolam 1.8 1.2 3 1.2
Ro15-4513 2.6 2.6 1.3 0.24
Zolpidem 1.7 291 357 >15000
L-655-708 48 27 24 0.45
7
How to Use the Table
Rules
• and 5 non-selective
• 1-3 anticonvulsant
• 1 sedation and hypnosis
• 2 and 5 anxiolytic
8
9
Benzodiazepines SAR1
47
• Know the SAR rules• basic characteristics
• Know names of BZD from class
Flumazenil (Anexate)
GABAA 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
NH2
13
OH
midazolam hydroxymethyl midazolam
Non-benzodiazepines (Non-BZD)
imidazopyridinespyrazolopyrimidinecyclopyrrolones
14
Insomnia Melatonin receptor (MT1 and MT2) agonist (No GABAA)
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)
Bisphosphonates (BP)
Ionization
A B
C
Bisphosphonates (BP)
Ca2+
BP complexed with Ca2+
History 1897 Von Baeyer and Hoffman 1960 Blazer and Worms- Ca2+ and Mg2+ 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) 2009- 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
2 x
3-isopentenyl pyrophosphate
dimethylallyl pyrophosphate
AB
Osteoclast Formation
Bone Breakdown
mevalonate pathway
General Understanding
Bisphosphonates and Bone Remodeling
localize at sites of bone resorption. 2 phosphonates chelate exposed Ca2+ 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
Bisphosphonatesuse 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