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