Week 7 - Medicinal Chemistry: Bisphosphonates for the Treatment of Osteoporosis

Question 1

What is the structure of bone

Answer 1

Osteoblasts produce corss-linked triple linked (helix) collagen fibres (protein-peptide)
- between helix have hydroxyapatite precipitate
- hydroxyapatite crystals (a mix calcium + phosphate) both insoluable = why bone doesn’t dissolve)

Question 2

What is the difference between osteoblasts and osteoclasts

Answer 2

Osteoblasts - rebuild / bone formation

Osteoclast - reabsorb bone + release calcium from bone into blood (as bone is broken down)

Question 3

What is Osteoporosis

Answer 3

Excessive bone reabsorption
- bones become fragile, weak + prone to fracture
- AIM: is to prvent falls, prevent fractures / bone breakage

More common in older women (post-menopausla) because osteoclast action (bone reabsorption) exceeds osteoblast action (bone formation)
- can still occur in men

Question 4

What are bisphosphonates and its structure

Answer 4

1st line treatment for osteoporosis

Are stable molecules
- OH, P-O group binds to Ca2+ strengthening bone
- interacts with hydroxyapetite preventing Ca2+ being released from bone (into blood)
- have ammonium cation which prevents bisphophonate being released from bone (by froming hydrogen / ionic bonds)
- NOT naturally occuring
- stability due to carbon-phosphate (C-P) bond more stable than C-O bond

PPi = inorganic phosphate
- which inhibits the dissoloution of hydroxyapatite crystals BUT was very unstable (hydrolysis)
- naturally occuring in body

Question 5

What is the drug action of bisphosphonates

i.e. what do they do

Answer 5

They are absorbed onto hydroxyapatite crystals in bone + slows growth, dissolution, break down / turnover
- turnover = doesn’t grow or shrink

• Have POOR oral bioavilability (0.6%)
• Not metabolised as they are synthetic (no enzyme to degrade it) = metabolically stable
• half life in human bones = 10 years approx.
  
  • released slowly from skeleton

NOTE: not all bisphosphonates are used to treat osteoprosis e.g. sodium clodronate is used to ↓ high calcium levels
Require dental check if have enamel missing = > to get bone / jaw issues

Question 6

List the 4 bisphosphonates used to treat osteoporosis

Answer 6

1. Alendronic Acid
2. Risedronate Sodium
3. Ibandroic Acid
4. Zoledronic Acid

ALL bind to hydroxyapatite

Question 7

How does Alendronic Acid interact with its target

Answer 7

1st line treatment

• 10mg daily, 30 minutes before food for 5 years
  - if taken with food bioavaiolability ↓ from 0.64% to 0% (as it will bind to Ca2+ in food instead)
• May take with vitamin D (if deficient)
• ↓ occurence of fractures
• Has very slow release from skeleton (over 10 years)

Why is the bioavailbity poor:
- low pKa, low logP
- poor membrane permeability
- as its hydrophillic, highly charged
- soluble in water has hydrogen groups can hydrogen bond with water

Question 8

How does Risedronate sodium interact with its target

Answer 8

5mg daily (more potent than alendronic so dose is halved) before first meal

• Similar to aledronic acid but has pyridne ring
• Can be adminsiter with vitamin D and calcium carbonate (if deficient)
• Has poor availability

Question 9

How does Ibandronic acid interact with its target

Answer 9

150mg once a month (orally in hospital)

• Can be oral or IV
  
  • IV can bypass bioavilability picture
• Pentile side chain makes drug more lipophilic

Question 10

How does Zoledronic acid interact with its target

Answer 10

IV infusion 40mcg/ml
- monthly dosing in hospital

• Good bioavailabilty as IV goes directly into blood
• has imidazole ring