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Carbonic Anhydrase Inhibitors for Treatment of Glaucoma

Carbonic Anhydrase Inhibitors for Treatment of Glaucoma. Example: Based on Presentation from: Parnian Eslami , Neeloufar Fakourfar, Mandana Moshtael. Desease : Glaucoma. Glaucoma- build up of fluid in the aqueous humor of the eye, the fluid presses against the optic nerve

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Carbonic Anhydrase Inhibitors for Treatment of Glaucoma

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  1. Carbonic Anhydrase Inhibitors for Treatment of Glaucoma Example: Based on Presentation from: ParnianEslami, Neeloufar Fakourfar, MandanaMoshtael

  2. Desease: Glaucoma • Glaucoma- build up of fluid in the aqueous humor of the eye, the fluid presses against the optic nerve • Untreated glaucoma can lead to permanent damage of the optic nerve and results in field loss, which can result into blindness • These two drugs help decrease the pressure in the eye • Add stats on Glaucoma

  3. Target: Carbonic Anhydrase CO2 + H2O <-----> HCO3- + H+ • An enzyme that drives the hydration of carbon dioxide and dehydration of Bicarbonate • Examples are found in: • Parietal Cells in Stomach • Pancreatic duct cells • Renal tubules • Red blood cells • CAH2 found in ciliary process, cornea, iris, and retina • Please ADD Connection with Glaucoma and pH

  4. Target: Structures of Carbonic Anhydrase • 5 Types: α,β,γ,δ,ε • Type αfound in humans • Others found in bacteria and plants • 4 broad subgroups • Cytosolic, mitochondria, secreted and membrane associate • with several isoforms in each (ex: CA2, CA13) • Length: ≈ 260 AA • MW: 29kDa

  5. Inhibitor action Target: Active site Zinc Mechanism of Action: Inhibitor binds to active site, blocking interactions of water bound to zinc and inhibiting enzymatic activity

  6. Target: Carbonic Anhydrase II • H+ + HCO3- H2CO3 CO2+ H2O • Inhibitors mostly sulfanomides • Metalloenzyme (has Zn2+ in active site) • Binds near the active site and disrupts the interactions of the water bound to the zinc ion, blocking enzyme action • Prolonged use can effect the same enzyme present in other tissues and can lead to kidney and liver damage

  7. Drugs Acetazolamide Dorzolamide For treatment of: Open angle glaucoma Ocular hypertension • For treatment of: • Open angle glaucoma • Drug induced edema • Centrencephalic epilepsies • Edema due to conjuctive heart failure • Metabolic alkalaemia • Periodic paralysis

  8. Acetazolamide Dorzolamide

  9. Acetazolamide rotatable bonds • Rotatable (essential) bonds: 2 • Restricted bonds: 2 • Estimated number of drug conformers: 32=9 • Estimated number gives energy contribution due to conformation entropy loss upon binding or crystallization is: • ΔGconf= 0.6 x 1= 0.6 kcal/mol

  10. Dorzolamide Rotatable bonds • Rotatable (essential) bonds: 3 • Restricted bonds: 0 • Estimated number of drug conformers: 33 = 27 • Estimated gives energy contribution due to conformation entropy loss upon binding or crystallization is: • ΔGconf= 0.6 x 3= 1.8 kcal/mol

  11. Ionization Acetazolamide - Dorzolamide Acidic Pka: 6.93 - Acidic pKa: 8.1 Basic pKa: -3.3 - Basic pKa: 7.14 LogS: -2.36 Sw: .002 M - LogS: -2.7  Sw: .004 M Solubility: .980mg/mL @ 30oC - Solubility: .699mg/mL

  12. Protein Binding • Acetazolamide • Protein Binding: 98% • Dorzolamide • Protein Binding: 33%

  13. Target binding

  14. Acetazolamide Drug Target Interaction Electrostatic Interaction: The high electron density of drug, is making strong interaction with positively charged Zinc. • Hydrogen bonding: 2 • Length: 1.67, 2.09 • Hydrogen bonding off of Threonine Van der Waals Interaction: Perfect steric

  15. Hydrogen bonding continued.. Hydrogen bond donors: 2 Hydrogen bond acceptors: 5 Hydrogen bond formation: 2 Unsatisfied donors and acceptors: 3

  16. Dorzolamide Drug Target Interaction Electrostatic Interaction: The high electron Density of drug is making strong Interaction with positively charged Zinc. Hydrogen bond: 3 Length: 1.68, 2.13, 2.16 Bonds off of Threonine and Glutamine Van der Waals interaction: Perfect steric fit.

  17. Hydrogen bonding continued… Hydrogen bond donors: 2 Hydrogen bond acceptors: 5 Hydrogen bond formation: 3 Unsatisfied donors and acceptors: 3

  18. Phase partitioning

  19. Polar surface area Acetazolamide • Hydrophilic • There are 9 polar atoms with total polar surface area of 115.04 A2 • Permeable for regular blood stream (<140A2 ) • Not permeable for brain (>75A2) Dorzolamide • Hydrophilic • There are 9 polar atoms with total polar surface area of 106.33 A2 • Permeable for regular blood stream (<140A2 ) • Not permeable for brain (>75A2)

  20. Pharmacokinetics Acetazolamide Dorzolamide Bioavailability: little to no systemic absorption • Oral bioavailability: >90% • Food co-ingestion: neither delays the rate of absorption nor reduces extent of absorption • Tmax: 2-4 hours

  21. Drug interactions • Acetazolamide: • Salicylates increase the effect of the inhibitor • Any other CAH2 inhibitor concurrent use will result in toxicity • Dorzolamide • Any other CAH2 inhibitor because of adverse effects

  22. Future • Acetazolamide is looking to make an eye drop more effective than Dorzolamide 2% • Using new formulation • High concentration of the drug • Surfactant gel preparations of Acetazolamide • Acetazolamide loaded into liposomes • Addition of cyclodestrins to increase solubility

  23. Questions?

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