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 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
Target: Carbonic Anhydrase CO 2 + H 2 O HCO 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
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 Target: Structures of Carbonic Anhydrase
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
Target: Carbonic Anhydrase II H + + HCO 3 - H 2 CO 3 CO 2 + H 2 O Inhibitors mostly sulfanomides Metalloenzyme (has Zn 2+ 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
Drugs Acetazolamide For treatment of: Open angle glaucoma Drug induced edema Centrencephalic epilepsies Edema due to conjuctive heart failure Metabolic alkalaemia Periodic paralysis Dorzolamide For treatment of: Open angle glaucoma Ocular hypertension
Stereoisomer None; 2 polymorphic forms A&B 4; stereoisomer of brand Trusopt MW g/mol g/mol Formulation 125mg, 250mg tab 500mg SR cap, 500mg/5cc IV Opthalmic solution 2% Nature Potent carbonic anhydrase inhibitor Half life 3-9 hours4 months Marketing status Acetamox, Diamox, Diluran, etc. Trusopt, Dorzolamide/timolol, Cosopt, etc. Acetazolamide Dorzolamide
Acetazolamide rotatable bonds Rotatable (essential) bonds: 2 Restricted bonds: 2 Estimated number of drug conformers: 3 2 =9 Estimated number gives energy contribution due to conformation entropy loss upon binding or crystallization is: ΔG conf = 0.6 x 1= 0.6 kcal/mol
Dorzolamide Rotatable bonds Rotatable (essential) bonds: 3 Restricted bonds: 0 Estimated number of drug conformers: 3 3 = 27 Estimated gives energy contribution due to conformation entropy loss upon binding or crystallization is: ΔG conf = 0.6 x 3= 1.8 kcal/mol
Ionization Acetazolamide - Dorzolamide Acidic Pka: Acidic pKa: 8.1 Basic pKa: Basic pKa: 7.14 LogS: Sw:.002 M- LogS: -2.7 Sw:.004 M 30 o C- Solubility:.699mg/mL
Protein Binding Acetazolamide Protein Binding: 98% Dorzolamide Protein Binding: 33%
Target binding AcetazolamideDorzolamide Kd (dissociation constant) 20 nM0.37 nM pKd (-logkd) ΔG bind (RTlnKd) kcal/mol kcal/mol
Hydrogen bonding: 2 Length: 1.67, 2.09 Hydrogen bonding off of Threonine Acetazolamide Drug Target Interaction Van der Waals Interaction: Perfect steric Electrostatic Interaction: The high electron density of drug, is making strong interaction with positively charged Zinc.
Hydrogen bonding continued.. Hydrogen bond donors: 2 Hydrogen bond acceptors: 5 Hydrogen bond formation: 2 Unsatisfied donors and acceptors: 3
Dorzolamide Drug Target Interaction Hydrogen bond: 3 Length: 1.68, 2.13, 2.16 Bonds off of Threonine and Glutamine Van der Waals interaction: Perfect steric fit. Electrostatic Interaction: The high electron Density of drug is making strong Interaction with positively charged Zinc.
Hydrogen bonding continued… Hydrogen bond donors: 2 Hydrogen bond acceptors: 5 Hydrogen bond formation: 3 Unsatisfied donors and acceptors: 3
Phase partitioning AcetazolamideDorzolamide LogP [Oct]/[H2O] Lipophilic or Hydrophilic Hydrophilic
Polar surface area Acetazolamide Hydrophilic There are 9 polar atoms with total polar surface area of A 2 Permeable for regular blood stream (<140A 2 ) Not permeable for brain (>75A 2 ) Dorzolamide Hydrophilic There are 9 polar atoms with total polar surface area of A 2 Permeable for regular blood stream (<140A 2 ) Not permeable for brain (>75A 2 )
Pharmacokinetics Acetazolamide Oral bioavailability: >90% Food co-ingestion: neither delays the rate of absorption nor reduces extent of absorption Tmax: 2-4 hours Dorzolamide Bioavailability: little to no systemic absorption
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
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
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