carbonic anhydrase inhibitors for treatment of glaucoma example: based on presentation from: parnian...
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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
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
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 AAMW: 29kDa
Target: Structures of Carbonic Anhydrase
Inhibitor actionTarget: 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+ + 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
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 222.245 g/mol 324.44 g/mol
Formulation 125mg, 250mg tab500mg SR cap, 500mg/5cc IV
Opthalmic solution 2%
Nature Potent carbonic anhydrase inhibitor
Potent carbonic anhydrase inhibitor
Half life 3-9 hours 4 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: 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
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
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
Target binding
Acetazolamide Dorzolamide
Kd (dissociation constant)
20 nM 0.37 nM
pKd (-logkd) 7.7 9.4
ΔGbind (RTlnKd) -10.64 kcal/mol -13.03 kcal/mol
Hydrogen bonding: 2Length: 1.67, 2.09Hydrogen 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: 2Hydrogen bond acceptors: 5Hydrogen bond formation: 2Unsatisfied donors and acceptors: 3
Dorzolamide Drug Target Interaction
Hydrogen bond: 3Length: 1.68, 2.13, 2.16Bonds off of Threonine and Glutamine
Van der Waals interaction: Perfect steric fit.
Electrostatic Interaction: The high electronDensity of drug is making strongInteraction with positively charged Zinc.
Hydrogen bonding continued…
Hydrogen bond donors: 2Hydrogen bond acceptors: 5Hydrogen bond formation: 3Unsatisfied donors and acceptors: 3
Phase partitioning
Acetazolamide Dorzolamide
LogP -0.26 -1
[Oct]/[H2O] 0.513 0.1
Lipophilic or Hydrophilic
Hydrophilic Hydrophilic
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)
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