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
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
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+ + 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
Dorzolamide
 For treatment of:
 For treatment of:
 Open angle glaucoma
 Open angle glaucoma
 Drug induced edema
 Ocular hypertension
 Centrencephalic
epilepsies
 Edema due to
conjuctive heart failure
 Metabolic alkalaemia
 Periodic paralysis
Acetazolamide
Dorzolamide
Stereoisomer
None; 2 polymorphic forms
A&B
4; stereoisomer of brand
Trusopt
MW
222.245 g/mol
324.44 g/mol
Formulation
125mg, 250mg tab
500mg 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, Trusopt, Dorzolamide/timolol,
etc.
Cosopt, etc.
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
Acidic Pka: 6.93
Basic pKa: -3.3
LogS: -2.36  Sw: .002 M
Solubility: .980mg/mL @ 30oC
- Dorzolamide
- Acidic pKa: 8.1
- Basic pKa: 7.14
- LogS: -2.7  Sw: .004 M
- Solubility: .699mg/mL
Protein Binding
 Acetazolamide
 Protein Binding: 98%
 Dorzolamide
 Protein Binding: 33%
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
Acetazolamide Drug Target
Interaction
Hydrogen bonding: 2
Length: 1.67, 2.09
Hydrogen bonding off of
Threonine
Electrostatic Interaction: The high
electron density of drug, is
making strong interaction with
positively charged Zinc.
Van der Waals Interaction:
Perfect steric
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
Electrostatic Interaction: The high electron
Density of drug is making strong
Interaction with positively charged Zinc.
Van der Waals interaction:
Perfect steric fit.
Hydrogen bonding continued…
Hydrogen bond donors: 2
Hydrogen bond acceptors: 5
Hydrogen bond formation: 3
Unsatisfied 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
Dorzolamide
 Hydrophilic
 Hydrophilic
 There are 9 polar atoms
with total polar surface
area of 115.04 A2
 There are 9 polar atoms
with total polar surface
area of 106.33 A2
 Permeable for regular
blood stream (<140A2 )
 Permeable for regular
blood stream (<140A2 )
 Not permeable for brain
(>75A2)
 Not permeable for brain
(>75A2)
Pharmacokinetics
Acetazolamide
Dorzolamide
 Oral bioavailability: >90%
 Bioavailability: little to no
systemic absorption
 Food co-ingestion: neither
delays the rate of
absorption nor reduces
extent of absorption
 Tmax: 2-4 hours
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
Questions?