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: ,,,,

- Type found 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 4; stereoisomer of brand

A&B Trusopt
MW 222.245 g/mol 324.44 g/mol
Formulation 125mg, 250mg tab Opthalmic solution 2%
500mg SR cap, 500mg/5cc
IV
Nature Potent carbonic anhydrase Potent carbonic anhydrase
inhibitor inhibitor
Half life 3-9 hours 4 months
Marketing Acetamox, Diamox, Diluran, Trusopt, Dorzolamide/timolol,
status 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:
Gconf= 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:
Gconf= 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 20 nM 0.37 nM
constant)

pKd (-logkd) 7.7 9.4

Gbind (RTlnKd) -10.64 kcal/mol -13.03 kcal/mol

 Acetazolamide Drug Target
Interaction

Electrostatic Interaction: The high

electron density of drug, is
making strong interaction with
Hydrogen bonding: 2 positively charged Zinc.
Length: 1.67, 2.09 Van der Waals Interaction:
Hydrogen bonding off of Perfect steric
Threonine
Hydrogen bonding continued..

Hydrogen bond donors: 2

Hydrogen bond acceptors: 5
Hydrogen bond formation: 2
Unsatisfied donors and
acceptors: 3
 Dorzolamide Drug Target Interaction

Electrostatic Interaction: The high electron

Density of drug is making strong
Hydrogen bond: 3 Interaction with positively charged Zinc.
Length: 1.68, 2.13, 2.16 Van der Waals interaction:
Bonds off of Threonine and 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 There are 9 polar atoms

with total polar surface with total polar surface
area of 115.04 A2 area of 106.33 A2

Permeable for regular Permeable for regular

blood stream (<140A2 ) blood stream (<140A2 )

Not permeable for brain Not permeable for brain

(>75A2) (>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?