Glaucoma and It's Treatment

A. M. Kudal

History: The term glaucoma goes back to hippocratic times. Its meaning is disputed; generally accepted to signify greenish -- like the colour of sea water -- Hirschberg has shown that it is much more likely to mean bluish. It would appear that in Hippocratic writings hypochyma and glaucosis were synonyms, and both vaguely referred to cataract. It is only with later Greek writers that a distinction was made between the two, glaucoma becoming the incurable condition as opposed to hypochyma which was curable, though not always so.

The cause of the increased intra-ocular pressure was seen by von Graefe in a serious choroiditis increasing the watery contents of the eye. To Donders it was due to an increased secretion of the choroid. Stellwag regarded it as the result of increased pressure in the ocular circulation, whilst Priestley Smith stressed faulty excretion rather than secretion, the immediate cause being abnormalities in the angle of the anterior chamber.

Definition

The term "glaucoma" encompasses a group of eye diseases, not a single entity. Glaucoma is described broadly in terms of aqueous fluid drainage through the trabecular meshwork, the major outflow pathway. There are two types: angle closure glaucoma and open angle glaucoma.¹

Classification: The American Academy of Ophthalmology defines primary angle closure glaucoma as, "An appositional or synechial closure of the anterior chamber angle caused by relative pupillary block in the absence of other causes of angle closure". The American Academy of Ophthalmology defines primary open angle glaucoma as a, "Multifactorial optic neuropathy in which there is a characteristic acquired loss of optic nerve fibers". Classifying glaucoma broadly into angle closure glaucoma or open angle glaucoma is helpful from both a diagnostic and pathophysiological perspective

Primary angle closure glaucoma

There are several forms of primary angle closure glaucoma. In these, the position of the peripheral iris blocks access of the aqueous fluid to the outflow pathway, i.e. the trabecular meshwork. Primary angle-closure glaucoma is usually episodic. When the angle closes rapidly in an acute episode, the IOP rises rapidly causing symptoms of blurred vision and pain. Some patients describe the appearance of multi-colored halos around lights.

Acute vs. subacute vs. chronic

Acute angle closure describes a situation wherein the entire circumference of the angle has suddenly closed. Pain is the hallmark. The eye is red and the vision is blurred.

Subacute angle closure is associated with milder signs and symptoms because only a portion of the circumference has functionally closed. Closure may be intermittent and repetitive.

Chronic angle closure implies a long-term condition. Misdiagnosing chronic angle closure as open angle glaucoma is a common diagnostic error.

Secondary angle closure glaucoma

The term "secondary angle closure" is assigned when a pre-existing pathological condition of the eye causes the angle to close. Retinal ischemia secondary to diabetic retinopathy or central vein occlusion can result in neovascular glaucoma in which new vessels occlude the angle. If the ciliary body swells as in uveitis, it can push the iris against the trabecular meshwork and occlude the angle.

Primary open-angle glaucoma (POAG)

About 70% of the diagnosed cases of glaucoma are POAG . The designation of 'Primary' indicates that there is no known association with another disease. Thus OAG, open angle glaucoma, is a broader term that includes both primary and secondary OAG.

Today,IOP data is integrated with data from other ophthalmological procedures to formulate a diagnosis . These data categories include:

• Optic nerve head (ONH) data only,
• Visual field data only, or,
• ONH and the visual field together.

Of those articles reviewed that do quantify IOP as a diagnostic criterion, about half specify an IOP greater than or equal to 22 mm Hg.

Epidemiology of Glaucoma

Studies have shown that glaucoma is the second leading cause of blindness in the United States as well as the second leading cause of bilateral blindness in the world [Quigley, 1996]. An obvious question becomes, "What is the first leading cause of blindness"? The answer is not simple since it is both age and race dependent.

In the United States, glaucoma is a common reason for patients to visit their ophthalmologist. Among patients over 65 years of age, between the years 1991 and 1992 glaucoma was the third most frequently reported reasons for a visit to the physician for a disease amongst all diseases . It was estimated that in 2000, United States residents would make 8.8 million office visits for glaucoma . In 2000, the number of people in the United States with primary open angle glaucoma (POAG) was estimated to be 2.47 million, i.e. 1.84 million white and 619,000 African Americans²

Incidence of angle closure glaucoma

The Baltimore Eye Survey was a cross-sectional study conducted in a multiracial urban area. In this study , 4,870 participants were dilated as part of the screening examination. Although none developed acute angle closure glaucoma, 38 patients who were referred did have occludable angles based on gonioscopy. A history of glaucoma was useful in predicting an occludable angle in African Americans. By comparison, a shallow anterior chamber identified on penlight examination was useful in predicting an occludable angle in Caucasian Americans. In the following figure, penlight examination of anterior chamber depth is shown.

Note that in the illustration of the shallow anterior chamber angle shown above, the bowing forward of the iris results in a shadow being cast on to the iris when a penlight is shown in from the side.³

Pathophysiology Of Open-Angle Glaucoma

Aqueous dynamics: formation and circulation of the aqueous fluid

The aqueous fluid is an ultrafiltrate of blood. It is clear, watery, and fills both the anterior and posterior chambers. Since both the posterior surface of the cornea (the endothelium) and the lens are avascular, the aqueous fluid is critical in delivering oxygen and nutrients. This means that the lens and the corneal endothelium rely on aqueous fluid as their source of nourishment and conduit for metabolic waste removal.

The flow of aqueous fluid plays an important role in the regulation of intraocular pressure, (IOP). The IOP is determined by the inflow as compared with the outflow of aqueous fluid. The total volume of intraocular aqueous fluid within the anterior segment (which has a fixed size) determines the IOP.

Think of the ciliary processes of the ciliary body as the faucet component of the equation and the trabecular meshwork/ canal of Schlemm as the drain. If outflow is equal to inflow, the IOP remains constant. If outflow is less than inflow, the IOP rises. Normal IOP is about 10 to 20 mm Hg.

The aqueous fluid, produced by the ciliary processes, flows:

• into the posterior chamber,
• across the posterior surface of the iris,
• around the border of the pupil,
• into the anterior chamber to interact with the surfaces of the lens and corneal endothelium, and,
• exits the anterior chamber at the anterior chamber angle primarily via the trabecular meshwork and the e canal of Schlemm. The canal is drained by the intra- and episcleral veins. Aqueous fluid mixes with venous blood and is returned to the heart.

The eye continuously forms and reabsorbs the aqueous fluid. The flow of aqueous fluid is less at night compared with during the day. During the day the flow is about 2 microliters/minute, or 120 microliters per hour. For sake of comparison, a drop is about 50 microliters. Thus, aqueous flows into the anterior chamber at the rate of about 2 drops per hour.

The anterior chamber angle is also referred to simply as "the angle". The iris makes up the base of the angle. The trabecular meshwork is found at the apex of the angle. The corneal endothelium makes up the top of the angle. In theory one could place a miniature protractor on the base of the angle and determine the width of the anterior chamber angle in degrees. A 45 degree angle would be considered wide (or "Open"). A 10 degree angle would be considered, "Narrow," or possibly, "Closed".

Most of the aqueous fluid leaves the eye through the trabecular meshwork and flows into the canal of Schlemm. The trabecular meshwork is a sieve-like structure that bridges the anterior chamber angle. Of note, about 10% of the aqueous fluid escapes from the anterior chamber by passing into the ciliary body. It is referred to as uveoscleral outflow. While uveoscleral outflow is not well understood, it appears that topically applied prostaglandins can increase uveoscleral outflow and lower the IOP^4,5

Intraocular pressure (IOP)

IOP is the pressure that the intraocular fluids (mostly the aqueous fluid) exert against the cornea and sclera. IOP is of particular importance in many types of glaucoma, since damage to the neurons of the optic nerve (also known as retinal ganglion cells) is associated with IOP elevation. All patients exhibit fluctuation in IOP over the course of a 24-hour period (diurnal fluctuation). The highest IOP levels are usually recorded in the morning An important quantitative relationship is provided below:

IOP = F / C + PV

Where, F = aqueous fluid formation rate,
C=outflow rate,
PV = episcleral venous pressure.

The above factors are those that drive IOP.

In the general population, IOP ranges between 10 and 21 mm Hg with a mean of about 15 or 16 mm Hg (plus or minus 3.5 mm Hg during a 24-hour cycle).⁶

Role of systemic blood pressure on GON progression

Systolic and diastolic blood pressure were collected in patients with POAG as part of the Baltimore Eye Survey [Tielsch et al., 1995].⁷ Perfusion pressure was defined as (blood pressure - IOP). Among older patients in particular, a lower perfusion pressure was associated with an increased prevalence of POAG, suggesting a relationship between POAG and ocular blood flow. The authors point out that patients with a low diastolic perfusion pressure had a higher prevalence of POAG although a lower systolic perfusion pressure was also associated with POAG.

In Hispanic subjects, diastolic perfusion pressure (which is the diastolic blood pressure - IOP) was plotted against the percentage of subjects with OAG [Quigley et al., 2001]. The prevalence increased four-fold at a lower perfusion pressure. In the Hispanic data set, the percentage of patients with OAG rises steeply as the diastolic perfusion pressure dips below about 60 mm Hg.

Blood flow, velocity and volume were the main outcome measures. Overall, the average blood flow in the ONH was 29% less in patients compared with controls. The average flow in patients without systemic hypertension was 26% less than those with systemic hypertension.

The authors suggest that decreased blood flow within the lamina may be secondary to connective tissue changes and vascular remodelling within the ONH. They further suggest that blood flow parameters within the lamina only partially predict visual field loss^,8

Diagnosis of open angle glaucoma (OAG)

The early stages of open-angle glaucoma are asymptomatic. Therefore an appropriate index of suspicion on the part of the clinician will improve early diagnosis. The diagnosis of OAG can be enhanced by having more primary-care clinicians:

• Recognize risk factors associated with the development of OAG,
• Develop a higher index of suspicion that OAG may actually be present,
• Actively question patients to uncover underlying risk factors.

Abnormal optic disc parameters

Whether using a conventional ophthalmoscope or a computer-assisted laser scanner to characterize the relative health of the optic nerve head, the data collected are markers of glaucomatous optic neuropathy (GON), i.e. the disease and not risk factors per se. Parameters that are often collected include:

·cup-to-disc ratio,

·neuroretinal rim width,

·cup volume,

·vessel 'hooking' or bridging,

·presence of a disc hemorrhage, and others.

As with IOP, there is no appropriate cut-off value for any of these parameters in the diagnosis of OAG. In the Beaver Dam Eye Study, the mean cup-to-disc ratio of participants without glaucoma was 0.36; these participants had a mean IOP of about 15 mm Hg .⁹

Optic nerve head (ONH) examination

To get a good view of the ONH using conventional instruments such as the direct ophthalmoscope, the pupil should be dilated; dilation is routine in ophthalmological practices. By comparison, internists and other physicians who are not ophthalmologists rarely dilate the pupil prior to ophthalmoscopy [Patel et al., 1995]. A primary concern may be provoking acute angle-closure glaucoma. In the Baltimore Eye Survey [Patel et al., 1995], 4,870 subjects were dilated; no subject developed acute angle-closure glaucoma although 38 were later judged to have occludable angles. These authors note that the risk of occluding a potentially occludable angle was less than 1:333. Prior to dilating, the physician should:

• perform a penlight evaluation of the anterior chamber angle, and,
• inquire about a prior history of glaucoma.

With a direct ophthalmoscope, the examiner can visualize the cup within the disk to:

• compute the cup-to-disk ratio (especially the vertical cup-to-disc ratio);
• analyze the neuroretinal rim width and color; and,
• estimate the cup depth.

The disadvantage of the direct ophthalmoscope is that the illumination is relatively dim and that can impair visualization of the ONH in eyes with a cloudy media, such as a cataractous lens. In addition, there is no stereoscopic perception of depth (since it is a monocular technique). The examiner's findings are hand drawn onto the patient's medical chart.

The following figure shows the normal appearance of the posterior pole, including the optic nerve head.   Figure-1

The next figure shows 'bean pot' cupping in advanced glaucoma.

The following figure provides a link between the contours within the structure of the optic nerve head and the appearance of the optic nerve head as seen upon ophthalmoscopy. Figure-2

Note how and where the Nerve Fiber Layer (NFL) corresponds to the rim area; the rim area is made up of retinal ganglion cells from the NFL. The rim area is an important parameter that changes in concert with the cup-to-disc ratio; the greater the cup-to-disc ratio, the less the rim area. Correspondingly, as the rim area declines, so does the number of viable retinal ganglion cells; loss of retinal ganglion cells is linked to visual field loss.

Another method uses the slit-lamp, which has a bright and well-controlled illumination source, in conjunction with one of several hand-held lenses, i.e. a +78 or a +90 lens. Since it is binocular, it also provides for stereoscopic viewing. The examiner's findings are hand-drawn on to the patient's medical chart.

A photographic method utilizes the fundus camera. The magnification as well as the illumination can be well controlled. The photographic data obviate the need for hand drawings. While truly a valuable clinical tool, the expense of a fundus camera is high.

Using the slit lamp or fundus camera, the examiner also evaluates the cup-to-disk ratio, the neuroretinal rim width and color and the cup depth and color. The advantage is that the thickness of the nerve fiber layer (NFL) can also be evaluated in those patients in whom it can not be viewed.

Confirming signs of glaucomatous optic neuropathy are:

• Thinning of the NFL on the disc rim,
• Notching (i.e. appearance of dents) of the NFL on the disc rim,
• Displacement of vessels on the disc rim (indicating a loss of underlying support secondary to neuronal loss),
• Vertical elongation of the optic cup.

In the last few years, devices have become commercially available that utilize confocal imaging, a sophisticated and expensive technique. Using scanning lasers and digitization technology, optical slices (tomographic sections) can be acquired and then reconstructed to provide 3-dimensional views of the in vivo ONH. Measurements obtained from the tomographic sections agree well with stereoscopic photographs taken with the fundus camera. Reproducibility of these images is good. . The HRT II and the GDx VCC are sophisticated laser scanners that collect lots of quantitative data for statistical analyses and longitudinal follow-up. The archival abilities of these computerized scanners are substantial and growing. These scanners are expensive ¹⁰

Perimetry

The general technique of mapping the visual field is referred to as perimetry. There are two fundamental methods: kinetic and static. The kinetic method uses a test object (usually a white spot of light) that is moved from 'non-seeing' to 'seeing'. This means that the white disc is either moved from the far periphery (non-seeing) towards the macula/fovea (seeing) or from inside of a scotoma outwards, i.e. non-seeing to seeing.

Static methods use a non-moving test object, hence the term static. A static light source is illuminated for a brief interval and patient is queried as to whether or not it was seen. Alternatively, the intensity of the light source is increased from dim to bright until the spot becomes visible. The latter method is referred to as static threshold perimetry

Advanced visual field techniques

Greater sensitivity to early glaucomatous changes and decreased variability are the goals of the advanced techniques along with improved sensitivity and specificity. Two techniques are discussed here, short-wavelength automated perimetry and frequency doubling perimetry.

Short-wavelength automated perimetry (SWAP)

'Short-wavelength' is another way of saying 'blue' since blue is a visual sensation derived from short wavelength visible light. For comparison, red is a sensation derived from long wavelength visible light. Blue-sensitive cones are cones that are stimulated by short-wavelength light.

Defects in blue-sensitive cones, in ganglion cells connected to the blue cones, or in both may be present early in the progress of glaucoma. These cones and the ganglion cells to which they are connected are part of the 'short-wavelength-sensitive pathways'. SWAP, as the acronym implies, is a perimetric device that selectively tests the blue-sensitive pathways.

SWAP technology is comparable to that of conventional automated perimetry except that the background is bright yellow and the target is blue. In conventional static perimetry the background is white and the target is white (W/W). Data suggest that the blue-on-yellow (B/Y) stimulus configuration may be more sensitive to early glaucomatous changes than (W/W) because the blue-sensitive pathway is compromised earlier in the course of GON.

The advantages of SWAP are:

• Visual field defects (scotomas) can be detected 2 to 5 years earlier,
• Progression of visual field defects can be detected 1 to 3 years earlier,
• The extent of the visual field defect can be mapped better,
• Areas of visual field loss mapped using SWAP correlate with specific damage to the ONH rim and NFL defects,
• During the progression of glaucoma, defects in the B/Y visual field and the NFL defects follow each other more closely than do NFL defects and the W/W field changes [Teesalu et al., 1998],
• In those patients with ocular hypertension, functional damage can be detected with B/Y perimetry before being detected with NFL imaging.

The disadvantages of SWAP are:

• Limitations are imposed by lens yellowing, which increases naturally with age,
• Diffuse NFL loss in advanced glaucoma or advanced cataracts skew the results,
• SWAP is even more tedious for elderly patients to perform than W/W automated perimetry. Fortunately, a SITA program has been worked out for SWAP, thus reducing the testing time.

Diagnosis of primary angle closure glaucoma

Angle closure glaucoma is diagnosed when aqueous fluid cannot reach the anterior chamber angle. Aqueous continues to be produced and accumulates behind the iris forcing the base of the iris to occlude the trabecular meshwork. Anything that causes the pupil to dilate can provoke an attack of primary angle closure glaucoma. Typically an attack occurs in a patient who already has a narrow angle.

Acute primary angle closure can be dramatic. Suddenly the eye becomes red. The pain can be severe. Patients frequently experience blurred vision, multi-colored halos around lights, headache, and sometimes nausea and vomiting. Examination of the eye reveals:

• conjunctival injection,
• corneal edema,
• cells and flare floating in the aqueous,
• a mid-dilated pupil,
• a shallow anterior chamber, and,
• an elevated intraocular pressure (which is sometimes dramatic).

Drug Treatment:

Drugs that reduce the formation of aqueous humour include the b-blockers and carbonic anhydrase inhibitors

Beta-blockers

Timolol: Timolol is a non-selective beta-blocker that hardly has sympathomimetic activity. Like propranolol, it binds reversibly with ß₁- and ß₂-adrenoreceptors. There are beta-receptors in the cardiac mauscle, in the arteries of the skeletal muscles and in the bronchi; however, they can also be found in the sphincter muscle of the iris and in the ciliary body.

Even though timolol generates the same cardiovascular effects as the other beta-blockers, the drug is nowadays primarily used in ophthalmology. Timolol causes a reduction in the production of aqueous humour and thus a reduction of the intra-ocular pressure.¹¹

Metipranolol: Metipranolol was originally available in three strengths in a multi-dose form. However, after reports of granulomatous fibrinous uveitis, the highest and then subsequently the two lower strengths of the multi-dose presentation were withdrawn. The only preparations currently available are the lower strength, single dose units.¹²
Like timolol, metipranolol is non-selective and does not possess intrinsic sympathomimetic activity. Its efficacy is similar to that of timolol and levobunolol but patient tolerability of the product is poor.^13,14

Betaxolol: Betaxolol is the only cardioselective drug among the topical b-blockers but it is not cardiospecific. After reports of bronchospasm following instillation of topical b-blockers, the Committee on Safety of Medicines warned that all b-blockers, including those with cardioselectivity, should be avoided in patients with obstructive airways disease.¹⁵ However, in patients who do not experience symptoms of obstructive airways disease, changing the topical b-blocker from timolol to betaxolol has been shown to improve cardiovascular and pulmonary parameters.¹⁶ In a small short term study of patients with glaucoma and asthma, patients intolerant of timolol used betaxolol without exacerbation of pulmonary symptoms or deterioration in measured pulmonary function tests.¹⁷
Betaxolol, due to its selective blockade of b1 receptors, does not lower the intraocular pressure as much as other topical b-blockers; however, it has shown a positive influence in visual field studies,¹⁸and is the only b-blockers to include a reference to the beneficial effect on visual function in the summary of product characteristics.

Carteolol:Carteolol, uniquely among the topical b-blockers, possesses intrinsic sympathomimetic activity¹⁹. Studies have shown that it is as effective as timolol, while the adverse local effects,²⁰ cardiovascular effects and adverse changes in lipid profile, are less pronounced with carteolol than with timolol.
The efficacy and tolerability of carteolol has also been compared with that of betaxolol, as either drug may be preferred to timolol in patients with cardiorespiratory problems. A small study of 20 patients found no significant difference in intraocular pressure lowering effect or cardiovascular or pulmonary parameters, although carteolol was better tolerated. Carteolol’s hydrophilicity may inhibit its passage across the blood-brain barrier, thereby reducing the possibility of adverse effects on the central nervous system.

Levobunolol: Levobunolol, another non-selective b-blocker devoid of intrinsic sympathomimetic activity, was the first of the group to be licensed for once daily administration. In a three month study, once daily use of levobunolol 0.5 per cent was shown to be as effective in reducing the intraocular pressure as twice daily instillation.²¹ Although this study showed that levobunolol 0.5 per cent administered once daily was more effective than timolol 0.5 per cent solution once daily, a four year study conducted with twice daily instillation of both drugs showed similar ocular hypotensive efficacy. Moreover, a comparison of levobunolol with the recently introduced gel-forming solution of timolol showed no difference in intraocular pressure lowering or tolerability.

Carbonic anhydrase inhibitors

This group of drugs inhibits carbonic anhydrase, an enzyme which facilitates the production of bicarbonate involved in the formation of aqueous humour in the ciliary process. Thus, inhibition of carbonic anhydrase II, the form of the enzyme found in the ciliary epithelium, results in a decrease in the production of aqueous humour.²² There are two carbonic anhydrase inhibitors available in acetazolamide, which is administered orally or by intramuscular or intravenous injection, and dorzolamide, which is used topically.
. Acetazolamide should be used with care in elderly patients, who may have unrecognised renal impairment,²³ as its use can lead to metabolic acidosis. An initial loss of potassium occurs but this is self-limiting, as is the diuresis, so potassium supplements are unnecessary unless the patient is hypokalaemic.

Dorzolamide Dorzolamide; a potent and selective inhibitor of carbonic anhydrase isoenzyme II, is the only topical carbonic anhydrase inhibitor available in the UK. It is licensed as an adjunct to b-blockers in OHT, POAG and pseudoexfoliative glaucoma (a secondary open angle glaucoma from decreased aqueous outflow due to exfoliated material in the trabecular meshwork) in patients unresponsive to b-blockers, or used alone if b-blockers are contraindicated.
Dorzolamide has been shown to be as effective as betaxolol, but is less effective than timolol. It does not cause the metabolic acidosis or electrolyte imbalances that are generally associated with long term use of systemic carbonic anhydrase inhibitors and has been shown to be a well tolerated and effective substitute for these drugs in POAG. However, it is ineffective in ACAG. Dorzolamide is administered three times a day when used as a single agent but twice a day when used in combination with a b-blocker²⁴

The most frequently reported symptoms and adverse effects with dorzolamide were transient bitter taste and burning and stinging of the eyes.
Other adverse effects and local symptoms include blurred vision, eye itching, tearing, headache, nausea, eyelid inflammation and fatigue.

References

1.www.stlukeseye.com/Conditions/Glaucoma.asp                                                                                                                 

2 http://www.medrounds.org/glaucoma-guide/2006/03/section-2-epidemiology-of-glaucoma.html

3 Patel KH, Javitt JC, Tielsch JM, et al. Incidence of acute angle-closure glaucoma after pharmacologic mydriasis. Am J Ophthal1995;120:709-717

4.Goodman & Gilman The Pharmacological Basis Of Theraputic 9 Th Edition Pg 1623 

 5 Grunwald JE, Piltz J, Hariprasad SM, et al. Optic nerve blood flow in glaucoma: effect of systemic hypertension. Am J Ophthalmol 1999;127:516-522.

6.www.merckmedicus.com/

 7 Tielsch JM, Katz J, Sommer A, et al. Hypertension, perfusion pressure, and primary open-angle glaucoma. Arch Ophthalmol 1995;113:216-221

 8 Quigley HA, West S, Rodriguez J, et al. The prevalence of glaucoma in a population-based study in Hispanic subjects. Proyecto VER. Arch. Ophthalmol. 2001;119:1819-1826

9. Schwartz B. Circulatory defects of the optic disk and retina in ocular hypertension and high pressure open angle glaucoma. Surv Ophthalmol 1994;38:S23-S34  

10.Progression of disc and field changes in early  glaucoma.Zeyen,et.al.Arch Ophthalmol, 1993,111,62-65                        

11. www.infomed.org/100drugs/timotoc.html

19 Zimmerman TJ. Topical ophthalmic beta blockers: a comparative review. Journ Ocul Pharmacol 1993;9:373-84.

20 Scoville B, Mueller B, White BG, Krieglstein GK. A double-masked comparison of carteolol and timolol in ocular hypertension. Ibid 1988;105:150-4.

 21.Wandel T, Charap AD, Lewis RA, Partamian L, Cobb S, Lue JC et al. Glaucoma treatment with once-daily levobunolol. Am J Ophthalmol 1986;101:298-304.

22. Wistrand PJ. The use of carbonic anhydrase inhibitors in ophthalmology and clinical medicine. Ann N Y Acad Sci 1984;429:609-19.

23. Maisey DN, Brown RD. Acetazolamide and symptomatic metabolic acidosis in mild renal failure. BMJ 1981;283:1527-8.

24. Gamero GE, Robison MY, Harmon H, Goldsmith LJ, Fechtner RD, Zimmerman TJ. The duration of action of dorzolamide 2 per cent with concomitant use of a topical beta adrenergic antagonist. Ibid 1997;37:S1102

About authors:

Mr.Anand M.Kudal

Working as Lecturer at MAEER’s,Maharastra Institute of Pharmacy, MIT Campus, Pune. He has completed M.Pharm in Medicinal and Pharmaceutical Chemistry from Department of Pharmacy, SGSITS,Indore, RGPV, Bhopal.
Email: a_kudal@rediffmail.com, Cell-9923090682 .

Kagzi Sarfaraj is a Final Year student at MAEER’s,Maharastra Institute of Pharmacy, MIT Campus,Pune.

Prof. Manish S. Wani

Working as Lecturer at MAEER’s,Maharastra Institute of Pharmacy,MIT campus,Pune.He has done his M.Pharm in Pharmaceutics from Pune University. He has also done his MBA from Pune University.

Prof. Satish A. Polshettiwar

Working as Lecturer at MAEER’s, Maharashtra Institute of Pharmacy, MIT Campus, Pune. He has done his M.Pharm in Quality Assurance from Nagpur University. He is a Life member of APTI. He has published and presented several research articles in national and International level E.Mail:contact_psatish@yahoo.co.in, Cell No. 09422842838