Evidence Of Ocular Blood Flow Change Biology Essay


Theoretically, there are 3 components contributing to ocular blood flow reduction in glaucoma patients increased local resistance to flow, (2) decreased ocular perfusion pressure (OPP), and (3) increased blood viscosity. (Shaarawy et. Al, 2009). All these component shows that ocular blood flow is important for us to understand the pathology & process of defect in glaucomatous eye.

The result indicate that nimodipine increases optic nerve head (ONH) and choroidal blood flow in normal tension glaucoma (NTG) patients and inproves color contrast sensitivity (CCS). The latter effect does not, however, seems to be direct consequence of the blood flow improvement. (Lukschet et. al, 2004). Dorzolamide/timolol fixed combination increased blood flow significantly at the neuroretinal rim showing a combination of hypotensive and heamodynamic effects. (Rolle et. al, 2008). These findings shows drug effect could induce changes on ocular blood flow and it proves that blood flow measurement is a worthy findings towards glaucomatous progression in the eye.

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The neuroretinal rim is the tissue between the outer edge of the cup and the disc margin. The normal healthy rim has an orange or pink colour and shows a characteristics configuration. The inferior rim is the broadest followed by the superior, nasal, and temporal, ISNT. (Kanski, 2007). Eyes with and without cilioretinal did not differ significantly in the areas of neuroretinal rim and alpha (α) and beta (β) zones of parapapillary atrophy, when measured in the whole optic disc and in the 4 sectors separately; in ratios of the temporal horizontal area to total area of rim and parapapillary atrophy; and in the ratio of temporal rim area to nasal rim area, neither in an interindividual comparison nor in an intraindividual intereye comparison. In contrast to the position of the central retinal vessel trunk, presence and position of cilioretinal arteries do not markedly influence the pattern of neuroretinal rim loss and progression of parapapillary atrophy in glaucoma. (Wido et. al, 2003). In some other findings, an important morphologic predictive factors for progression of the glaucomatous appearance of the optic nerve head in white persons are small size of neuroretinal rim and large area of β zone of parapapillary atrophy. Progression of glaucomatous optic nerve head changes is independent of size and shape of the optic disc, size of α zone of parapapillary atrophy, retinal vessel diameter, and optic cup depth. (Jonas et. al, 2002).

Findings in early 2000, glaucoma patients exhibit reduced ocular blood flow at the neuroretinal rim, which seems to affect high velocity flow more profoundly than low velocity flow. (Hosking et. al, 2001). The glaucoma subjects had significantly lower the retinal haemodynamics than the control subjects. There were no significant differences in HRF parameters between the NTG and POAG subjects. The discs had been identified as having abnormal segments had lower HRF values than those with a corresponding normal segment. Logan et. al, 2004 study show the relation between structural damage of the optic nerve head and the level of retinal blood flow and this may indicate an early marker of the pathological process. On the other research findings, specific location is identified that inferior sector of retinal nerve fibre layer and the optic nerve head may have lower blood flow per unit nerve tissue volume compared to the superior sector. This results suggest that the inferior sector is more vulnerable to elevated intraocular pressure (IOP) and ischaemic insults in glaucomatous optic neuropathy. (Harris A. et. al, 2003). Hafez et. al, 2003 stated that mean neuroretinal rim blood flow was significantly higher in OHT patients with C/D ratios less than 0.4 when compared to OHT patients with larger C/D ratios. This suggests that reduce neuroretinal rim blood flow in higher risk ocular hypertension may be an early event in the development of glaucomatous optic neuropathy, appearing prior to the manifestation of visual field defects. Changes in neuroretinal rim & changes in blood flow works along as an early sign to manifest visual field defect.

Association between blood flow measurement in cup & pulsation amplitude in cup, and association between mean defect from visual field testing and ocular hemodynamic parameter were also significant. Reduced optic disc perfusion in patients with open-angle glaucoma is evidenced from two independent methods in the present study. Moreover, the data indicate that reduced ocular blood flow in these patients is linked to visual field changes. It remains to be established whether compromised optic disc and choroidal blood flow contributes to optic disc damage in glaucomatous eye or is a secondary functional phenomenon. (Findl O. et. al, 2000). Ocular blood flow alteration in glaucoma patient seems, at least partly, to be related to a systemic vascular dysregulation. (Emre et. al, 2004). There is another follow up findings, states that, for subjects with asymmetric glaucoma damage between eyes, flow and velocity were significantly lower in the eyes with worse glaucoma damage. When comparing optic disc displaying within-eye asymmetry, the hemidisc with greater damage showed significantly lower blood velocity than the hemidisc with less damage, but however, no difference in blood flow or volume was detected. This provide evidence that impaired optic nerve circulation is associated with the extent of glaucomatous pathology. (Lam A. et. al, 2005).

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Inferior rim blood flow is less than superior rim blood flow in patients with superior hemifield defect, and superior rim blood flow is reduced compared to the inferior in patients with inferior hemifield defect. The blood flow in the neuroretinal rim was found to correspond to the regional visual field defect in eyes with NTG. Reduction in flow were associated with reduction in function. (Sato et. al, 2006).

The measurement taken with Heidelberg Retinal Flowmetry (HRF) was used to conduct the study of blood flow through retinal vessels which the flow of the optic nerve head. According to Boehm et. al (2005), the blood capillary velocity, flow and volume were found to be reduced significantly with the age. The research conducted by Boehm et. al (2005) includes 103 healthy subject ranging age 22 to 76 years old. They also accounted progression of IOP, blood pressure, heart rate and gender, and found that the blood flow reduction increase with age involving decrease overall blood flow. This may suggest that the resistance involve decrease number of the blood capillary or the diameter of the capillary. Kerr J. et. al (1998) examined 14 hypertensive and 10 primary open angle glaucoma patients with equal IOP status, the pulsatile ocular blood flow reading were performed in sitting, standing, and supine positions. No treatment were given during the test and the result shows that a significant reduction in volume, flow, and velocity were found at lamina cribosa and the temporal neuroretinal rim in glaucoma (POAG) compared to ocular hypertension subject. Somehow, result doesn't show any changes at nasal neuroretinal rim and juxtapapillary retina. Their evaluation suggest that short posterior ciliary artery and choroidal were also reduce in flow but the mechanism is yet still unknown on glaucomatous optic atrophy. The other findings by done by Michelson G. et. al (1996), by using scanning laser Doppler flowmetry (SLDF) to assess 43 patients with POAG and 43 healthy individuals. POAG subject were found significantly reduced both juxtapapillary retinal blood flow and neuroretinal rim area blood flow compared with normal subject. The difference was up to 71% and 49% for both neuroretinal rim area flow and juxtapapillary retinal blood flow. Furthermore, reduction of neuroretinal rim area blood flow were found to be significant with cup/disc ratio and juxtapapillary blood flow were found to be significant with glaucomatous with/out instillation of any glaucomatous therapy compared to control subject. Research conducted by Embleton S.J. et. al (2002), by using SLDF on 15 healthy subject (young), 15 healthy subject (adult). The study found a reduce in ocular blood flow at neuroretinal rim on matured subject compared to young subject (flow and velocity) and a decline in lamina cribosa and retinal volume but not with the flow and velocity.

Michelson et. al (1996) prove that there is relation between age and retinal blood flow but no relationship between lamina cribosa and neuroretinal rim. Comparison between all research conducted by Boehm et. al (2005), Kerr J. et. al (1998), Michelson G. (1996) and Embleton et. al (2002) show a variety number of participant involved (103, 24, 86, 30) respectively with different age level. In short, we tend to put more weight on Boehm et. al study because it is the most recent study that have the largest participant involved although the result may not strong enough due to HRF is quite new to ophthalmic assessment. Recent study on 24-hour blood flow in optic nerve head and macula of healthy human eyes shows that significant diurnal-to-nocturnal decreases at those location for older subject compared to younger subjects. In addition, the changes were found to be independent of the change in ocular perfusion pressure. (Kida et. al, 2008).

2.2 Autoregulation of the blood flow of the optic nerve head

Autoregulation is the ability of a vascular bed to maintain blood flow despite changes in perfusion pressure. In other words, autoregulation may also refer to the intrinsic ability of tissue to maintain relatively constant blood flow in the face changes in perfusion pressure or its ability to modify blood flow response to varying metabolic demand. Optic nerve head (ONH) partly shares blood flow physiologic of the brain and act as a continuation of the central nervous system. (Flammer J. and Orgul S., 1998). Central retinal artery (CRA) is the only source of the blood supply and feeds the retinal arteries. These distal vessel nourish the retinal ganglion cells and the confluence of unmyelinated nerve fibres anterior to the lamina cribosa. (Onda E. Et. Al, 1995). Previous literature have conclusively shown that glaucoma is a disease that cause the death of the retinal ganglion cells and erosion of the optic nerve head.

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Regulation of the blood flow is important during posture change to maintain proper circulation status in many organs. In a condition of upright posture, the gravity pulls the blood away from organs above the heart and towards organs below the heart. Appropriate blood flow is ensured by constricting the vessel to block hyperaemia and oedema when changing from supine to upright posture while the vessels above the heart dilate to offset falling perfusion. Evans D.W. et. al (1999), proved that glaucoma patients demonstrate faulty autoregulation of ocular blood flow during posture change. Another extensive research, the anatomy of the microvascular and the blood flow regulation of the ONH remains difficult to ascertain according to Harris A. et.al (2003). Recent study to assess the autoregulation retinal blood flow in healthy young subject, along with the systemic blood pressure and IOP suggest no significant change in retinal blood flow was found. This prove that a normal subject has the ability to compensate the increase of blood pressure and maintain a stable retinal blood flow after exercise. (Lester M. Et. al, 2007).

Cerebral circulation was proved to be dependent on local blood gas perturbations. (Haggendal et. al, 1969). These finding may also applied at autoregulation of ONH as the blood flow decreases, whereby the local metabolic vascular response is primarily oxygen-dependent. (Kontos et. al, 1978). According to Flammer et. al (1998), hypocapnia and hyperoxia mediate arteriolar constriction and a subsequent decrease in ONH blood flow, while hypercapnia and hypoxia does not show any significant. (Flammer and Orgul 1998). Research on inhalation of different mixture of oxygen and carbon dioxide may effect retinal blood flow. Retinal blood velocity, retinal vessel diameter and retinal blood flow were found to be decreased during all breathing periods as the mixture of gases had little effect on systemic haemodynamics. (Luksch A. et. al, 2002). Breathing with totally oxygenated environment can cause increase in oxygen saturated level (SaO2) and a decrease in end-tidal carbon dioxide (EtCO2). The test was done with 20 young adult in pure oxygenated room to understand the changes in retinal vessel diameter during physiological stress or pathologic conditions. Although the study were based on individual fundus photograph, the main objective was to detail the time course and amplitude changes in the diameter of arteries and veins across all retinal quadrants, during and after hypertoxic vascular stress. The findings shows that during systemic hypertoxic stress, the retinal vessels change in calibre uniformly across retinal quadrants in healthy young adults. (Jean-Louis et. al, 2005).

Research of The Singapore Malay Eye Study done by Koh et. al (2010), cross-sectional study was conducted in Malay persons aged 40-80 years residing in Singapore, by using confocal scanning laser ophthalmoscope, optic disc measurements including disc area, rim area, and rim-to-disc area (RDA) ratio were taken. A significant findings of global RDA ratio suggest retinal venular tortuosity demonstrated a stronger association with RDA ratio compared to the arteriols. Thinning of neuroretinal rim were significantly associated with straight retinal vessel. Geometric retinal vascular changes noticeable in early glaucomatous optic neuropathy, this findings may provide an additional fact about blood vessel architecture and its role in physiology. (Koh V. Et. al, 2010). Additionally, concentration of K+, H+, adenosine, and intercellular osmolarity are known to effect local vascular tone. (Orgul et. al, 1995a).

The mechanism of autoregulation depends on 2 type of stimuli, metabolic and myogenic whereby can induce an autoregulatory responce from local vasculature. (Johnson P.C., 1986). Metabolic stimuli can alter vascular tone include the osmolarity of extracellular fluid and its concentration of CO2, K+, H+, O2 and adenosine, and were known to modifies the oxygen and nutrient requirement by local tissue. (Orgul S. Et. al, 1999). In the retina there is general agreement that blood flow adapts in response to different conditions of light and darkness including diffuse luminance flicker. The measurement were taken before, during and after stimulation with diffuse luminance flicker. Flicker light is a flashes of light at wavelength below 550nm and retinal irradiance of 140 µW/cm. The study clearly demonstrates that diffuse luminance flicker increases optic nerve blood flow but shows no effect on choroidal blood flow, thus choriodal blood flow appears to be work independently of the alteration in retinal metabolism. (Garhǘfer G. et. al, 2002). Myogenic appear to actively contribute to the autoregulation of retinal blood flow. (Rosa R.H., 2004). In ocular tissue, autonomic nervous system contributes extensively to the retrobulbar and choroidal circulatory system, but the retinal and ONH vasculature still lack direct innervations. (Funk 1997). As for sympathetic stimulation, it only provides indirect influence on ONH perfusion neurogenic contribution to the vascular responce is minimal. (Harris et. al, 2003).

According to Mchedlishvili 1981, vasospasm can cause a reduction in luminal diameter and respective the blood flow. (Mchedlishvili 1981). Consequent ischemia surrounding tissue may originate from vasoconstriction or insufficient dilatation of the microcirculation. Dysregulation of the blood flow can lead to an over- or underperfusion. As for long term damage can come from a steady overperfusion of the blood flow. While under perfusion can lead to tissue atrophy and cell infarction. Systemic regulation can be primary or secondary of nature.

Autoimmune disease such rheumatoid arthritis, gaint cell arteritis, systemic lupus erythematodes, multiple sclerosis, colitis ulcerosa or Chrohns disease are categorize as a secondary dysregulation. According to Gasser P. (1991), vasospasm are not only occur in Raynaud's disease, migraine, Prinzmetal's variant angina, visual filed defects and partially in low-tension glaucoma, but may also be involved in pathogenesis of Crohn's disease. In other words, vasospasm does occur in the eye. Increase of endothelin-1 circulation leads to a reduction of blood flow in both choroid and optic nerve head in secondary vascular dysregulation. The primary vascular dysregulation has a little influence on ocular blood flow but still interferes with autoregulation. This seems to be a relevant component in pathogenesis of glaucomatous optic neuropathy. (Greishaber M.C. et. al, 2007; Emre M. Et. al, 2004). Normal tension glaucoma (NTG) reported twice female than male and considered to be an independent risk factor for visual field loss progression in NTG. (Orgul S. Et. al, 1994; Drance S. Et. al, 2001). Estrogen is known to have vasodilatory effects in systemic circulation. Decrease in estrogen levels during menopause may therefore complicate or contribute to ocular pathologies as estrogen receptors are found in both retinal and choroidal tissue. Therefore, the susceptibility in females may due to falling to estrogen level under post-menopause. (Seisky et. al, 2008).

Vasospasm has been associated with glaucoma, but the mechanism have not been clearly elaborated. A potent endogenous vasoconstrictor, endothelin (ET)-1 were increase in patient with glaucoma compared to normal subject. They also found that glaucoma patient with acral vasospasm, more likely to show deterioration in visual fields after cooling than patient without acral vasospasm. In other words, glaucoma patient with evidence of vasospasm have the risk of worsening visual fields under cooling induced than nonvasospastic patients. (Nicolela et al 2003). Vasospasm were also identified in migraine, which commonly found in females and associated with NTG. (Cursiefen et al 2000). McKendrick A.M. et. al (2000), suggest that migrainous pattern shares some features in early stages of glaucoma and this raises to the possibility that vascular involvement occur in these cases. Disability to remain constant of ocular blood flow during physiological condition, may categorized as having ocular vasospasm or dyregulation. NTG patient had significantly lower ophthalmic artery blood flow velocities and higher vascular resistance than normal subject. Reversible vasospasm in NTG is noticeable with elevated CO2 breathing compared to normal subject. (Harris et. al, 1994).

A inverse response pattern were found in ONH and choroidal with female that has vasospasm regarding blood gas perturbation compared to without vasospasm. (Gugleta et. al, 2005). A differentiation during blood gas perturbations and calcium channel blockers may demonstrate which persons are at greatest risk for vasospasm, impaired ocular blood flow and possibly OAG. Although, vasospasm is associated with multiple disease states including OAG with NTG patients and women appearing to be the most at risk for vasopastic contributions to disease processes. Fluctuations in ocular perfusion, ischemia, and/or reperfusion injury to the ocular tissues are possible vasospasm effect. Vasospasm also probably classified to be reversible (treatable). Blood gas perturbations test on OAG should be further explored, especially in patients that demonstrate a vasospastic criteria. Vascular endothelium secretes vasodilator nitric oxide (NO) and vasoconstrictor endothelin-1 (ET-1) that effect the microcirculation of the blood flow. (Adams J.A., 2006). Prostacyclins, acetylcholine, bradykinin, and histamine were activated by endothelium derivation. (Flammer and Orgul 1998; Adams 2006). Vasodilation were promoted on smooth muscle when secretion of NO from endothelial cells. (Toda and Nakanishi-Toda 2007). Velocity of lower diastolic and systolic ophthalmic artery blood flow of NTG has a decrease of cyclic GMP (indicator of NO) in plasma and aqueous humor of glaucoma patients. (Laude et al 2004). Blood flow reduction at anterior optic nerve were demonstrated when ET-1 applied on particular region of the anterior optic nerve. (Orgul et al 1996).

2.3 Ocular Blood Flow & Visual Field

Plange et. al found that asymmetric glaucomatous visual field loss was associated with asymmetric flow velocity in cetral retinal and ophthalmic arteries in POAG patients. (Plange et al, 2006). In addition, Zeitz et al found glaucoma progression to be associated with decreased blood flow velocities in the short posterior ciliary arteries. (Zeitz et. al, 2006). Zink et al Found an association between lower optic nerve laser Doppler blood volume measurement and glaucomatous visual field progression. (Zink et al, 2003). Galassi F. Et. al (2003), reported that patient with a stable visual field had a higher diastolic velocity and a lower resistivity index in the ophthalmic artery (OA) compared to those with a deteriorating visual field during the study. Patient with a vascular resistance greater than 0.78 in the OA had 6-times the risk of visual field deterioration.

Following research by Martinez et. al (2005), suggesting a correlation between RI greater than 0.72 in the OA and increased VF progression over a period of 3 years. Independent of the progression rate of glaucomatous visual field damage statistically correlates with retrobulbar hemodynamic variables as the faster rate in progression of glaucomatous damage, a lower baseline end diastolic blood flow velocity in the central retinal artery. (Satilmis M. et. al, 2003). The evaluation of glaucoma damage were also conducted between the extent of glaucoma damage and optic nerve blood flow, found that when both of the eyes have glaucoma, the hemidisk with greater damage showed significantly lower blood velocity than the hemidisk with less damage. (Lam A. et. al, 2005). This study provides additional evidence that impaired optic nerve circulation is associated with the extent of glaucomatous pathology. Sato and associates reported that reduction of capillary blood flow at neuroretinal rim in normal tension glaucoma patients was associated with regional visual field loss.

Sclera buckling for a rhegmatogenous retinal detachment (RPD) were also found to cause a reduction in blood flow at neuroretinal rim. Upon removing the buckle, the blood flow were improved to normal levels and a further worsening of the visual field was not detected. These result suggest that an encircling of sclera buckle may impair choroidal circulation and lead to visual field defects similar to eyes with normal tension glaucoma. (Sato E.A. et. al, 2008). Research done by Vassilos and associates with 13 male & 3 female with bilateral carotid stenosis, found that postoperatively peak systolic velocity had significantly improved in all vessels examined in the carotid that was operated on, but only in the OA and short posterior cilary artery in the fellow side.

Ocular blood flow deficits may therefore represent either a primary insult or are secondary to vascular regulatory dysfunction during diurnal fluctuations in vascular risk factors in certain OAG patients (Grieshaber and Flammer 2005).

2.4 Clinical therapeutic drug effect on optic disk blood flow with glaucomatous eye.

Some evidence of blood flow deficit in glaucoma derived from flourescein angiography since flourescein is a safe consistent drug to be use for staining and should be considered in high-risk patients. (Kwan A.S. et. al, 2006). Previous findings conducted by Harris A. et. al on NTG patients found that dorzolamide also accelerated retinal arteriovenous passage time (AVP) of flourescein dye, at constant retinal arterial and venous diameter, but failed to change flow velocities in any retrobulbar vessel. (Harris A. et al, 1999). Similar findings were found on healthy volunteers by using brinzolamide which reduction IOP level but showed no significant change in retrobulbar haemodynamics, but shortening of AVP. Since in glaucoma AVP is prolonged indicating vascular dysfunction this effect might be beneficial in glaucoma therapy. (Kaup M. et. al, 2004). Dorzolamide is a carbonic anhydrase inhibitor, an anti-glaucoma agent and topically applied in the form of eye drop was treated as placebo drug. Following study with dorzolamide found that there is no measureable vascular effects from topical dorzolamide treatment in previously untreated glaucoma eyes. (Bergstrand I.C. et. al, 2002). According to Ali S.H. et. al, reduction of IOP in OAG after therapeutic IOP reduction had a statistically significant improvement of blood flow in neuroretinal rim of the ONH, where as OHT patients does not demonstrate any changes. (Ali S.H. et. al, 2003).

Another topical drug can be use to reduce IOP elevation is latanoprost. A study has been conducted to evaluate the effect of a single instillation of latanoprost on human ONH and retinal circulation within certain time. Yasuhiro T. et. al found that tissue blood velocity in the ONH increased at least temporarily following a single instillation of topical latanoprost even the mechanism of the increases remain unclear. This may indicate that the effect of latanoprost on ONH tissue circulation in human may have clinical implication. (Yasuhiro et. al, 2004). The usage of topical nipradilol caused a transient, but significant increase in the ipsilateral ONH blood velocity after twice instillation in a week which indicate that the increase in ONH blood velocity in human was not a secondary effect accompanied by a decrease in IOP in the ipsilateral eye. (Ken M. et. al, 2002). This may be nipradilol attribute on vasodilative action. (Okamura T. et. al, 1996). It had been reported that topical nipradilol increases the ONH blood velocity in rabbits and suggest is partly attributable to local penetration of the drug. (Kanno K., 1998). Similar scenario also had been reported with topical betaxolol. (Araie M. et. al, 1997). Nipradilol also has been use in dogs, whereby reduction of IOP by nipradilol was similar to that by an existing β-adrenergic antagonist, timolol maleate, but nipradilol was associated with fewer systemic side effects in dogs. Nipradilol lowered IOP to an equivalent degree to timolol maleate but its hard enough to evaluate blood flow relationship between human and animal ocular haemodynamics. (Maehara S., 2004).

Findings through topical unoprostone also effect the tissue blood velocity in the ONH, the author recorded and increase temporarily following instillation of unoprostone twice daily for 7 days. The increment implication is unclear but the effect of topical unoprostone on human ONH circulation deserve further consideration. (Yasuhiro T. et. al, 2004).

Ocular blood flow appears to be related to any disease that involve blood circulation. As for epilepsy patients exhibit reduced neuroretinal capillary blood flow, volume, and velocity compared with normal subjects. A reduction in ocular perfusion may have implication for visual function in people with epilepsy. (Emma J.R.H., 2002).

Study also shows that the usage of dormolamide increase the blood flow in temporal neuroretinal rim and the cup of the optic nerve head, and fundus pulsation amplitude. (Fuchsjager-Mayrl G. Et. al, 2005). Recent study done by Andrzej S. et.al, additive effect of dorzolamide hydrochloride (Trusoft) and a morning dose of bimatoprost (Lumigan) on IOP and retrobulbar blood flow in patients with POAG reduces IOP significantly with these combined treatment whereby the vascular resistance in ophthalmic artery decreases. (Andrzej S. et. al, 2010). Vascular retinal artery in untreated or progressive POAG after treated with topical 2% of dorzolamide for 2 weeks show increase in diameter, velocity, and flow in response to normoxic hypercapnia. Similar trends were noted for ONH vascular reactivty too. (Subha T.V. et. al, 2010). Most of the study shows that the ocular blood flow is a good indicator for pathogenesis of glaucoma and it proves that blood flow measurement is a worthy findings to be exposed.

The goal for drug therapy originally to reduce IOP elevation or slow down the visual field loss progression. The visual field and optic nerve assessment can be evaluated through fundus photograph to confirm the sign of change regarding IOP elevation. There are several classification on IOP therapeutic drug such as beta blockers, prostaglandin, carbonic anhydrase inhibitors, adrenergic agonists, cholinergic blocking agents and a combination of products. For a drug to be fully effected, therapies must penetrate the anterior surface of the eye, reach at the tissue of interest, and execute the physiologic effect. The most common topical therapies being use is timolol whereby it blocks the β-adrenergic receptors on the ciliary epithelium to reduce the aqueous humour production. β-adrenergic receptors mediate relaxation of vascular smooth muscle. (Tsujimoto G. Et. al, 1985; Virginia P.A. et. al, 2006)). If β-adrenergic were blocked, this may cause vasoconstriction in the tissue and the receptor were found on retina and the optic nerve head. (Nies A.S. et. al, 1973; Elena P.P. et. al, 1987; Dawidek G.M.B., 1993). Timolol effect on ocular blood flow in glaucoma is still controversial and not consistent, so suggested to be limited in terms of ocular vasculature effect.

Topical carbonic anhydrase inhibitors (CAIs) like brinzolamide and dorzolamide were found to be helpful to reduce IOP elevation in the eye. By terms of pharmacology process, carbonic anhydrase is an enzyme that helps fluid balance in body and transform carbon dioxide along with water into carbonic acid. Finally dissociates into protons and bicarbonate whereby bicarbonates ions regulate the formation of aqueous humor via osmosis. CAI will bind to active site of the enzyme and prevent formation of carbon dioxide, water, bicarbonate and a proton. CA-II were inhibited by CAI which the concentration found at ciliary body. The inhibition process found to reduce IOP elevation. (Virginia P.A. et. al, 2006). According to various research, CAI were the found to be the most effective therapeutic drug to alter the ocular blood flow. (Fuchsjager-Mayrl G. et. al, 2005; Andrzej S. et. al, 2010; Subha T.V. et. al, 2010).