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OCULAR PHARMACOLOGY
PROJECT
2018

TOPIC:
GLAUCOMA
GROUP MEMBERS:
SUHLA SEMETHE
MASIXOLE MAYIFELE
JULIAN MAKUNJE 201418978
XOLANI NDLOVU
OLIVIA LEKOADU 201433310
TOC o “1-4” h z u What is Glaucoma? PAGEREF _Toc514412915 h 2MAINTENANCE OF THE INTRAOCULAR PRESSURE PAGEREF _Toc514412916 h 3CATEGORIES OF GLAUCOMA PAGEREF _Toc514412917 h 3Primary open angle glaucoma PAGEREF _Toc514412918 h 3Pathophysiology of POAG PAGEREF _Toc514412919 h 3Signs Symptoms of POAG PAGEREF _Toc514412920 h 4Acute Angle Closure Glaucoma (Narrow Angle Glaucoma) PAGEREF _Toc514412921 h 4Pathophysiology of Acute Angle Closure Glaucoma PAGEREF _Toc514412922 h 4Signs and Symptoms PAGEREF _Toc514412923 h 4Normal tension glaucoma PAGEREF _Toc514412924 h 5Primary angle closure glaucoma PAGEREF _Toc514412925 h 5Pigment Dispersion PAGEREF _Toc514412926 h 5Neovascular glaucoma PAGEREF _Toc514412927 h 5Inflammatory glaucoma PAGEREF _Toc514412928 h 6Traumatic glaucoma PAGEREF _Toc514412929 h 6Primary congenital glaucoma PAGEREF _Toc514412930 h 6Juvenile glaucoma PAGEREF _Toc514412931 h 6EXAMPLES OF DRUGS WITH THEIR PREFERENCES, CONCENTRATION, INDICATION AND CONTRAINDICATIONS PAGEREF _Toc514412932 h 6Beta adrenergic antagonist PAGEREF _Toc514412933 h 6Choligernic agonist PAGEREF _Toc514412934 h 8Carbonic anhydrase inhibitors PAGEREF _Toc514412935 h 10Acetazolamide: PAGEREF _Toc514412936 h 10Recent advances in treatment of Glaucoma PAGEREF _Toc514412937 h 11Conclusion PAGEREF _Toc514412938 h 14References PAGEREF _Toc514412939 h 14INTRODUCTIONWhat is Glaucoma?Glaucoma is defined as a complicated condition that affects the optic nerve. The intraocular pressure increases as a result of inadequate drainage of the aqueous humour. The causes of glaucoma vary a lot depending on the underlying alteration of the anatomy of the eye; it may be congenital, traumatic, acquired etc. (Vision eye institute, 2017)
The aqueous humour plays an important role in maintaining good health of the eye, by providing nutrients to the cornea and the crystalline lens such as amino acids and glucose. Its primary function besides those mentioned above is to maintain the intraocular pressure of the eye (Vision eye Institute, 2017).

MAINTENANCE OF THE INTRAOCULAR PRESSUREThe aqueous humour is continuously produced by the ciliary bodies found in the anterior chamber next to the crystalline lens. In order for this fluid to function properly as it should the rate of its production must be adequately balanced by its drainage at the same rate. With minor variation in the drainage or the outflow due to alteration in ocular anatomy this has a greater impact on the intraocular pressure, and if not controlled the increment in IOP may lead to GLAUCOMA (Vision eye Institute, 2017).

CATEGORIES OF GLAUCOMAGlaucoma can be classified in different categories based on its causes:
Primary open angle glaucomaIt is the most commonly symmetrical disease which can be characterized by many factors such as elevated IOP (Intra-ocular pressure) which is more that 21mmHg, wide anterior chamber angle, and visual field loss at a later stage of the disease( Schellack, 2015).

Pathophysiology of POAG As it has been outlined earlier, POAG is the most common type of glaucoma. The drainage canals of the eyes are blocked in a case of POAG. Consequently, this lack of balance in the eye’s drainage system causes an increase of pressures within the eye. Sufficiently high IOPs are capable of damaging the optic nerve, the vehicle of exchange of signals between the brain and the eyes. Loss of vision is significantly gradual but surely progressive. This type of glaucoma manifests with a strong genetic predisposition. If one’s siblings and parents suffer from this glaucoma, that person is prone to developing the disease too. It is more prevalent in African people. Diabetic and cardiovascular disease patients are also at increased risk, and the risk rapidly increases with age Salowe R. et al. 2015.

Signs Symptoms of POAGThere are usually no known signs and symptoms of POAG. Its development is gradual and may sometimes occur without noticeable loss of vision for a long time. These patients feel like they are fine and nothing is happening to their vision initially because loss of vision begins peripherally. At this stage their visual acuity is still sharp and only deteriorates when peripheral vision loss progresses centrally( at its advanced stage) and vision loss is not reversible and can be cured with neither medication nor surgery (Bochmann F. et al. 2017).
Acute Angle Closure Glaucoma (Narrow Angle Glaucoma)Acute glaucoma is the second most common form of glaucoma. It is regarded as an emergency of ophthalmology resulting from IOPs greater than 22 mmHg.

Pathophysiology of Acute Angle Closure Glaucoma It can be caused by a variety of systemic diseases and topical ocular and systemic medications. These medications are often anticholinergic ,Unilateral angle closure is more common but bilateral angle closure is most often as a result of disorders like AIDS, Herpes Zoster, congenital anomalies and side effects of drugs (Hashemian AM. Et al. 2015). Some sulpha based drugs namely: Topiramate, Acetazolamide and Cotrimoxazol, can cause ciliary body edema leading to acute closure angle glaucoma. A narrow iridocorneal angle is the major reason for acute closure angle glaucoma attacks. The oral intake of Topiramate has a side effect of bilateral ciliochoroidal detachment and leads to bilateral acute closure angle glaucoma. Bilateral acute closure angle glaucoma is rare and is often triggered by an external source. A high dose of Organophosphate poisoning treatment and atropine causes glaucoma depending on individual susceptibility. This reportedly occurs following prolonged mydriasis and prolonged mydriasis after the use of topical amlodipine. Either case causes acute closure angle glaucoma. Side effects of edema and the thickening of the lens, ciliochoroidal detachment and ciliochoroidal effusion are additional causes of this type of glaucoma. Any type of glaucoma damages the optic nerve, causing little or no communication between the eyes and the brain. Therefore there is partial or complete loss of vision (Bochmann F. et al. 2017).

Signs and SymptomsHazy or blurred vision
Around bright lights patient sees rainbow-colored circled
Nausea and vomiting
Sudden loss of sight
Severely paining eyes
Excessive tearing
Increased IOPs
Also watch out for a large cup to disc ratio
Normal tension glaucomaIt is also known as low tension or normal pressure glaucoma, as the name suggest pressure is not elevated nor reduced it’s is consistently equal, open anterior chamber angle, visual field loss at a later stage of the disease and optic nerve damage ( Schellack, 2015).

Primary angle closure glaucomaIt is caused by the obstruction of aqueous outflow due to the trabecular meshwork being occluded by the iris, angle closure can be primary or secondary, and it is primary when it occurs in a very susceptible eye and secondary cues to ocular or systemic condition (Bowling, 2016)
Pigment DispersionPigment dispersion syndrome is characterized by release of pigment granules from iris pigment epithelium and expulsion throughout the anterior chamber (Saxena, 2002)
Neovascular glaucomaOccurs due to excess iris neovascularization which can be caused by various factors like ischemic central retinal vein occlusion, diabetic mellitus, arterial retinal vascular disease and miscellaneous disorders (Archer, 2015).

Inflammatory glaucomaIt is subdivided into Angle closure glaucoma with pupil block, Angle closure glaucoma associated with uveitis; they are all characterized by elevated IOP which is secondary to inflammation (Saxena, 2002).

Traumatic glaucomaThey are not as big as another type and elevated of IOP may be due to red blood cells obstructing trabecular meshwork or due to blood clot causing angle closure, prolonged occlusion may cause damage to the optic nerve (Schellack, 2015)
Primary congenital glaucomaIt is a rare condition, which can be bilateral or asymmetrical and classified into true congenital glaucoma (IOP elevated), infantile glaucoma which presents itself before age 3 and juvenile glaucoma which IOP starts to rise from age 3-16 years of age (Schellack, 2015).

Juvenile glaucomaWith this type of glaucoma the IOP start to rise from age 3 to 16 years of age (Archer, 2015).

EXAMPLES OF DRUGS WITH THEIR PREFERENCES, CONCENTRATION, INDICATION AND CONTRAINDICATIONS.

Beta adrenergic antagonist Drugs that bind to beta adrenergic receptors then preventing norepinephrine and epinephrine from binding to the receptors, their agents including timolol and betaxolol. These drugs aim at reducing aqueous humour production and reduce IOP; they are first choice to consider for treating all glaucoma types due to their reduced systemic effects (Bowling, 2016).

Beta adrenergic antagonists have advantages over cholinergic, adrenergic agonist, and miotic as they have little effects on pupil size, accommodation and minimal decreased vision in dim illumination (Bowling, 2016).

Indication of use for timolol Contraindication for timolol( use with caution to patients with following conditions)
Treatment of open angle glaucoma. Patients with asthma (bronchial).

Treatment of secondary glaucoma in aphakic patients. Patients with obstruction of pulmonary.

Treatment of angle closure glaucoma in children. Blockage of atrioventricular.

Systemically can be used for treatment of heart disease and hypertension. Sinus bradycardia and cardiogenic shock.

Timolol can be given as a solution or gel and in combination with other drugs like timolol hemihydrate 0.5% solution once in a day, similarly to timolol gel 0.5% once in a day (Schellack, 2015).

 
Agents Instillation and concentration
Timolol Instil one drop of timolol solution of strength 0.25% or 0.5% two times a day with their duration ? 7 hours.
Betaxolol 0.5% beaxolol hydrochloride ophthalmic solution two times in a day.
Betaxolol hydrochloride is a cardio-selective beta adrenergic antagonist which is less effective in lowering IOP and reducing aqueous outflow compared to timolol.

Betaxolol has 30 min onset of action, reaching maximum effect in 2 hours after instillation and it has one advantage over timolol which is minimizing respirator side effects (Schellack, 2015).

Indication of use for betaxolol Contraindication for betaxolol( use with caution to patients with following conditions)
Treatment of ocular hypertension History of asthma
Treatment of chronic open angle glaucoma Sinus bradycardia
Blockage of atrioventricular
Cardiogenic shock
Preferences between timolol and betaxolol, comparing side effects and effectiveness of the two showed that timolol is more preferable than betaxolol due minimized side effects (Saxena, 2002).

Cholinergic agonistMiotic used to be first choice for managing glaucoma and due to their strong side effects they have degraded from being first choice to manage glaucoma, they are divide into direct acting miotics and cholinesterase inhibitors , agents include pilocarpine( direct acting miotic) and physiostigmine
(acetyl cholinesterase inhibitors).Pilorcapine; It liberates pupillary block and widens anterior chamber by pulling iris away from anterior chamber angle and also increase outflow of aqueous at trabecular meshwork. They have onset of action 30-60 minutes with 4-8 hours of duration (Bowling, 2016).

Indication of use for pilorcapine( direct acting miotic/cholinergic) Contraindication for pilorcapine(direct acting miotic/cholinergic)
Primarily used to treat glaucoma (POAG and CNAG mostly). Use with extreme caution to patients with asthma.

When confirming diagnosis for Addie’s pupil. Should avoid using more than 2% of solution in acute angle closure.

When reversing mydriatic pupil. Should avoid using more than 4% solution in closed narrow angle glaucoma( CNAG)
To liberate pupil block. Should be used with caution in glaucoma associated with inflammation.

Pilocarpine is very effective in less pigmented eyes and if used for long term can cause miosis permanently (Archer, 2015).

Agents(Miotic) Instillation and concentration)
Pilocarpine 0.5~6%, 1 eye drop 2-4 times in a day. Concentration depends on a type of glaucoma.

For POAG and CNAG instil 1 drop of a solution four times a day of 4%.

For acute angle closure instil 1drop of a solution four times a day of 2%.

For pigmented glaucoma instil 1 drop  of a solution of 6%
Pilocarpine nitrate of 2% solution and 1 drop(0.5ml)
Physiostigmine 0.25-0.5% eye drops 4 times in a day.

Physiostigmine: It reduces IOP by increasing outflow of aqueous humour.
Indication of use for physiostigmine Contraindications to physiostigmine
Can be used as antidepressant overdose. Use with caution in Asthmatic patients.

Can be used in POAG treatment. Use with caution taking any choline esters chronically.

Used as a reversal agent to mydriatic pupil. Should not be used in cardiovascular disease.

Used as treatment of Pthiriasis palpebrum. Extreme caution in diabetic patients.

Preferences between Physiostigmine and pilcarpine based on Side effects and effectiveness, Pilocarpine is highly preferred and is available in most countries with minimized systemic effects (Archer, 2015).

Carbonic anhydrase inhibitorsThey can be used in acute angle glaucoma and in open angle glaucoma topically by reducing secretion of aqueous humour by inhibiting carbonic anhydrase which lead to reduction of bicarbonate accumulation in the posterior chamber with a resultant decrease in sodium and fluid movement to the bicarbonate ion and subsequently lowers IOP due to metabolic acidosis, they have a short duration of action and they are less effective. E.g. Acetazolamide (Diamox) (Bowling, 2016).

Acetazolamide:
They reduce Aqueous humour formation by inhibiting carbonic anhydrase on secretory ciliary epithelium which in turn lead to lowering of IOP about 40-60%, onset of action is about an hour and maximum efficacy after four hours of instillation. Recommended dose is 250mg every four hours for short-term or 500mg twice a day for long lasting effects (Saxena, 2002).

Indication of use  for Acetazolamide Contraindication of Acetazolamide
Used primarily in treatment of Open angle glaucoma. Patient with liver diseases.

Used in treatment of secondary glaucoma. Patients with liver dysfunctions.

Can be applied to patients with acute-angle closure glaucoma to lower IOP before they go for their surgery.

Acetazolamide is available as tablets and as capsules and patients stops the drug them being unable to tolerate the side effects (Archer, 2015).

Agents of carbonic anhydrase inhibitors. Concentration and dosage of agents.

Acetazolamide. 250mg tablet, 2~4 times in a day.

Methazolamide. 50 mg tablets, 2~3 times in a day.

Methazolamide is stronger than acetazolamide and indicated where acetazolamide is not as effective as it should be as well as in patients with open angle glaucoma (Bowling, 2016).

Preference for carbonic anhydrase inhibitors agents is Acetazolamide over methazolamide due to strength of methazolamide as it can cause more damage and it can penetrate aqueous barrier 50 times more than acetazolamide due to good lipid solubility and low plasma binding (Bowling, 2016).

RECENT ADVANCES IN TREATMENT OF GLAUCOMAGlaucoma is the most common ocular disease involving progressive degeneration of retinal ganglion cells (RGCs) and the optic nerve axons that cause irreversible blindness, if left undiagnosed or untreated. It is also considered as one of the major leading eye disease that leads to blindness world-wide, accounting approximately 12.3% of the total blindness. Usually with the early stages of glaucoma the symptoms are often minimal or sometimes non-existent. It is classified into different types of categories namely primary or secondary open-angle or angle closure glaucoma. Secondary open-angle or angle closure glaucoma is caused by different systemic or other ocular diseases. When a patient recently had glaucoma normally topical prostaglandins analogue, topical selective or non-selective beta-blockers are usually the first line treatment for early onset of glaucoma (Lee and Higginbotham, 2005).

With progressive glaucomatous eye usually treated with alpha-agonists and topical carbonic anhydrase inhibitors which are considered as secondary line drugs of choice. When glaucoma progresses and become even more severe, parasympathomimetic agent(s), most commonly pilocarpine is considered as third line treatment of choice. Recent studies have suggested that not all patients respond well to anti-glaucoma medications. For those patients who don’t respond to anti-glaucoma drugs, incisional surgery (tubes/ valve) and laser trabeculoplasty are further surgical treatment methods which are used to decrease intraocular pressure (IOP) (Lee and Higginbotham, 2005).

In nowadays clinicians such like ophthalmogists are faced with limitless choices regarding glaucoma therapy.
Medications that they prescribe to decrease IOP in glaucoma patients includes topical Beta-adrenergic antagonists (betaxolol, timolol), carbonic anhydrase inhibitors (dorzolamide, brinzolamide, acetazolamide) are used in acute angle glaucoma and in open angle glaucoma topically by decreasing production of aqueous humour, Alpha-adrenergic agonists (brimonidine) used to treat posterior open angle glaucoma but cannot be used in neonates, cholinergics (pilocarpine), prostaglandins (travopost, latanoprost) and prostamides (bimatoprost). Studies have proven that combining timolol-dorzolamide and brimonidine-timolol drugs has successfully show good outcomes in reducing IOP in glaucoma patients, but depends on individual dosing. Each and every medication being used has side effects and the risk of those side effects must be equally balanced with the potential benefits arising from reducing IOP in glaucoma patients (Wood and Alward, 1998).

Using combination of drugs prior to decrease IOP can be risky sometimes since other patients can be exposed to ophthalmic medications preservatives known as benzalkonium chloride that is packaged in multi-dose containers. There is a build-up of benzalkonium chloride in ocular tissues at high concentrations and this induces cell death in a dose-dependent manner. Therefore it is worth it to give patients once-a-day monotherapeutic regimen rather than multiple medications given in multiple doses. With regards to glaucoma treatments there must be a regular follow up for every six months and visual field(s) should be performed once a year with glaucoma patients (Wood and Alward, 1988).

Eye drops (e.g. Pilocarpine, Brimonidine etc.) are used to lower IOP up to approximately 27% by decreasing the production of aqueous humour or by increasing drainage rate of aqueous humour in the eye. It important to ensure that glaucoma drops are used as prescribed by the ophthalmologists. Most patients can tolerate eye drops but other patients may experience mild stinging, headaches, redness or other ocular related side effects. Since early stages of glaucoma often show minimal or unnoticeable symptoms, patients tend to stop using medications. It very important for patients to use glaucoma drops regularly as indicated by ophthalmologists to ensure that the disease is monitored. It is also glaucoma specialist duty to ensure that patients are shown how to use eye drops in order to make sure they work effectively and to clarify that it cannot be used in neonates from two years and below (Seibold, Soohoo and Kahook, 2015).

Laser trabeculoplasty is a glaucoma treatment that ensures that intraocular pressure is reduced by opening the drainage pathway, therefore helps fluid (aqueous humour) to be drained out of the eye. A laser is applied by directing a light beam straight into eyes drainage area. Patient(s) may see flashes of light but with no pains or discomfort. This procedure takes approximately 5 to 10 minutes and vision is not affected after the procedure is completed. If both eyes are diagnosed with glaucoma, only one eye is treated at a time similar to cataract surgery, and the laser for the other is arranged for a days or weeks apart (Seibold, Soohoo and Kahook, 2015).  
Conventional surgery is the treatment for glaucoma that is done after the above mentioned treatments have failed or with progressive glaucoma regardless the use of medications. Trabeculectomy, also known as Filtration surgery is one of the conventional surgeries for glaucoma which makes a new alternative drainage pathway for fluid (aqueous humour) to be drained out of the eye to underneath the conjunctiva. They make a small hole in the sclera and remove part of the eyes trabecular meshwork. After completion of this surgery has been completed patients must ensure that they put drops in the eye to fight infections (Jay and Murray, 1988).

A recent surgical versatile treatment for refractory glaucoma called endoscopic cyclophotocoagulation (ECP), decreases aqueous humour production by applying an energized diode laser of approximately 810 nm. This laser passes conjunctiva and sclera and is absorbed by pigmented ciliary body tissues and ciliary process to produce thermal energy for coagulation while maintaining a safety profile. Advanced Glaucoma Intervention Study (AGIS) is a study that recommended that patients with open angle glaucoma need pressure lowering both in amount and consistently over time (Schwartz, etc. 1999).

CONCLUSIONGlaucoma is treatable but cannot be cured. The optic nerve damage as a result of glaucoma cannot be reversed, but lowering the IOP can help to prevent progressive damage to the optic nerve and loss of peripheral vision. Early diagnosis, adequate, consistent treatment and availability of low vision and services to rehabilitate vision can assist people with glaucoma to have a better visual life.REFERENCESArcher, M. Steinroat, C and Orderda, G. 2015. Ophthalmic beta adrenergic antagonist. Drug class review, 52:40.

Alastair, J.J and Wallace, medical management of glaucoma, 339(10), pg. 129-139
Bochmann F, Stürmer J. Chronic and Intermittent Angle Closure Caused by In-The-Bag Capsular Tension Ring and Intraocular Lens. Dislocation in Patients with Pseudo exfoliation Syndrome. J Glaucoma. 2017; 26:1051–1055.

Coca-Prados M, Escribano J. New perspectives in aqueous humour secretion and in glaucoma: the ciliary body as a multifunctional neuroendocrine gland. Prog Retin Eye Res.2007; 26:239–262. Bowling, B.2016. Kanski’s clinical ophthalmology: A systemic approach. 8thedition.Sydney; Elsevier.

D.A and Higgibothem, E.J (2005), American journal of health-system pharmacy, 67 (7) pp.691-699
Hashemian AM, Vafadar E, Salarirad M, Fadavi H (2015) Bilateral Acute Angle-Closure Glaucoma Following Acute Poisoning with Organophosphate. J Clin Toxicol 5: 223. doi:10.4172/2161-0495.1000223
Jay I.L and Murrey (1988), Early Trabeculotomy vs. Conventional management in primary open angle glaucoma, B.J Ophthalmology, 72 (10) pp.881-887.

Salowe R, Salinas J, Farbman NH, Mohammed A, Warren JZ, et al. (2015) Primary Open-Angle Glaucoma in Individuals of African. Descent: A Review of Risk Factors. J Clin Exp Ophthalmology 6: 450. doi:10.4172/2155-9570.1000450.

Saxena, R. Prakash, J. Mathur, P and Gupta, S.K.2002. Pharmacology of glaucoma. Indian journal of pharmacology, 34:71-85.

Schellack, N. Schellack, G and Bezuidenhout, S.2015. Glaucoma a brief review. SA pharmaceutical journal, 82(5); 18-22.

Schwartz A.L, Van Veldhuisen P.C (2000), advanced glaucoma intervention studies, 127(5), pp. 8-19.

Soohoo S.R, Seibold L.K and Kohook M.Y (2015), Ultra structural changes in human trabecular meshwork tissue after trabeculoplasty, 47(9), pp.10-15.

Vision Eye Institute, 2017, www.visioneyeinstitute.com.au. Accessed: 25/04/2018

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