1. Ahmed Shaman Clinical Pharmacy Department shaman@ksu.edu.sa
Ophthalmic Diseases
Ahmed Shaman
Clinical Pharmacy Department

2. Glaucoma

3. What is glaucoma?
Optic neuropathy that is the leading cause of irreversible blindness in the world
Major types are open angle and closed angle
Glaucoma is commonly associated with elevated intraocular pressure (IOP), but the disease can occur with normal IOP
Our understanding and treatment of the disease is very focused on IOP
The diversity of diseases that fall under the name ‘glaucoma’ make a precise definition of the disease hard to come by. Most clinicians call any condition in which the intraocular pressure is elevated glaucoma. But, this is not a sufficient definition of the disease. Glaucoma is not a single entity.
Glaucoma is the leading cause of irreversible blindness in this country
However, our understanding of the disease and approach to treatment is very centered around the intraocular pressure. As such, it is important that we understand the dynamics of aqueous humor flow.

4. What is glaucoma?
Clear liquid called aqueous humor circulates inside the front portion of the eye
To maintain a healthy level of pressure within the eye, a small amount of aqueous humor is produced constantly, while an equal amount flows out of the eye through a microscopic drainage system
the trabecular meshwork
With glaucoma, aqueous humor does not flow through the trabecular meshwork properly
Over time, eye pressure increases, damaging the optic nerve fibers

5. Effect of Glaucoma

6. Classification Two main categories of primary glaucoma:
Open-angle glaucoma: the most common form of glaucoma
Closed-angle glaucoma: a less common and more urgent form of glaucoma

7. Open-angle glaucoma
Trabecular meshwork becomes less efficient at draining aqueous humor
Intraocular pressure (IOP) builds up, which leads to damage of the optic nerve
Damage to the optic nerve occurs at different eye pressures among different patients.
Typically, glaucoma has no symptoms in its early stages

8. Closed-angle Glaucoma
The drainage angle of trabecular meshwork becomes blocked by the iris (the colored part of the eye)
IOP builds up very fast
Symptoms include severe eye or brow pain, redness of the eye, decreased or blurred vision
Must be treated as a medical emergency
Without treatment, blindness in as little as one or two days

9. Open vs. Closed angle Glaucoma

10. Risk factors for glaucoma include:
Age
Family history
Elevated eye pressure (IOP)
Nearsightedness or farsightedness
African, Hispanic or Asian ancestry
Diabetes
Previous eye injury
Thin cornea

11. Glaucoma Management Treatment Options: Medical: Surgical: Topical
systemic medications (PO or IV)
Laser:
Iridotomy
Iridoplasty
Trabeculoplasty
Surgical:
Filtration Surgery (e.g. Trabeculectomy)
Tube shunt
Destruction of the ciliary body (cyclodestruction)

12. TREATMENT RATIONALE LOWER IOP BY:
Decreasing Production of Aqueous Humor
Increasing Outflow of Aqueous Humor

13. DRUGS THAT DECREASE AQUEOUS PRODUCTION
Beta-Blockers [levobunolol, timolol, carteolol, betaxolol]
-Mechanism: Act on ciliary body to  production of aqueous humor
-Administration: Topical drops to avoid systemic effects
-Side Effects: Cardiovascular (bradycardia, asystole, syncope), bronchoconstriction (avoid with b1-selective betaxolol), depression
Alpha-2 Adrenergic Agonists [apraclonidine, brimonidine]
-Mechanism:  production of aqueous humor
-Administration: Topical drops
-Side Effects: Lethargy, fatigue, dry mouth [apraclonidine is a derivative of clonidine (antihypertensive) which cannot cross BBB to cause systemic hypotension]
Carbonic Anhydrase Inhibitors [acetazolamide, dorzolamide]
-Mechanism: Blocks CAII enzyme production of bicarbonate ions (transported to posterior chamber, carrying osmotic water flow), thus  production of aqueous humor
-Administration: Oral, topical
-Side Effects: malaise, kidney stones, possible (rare) aplastic anemia

14. DRUGS THAT INCREASE AQUEOUS OUTFLOW
Nonspecific Adrenergic Agonists [epinephrine, dipivefrin]
-Mechanism:  uveoscleral outflow of aqueous humor
-Administration: Topical drops
-Side Effects: Can precipitate acute attack in patients with narrow iris-corneal angle, headaches, cardiovascular arrhythmia, tachycardia
Parasympathomimetics [pilocarpine, carbachol, echothiophate]
-Mechanism:  contractile force of ciliary body muscle,  outflow via TM
-Administration: Topical drops or gel, (slow-release plastic insert)
-Side Effects: Headache, induced miopia. Few systemic SE for direct-acting agonists vs. AchE inhibitors (diarrhea, cramps, prolonged paralysis in setting of succinylcholine).
Prostaglandins [latanoprost]
-Mechanism: May  uveoscleral outflow by relaxing ciliary body muscle
-Side Effects: Iris color change

15. TREATMENT: OPEN-ANGLE GLAUCOMA
Several large, randomised controlled trials have demonstrated the benefits of early diagnosis and treatment
Some controversy exists as to whether the initial therapy of glaucoma should be surgical trabeculectomy (filtering procedure), or selective laser trabeculectomy, or medical therapy
Drug therapy remains the most common initial treatment modality
Drug therapy of patients with documented glaucomatous change with either elevated or normal IOP is initiated in a stepwise manner 

16. TREATMENT: OPEN-ANGLE GLAUCOMA
The goal of therapy is to prevent further visual loss
A "target" IOP is chosen based on a patient baseline IOP and the amount of existing visual field loss as well as other risk factors
An initial target IOP reduction of 20-30% is desired
Greater reductions (30–50%)may be desired for patients with
very high baseline IOPs or advanced visual field loss.
Patients with normal baseline IOPs (normal-tension glaucoma) may have target IOPs of less than 10 to 12 mm Hg

18. TREATMENT: OPEN-ANGLE GLAUCOMA
Drug choice
The prostaglandin (PG) analogues (bimatoprost, latanoprost and travoprost) are replacing beta-blockers as first-line agents.
Brimonidine or topical carbonic anhydrase inhibitors (brinzolamide, dorzolamide) tend to be used as alternatives
Unless there are contraindications to using beta-blockers or PG analogues
Use of pilocarpine is declining, although it may still be useful as adjunctive treatment

19. Practice Points
Up to 50% of patients fail to use their medication correctly
One strategy to aid compliance is to use an eye drop containing 2 drugs, eg timolol with a prostaglandin analogue
Simple dosage regimens and patient education help compliance
To reduce systemic absorption (by up to 70%)
close eyes and press on the tear duct for 3 minutes after instillation of each eye drop
When >1 type of eye drop is to be instilled at the same time, separate administration by at least 5 minutes

20. Nasolacrimal occlusion

21. Comparative Information
Drug class
Effect
Doses per day
beta-blocker, eg timolol
+++
1–2
prostaglandin analogue, eg latanoprost 1
carbonic anhydrase inhibitor, eg dorzolamide ++
2–3
alpha2 agonist, eg brimonidine
cholinergic (pilocarpine)
2–4

22. Beta-blockers (eye)
Timolol, levobunolol, metipranolol and carteolol are nonselective
Betaxolol has β1-selective properties
Mode of action
Reduce aqueous humour formation, probably by blockade of beta receptors on the ciliary epithelium
Indications
All types of glaucoma
Ocular hypertension
Precautions
Reversible airways disease, eg asthma—use is generally contraindicated, however cardioselective agents, ie betaxolol, may be used with care.

23. Beta-blockers (eye) Cardiovascular
Consider effects of systemic beta-blockade
Use is contraindicated in bradyarrhythmia or second- or third-degree atrioventricular block.
Treatment with a systemic beta-blocker reduces intraocular pressure (but less than with a topical beta-blocker).
Avoid treatment with verapamil due to potential for profound bradycardia

24. Beta-blockers (eye) Elderly
Systemic adverse effects are more common, e.g. hypotension (may cause falls)
Children
May cause apnea in neonates and bradycardia in children.
Pregnancy
May cause fetal bradycardia;
Breastfeeding
Unlikely to cause adverse effects at usual doses.

25. Beta-blockers (eye) Adverse effects
The most important adverse effects are systemic
Common
Stinging on instillation (especially betaxolol solution), bradycardia, blurred vision
Infrequent
decreased corneal sensation, hypotension, syncope, fatigue, confusion, hallucinations, bronchospasm

26. Beta-blockers (eye) Comparative information
Timolol (nonselective beta1 and beta2 receptor blocker)
Reduces intraocular pressure by 25% when used in 0.25% solution
<local adverse effects than betaxolol
Betaxolol (selective for beta1 receptors)
Reduces intraocular pressure by about 20%.
?Less likely to cause bronchospasm
Suspension less stinging than solution

27. Beta-blockers (eye) Practice points
Slight decrease in effect may occur during the first month of treatment;
tolerance may develop after 1 year or more of treatment
After stopping topical beta-blockers intraocular pressure may not return to baseline for 2–4 weeks
If single daily dosage is required, consider timolol gel or Timoptol-XE®

28. Beta-blockers (eye) Dosage – Betaxolol
Adult, child, 1 drop twice daily.
Dosage – Timolol
Use the same way for adults and children.
Conventional drops, 1 drop of 0.25% once or twice daily.
Maximum 1 drop of 0.5% twice daily.
Timoptol-XE®, 1 drop of 0.25% once daily
if necessary, increase to 1 drop of 0.5% once daily.
Gel 0.1%, 1 drop once daily
Infant <12 months
1 drop of 0.25% (of either formulation) once daily

29. Beta-blockers (eye) Counselling
Gel: store bottle upside down after opening so that gel collects in the bottle neck and stops bubbles forming as it is applied.

30. Prostaglandin analogues (eye) Ocular Hypotensive Lipids
Bimatoprost , latanoprost and travoprost
Mode of action
Reduce intraocular pressure by increasing uveoscleral outflow of aqueous humour.
Indications
Glaucoma
Ocular hypertension

31. Prostaglandin analogues (eye) Ocular Hypotensive Lipids
Pregnancy
Avoid use; no data available;
Breastfeeding
Unlikely to be of concern; latanoprost is safe to use.

32. Prostaglandin analogues (eye) Ocular Hypotensive Lipids
Adverse effects
Common
Iris hyperpigmentation , eyelash changes , eye irritation (itching, stinging), allergic conjunctivitis, blurred vision, blepharitis, headache
Infrequent
Reversible macular oedema, eyelid and conjunctival oedema, darkening of eyelid skin, iritis or uveitis

33. Prostaglandin analogues (eye) Ocular Hypotensive Lipids
Iris hyperpigmentation
Gradual (over months to years), usually irreversible, increase in iris pigmentation in treated eyes
Eyelash changes
Gradual darkening, lengthening and thickening of the eyelashes; reversible when treatment stopped.

34. Prostaglandin analogues (eye) Ocular Hypotensive Lipids
Comparative information
Bimatoprost, latanoprost and travoprost appear to have similar efficacy.
Counselling
These eye drops may slowly change the colour of your eye making the iris appear darker.
This change is permanent and may be more noticeable when only one eye is being treated.
Practice points
Instil in the evening for optimal effect
Drugs in this class are structurally different; if response to one is poor, consider trying another
a paradoxical increase in intraocular pressure may occur if 2 ocular prostaglandin analogues are used together; avoid combination

35. Alpha2 agonists Brimonidine and apraclonidine Mode of action
Reduce IOP by suppressing formation and increasing outflow of aqueous humour
Indications
Chronic open-angle glaucoma
Prevention of ocular hypertension following laser surgery
Acute closed-angle glaucoma (before laser iridotomy)

36. Alpha2 agonists Precautions
Severe cardiovascular disease—may worsen; use with caution.
Pregnancy
Apraclonidine: avoid use;
Brimonidine: suitable if necessary;
Breastfeeding
No data available; unlikely to be a concern.

37. Alpha2 agonists Comparative information Apraclonidine Brimonidine
Reduce IOP by 25%
Effect declines after a month
Short-term use (up to 3 months)
High incidence of allergic blepharoconjunctivitis with chronic use
Brimonidine
Reduce IOP by 20%
Effective and well tolerated on chronic use

38. Blepharoconjunctivitis

39. Topical Carbonic anhydrase inhibitors
Dorzolamide and brinzolamide
Mode of action
Inhibit carbonic anhydrase II (predominant subtype found in the eye), which reduces aqueous humour formation
Indications
Ocular hypertension
Open-angle glaucoma

40. Topical Carbonic anhydrase inhibitors
Precautions
Allergy to sulfonamides—may increase risk of allergy to carbonic anhydrase inhibitors
Pregnancy
Avoid use; no human data available; Australian category B3.
Breastfeeding
No human data available.

41. Topical Carbonic anhydrase inhibitors
Adverse effects
Common
Ocular irritation, foreign body sensation, bitter taste
Infrequent
Blepharitis, vision changes, corneal staining, GI disturbance, headache, paraesthesia, dizziness, dermatitis
Rare
allergic reactions, eg urticaria, angioedema, bronchospasm

42. Topical Carbonic anhydrase inhibitors
Counselling
Your eye may feel uncomfortable for a little while after you have put in the drop.
If you have blurred vision, avoid driving or operating machinery until your sight improves.
Practice points
May be used when beta-blocker is ineffective or not tolerated
May be used in combination with ophthalmic beta-blockers

43. Other Drugs for Glaucoma
Acetazolamide (Systemic Carbonic Anhydrase Inhibitors)
Hyperosmotics
Glycerin, isosorbide, and mannitol
Cholinergic Agents
Pilocarpine and carbachol
Nonselective Adrenergic Agonists
Epinephrine and its prodrug, dipivefrine

44. Acetazolamide Systemic carbonic anhydrase inhibitor Mode of action
Inhibits carbonic anhydrase and therefore bicarbonate synthesis
In the eye this reduces aqueous humour secretion and IOP
Indications
Perioperative reduction of intraocular pressure, eg acute closed-angle glaucoma
Chronic open-angle glaucoma where other treatments have failed

45. Acetazolamide Precautions
Adrenal or respiratory failure or metabolic acidosis—contraindicated (increased risk of profound acidosis).
Sodium or potassium depletion—contraindicated (will worsen depletion).
Gout—may worsen.
Allergy to sulfonamides—may increase risk of allergy to acetazolamide; manufacturer contraindicates use.

46. Acetazolamide
Renal
Contraindicated when CrCl <10 mL/minute (increased risk of profound acidosis); reduce dose if CrCl 10–30 mL/minute.
Acetazolamide increases risk of recurrence of urolithiasis.
Hepatic
Contraindicated in hepatic impairment or cirrhosis due to the risk of hepatic encephalopathy.
Elderly
Increased risk of adverse effects, eg metabolic acidosis.

47. Acetazolamide Adverse effects
Up to 50% of patients do not tolerate acetazolamide.
Common
paraesthesia (of hands, face, feet or mucocutaneous junctions), fatigue, drowsiness, depression, decreased libido, bitter or metallic taste, nausea, vomiting, abdominal cramps, diarrhoea, black faeces, polyuria, renal stones, metabolic acidosis, electrolyte changes (hypokalaemia, hyponatraemia)
Infrequent
transient myopia (ciliary body swelling), bullous skin eruptions (Stevens-Johnson syndrome)
Rare
aplastic anaemia (especially in the first 6 months), thrombocytopenia, agranulocytosis or neutropenia, anaphylaxis

48. Mannitol Hyperosmotic agent Mode of action
Increases plasma osmolality; dehydrates vitreous body. Produces a rapid (30 minutes) but temporary (6 hours) drop in intraocular pressure.
Indications
Acute closed-angle glaucoma unresponsive to conventional treatment
Intraocular pressure reduction before intraocular surgery (prevents prolapse of intraocular contents)

49. Mannitol Adverse effects Adverse effects are generally infrequent
Fluid and/or electrolyte shift can produce pulmonary congestion, acidosis, electrolyte loss, dry mouth, thirst, oedema, headache, blurred vision, seizures and heart failure.
Nausea, vomiting, local pain, skin necrosis and thrombophlebitis (injection site), chills, dizziness, urticaria, hypotension, tachycardia, fever, angina-like chest pains
Dosage – Mannitol
Adult, IV 1–2 g/kg (5–10 mL/kg of 20% solution) over 30 minutes.

50. Mannitol Administration advice
Mannitol crystallises at low temperatures (especially 20% solution); redissolve by warming in hot water and shaking vigorously; allow to cool to body temperature before giving via infusion set with filter.
Practice points
Mannitol produces a marked osmotic diuresis; urinary catheterisation is required for anaesthetised or unconscious patients
The hyperosmotic agent most often used in the treatment of acute ocular hypertension is IV mannitol (oral glycerol is used infrequently)

51. Cholinergic Agents Mode of action
Pilocarpine and carbachol
Mode of action
Cholinergic effect contracts Iris sphincter and ciliary muscle
Increases outflow through the trabecular meshwork
Indications
Chronic open-angle glaucoma
Acute closed-angle glaucoma

52. Cholinergic Agents Adverse effects Common Infrequent Rare Headache
blurred vision, headache, ocular irritation (eg burning, itching), myopia, miosis
Infrequent
lacrimation
Rare
retinal detachment
Headache
Accommodative spasm and frontal headache (browache) are common initially
usually decrease after 2–4 weeks; simple analgesics may reduce pain
Miosis
Causes blurred vision, occurs infrequently but is potentially permanent with long-term use and may reduce vision in dim light, worsen the effect of a central visual opacity and constrict the visual field

53. Nonselective Adrenergic Agonists
Dipivefrine
Pro-drug, enzymatically cleaved to epinephrine
Increase the outflow of aqueous humor through the trabecular meshwork
Reduce IOP by 15% to 25%
Rarely used now
Adverse effects
Ocular irritation (include allergic blepharoconjunctivitis)
mydriasis, conjunctival hyperemia and frontal headache
Not used in patients with narrow angles since these agents can cause acute angle closure

54. DRUG-INDUCED GLAUCOMAS
Anticholinergics
Sympathomimetics
Sulfa-based drugs
Corticosteroids increase IOP
Ophthalmic corticosteroid preparations carry the highest risk of increasing IOP

55. TREATMENT: OCULAR HYPERTENSION
Ocular hypertension; i.e., patients with IOP >22 mm Hg [>2.9 kPa]
Ocular Hypertensive Treatment Study (OHTS) helped to identify risk factors for treatment
Patients with
IOPs higher than 25 mm Hg (3.3 kPa)
vertical cup-to-disk ratio of more than 0.5
central corneal thickness of less than 555 µm
Are at greater risk for developing glaucoma
Risk factors such as family history of glaucoma, black ethnicity, severe myopia, and patients with only one eye must also be taken into consideration

56. TREATMENT: OCULAR HYPERTENSION
Patients with significant risk factors usually are treated with a well- tolerated topical agent such as
β-blockers
Prostaglandin analog
a2-Adrenergic Agonist (brimonidine)
Topical carbonic anhydrase inhibitor
Depending on individual patient characteristics.

57. TREATMENT: OCULAR HYPERTENSION
Optimally, therapy is initiated in one eye to assess efficacy and tolerance
Use of second- or third-line agents (e.g., pilocarpine or dipivefrin) when first-line agents fail to reduce IOP depends on the risk-to- benefit assessment of each patient

58. Acute closed-angle glaucoma
This is a rare ophthalmic emergency
Treatment is by peripheral laser iridotomy
Oral, IV, and topical medication is necessary to stabilise the eye and lower the pressure before laser iridotomy
IV acetazolamide,
Topical pilocarpine,
A topical beta-blocker,
IV Mannitol or oral glycerol

59. Glaucoma surgery
Laser iridotomy: creates a small hole in the iris to improve flow of aqueous humor into drainage angle.

60. Glaucoma surgery
Laser trabeculoplasty: stimulates the trabecular meshwork (drainage angle) to function more efficiently

61. Glaucoma surgery
Trabeculectomy: creates new drainage channel for the eye
Goal is to stabilize disease and prevent further damage/vision loss
Does not reverse damage to the optic nerve
Performed on an outpatient basis

62. Regular Eye Exams
Everyone should regularly visit their ophthalmologist at the following intervals:
Age years: At least once during this period
Those with risk factors for glaucoma (people of African descent or those who have a family history of glaucoma) should be seen every 3-5 years
Age years: At least twice during this period
Those with risk factors for glaucoma (people of African descent or those who have a family history of glaucoma) should be seen every 2-4 years
Age years: Every 2-4 years
Age 65 years or older: Every 1-2 years