DRUGS IN GLAUCOMA
Dr. Anshu Mallik
1st Year Resident
Tilganga Institute of Ophthalmology

Target IOP
“A pressure rather a range IOP level within which progression
of glaucoma and visual field loss will be delayed or halted”
30
40
30
20
0
5
10
15
20
25
30
35
40
Mild
Damage
Advance
Damage
NTG OHT
30
40
30
20
%
reduction
from
baseline
AAO Guidelines Target IOP

Target IOP is based on overall glaucomatous damage
Target
IOP
Optic
Nerve
Damage
Risk
Factors
Visual
Field
IOP

Calculated as:
Target IOP = Maximum IOP - % of maximum IOP – Z
Z: optic nerve damage severity factor
0 : normal disc and normal visual field
1: abnormal disc and normal visual field
2: visual field loss not threatening fixation
3: visual field loss threatening fixation
Jample et al. Target pressure in glaucoma therapy. J Glaucoma. 1997;6:133-8.

Therapeutic Goal
The primary treatment in glaucoma is to prevent vision loss caused by
damage to optic nerve.
Though elevated IOP is just one of several risk factors that have a casual
relationship to production of glaucomatous field loss, our therapeutic
approach is primarily limited to reduction of IOP.

Ideal Pharmacotherapy
Control primary risk factors- IOP
Prevent release of damaging stimuli
Prevent apoptosis
Neuroprotection and neuroregeneration

Drugs are divided into several groups based on their chemical structure and pharmacologic action.
The group of agents in common clinical use includes-
1. Prostaglandin analogues
2. β adrenergic antagonists (non selective and selective)
3. α adrenergic agonists
4. Carbonic anhydrase inhibitors (oral and topical)
5. Parasympathomimetic (miotic) agents, including cholinergic and anticholinesterase agents
6. Combination medications
7. Hyperosmotic agents

Prostaglandin Analogues
Most recent class of drugs for long term management of glaucoma
Replaced β-blockers as 1st line of therapy
Converted to active compound by corneal esterase
4 PG analogues are approved for clinical use
• Latanoprost 0.005%
• Travoprost 0.004%
• Bimatoprost 0.01%, 0.03%
• Tafluprost 0.0015%

PG Analogues Mechanism Of Action
By increasing uveoscleral outflow facility
Binds and activate FP receptors in ciliary muscle
Relaxation of ciliary body muscle and dilate spaces between ciliary
muscle bundles
Mediated through modulation of tissue matrix metalloproteinases

Latanoprost (0.005%)
• Prodrug
• Single drop (about 1.5µg) for once daily use at night
• Onset: 2 - 4 hours
• Peak effect: 10 -12 hours after instillation
• Washout: 4 - 6 weeks

• Reduced IOP by 25-34% by increasing uveoscleral outflow
• Additive reduction of IOP of 14-28% when combined with timolol
• Maximum IOP lowering effect take up to 6 weeks
• Requires refrigeration for long-term storage
as well as protection from sunlight

Travoprost (0.004%)
• Synthetic prostaglandin (F2α analogue)
• Prodrug
• Effects similar to latanoprost
• Reduced IOP by 25-34% by increasing uveoscleral outflow
• Does not require refrigeration and protection from sunlight
• In clinical trials, travoprost 0.004% once daily, used as monotherapy, produced greater
IOP reduction than timolol 0.5% twice daily and equal or greater reduction than
latanoprost 0.005%
1Li N et al. Travoprost compared with other prostaglandin analogues or timolol in patients with open-angle glaucoma or ocular hypertension: meta-
analysis of randomized controlled trials. Clin Experiment Ophthalmol. 2006;34:755–64

Bimatoprost (0.01%, 0.03%)
• Prostamide analogue
• Administered once daily in evening
• Reduced IOP by 27-33%
• Causes 50% increase in uveoscleral outflow and
35% increase in trabecular outflow
• A six-month trial study revealed, IOP-lowering efficacies
of Bimatoprost and timolol-dorzolamide combination were similar1
• Does not require refrigeration to maintain stability
1Ozturk F et al. Comparison of the ocular hypotensive effects of bimatoprost and timolol-dorzolamide combination
in patients with elevated intraocular pressure: A 6-month study. Acta Ophthalmol Scand. 2007;85:80–3

Tafluprost (0.0015%)
• Prostaglandin F2α analogue
• Prodrug
• MOA: Same as Latanoprost
• Onset of action: 2-4 hours
• Peak: 12 hours

Side Effects Of PG Analogues
Ocular
• Conjunctival hyperemia
• Iris hyperpigmentation
• Blurred vision
• Hyperpigmentation of periorbital skin (reversible)

• Foreign body sensation
• Exacerbation of herpes keratitis, cystoid macular edema and uveitis
• Eyelash: lengthening, thickening, hyperpigmentation, hypertrichosis

Systemic
• Relatively uncommon
• Includes:
• Flu like symptoms
• Cough
• Occasional headache
• Precipitation of migraine
• Skin rash
• Contraindicated in pregnancy (teratogenic)

Advantage Of Prostaglandin Analogues
• It is used only once daily
• It has less cardiopulmonary side effects
• Can be used as additive to other anti-glaucoma medications

Contraindications Of Prostaglandin Analogues
• Known allergy
• Pregnant and nursing mother
• Children
• Uveitic glaucoma
• Immediate post operative period
• Healed or active herpes simplex keratitis

β-adrenergic antagonists (β blockers)
Nonselective (β1 and β2 blocker)
• Timolol maleate 0.25%, 0.5%
• Timolol hemihydrate 0.25%, 0.5%
• Levobunolol 0.25%, 0.5%
• Metipranolol 0.3%
• Carteolol hydrochloride 1%
Selective β1 blocker
• Betaxolol 0.25%

Mechanism Of Action
Lowers IOP by suppressing formation of aqueous humour
Binding of an agonist molecule to a beta receptor stimulates regulatory protein
(G protein) to activate adenylate cyclase
This enzyme catalyses conversion of adenosine triphosphate (ATP) to cyclic
adenosine monophosphate (cAMP), which act as a second messenger to
trigger a cascade of biochemical events
In ciliary epithelium cAMP is believed to regulate ion channels (Na+/K +
pump) and the enzymes involved in secretion of aqueous humour

β-blockers decrease cAMP levels and decrease IOP production by 20-50%
(i.e 2.5 µl/min to 1.9 µl/min) and thus decrease IOP by 20–30%
β2 antagonists have greater effect on aqueous secretion than β1 antagonists
Systemic absorption occurs so IOP lowering effect seen in contralateral
untreated eye
Dose given in morning to blunt early morning rise in IOP

Drugs Concentration Dosing IOP decrease Peak and washout
Timolol 0.25%, 0.5%
solution and gel
(also 0.1%)
1-2 times daily 20-30% Peak: 2-3 hours
Washout:1 month
Levobunolol 0.25%, 0.5%
solution
1-2 times daily 20-30% Peak: 2-6 hours
Washout:1 month
Metipranolol 0.3% 2 times daily 20-30% Peak: 2 hours
Washout:1 month
Carteolol
hydrochloride
1.0% 1-2 times daily 20-30% Peak: 4 hours
Washout:1 month
Betaxolol 0.25% 2 times daily 15-20% Peak: 2-3 hours
Washout:1 month

Advantage of betaxolol
It is cardioselective β blocker and
can be used in bronchial asthma
and other pulmonary problem as
it cause less bronchoconstriction
Advantage of levobunolol
Action lasts longer
Advantage of carteolol
Less stinging
In POAG best choice for patients
having association with
hyperlipidaemia or artherosclerotic
damage since it has more selective
action on eye than on
cardiopulmonary system

Side Effects Of β-blockers
Ocular
• Blurring of vision
• Irritation, discomfort
• Corneal anesthesia
• Punctate keratitis
• Allergy
• Dry eyes

Systemic
• Bradycardia
• Heart block
• Myocardial infarction
• Lowered blood pressure
• Bronchospasm
• Asthma
• Decreased libido
• CNS depression
• Mood swings
• Reduced exercise intolerance
• Hyperthyroidism (abrupt withdrawal)
• Alteration of serum lipid
• Aggravation of myasthenia gravis

Contraindications
• Asthma
• COPD
• Bradycardia <55 bpm
• 2nd or 3rd degree heart block
• Congestive heart failure
In patient with diabetes, masking of hypoglycemic sign and symptoms can occur

α2 Adrenergic Agonists
• Nonselective α2 agonists
• Epinephrine 0.5%, 1%, 2%
• Dipivefrin Hydrochloride 0.1%
• Selective α2 agonists
• Apraclonidine Hydrochloride 0.5%, 1%
• Brimonidine Tartrate 0.1%, 0.15%, 0.2%

Nonselective α2 agonists
• Increase conventional trabecular and uveoscleral outflow
• Dipivefrin is prodrug of epinephrine, with better corneal penetration
(lipophilic)
• IOP reduction with both drugs are comparable (15-25%)
• Both drugs are replaced by other classes of drugs and are no longer in use

Selective α2 agonists
Apraclonidine hydrochloride (0.5%, 1%)
• α2 agonist and clonidine derivative that prevents norepinephrine release at
nerve terminal
• Decreases aqueous production and episcleral venous pressure
• Improves trabecular outflow
• True ocular hypotensive mechanism not known

• Used to diminish acute rise in IOP after
• Laser iridectomy
• Argon laser trabeculoplasty
• Nd:YAG laser capsulotomy
• Cataract extraction
• IOP decreases by 20 to 30%, with peak at 1 to 2 hours, and wash out up to
7-14 days
• Effective for short term lowering of IOP but there is risk of development
of topical sensitivity
• Tachyphylaxis limits long term use

Brimonidine Tartrate (0.1%, 0.15%, 0.2%)
• Reduce aqueous production as well as increase uveoscleral outflow
• Dose: 2-3 times daily
• Peak IOP reduction 20-30% (2 hours postdose)
• At peak, comparable to non selective β blocker
and superior to selective β blocker

• At trough 14-15% reduction of IOP (12 hours postdose)
• Washout 7-14 days
• Brimonidine 0.1%, preserved with purite has been shown to be as efficacious
as brimonidine 0.2% preserved with benzylalkonium chloride and have lower
incidence of side effects (fatigue, depression, allergy)
• It contains a lower concentration of brimonidine tartrate at a neutral pH

• Brimonidine is more selective for the α2 receptor than apraclonidine
• Tachyphylaxis occur less with brimonidine
• Brimonidine should not be used in young children or infant because of risk
of respiratory arrest, apnea, hypotension, seizures, and serious derangement
of neurotransmitter in CNS due to increased CNS penetration

Side Effects Of α2 Adrenergic Agonists
Ocular
• Allergy/Contact dermatitis
• Blurred vision
• Burning/stinging
• Follicular conjunctivitis
• Hyperemia
• Itching
• Photophobia
• Foreign body sensation
• Eyelid edema
• Dryness

Systemic
• Dry mouth, nose
• Fatigue
• Sedation
• Drowsiness
• Headache
• Hypotension
• Bradycardia and hypothermia in neonates

Carbonic Anhydrase Inhibitors (CAIs)
• Belong to sulfonamide class of drugs
• Oral
• Acetazolamide (250mg, 500mg)
• Methazolamide (50mg)
• Dichlorphenamide (50mg)
• Topical
• Dorzolamide 2%
• Brinzolamide 1%

Oral Carbonic Anhydrase Inhibitor
• Basically used for short term treatment, particularly in patients with acute glaucoma.
Because of their systemic side effects, long term use is reserved for patients at high
risk of visual loss.
• Sulphonamide allergy is relative contraindication
as they are derived from sulpha drugs.
• Concentration: Acetazolamide - 250 mg, 500 mg
Methazolamide - 25, 50, 100 mg
• Dosing: Acetazolamide 250 mg is given 2-4 times daily, while 500 mg 2 times daily
Methazolamide is 2-3 times daily

• MOA- Decrease aqueous production by direct antagonist activity on ciliary
epithelial carbonic anhydrase. >90% of enzyme activity must
be abolished to decrease aqueous production and lower IOP.
• IOP decreases by 15 to 20%
• Oral drugs
• Onset of action: 1 hour
• Peak effect: 2 hours, 8 hours (SR)
• Duration of action: 6 hours, 12 hours (SR)

• Methazolamide has longer duration of action and is less protein bound than
Acetazolamide so needs small dose. However, it is less effective than
Acetazolamide.
• Methazolamide is metabolized by liver thereby decreasing some systemic side
effects whereas Acetazolamide is not metabolized and is excreted by urine.

Intravenous Carbonic Anhydrase Inhibitor
• Intravenous
• Dose: Powder 500mg vials
• Onset of action: 2 minutes
• Peak effect: 15 minutes
• Lasts up to 4 hours

Topical Carbonic Anhydrase Inhibitor
• Concentration: Dorzolamide 2%
Brinzolamide 1%
• Dosing: 2-3 times daily
• MOA- Decrease aqueous production by direct
inhibition of carbonic anhydrase in ciliary body.
• IOP decreases by 15 to 20% with peak at 2-3 hours and washout at 48 hours.

Side Effects Of Oral Carbonic Anhydrase Inhibitor
Gastrointestinal: Diarrhea, weight loss, anorexia, abdominal cramp, poor tolerance
to carbonated beverages
CNS: Malaise, fatigue, depression, drowsiness, decrease libido
Genitourinary: Nocturia, urolithiasis, impotence
Blood dyscrasias: Thrombocytopenia, agranulocytosis, aplastic anemia,
neutropenia, leg cramps

Electrolyte imbalance: Metabolic acidosis, hyperkalemia, uric acid retention
Paresthesia of fingers, toes
Dermatologic: Rash, exfoliative dermatitis, pruritis, hirsutism

Side Effects Of Topical Carbonic Anhydrase Inhibitor
Ocular
• Blurred vision
• Burning and stinging (Dorzolamide has more stinging and transient
burning because of its lower pH)
• Blepharoconjunctivitis
• Itching
• Dry eyes
• Superficial punctate keratopathy

Systemic
• Less likely to cause systemic effect but may cause bitter taste
• Headache
• Dizziness
• Gastrointestinal distress
• Neutropenia

Contraindications Of Carbonic Anhydrase Inhibitor
• Hypersensitivity to sulphonamide
• Chronic respiratory acidosis
• Clinically significant liver disease
• Secondary glaucoma
• Renal disease including kidney stone
• Pregnancy
• Addison’s disease, adrenal insufficiency

Parasympathoimetics (Miotics)
Classification
1. Cholinergic Agonist (Direct Acting)
a) Pilocarpine Hydrochloride and gel
2. Anti Cholinesterase Agent (Indirect Acting)
a) Echothiophate iodide (phospholine iodide)
3. Dual action parasympathomimetic
a) Carbachol

Mechanism Of Action
• In primary open angle glaucoma
• Contraction of the longitudinal ciliary muscle
Pulls scleral spur, alters configuration of Trabecular Meshwork and Schlemm's canal
Increase aqueous outflow

• In primary angle closure glaucoma
• Contraction of sphincter pupillae and the resultant miosis, pulls the
peripheral iris away from the trabecular meshwork thus opening the angle

• Dose:
Pilocarpine Hydrochloride drops (1.0%, 2.0%, 4.0%) and gel- 4.0%
Applied 2-4 times daily for drops, twice daily for combination therapy
and once daily at night time for gels
Echothiophate (0.125%) applied 1-2 times daily
• Peak effect: 2-3 hours
• Washout: 48 hours
• Lower IOP by 15-25%
• Additive to β blockers, adrenergic agent and carbonic anhydrase inhibitors

• Delivery systems for pilocarpine
• Pilocarpine Hydrochloride gel 4%:
• Applied once daily at bedtime
• Reported to produce significant reduction
in IOP for 24 hours
• Membrane-controlled delivery system (Ocusert):
• Insert placed in cul-de-sac, where it gradually releases pilocarpine at the rate
of 20µg/hour, roughly equivalent to 2% eye drops
• Effective for seven days

Carbachol
• It has dual action i.e it is agonist as well as weak cholinesterase inhibitor.
• Indication: Good alternative to pilocarpine in resistant or intolerant cases.
• Available: 0.75% and 3% eyedrop
• Dose : Action starts in 40 minutes and lasts 12 hours,
so used 2-3 times daily

Side Effects Of Parasympathomimetic Agents (Miotics)
Ocular
• Induced myopia due to ciliary muscle contraction
• Brow ache accompany ciliary spasm
• Posterior synechiae
• Keratitis
• Miosis

• Cataract growth (more in indirect-acting agents)
• Retinal tear, detachment
• Change in retinal sensitivity
• Color vision changes
• In child and adult it may cause epiphora by both punctal stenosis and lacrimal
stimulation

• In children induced formation of iris pigment epithelial cyst
• Paradoxical angle closure- contraction of ciliary muscle causes forward
movement of lens-iris-diaphragm leading to pupillary block in eye with
large lens
• Miotics break the blood aqueous barrier so it must be avoided in uveitic
glaucoma.

Systemic
• Increased salivation
• Increased secretion, sweating, lacrimation
• Weakness, muscle spasm
• Bronchospasm, asthma
• Diarrhea
• Nausea, vomiting, abdominal pain, abdominal cramps

Fixed Combinations
• Medications that are combined in a single bottle
• Improved convenience
• Compliance
• Reduced cost
• Fixed combinations usually consist of timolol and another agent

S.N Combination Concentration Dosing MOA IOP
Decreases
1. Timolol/
Brinzolamide
0.5%/1% 2 Times
Daily
Reduces Aqueous
Secretion
25-30%
2. Timolol/
Dorzolamide
0.5%/2% 2 Times
Daily
Decreases
Aqueous
Production
25-30%
3. Timolol/
Latanoprost
0.5%/0.005% 1 Time
Daily
(Night)
Same As Non
Selective β
Blocker And
Latanoprost
Greater Than
Monotherapy
With Each
Drug
Individually

S.N Combination Concentration Dosing MOA
4. Timolol/
Travoprost
0.5%/0.004% 1 Time Daily
(Night)
Same As Non
Selective β Blocker
And Travoprost
5. Timolol/
Bimatoprost
0.5%/0.03% 1 Time Daily
(Night)
Same As Non
Selective β Blocker
And Bimatoprost
6. Timolol/
Brimonidine Tartrate
0.5%/0.2% 2 Times Daily Same As Non
Selective β Blocker
And Brimonidine

Hyperosmotic Agents
Control acute episodes of elevated IOP
Agents
• Mannitol 20% (I/V)
• Glycerol 50% solution (Oral)
• Isosorbide 50% solution
Clinical uses
• Acute angle closure glaucoma
• Prior to intraocular surgery when IOP is very high

Mechanism Of Action
Increase blood osmolality
Osmotic gradient between blood and
vitreous
Water drained out of vitreous
Decreases IOP

Mannitol
• Concentration: 20%
• Route: Parenteral (I/V)
• Dosing: 0.5 - 2 gm/kg body weight over 30-60 minutes
• Peak action occurs within 30 minutes
• Duration of action: 6 hours
• MOA- Creates osmotic gradient; dehydrates vitreous

Side Effects Of Mannitol
Ocular
• IOP rebounds
• Increased aqueous flare

Systemic
• Urinary retention
• Congestive heart failure
• Expansion of blood volume
• Diabetic complications
• Nausea
• Vomiting
• Diarrhea
• Electrolyte disturbance
• Renal failure
• Headache
• Mental confusion
• Backache
• Myocardial infarction

Glycerol
• Concentration: 50%
• Route: Oral
• Dosing: 1-1.5 gm/kg body weight
• Peak action occurs within 1 hour
• MOA- Creates osmotic gradient; dehydrates vitreous

Side Effects Of Glycerol
Ocular
• IOP rebounds
• Increased aqueous flare
Systemic
• Similar to mannitol
• Can cause problem in diabetic patients as glycerol is metabolized to glucose
and ketone bodies, it may cause hyperglycemia and ketoacidosis.

Pregnant And Lactating Mothers
Majority of glaucoma medications are within pregnancy category C
Brimonidine has pregnancy category B rating
β-blockers are concentrated 5-fold in breast milk
Brimonidine to be avoided in nursing mothers
Prostaglandins increase uterine contractility and may induce premature labour

Neuroprotection
• Neuroprotection is a therapeutic paradigm that slows or prevent neuronal death
• Maintains physiological functioning
• Blocks primary cell destructive events and enhance cell survival mechanisms
• The rationale for neuroprotection in neuro ophthalmology includes blocking of
retinal ganglion cells apoptosis through interruption of excitotoxic factors like
Glutamate, N-methyl-D-aspartate (NMDA) receptors, Nitric oxide and
delivery of neurotrophins to enhance cell survival.

Glutamate
• It is a excitatory neurotransmitter found in brain and retina
• In glaucomatous eye, increase fold of glutamate has been found in posterior
vitreous.
• It is most reactive to NMDA receptors
• When glutamate binds to NMDA receptors it opens channel which allow
influx of calcium. This calcium initiate apoptotic mechanism.

Nitric Oxide
• It is formed from L- arginine by NO synthetase (NOS).
• There are 3 forms of NOS
NOS-1: It is neuronal, a constitutive enzyme that has been detected in
diminished nerve fiber bundle at prelaminar region and lamina cribrosa
of glaucomatous eye
NOS-2: It is an inducible enzyme produced in response to high IOP, it
also has genetic associations in patient with POAG
NOS-3: It is endothelial, constitutive enzyme found in pre laminar region
of optic nerve which functions as vasodilators

Evidence On Currently Available Topical Drugs
α2 adrenergic agonist:
• These receptor are located in ganglion cell layers of retina
• Activation of these receptors inhibit neuronal cell death as it inhibit pro apoptotic
pathway, glutamate release
• They activate the phosphatidyl inositol kinase and protein kinase which are major
pathway for cell survival
Neuroprotection of brimonidine
• It confers neuroprotection by upregulation of brain derived neurotropic receptors

β blockers:
• It inhibit calcium and sodium ion influx into neuron which occurs in hypoxia,
ischaemia, excitotoxicity.
• It reduced NMDA and glutamate affinity thereby reducing calcium ion influx in
retinal ganglion cells
Prostaglandins:
• They exert neuroprotection effect by impending glutamate and hypoxia induced
apoptosis and is postulated to act by negative cyclooxygenase 2 pathway

References
• Becker-Shaffer's Diagnosis and Therapy of the Glaucomas
• Glaucoma: The American Academy of Ophthalmology, 2018-2019
• Fundamentals and principles of ophthalmology, 2018-2019
• Intraocular inflammation and uveitis The American Academy of
Ophthalmology, 2018-2019