Joseph Sowka, OD, FAAO, Diplomate Despite all of the new knowledge in glaucoma pathophysiology and all of the new therapies under study, our only therapeutic option currently available is intraocular pressure reduction. Ocular Parasympathetic receptors
Ciliary body: accommodation and trabecular meshwork opening
Because these organs are more controlled by the sympathetic system, there is less systemic affects by parasympathomimetic drugs than would be expected.
Gastrointestinal tract: increased motility
Urinary tract: increased motility
Stimulation of parasympathetic system often results in increased sweating, bradycardia and syncope, vomiting, and incontinence. You will eventually see these reactions when a patient undergoes vasovagal syncope from over stimulation of the vagus nerve. This can result from everting an eyelid or instilling medications into an eye. True anaphylaxis is extremely rare with ocular medications. If a patient has a medical situation following diagnostic medication instillation, consider vasovagal syncope as the cause.
Parasympathetic Agents: Pilocarpine
Direct acting cholinergic agonist
Ciliary body contraction
Increases outflow of aqueous through trabecular meshwork (conventional pathway). Tends to decrease outflow through uveoscleral pathway (unconventional pathway).
Accommodation- myopic shift
4-8 hrs IOP effect
Oldest anti-glaucoma medication
Generic and inexpensive
0.25%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 8%, 10%
1%, 2%, 4% most commonly used
Very unfriendly dosing schedule
4% Pilopine Gel HS: side effects occur during sleep and may be better tolerated
Concurrent use of prostaglandin analogs (relative contraindication)
Clinical Pearl: NEVER USE MIOTICS ON ANY CASE OF UVEITIS OR INFLAMMATORY GLAUCOMA! Clinical Pearl: Miotics are losing popularity as glaucoma treatment, due mostly to local side effects and the advent of newer medications. Miotics are rarely used today in modern glaucoma therapy. However, any patient with primary angle closure glaucoma should be on this medication prior to laser surgery. Clinical Pearl: Occasionally, to reduce IOP in acute situations, doctors will liberally use pilocarpine. This strategy only works if the mechanism is acute angle closure. If the patient has uveitis, the outcome can be disastrous. In reality, pouring pilocarpine into a patient is likely only to give them diarrhea. Sympathetic Agents
Blood vessels of ciliary body: vasoconstriction, which reduces blood flow and aqueous production.
Stimulation results in diminished release of norepinephrine
Stimulation here result in decrease in norepinephrine release, thus a reduction in sympathetic tone and reduction in aqueous production
Use of MAO inhibitors: enhances the affects of adrenergic drugs and can trigger a catecholamine induced hypertensive crisis
Clinical Pearl: Epinephrine is practically never used in current glaucoma therapy. Adrenergic Agonists: Dipivefrin 0.1%
Pro-drug- concentration in anterior chamber equal to traditional epinephrine 1%
Lower side effects than epinephrine
Avoid in aphakes and pseudophakes due to cystoid macular edema (CME)
Clinical Pearl: Propine has lost a great deal of popularity. It is used more commonly than epinephrine, but today most doctors avoid this medication due to its weak actions in lowering IOP. Today, Propine is virtually never used. Adrenergic Agonists: Apraclonidine 1% & 0.5%
Iopidine 0.5% (ophthalmic bottle), 1% (single use containers)
Alpha-2 agonist: acts presynaptically to inhibit release of norepinephrine and reduces adrenergic receptor stimulation. The reduced sympathetic activity in ciliary body reduces aqueous production. Inflow reduction
1% used during laser surgery to prevent IOP spike
Has been used for acute angle closure
0.5% concentration- used for POAG management
Initially was not viewed for long-term treatment (beyond 3 mos) due to tachyphylaxis.
20-30% incidence of allergic ocular reactions requiring discontinuation.
Clinical Pearl: Apraclonidine is virtually never used in modern glaucoma chronic therapy. Adrenergic Agonists: Brimonidine tartrate (Alphagan)
Alphagan 0.2% (available generically only)
Brimonidine tartrate 0.15% and 0.1% preserved with Purite®
Comparable effectiveness to Alphagan
Reduced (by 40%) incidence of local toxic adverse effects
Does not affect headache, somnolence or other problems associated with the medication, not the vehicle
30 fold more selective for alpha 2 receptors than apraclonidine
Decreases aqueous production (and possibly increasing uveoscleral outflow- not a big component of action)
Selective alpha-2 agonist
Seems to work via inhibition, thus no effects on heart and blood pressure as seen with sympathomimetics
IOP reduction of approximately 4-6 mm hg (25-30%)
Often used initially BID.
BID dosing can leave the patient with uncontrolled IOP at certain times of the day.
This is significant for monotherapy
Patients on polytherapy may be able to get away with BID dosing
Approximately 7% of patients have toxic allergic responses that require discontinuation of the drug
The most significant side effects are drowsiness and fatigue, and dry mouth
These effects are most significant in smaller patients and children
This medication has induced fatigue, drowsiness and even coma in children
Other side effects: conjunctivitis, blurring, burning, headache
No effect on blood pressure, pulse, or pulmonary function
Minimal cardiovascular and pulmonary responses- not frankly contraindicated in patients with cardiovascular disease, but use caution in patients with ischemic heart disease or prior MI
Concurrent use of MAO inhibitors (anti-depressants) are a strict contraindication to the use of Alphagan
Has been said to have a neuro-protective effect.
At this point, Alphagan is not proven to be nor is considered to be neuroprotective. It is not responsible to use this medication for any perceived neuroprotective effects
This is currently a popular and important medication (both as primary and adjunctive therapy)
Clinical Pearl: Alphagan is a more popular alpha 2 agonist than Iopidine and is one of the most popular glaucoma medications in use. Clinical Pearl: Do not use Alphagan in smaller patients or children. Clinical Pearl: No currently approved medication has been proven to be neuroprotective. You should not use any medication for this reason. Beta Antagonists (Blockers):
All forms block norepinephrine and thus blocks aqueous formation- considered aqueous suppressants
May be selective
Beta 1 specific (blocks only beta 1 receptors)
Most are non-specific and block both beta 1 and beta 2
Reduced sympathetic activity
Bilateral effects when using in only one eye due to systemic absorption
Short term escape
After an initial decrease in IOP from several days to weeks, a rise in IOP will occur. After an additional 2-4 weeks, the IOP will stabilize, often below pre-treatment levels.
Long term drift
A slow steady rise in IOP after months to years of treatment.
Ocular allergic reactions (generally insignificant magnitude, but may necessitate discontinuation of the medication)
BP decrease (beta 1)
Bradycardia (beta 1)
Pulmonary bronchiole contraction (beta 2)
Approximately 40 deaths from topical beta blocker use have been reported in the literature
Though accepted as fact by many practitioners, there is scant evidence from placebo-controlled trials to link systemic beta blocker therapy with sexual dysfunction. There appears to be no reason to withhold topical beta blocker therapy in patients for fear of inducing sexual dysfunction, even if they have a pre-existing history.
Diarrhea, nausea, cramps
Altered lipid profiles
Decreased high density lipoproteins
Increased triglyceride levels
Depression has been reported, but there is no reason to expect that topical beta blocker therapy will induce depression in an otherwise normal individual. However, the impact of beta blockers in patients that already suffer from depression is presently unknown.
Most of the above mentioned effects are anecdotal cases or case series. Very few controlled studies have been performed to identify true adverse reactions and contraindications.
Beta Blockers: Contraindications
Bradycardia: Beta blockade can result in slowing of sinus nodal discharge with resultant dose-dependent bradycardia. In most cases, the degree of bradycardia is asymptomatic and does not impact a patient’s life.
Patients using topical beta blockers who develop symptomatic bradycardia -- as manifested by diminished capacity for physical activity or undiagnosed syncope -- likely have coexistent pathology of the sinus AV node or conduction pathways and should be referred to a cardiologist.
Beta blocker therapy can be implemented in a patient with an implanted pacemaker following approval from the treating cardiologist.
Topical beta blocker therapy should be avoided in patients with asymptomatic bradycardia and heart block. Patients with symptomatic bradycardia often present with syncope and dizziness, and are identified prior to ophthalmic examination.
Asymptomatic patients without aerobic conditioning (i.e., athletes) with resting pulse rate under 55 beats per minute should be evaluated by a cardiologist. However, patients with normal resting pulse rates and with no history of syncope or dizziness are unlikely to experience any serious bradycardia effects from topical beta blockers.
Can worsen myasthenia gravis
Greater than 1st degree heart block
Beta blockers are bad for athletes as it prevents heart rate from exceeding 135 BPM. Athletes cannot train through this block.
Every patient considered for a topical beta blocker needs baseline blood pressure and resting pulse measurement in addition to review of medical history.
Congestive heart failure (CHF) has long been a contraindication to the use of topical and systemic beta blockers. Possibly, this warning came from the potential for beta blockers to reduce cardiac contractility and therefore worsen cardiac output.
Currently, it is accepted that beta blockade benefits patients with CHF and actually reduces mortality.
Reduced resistance to ejection actually improves cardiac output.
Beta blockers also function as anti-arrhythmics, likely by inhibiting cardiac sympathetic stimulation, thus reducing sudden death from arrhythmia.
In contrast to early concerns, beta blockade is now a well-accepted therapy for patients with stable class II-III CHF
There is at present no conclusive evidence-based information regarding the effects of topical beta blocker therapy on the intrinsic recovery of plasma glucose levels in patients with diabetes. It may be that patients requiring insulin in an advanced stage of diabetic disease may be at greater risk from beta blocker-induced prolongation of hypoglycemia. However, topical beta blockers are quite safe for the vast majority of diabetic patients.
Clinical Pearl: Topical beta blockers have the same systemic effects as 20 mg of oral beta blocker therapy. Beta Blockers: Shattering the Myths
Can be used in hypertensive patients
Can be used even if the patient is on systemic beta blockers for hypertension
However, systemic beta blockers reduce effectivity of topical beta blockers
Those on both forms experienced a greater degree of bradycardia
Beta Blockers: Timolol maleate
0.25% (blue cap)
0.50% (yellow cap)
Considered to be the gold standard against which all other anti-glaucoma medications are measured
Beta 1 & 2 blocker (non-selective)
30% decrease in IOP
Timoptic XE: forms a gel for better contact and penetration. Same concentrations, but is designed to be used QD. However, new understanding of diurnal pressure variations make QD AM dosing suspect
Reduced systemic absorption with reduced systemic adverse effects
Istalol: timolol maleate 0.5%: QD dosing approval
New and not especially impressive
Clinical Pearl: Beta blockers are still popular glaucoma medications and Timoptic is the most popular beta blocker.
Beta Blockers: Timolol hemihydrate
Betimol 0.25% and 0.5%
Beta Blockers: Levobunolol
Brand name Betagan no longer available. Only available as generic
0.25% (blue cap) and 0.5% (yellow cap)
Clinically equivalent to Timoptic
Same side effects and contraindications as Timoptic
Beta Blockers: Betaxolol
Betoptic S 0.25% suspension – blue cap
Beta 1 selective
Pulmonary friendly (but not perfect)
May still exacerbate asthma- caution required
Affects heart as does previous beta blockers
Weaker than previous beta blockers
May have action to increase optic nerve perfusion and is favored by many practitioners for this reason- controversial
May exhibit calcium channel blocking activity through a secondary receptor stimulus and thus may be neuroprotective. Absolutely unproven
Beta Blockers: Metapranolol
There may be an association in the development of granulomatous uveitis
Beta Blockers: Carteolol 1%
Has intrinsic sympathomimetic activity (ISA) and transient agonist activity and is the beta blocker least likely to cause bradycardia even though it is non-selective. There remains some agonal tone, which allows for more normal cardiac rhythm. There appears to be incomplete beta 2 receptor blockages. Less likely (of non-selective beta blockers) to cause bronchospasm and bradycardia.
Clinical Pearl: Beta blockers work well and are generally safe in children. Beta blockers tend not to work well in cases of uveitic glaucoma. Clinical Pearl: Beta-blockers should not be dosed at bedtime for two reasons. Some patients have nocturnal hypotension and this may lower blood pressure further. Also, aqueous formation decreases in the evening during sleep and topical beta-blockers have less effect. Carbonic Anhydrase Inhibitors
Carbonic anhydrase catalyzes the hydration of carbon dioxide to carbonic acid that then dissociates into bicarbonate ions and hydrogen.
CO2 + H2OCA H2CO3H+ + HCO3-
Bicarbonate diffuses into the eye, making it hypertonic in relation to plasma, and fluid flows osmotically into the eye from plasma.
Significantly more comfortable and better tolerated than Trusopt
Less incidence of allergic reactions
Clinically equivalent to Trusopt
Clinical Pearl: Topical CAI’s work very well in cases of uveitic glaucoma. Also, they work very well and are well tolerated in children. Clinical Pearl: While dosing is TID, many prescribe topical CAIs BID. This is probably acceptable as part of polytherapy, but is questionable for monotherapy. Clinical Pearl: Avoid using topical CAI’s in patients with compromised corneal endothelium, an allergy to sulfa medications, and a history of renal stones. Clinical Pearl: Due to the safety of topical CAI’s compared to oral CAI’s, the therapeutic index indicates that orals CAI’s are no longer appropriate in the chronic care of glaucoma.
Prostaglandins and Prostaglandin-like Medications
Prostaglandins are chemical mediators of inflammation which have the ability to reduce IOP by increasing uveoscleral outflow
Prostaglandin analogs (PGA): One of the newest and most heralded medications in glaucoma management. Is considered by some to be revolutionary
Dosing QD HS
Independent of episcleral venous pressure (drug of choice in glaucoma secondary to idiopathic elevated episcleral venous pressure and carotid cavernous fistula and dural arteriovenous shunt/malformation within the cavernous sinus).
Ocular adverse and side effects: hyperemia, periorbital skin darkening, punctate keratopathy, increased eyelash and nose hair growth, blurred vision, dry eye, increased iris coloration, anterior chamber cells/flare (anecdotal evidence of uveitis). Increased iris coloration and the potential to cause uveitis are reasons that FDA has not typically viewed prostaglandins as first line therapy (See clinical pearl below). Only now are they being approved as first-line agents. Unilateral usage should be used with caution due to iris color changes. Anecdotal evidence of cystoid macular edema (CME) in aphakes and pseudophakes. Prostaglandins been associated with pseudodendritic keratopathy as well as inducing recurrence of herpes simplex dendritic ulcers.
About 10-20% of population does not respond. For those that do respond, IOP reduction can be dramatic.
Systemic side effects: none
Systemic contraindications: none
Additional thoughts: avoid prescribing miotics (pilocarpine) in combination with prostaglandins in that miotics reduce uveoscleral outflow and may potentially interfere with the efficacy of prostaglandins
Prostaglandins are not indicated in secondary inflammatory glaucoma or any clinical entity that has anterior segment inflammation as a component
Not likely to hurt, but not likely to help, either
Clinical Pearl: Prostaglandins are important in that they flatten the diurnal IOP curve as well as giving lingering IOP reduction even as much as 60 hours after dosing. Thus, they are more forgiving of patients that miss dosages. Clinical Pearl: The most commonly encountered adverse effects from prostaglandin usage are hyperemia, eyelash growth, and periorbital skin darkening. Clinical Pearl: Hyperemia is reversible with medication cessation. Iris color changes appear to be irreversible. Periorbital skin darkening may be reversible if the medication is stopped soon enough, but may indeed be permanent. Prostaglandin Analogs: Latanoprost 0.005%
Mean IOP reduction: 27-33.7%
Can exceed 50%
Latanoprost is very oculoselective
Peak action: 8-12 hours after instillation
Should be refrigerated in storage, but for clinical usage, refrigeration may not be necessary. Shouldn’t be exposed to high temperature or intense light
Half-life is 17 minutes, thus very low degree of systemic effects
Initial short-term response to Xalatan is likely due to PF-2 receptor stimulation. Later response may be due to Xalatan actually changing the ground substance in the cellular matrix of the ciliary meshwork.
Long term IOP control is excellent with Xalatan and may be better than other meds, even if patients miss dosages.
Xalatan is as effective at 24 hours as at 4 hours.
Clinical Pearl: It takes about 3-5 weeks to appreciate the full pressure lowering effects of Xalatan. Don’t check IOP too early after starting therapy.
Clinical Pearl: IOP lowering effects of Lumigan are appreciated very fast, usually within a few days. Clinical Pearl: Many drugs promote the fact that they increase ocular blood flow. This is nearly meaningless. Any medication that reduces IOP will increase perfusion by reducing blood flow impedance. Further, these studies are all in normal patients or animal models that likely have no bearing on glaucomatous patients. Clinical Pearl: Every prostaglandin analog and prostaglandin-like drug has the same potential adverse effects and contraindications. Clinical Pearl: Use prostaglandins cautiously in patients with know previous outbreaks of herpes simplex keratitis. Clinical Pearl: Avoid using prostaglandins in cases of uveitis. Clinical Pearl: Prostaglandins are the drug of choice in IOP rise secondary to carotid cavernous sinus fistula and other cases where the episcleral venous pressure is elevated.
Clinical Pearl: Hyperemia from prostaglandin use is not an allergic reaction, but a response to the prostaglandin, which mitigates inflammation. Clinical Pearl: Due to chemical differences, each prostaglandin behaves differently. If a prostaglandin reduces IOP, but causes unacceptable redness, try another prostaglandin. Further, if the desired IOP reduction is not optimal with one prostaglandin, try another. Caveat- don’t expect dramatic pressure reductions from switching prostaglandins. For example, if IOP is reduced to 18 mm Hg with a one prostaglandin and your target is 15 mm Hg, then switching prostaglandins may work. Don’t expect much more. Clinical Pearl: While uveitis and cystoid macular edema have occurred from prostaglandins usage (notably in patients who have had previous bouts of uveitis and CME), these side effects are unlikely to occur in a previously normal patient. Clinical Pearl: Travatan, Xalatan, and Lumigan account for the vast majority of prescriptions for glaucoma written today.
Clinical Pearl: While prostaglandins are not wholly approved for first line therapy, standard of care indicates that they are the preferred category of medication today. Sorting Out the Prostaglandins: The XLT study
XLT (Xalatan-Lumigan-Travatan) study by Parrish and associates, was the first study performed that simultaneously compared the clinical outcomes associated with the use of latanoprost, bimatoprost, and travoprost. This multi-center, randomized, masked-evaluator prospective study compared not only the effectiveness of IOP reduction of the three medications, but also examined the adverse effects and tolerability of the medications.
In terms of efficacy of pressure reduction, at the conclusion of the study, the IOP was significantly reduced from baseline for all three medications. The magnitude of the reduction was not statistically significant between the medications.
This indicated that all three prostaglandins performed equally in their ability to reduce IOP, with equal persistence and stability of pressure reduction.
There were fewer reported symptoms of hyperemia in the latanoprost treated group. The intensity of the hyperemia was also less in the latanoprost group compared to the travoprost and bimatoprost groups.
While the latanoprost treated group had less hyperemia, it must be noted that the mean hyperemia score of all three medications was less than Grade 1. Thus, it was seen that all three medications were well tolerated ocularly. All three medications were well tolerated systemically as well.
Approved for several years in Canada; recently approved in USA
Better convenience and compliance
This is a popular and important medication currently
Clinical Pearl: It is extremely difficult to get FDA approval for combination agents. The FDA demands that a combination agent reduce IOP by more than 2 mm Hg compared to either sole agent throughout every time period tested. Most combination agents cannot demonstrate this degree of efficacy. Osmotics
Not for use in chronic care at all – one time only
Clinical Pearl: If you are going to give a patient oral osmotic in order to decrease IOP in the office, have a waste basket or emesis basin ready and watch out for your shoes.
Current Therapy: Used Commonly:Available, but not used commonlyNot Used:
Beta blockers Pilocarpine all other miotics
Alphagan Propine, Iopidine epinephrine
Topical CAI’s oral CAI’s
Medically Managing Glaucoma:
The goal of treatment in open angle glaucoma is to reduce IOP to a level below which optic nerve and visual field damage will not occur or progression of existing damage is prevented.
Based upon diagnostic evaluation, weighing risk factors, and considering risk-to-benefit ratio of treatment, the decision to initiate medical therapy is made. Once the decision to treat is made, a target pressure is chosen. This pressure is the one that is felt to be a safe level for a given patient.
Glaucoma suspects/ocular hypertensive patients who have normal discs and fields and no other associated risk factors could be followed without medical treatment. As numbers of risk factors increase, then the decision to treat may be initiated.
Treatment is recommended when visual field and/or optic nerve changes occur which are consistent with glaucoma independent of the IOP level.
Based upon age, expected life span, and degree of damage, some patients may be followed without therapy.
Once patient is controlled, examine Q3-4months. Always record the exact time that the patient used the medications on the day of follow-up (a surprisingly high number of glaucoma patients believe that they should skip their medications on the day that they are scheduled to come in for a visit).
Always measure pulse rate and BP if patient is using beta blockers
Never change therapy based upon one bad IOP reading
Medical contraindications necessitate your choosing different therapeutic paths.
Eachfamilyof glaucoma medications can potentiate pressure-lowering effects.
There is no synergy within families, only increasing side effects.
You can't mix 2 beta blockers or two prostaglandins together and expect a better effect than with either one alone.
If IOP is lowered with a drug, but not sufficiently, add another drug to the initial drug. If the initial drug fails to reduce IOP (i.e., is ineffective), discontinue the initial drug and move on to another.
Sequential monotherapy- a practice where each medication family is tried independently to see which one works best in each individual patient and if one medication can control IOP adequately
Never add more than one drug at a time!
Can’t tell if a single drug is effective or not
Climbing the Therapeutic Ladder
Start with one of the commonly used medications (typically a prostaglandin analog)
If IOP not controlled, add beta-blocker or a topical carbonic anhydrase inhibitor or alpha-2 agonist
If IOP not controlled, add another choice from #2 and continue until IOP acceptable
If CAI and beta blocker are both effective, they can be both discontinued and replaced with Cosopt
If alpha-2 agonist and beta blocker are both effective, they can be both discontinued and replaced with Combigan
Some practitioners will not put patients on any more than two medications and others will use three or four
Laser trabeculoplasty is an option if medications are insufficient
Surgery is an option if medications and/or laser fail
Clinical Pearl: There is not “standard” medical regimen that is appropriate for every patient. Clinical Pearl: While Alphagan, a beta blocker, a prostaglandin analog, and a topical CAI are considered maximal medical therapy, many practitioners will not use this much medication. Some practitioners consider three medications and sometimes two medications to be the maximal tolerable therapy for patients and feel that laser or surgery should be used beyond that point.
Target Pressure Re-examined
The myth of 21
There is no guarantee that IOP less than 21 will preserve a patient’s vision.
The greater the degree of damage, the lower the IOP needs to be due to fragility of the already damaged nerve.
Clinical Pearl: Some experts have developed complex algorithms with which to develop a target pressure. Frankly speaking, the most complicated algorithm in the world is no more accurate than guessing. Clinical Pearl: Target pressure can be considered a range of IOP level, which must not be consistently breached if optic nerve damage is to not occur. This has been seen with zero tolerance. This is not necessary. Any pressure reduction will buy the patient some time. Clinical Pearl: Glaucoma is not like pregnancy. You can have a ‘little’ glaucoma. You must take into account the detrimental effects on a patient’s life that IOP lowering is likely to have, especially when compared to a small visual field loss that the patient doesn’t notice. You must take into account the side effects of the medications as well as other factors such as cost that reduce the quality of life when treating a patient when you pick a target pressure. The quality of the patient’s life can go down as you force the IOP lower. Clinical Pearl: What if you don’t reach the target IOP? Did you fail? The most important mm Hg is not the last mm Hg, but the first mm Hg, and the second…and so on. So, what is the most important thing that we can say about target pressures?
A target pressure is that pressure at which the sum of the impact of the glaucomatous vision loss upon the patient and the impact of treatment upon the patient is minimized. Once treatment is started, the goal is not to make the IOP ‘normal’, but safe for the patient. Clinical Pearl: There is absolutely no reason to heroically lower IOP in office in patients with chronic glaucoma.