The Wonderful New Drugs Have Made a Difference
The Wonderful New Drugs Have Made a Difference?
The Wonderful New Drugs Have Made a Difference!
Ronald
L. Gross, M.D.
Professor
of Ophthalmology
Clifton R. McMichael
Chair in Ophthalmology
Cullen
Eye Institute
Department
of Ophthalmology
Baylor College of Medicine
Houston, Texas,
U.S.A.
I. Wonderful
A.
Assessing Therapy
1. Efficacy in treating the disease- structure
and function
a. Human Glaucoma Today = IOP Reduction
b. Glaucoma in the future
i. “Blood flow of the optic nerve”
ii. “Neuroprotection”
2. Systemic Safety- Will it harm the patient’s
health?
3. Tolerability- Will the patient not like the treatment?
4. Compliance- the great unknown!
B.
What Would Be an Ideal Therapy?
1. Lower IOP to < 12 mm Hg - at
all times
2. Reduce optic nerve loss to baseline- even
reduce it further through enhanced perfusion or neuronal protection
3. A single intervention- effective life-long
4. No systemic side effects
5. Make the iris color bluer
6. Make eyelashes grow
7. Remove wrinkles
8. No $$$ Cost
C.
Are Our Therapies Wonderful?
1.
Can we get IOP lower, more consistently?
a.
New Medications are more effective at lowering IOP
b.
Target Pressures more aggressive
c.
NIH/NEI Trials consistent outcomes
2. Can we assess optic nerve
structure
and function?
3. Can we assess compliance?
4. Can we afford the therapy?
II. New
A.
Topical Carbonic Anhydrase Inhibitors
B.
Adrenergic Agonists
C.
Lipids
D.
Surgical Adjuncts
1.
Non-selective Antimetabolites
2. Selective Wound Healing Modulators
III. Drugs
A. The Previous Paradigms
1. 1963- miotics, epinephrine, oral CAI
2. 1983- timolol, dipivefrin, miotics, oral CAI
3. 1993- beta-blockers, adrenergic agonists,
miotics, oral CAI, ALT
B. The Current Paradigm – 2003
1. Monotherapy- more achievable
2. Switch rather than add if possible
3. One-eyed therapeutic trials- forward and
reverse
4. Patient education and involvement
C. The Agents that have made the difference-
[adapted from AAO Basic and Clinical Science Course]
Beta-Adrenergic
Antagonists (Beta Blockers)
Topical
beta-blocking agents lower IOP by inhibiting cyclic adenosine
monophosphate (cAMP) production in ciliary epithelium, thereby reducing aqueous
humor secretion 20%–50% (2.5 ml/min
to 1.9 ml/min), with a
corresponding IOP reduction of 20%–30%. The effect of beta-blockers
on aqueous production occurs within 1 hour of installation and
can be present for up to 4 weeks after discontinuation.
Evidence suggests that beta-blockers decrease aqueous production
during the day, but have much less effect during the night.
As systemic absorption occurs, a contralateral effect
with lowering of the IOP in the untreated eye can also be observed.
Most beta- blockers are approved for twice daily
therapy. In many cases once daily with the non-selective
agents is possible. Generally
dosing first thing in the morning is preferred to effectively
blunt an early morning pressure rise while minimizing the risk
of systemic hypotension during sleep.
Many non-selective beta-blockers are available in more
than one concentration. For example, timolol ¼% is as effective in lowering
IOP as timolol ½% in many patients.
Approximately
10%–20% of the patients treated with topical beta blockers fail
to respond with significant lowering of the IOP. It should be
noted that if a patient is on systemic beta-blocker therapy, then
the addition of a topical beta-blocker may be significantly less
effective. Extended use of beta-blockers may reduce their effectiveness,
as the response of beta receptors is affected by constant exposure
to an agonist (long-term drift, tachyphylaxis). Similarly, receptor
saturation (drug-induced upregulation of beta receptors) may occur
within a few weeks, with loss of effectiveness (short-term escape).
Six
topical beta-adrenergic antagonists are approved for use for the
treatment of glaucoma in the United
States: betaxolol, carteolol,
levobunolol, metipranolol, timolol maleate, and timolol hemihydrate.
All except betaxolol are non-cardioselective beta1
and beta2 antagonists. Beta1 activity is
largely cardiac and beta2 activity is largely pulmonary.
Since betaxolol is a selective beta1 antagonist, it
is safer than the nonselective beta-blockers when pulmonary, CNS,
or other systemic conditions are considered, but beta-blocker
related side effects can still occur.
The IOP-lowering effect of betaxolol is less than the nonselective
beta-adrenergic antagonists.
Concerns about potential systemic side effects of beta-adrenergic antagonists
are important to consider. They include bronchospasm, bradycardia, increased heart block,
lowered blood pressure, reduced exercise tolerance, and CNS depression.
Diabetic patients may experience reduced glucose tolerance and
masking of hypoglycemic signs and symptoms. Abrupt withdrawal
of ocular beta-blockers can exacerbate
symptoms of hyperthyroidism. It is important to determine if the
patient has ever had asthma prior to the prescription of a beta-blocking
agent, which may induce severe bronchospasm in susceptible patients.
The pulse should be measured and the beta-blocker
withheld if the pulse rate is slow or if more than first-degree
heart block is present. Myasthenia gravis may be aggravated by
these drugs. The use of a gel vehicle has been shown to decrease
the plasma concentration of beta-blockers compared to the solutions.
Other
side effects of beta-blockers include lethargy, mood changes,
depression, altered mentation, light-headedness, syncope, visual
disturbance, corneal anesthesia, punctate keratitis, impotence,
reduced libido, allergy, and alteration of serum lipids.
Beta-blockers should be used with caution in children due
to the relatively high systemic levels achieved.
Although topical beta-blockers have been shown to decrease
HDL and increase cholesterol levels, there is no evidence that
this translates into an actual increase in cardiovascular risk.
However, this effect on plasma lipid profile should be
considered, particularly in those patients taking medications
that affect plasma lipids.
The
use of naso-lacrimal occlusion or eyelid closure decreases systemic
absorption and increases absorption of all medications and is
particularly important with the use of beta-blockers.
Many of the beta-blockers are available as generic agents.
Although these may be less expensive, it is important to
realize that in most cases there is little data proving or disproving
equivalent efficacy or similar side effect profiles between branded
and generic medications. Additionally, since multiple generics are available
for a given agent, the possibility that differences exist between generic agents and could affect patient
care.
Topical Carbonic Anhydrase Inhibitors
These
agents decrease aqueous humor formation by direct antagonist activity
upon ciliary epithelial carbonic anhydrase and perhaps, to a lesser
extent only with systemic administration, by producing a generalized
acidosis. The enzyme carbonic anhydrase is also present in many
other tissues, including corneal endothelium, iris, retinal pigment
epithelium, red blood cells, brain, and kidney. Over 90%
of the ciliary epithelial enzyme activity must be abolished to
decrease aqueous production and lower IOP.
The systemic agents are most
useful in acute situations (e.g., acute angle-closure glaucoma).
They can be given orally, intramuscularly, and intravenously. Because of the side effects of the systemic carbonic
anhydrase inhibitors, however, chronic therapy with these agents
should be reserved for patients whose glaucoma cannot be controlled
by alternative topical therapy.
Topical
CAI agents are also available for chronic treatment of IOP elevation.
Dorzolamide and brinzolamide are sulfonamide derivatives that
reduce aqueous formation by direct inhibition of carbonic anhydrase
in the ciliary body with fewer systemic side effects than the
oral agents. Dorzolamide and brinzolamide are currently available
for use three times daily, although reduction of IOP is only slightly
greater when compared to twice-daily therapy. Both agents are
equally efficacious and reduce IOP (monotherapy) by 14%–17%,
not as great a reduction as the oral CAIs.
In patients on an adequate oral CAI dose, there is no advantage
to also using a topical CAI.
Common
adverse effects of topical CAIs include bitter taste, blurred
vision, and punctate keratopathy. Ocular surface irritation with
dorzolamide may be a result of the relative greater acidity (lower
pH) when compared with brinzolamide. Eyes with compromised endothelial
cell function may also be at risk for corneal decompensation.
The brinzolamide suspension may cause more blurring than the dorzolamide
solution. Systemic lassitude is a side effect as well.
Alpha
Adrenergic Agonists
Apraclonidine
hydrochloride (para-amino-clonidine)
is an alpha2-adrenergic agonist and a clonidine derivative
that prevents release of norepinephrine at nerve terminals. It
decreases aqueous production as well as episcleral venous pressure
and improves trabecular outflow. However, its true ocular hypotensive
mechanism is not fully understood. When administered pre- and
postoperatively, the drug is effective in diminishing the acute
IOP rise that follows argon laser iridectomy, argon laser trabeculoplasty,
Nd:YAG laser capsulotomy, and cataract
extraction. Apraclonidine hydrochloride may be effective for the
short-term lowering of IOP, but development of topical sensitivity
and tachyphylaxis often limits long-term use.
Brimonidine
tartrate is more specific for the alpha2-adrenergic
receptor and encounters less tachyphylaxis than apraclonidine
in long-term use, and allergenicity such as follicular conjunctivitis
and contact blepharitis-dermatitis is also lower (up to 40% for
apraclonidine, less than 15% for brimonidine 0.2%, and
less than 10% for brimonidine Purite 0.15%). Brimonidine-Purite
0.15% has been shown to have equal efficacy as brimonidine 0.2%
while a lower incidence of all side effects. It is a lower concentration without benzalkonium
chloride as a preservative at neutral pH. Cross sensitivity to brimonidine in patients
with known hypersensitivity to apraclonidine is minimal. Systemic side effects include dry mouth and
lethargy. The use of brimonidine
in infants and young children should be avoided due to
an increased risk of somnolence, hypotension, seizures, apnea,
and serious derangements of neurotransmitters in the CNS
presumably due to an increased CNS penetration of the drug. Brimonidine lowers IOP by decreasing aqueous
production and increasing uveoscleral outflow.
Brimonidine’s peak IOP reduction is approximately 26% (2 hours post-dose). At peak it
is comparable to a nonselective beta blocker and superior to the selective beta blocker betaxolol,
although at trough (12 hours post-dose) the reduction is only
14%–15%, or less effective than the nonselective beta blockers
but comparable to betaxolol during the first 6–12 months
of therapy. Although approved for TID therapy, brimonidine is commonly
used BID, particularly when used as an adjunctive agent.
Hypotensive
Lipids (Prostaglandin Analogues,
Prostamide, Decosanoid)
Hypotensive
lipids are a relatively new class of ocular hypotensive agents.
Currently, four hypotensive lipids have been approved for
clinical use. Two are prostaglandin analogues: travoprost
and latanoprost. Latanoprost has the most extensive clinical experience
and is approved for initial therapy for glaucoma. Two other hypotensive lipids (bimatoprost
and unoprostone isopropyl) are also available. All of these
drugs work by increasing aqueous outflow.
All have a component of pressure-independent outflow (usually
thought of as uveoscleral outflow).
The effect of these drugs on pressure-dependant outflow
(usually thought of as trabecular outflow) is controversial with
some studies demonstrating an effect (bimatoprost and latanoprost)
whereas others show none (latanoprost and travoprost). The exact mechanism by which these drugs
increase outflow is not known, however it has been shown that
latanoprost results in increased spaces between the muscle fascicles
within the ciliary body, presumably increasing aqueous flow and
uveoscleral outflow.
Latanoprost and travoprost are pro-drugs
that penetrate the cornea and become biologically active after
being hydrolyzed by corneal esterase. Both latanoprost and travoprost
reduce IOP by 25%–32%. Bimatoprost
lowers IOP by 27%–33%; while unoprostone is less effective,
lowering IOP 13%–18%. Latanoprost, travoprost, and bimatoprost
are used once a day, usually at night, and are less effective
when used BID than once daily, while unoprostone is used
twice daily. The once-daily
members of this class are the most effective single agents currently
available for reducing IOP. When
combined with an excellent safety profile, the result is that
they represent the new “gold standard” of glaucoma
medical therapy.
An
ocular side effect unique to this class of drugs is the darkening
of the iris and periocular skin as a result of increased numbers
of melanosomes (increased melanin content — melanogenesis)
within the melanocytes. The risk of iris pigmentation is permanent
and correlates with baseline iris pigmentation. Blue irides
may experience increased pigmentation in 10%–20% of eyes
in the initial 18–24 months of therapy, whereas nearly 60%
of eyes that are light brown, blue-green, or two-toned may experience
increased pigmentation over the same time period. The long-term
sequelae of this side effect is unknown,
but there is no data to suggest any additional risk. Other
side effects reported in association with the use of a topical
hypotensive lipid include conjunctival hyperemia, hypertrichosis,
trichiasis, and distichiasis of the eyelashes, hyperpigmentation
of the eyelid skin, and hair growth around the eyes.
These effects appear to be reversible with drug discontinuation. Exacerbations of underlying herpes keratitis,
cystoid macular edema, and uveitis have been reported. The latter
two side effects are more common in eyes with preexisting risk
factors for either macular edema or uveitis. Studies to date have
demonstrated that the incidence of these side effects varies among
these four agents. Hyperemia is more common with bimatoprost and
travoprost, whereas differences between the other side effects,
if present have not been definitively demonstrated. Because
bimatoprost, latanoprost, and travoprost reach peak effectiveness
10–14 hours after administration, bedtime application is
recommended to maximize efficacy and decrease patient symptoms
related to vascular dilatation.
Combined
Medications
Medications that are combined and placed
in a single bottle have the potential benefits of improved efficacy,
convenience, and compliance, as well as reduced cost.
Cosopt, the fixed combination of a beta blocker (timolol
maleate 0.5%) and topical carbonic anhydrase inhibitor (dorzolamide
2%), has demonstrated similar efficacy compared with the two agents
given separately: timolol maleate 0.5% twice daily and Trusopt
2% given three times daily. The advantage of this combined therapy
may be the convenience and lessened confusion of one bottle rather
than two, which may increase the potential for greater compliance.
However, the twice-daily dosing may create greater exposure to
the potential beta-blocker systemic side effects, as beta blockers
alone are generally equally effective when given only once
daily. The ocular side effects are the same as for both drugs
individually. The indications for this combined medication may
be as a substitute for both a beta blocker and topical carbonic
anhydrase inhibitor. If Cosopt is used as monotherapy, a monocular
trial of timolol should be tried first. If timolol is effective
in significantly, but not sufficiently lowering the IOP,
then a monocular trial of dorzolamide should be used with timolol.
It is important to prove that both the timolol component and the
dorzolamide component each have an effect on IOP before choosing
the combined medication except in emergent situations.
iv. Difference
A.
Disease- Will fewer glaucoma patients
1.
Develop glaucoma? - OHTS
2.
Have progressive glaucoma damage? - CIGTS, EMGT
3.
Become symptomatic from their visual loss? - ?
4.
Go blind? - ?
B.
Compliance- Will we ever be able to measure?
C.
Rate of Surgical Intervention- Currently decreasing!
D.
Achievable Target Pressures
1. Magnitude of IOP Reduction
2. Frequency of IOP Reduction
References:
1. Van
Buskirk, EM. Adverse reactions from timolol
administration. Ophthalmology 1980; 87:447-450.
2. Novack GD. Ophthalmic beta-blockers since
timolol. Surv Ophthalmol 1987; 31:307-327.
3. Strahlman E, Tipping R, Vogel R, et al. A
double-masked, randomized 1-year study comparing dorzolamide (Trusopt),
timolol, and betaxolol. Arch Ophthalmol
1995; 113: 1009-1016.
4. Robin
AL. Argon laser trabeculoplasty medical therapy to prevent the
intraocular pressure rise associated with argon laser trabeculoplasty.
Ophthalmic Surg 1991; 22:31-37.
5. Schuman
JS, Horwitz B, Choplin
NT, et al. A 1-year study of
brimonidine twice daily in glaucoma and ocular hypertension: a
controlled, randomized, multicenter clinical trial. Arch
Ophthalmol 1997; 115: 847-852.
6. Camras CB, Alm A, Watson PG, Stjernschantz
J. Latanprost, a prostaglandin analog,
for glaucoma therapy: efficacy and safety after 1 year of treatment
in 198 patients. Latanoprost Study Group. Ophthalmology
1996; 103:1916-1924.
7. Netland PA, Landry T, Sullivan EK, et al. Travoprost compared
with latanoprost and timolol in patients with open-angle glaucoma
or ocular hypertension. Am J Ophthalmol
2001; 132:472-484.
8. Higgingotham EJ, Schuman JS, Goldberg I, et al. One-year,
randomized study comparing bimatoprost and timolol in glaucoma
and ocular hypertension. Arch Ophthalmol 2002; 120:1286-1293.
9. Strohmaier K, Snyder E, DuBiner
H, Adamsons
IA. The efficacy
and safety of the dorzolamide-timolol combination versus the concomitant
administration of its components. Dorzolamide-Timolol Combination
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