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Glaucoma Therapy: The
“Art” of Medical
Management
J. James
Thimons,O.D.,FAAO
Medical Director,
Ophthalmic Consultants
of CT
The Role of IOP
Management in
Glaucoma
PEAK Effect with Evening Dose
Once daily drug:
•
Peak effect (8
mm Hg) at 12-14
hrs post dose
•
Trough effect (2
mm Hg) at 22-24
hrs
post dose
9
IOP Reduction (mm Hg)
8
7
6
5
4
Trough
3
2
1
Office hours
0
0
200
2:00
400
4:00
600
6:00
800
8:00
am
am
am
am
1000
1800
2000
2200
10:00 1200
12:00 1400
2:00 1600
4:00
6:00
8:00
10:00 2400
12:00
am
pm
pm
Time of Day (hr)
Time of Day (hr)
pm
pm
pm
pm
am
Dose
Courtesy of David B. Yan, M.D., F.R.C.S.(C)
3
IOP Variability
Highest (peak) IOP may commonly occur
outside of usual clinic office hours1,2
 In spite of achieving target IOP during
office hours patients may experience:

– “damaging”/above target IOPs at other times
of the day
– disease progression

Are we missing IOP spikes, peak,
damaging IOP, IOPs at other times of
day3?
1. Nakakura S, et al. J Glaucoma 2007; 16(2): 201-204.
2. Mosaed S, et al. Am J Ophthalmol. 2005; 139(2): 320–324.
3. Hughes E, et al. J of Glaucoma 2003; 12: 232-236.
4
Peak IOP Outside Office Hours
PURPOSE: To determine the relationship between office
IOP and peak IOP
METHODS (Study One)1:
 42 patients with OAG
 Treated with 3 different IOP lowering eye drops
 24 hr IOP values obtained in sitting position with
Goldmann applanation tomography at 3 hr intervals
METHODS (Study Two)2:
 103 patients with OAG (including 35 untreated)
 24 hr IOP values obtained at 2 hr intervals using a
pneumatometer, in sitting and supine positions during
the diurnal/wake period and in the supine position
during the nocturnal/sleep period
1.Nakakura S, et al. J Glaucoma 2007; 16(2): 201-204.
2.Mosaed S, et al. Am J Ophthalmol. 2005; 139: 320-324.
5
Peak IOP Outside Office
Hours
Study 1
Study 2
Times at which maximum and
minimum IOP occurred in a 24hr period1:
Number of eyes
40
•
30
10
8
28
20
10
0
19
23
20
3am6am
67% of peak
IOP occurs
outside office
hours2
10
12
9am12pm
3pm6pm
9pm12am
Time of minimum IOP in 24-hour
Time of maximum IOP in 24-hour
1.Nakakura S, et al. J Glaucoma 2007; 16(2): 201-204.
2.Mosaed S, et al. Am J Ophthalmol. 2005; 139: 320-324.
6
IOP is Higher at Night
Habitual IOP of glaucomatous eyes
Habitual IOP of healthy eyes
n=24
Clock Time
IOP (mm Hg)
Diurnal
Sitting
3:30 PM
5:30 PM
7:30 PM
9:30 PM
11:30 PM
1:30 AM
3:30 AM
5:30 AM
7:30 AM
9:30 AM
11:30 AM
1:30 PM
IOP (mm
Hg)
26
25
24
23
22
21
20
19
18
17
16
15
14
Diurnal Sitting Nocturn
al
Supine
Diurnal Sitting Noctur
nal
Supine
26
25
24
23
22
21
20
19
18
17
16
15
14
Diurnal
Sitting
n=24
*Error bars = SEM
3:30 AM
5:30 AM
7:30 AM
9:30 AM
11:30 AM
1:30 PM

Higher nocturnal supine IOP than diurnal sitting IOP
(healthy and OAG)
Supine IOP higher than sitting IOP, regardless of time of
day
3:30 PM
5:30 PM
7:30 PM
9:30 PM
11:30 PM
1:30 AM

Clock Time
Liu JH et al. Invest Ophthalmol Vis Sci. 2003; 44: 1586-1590.
7
Diurnal Fluctuations in IOP:
Independent Risk Factor?
PURPOSE: To study the risk associated with diurnal IOP variations in
patients with OAG
METHODS:
• 64 patients with OAG and IOP below 25 mm Hg (over 5 year
follow-up)
• Patients successfully performed tonometry with a self-tonometer
5 times a day for 5 days
• Baseline status and time to progression of visual field loss
identified from clinical charts
• Level and variability of diurnal IOP characterized and risk of
progression analyzed using a nonparametric time-to-event model
Asrani S, et al. J Glaucoma 2000; 9: 134-142.
8
Relative risk of disease
progression within 5 years
Diurnal Fluctuations Correlate
with Visual Field Progression
6
5
4
5.76
3
2
1
0
1.0
Diurnal IOP range
Diurnal IOP range
3.1 mm Hg
5.4 mm Hg
Hazard ratio between higher quartile and lower quartile for
“Range in Home IOP” was 5.7
Asrani S, et al. J Glaucoma 2000; 9: 134-142.
9
Patients on More Than
One IOP-Lowering Medication
2 Medications
24.4%
3 Medications
5.6%
0.2%
4 Medications
69.8%
1 Medication
Source: Verispan’s PDDA, MAT Nov 2006.
Pathways to lower Intraocular
Pressure
 Inflow
–Alpha 2agonists
–B1 blockers
–CAI
 Outflow
–Alpha 2–
agonists
–Cholinergics
–Prostaglandins
/ Prostamindes
Beta-blockers

30 year history of successfully lowering
IOP

Reduces aqueous humor formation

Adrenergic agonists

Lowers IOP 22-28%

Ocularly well tolerated
Beta Blockers




Beta receptor in the ciliary body epithelium
Beta 1 receptors >> Beta 2 receptors in the
eye
Beta receptors stimulate productions of
aqueous.
Beta blockers suppress aqueous production
Beta-blockers
 Timolol
maleate – Timoptic,
Timoptic XE (1/2, 1/4 %)
 Carteolol – Ocupress 1%
(Intrinsic sympathomimetic
activity)
 Levobunolol – Betagan ½%
 Timolol hemihydrate – Betimol
¼, ½%
 Istalol ¼,1/2% - QD dosing
indication
Systemic
 Bradycardia
 Congestive
heart failure
 Exacerbation of heart block
 Bronchospasm
 Mood change
 Impotence
 Lipid profile
Contraindications
 Asthma
 Severs
COPD
 CHF
 Heart
block
 Myasthenia gravis
 Diabetes
Lama study (AJO 11/02)
 Conclusions:
– ...identifies no scientific studies
supporting the development of
worsening claudication, depression,
hypoglycemia,sexual dysfunction or
impaired neuromuscular transmission
– Recommends careful medical history
and checking pulse rate and rhythm
 So?
Timolol
Equally effective in
AA’s and Whites
 IOP decrease 3060 min
 Long term drift

– 47% decrease at 1
wk
– 25% at 1 yr
Carteolol (ocupress)


Intrinsic
sympathomimetic
activity
Less likely to
increase systemic
lipid profile
Ocular Side Effects
 Punctate
 Corneal
DESx)
keratopathy
anesthesia ( Watch for
 Blepharoconjunctititis
Brimonidine 0.1% Alphagan
alpha-2







Decrease aqueous production
Also increase uveoscleral outflow
(small amount)
Not as effective as timolol but
close
May be neuroprotective
More effective than or
dorzolamide?
Can cause mild mydriasis
Comes in 0.1%, 0.15%, 0.2%
Brimonidine:
Dual Mechanism of IOP Lowering
 Enhances
uveoscleral
outflow
 Suppresses
aqueous
humor
production
(inflow)
Toris et al. 1995 and 1999.
Brimonidine Formulation
Comparison
ALPHAGAN® P
Concentratio
n of
Brimonidine
pH
Preservative
Viscosity
agent
Electrolytes
ALPHAGAN®
0.1%
0.15%
0.2%
7.7
7.2
6.3-6.5
PURITE®
BAK
Carboxymethylcellul
ose
Polyvinyl alcohol
Potassium chloride,
calcium chloride
dihydrate,
magnesium chloride
–
Side effects
10-30% dry mouth
 10% allergy rate
 Avoid with MAO
inhibitors
 Alphagan P 0.1%

– Better tolerated
Mean IOP at Peak (10 am)
Mean IOP (mm Hg)
30
28
Brimonidine-PURITE® 0.15% (N = 372)
26
Brimonidine 0.2%* (N = 376)
24
22
20
18
16
0
2
4
6
8
10
12
Months of treatment
*Original ALPHAGAN®
Katz. J Glaucoma. 2002.
Mean IOP at Trough (8 am)
30
Brimonidine-PURITE® 0.15% (N = 372)
Mean IOP (mm Hg)
28
Brimonidine 0.2%* (N = 376)
26
24
22
20
18
16
0
2
4
6
8
Months of treatment
10
12
*Original ALPHAGAN®
Katz. J Glaucoma. 2002.
Alpha Agonists-side effects

Ocular– dermatitis,
– lid retraction,
– conjunctival
blanching,
– allergic reactions

Systemic
– dry mouth,
– dry eye
– lethargy,
– apnea in
children,
– hypotension
Contraindication
 Children
 MAO
inhibitors
Nocturnal Efficacy:
Brimonidine Monotherapy
PURPOSE: To investigate the effect of brimonidine monotherapy on
IOP during the nocturnal/sleep period
DESIGN: Prospective, open-label study
METHODS:
• Baseline data of 24 hr IOP in untreated patients collected in a
sleep laboratory
• Measurements of IOP taken using a pneumatonometer every 2 hrs
in sitting and supine positions during the 16 hr diurnal period and in
supine position during the 8 hr nocturnal period
• Patients treated afterward with brimonidine 0.1% 3 times per day
for 4 weeks, and 24 hr IOP data were collected under the same
laboratory conditions
Liu JH, et al. Ophthalmology 2010; 117: 2075–2079.
29
NOCTURNAL/SLE
DIURNAL/WAK
EP
brimonidin E
brimonidin
e
DIURNAL/WAK
E
brimonidin
e
1.30PM
7.30AM
5.30AM
3.30AM
1.30AM
11.30PM
9.30PM
7.30PM
11.30AM
Baseline
Brimonidine
Error bars = SEM
N = 15
9.30AM
e
5.30PM
28
26
24
22
20
18
16
14
12
10
8
6
4
2
0
3.30PM
Habitual IOP (mmHg)
Brimonidine Efficacy
During Nocturnal Period
Clock Time
Liu JH, et al. Ophthalmology 2010; 117: 2075–2079.
30
Glaucoma & Pregnancy
 BJO
2009; JD Ho:
 244 pregnant women treated for
glaucoma analyzed for birth weight
 1,952 age matched controls
 No significant difference between
women on BB’s vs: no Tx
 Herndon, L: D/C Brimonodine several
weeks before d/t risk of apnea
COMBIGAN™
(Brimonidine Tartrate/Timolol
Maleate Ophthalmic Solution)
0.2%/0.5%
Diurnal Mean IOP at Month 12
Dose all treatments
Dose brimonidine
Mean IOP (mm Hg)
20
16
*
**
12
*
**
*
**
*
Brimonidine (n = 382)***
Timolol (n = 392)***
Fixed brimonidine/timolol (n = 385)
8
4
*P < .001 vs timolol
**P < .001 vs brimonidine
0
8 AM
10 AM
3 PM
5 PM
***Brimonidine and timolol monotherapies are approved for first line therapy.
Statistical significance does not necessarily correlate to clinical significance.
Sherwood et al. Arch Ophthalmol. 2006.
Treatment-Related Adverse Events
40
Fixed Brimonidine/Timolol BID (n = 385)
Percentage of patients
35
Brimonidine 0.2% TID (n = 382)***
Timolol 0.5% BID (n = 392)***
30
25
20
15
* P ≤ .03 vs brimonidine 0.2% TID
** P ≤ .02 vs timolol 0.5% BID
*
**
10
*
*
*
**
*
**
5
*
0
Conjunctival
hyperemia
Ocular
stinging
Eye
pruritus
Conjunctival
Allergic
follicles
conjunctivitis
Oral
dryness
***Brimonidine and timolol monotherapies are approved for first line therapy.
Sherwood et al. Arch Ophthalmol. 2006.
COMBIGAN™ in Adjunctive Therapy
With a PGA: Mean IOP
Mean IOP (mm Hg)
24
21.9
Added to a PGA baseline
-6.9
mm Hg
(29%)
20
16
15.2
*
15.3
*
12
COMBIGAN™(brimonidine tartrate/timolol maleate
8
ophthalmic solution) 0.2%/0.5% + PGA (n = 37)
4
*P < .0001 vs baseline
0
0
1
2
3
Month
1Nixon
and Hollander. 2AAO, 2007. Data on file, Allergan, Inc.
COMBIGAN™ and




®
Cosopt
Randomized, investigator-masked, 3-month,
parallel comparison
Pooled data from 2 studies at 10 sites with
identical protocols (Canada)
Patients with OAG/OHT requiring additional IOP
lowering
Two subgroups
– Monotherapy: COMBIGAN™(brimonidine tartrate/timolol
maleate ophthalmic solution) 0.2%/0.5% (n = 54) and Cosopt®
(dorzolamide hydrochloride-timolol maleate ophthalmic solution)
(n = 47)
– Adjunctive: COMBIGAN™ added to PGA (n = 37) and
Cosopt® added to PGA (n = 42)

IOP 2 hours after morning dose

Visits at baseline, 1 month, and 3 months
PGA = prostaglandin analogue
1Nixon
and Hollander. AAO. 2007; 2Data on file, Allergan, Inc.
COMBIGAN™ and Cosopt® as
Monotherapy: Mean IOP
Mean IOP (mm Hg)
24
23.6
20 23.0
17.2
16.3
*
16
15.8
15.6
12
*P = 0.04 (mean change from baseline)
Cosopt® (dorzolamide hydrochloride-timolol maleate
ophthalmic solution) (n = 47)
8
4
COMBIGAN™ (brimonidine tartrate/timolol maleate
ophthalmic solution) 0.2%/0.5% (n = 54)
0
0
1
2
3
Month

Mean IOP reductions from baseline at month 3 were 7.7 mm Hg
with COMBIGAN™ and 6.7 mm Hg with Cosopt® (P = .040)
1Nixon
and Hollander. AAO. 2007; 2Data on file, Allergan, Inc.
Percentage of patients with
rating of moderate or severe
COMBIGAN™ and Cosopt ®
Tolerability and Comfort
COMBIGAN™(brimonidine tartrate/timolol
40%
maleate ophthalmic solution) 0.2%/0.5% (n = 85)
Cosopt® (dorzolamide hydrochloride-timolol
30%
maleate ophthalmic solution) (n = 86)
20%
10%
0%
Stinging
Burning
Unusual taste
P = .0001
P = .0149
P = .0047
1Nixon
and Hollander. 2AAO, 2007. Data on file, Allergan, Inc.
Carbonic Anhydrase Inhibitors
4 types of isoenzymes
 I erythrocytes and corneal epithelium
 II non pigmented ciliary body
epithelium , iris retinas lens
 III skeletal muscle
 IV kidney
Carbonic Anhydrase Inhibitors
 Aqueous
humor formation depends
on secretion of bicarbonate from the
ciliary processes when bicarbonate is
formed, it tied with sodium and
water follows
 Similar process in CSF production
and in kidney
CAI
 Dorzolamide
 Brinzolamide
 Acetazolamide
500mg sequels
 Methazolamide
2%
1%
125, 250,
25, 50 mg
Systemic Side Effects Oral Use





Malaise and fatigue
Weight loss
Anorexia
Loss of libido
Depression
Sulfa allergies
 Sickle cell





Marked kidney/liver
Low potassium
Low sodium level
Transient myopia
– Swelling of CB

Pregnancy Category C
Paresthesia
Tinitus
Nausea
Taste alterations

Metabolic acidosis




Contraindications to Oral Therapy
 Sulfa
allergies
 Sickle cell
 Marked kidney/liver
 Low potassium
 Low sodium level
 Pregnancy Category C
 Metabolic acidosis
CAIs make wonderful partners
 Feldman,
et al 2006 –
 1.5-1.8 mm lower IOP as compared
to brimonidine 0.15% when added to
travaprost
 This significance was present at all
time points
 BID dosing
Companion study #2
 When
compared to brimonidine 2%
adding them to Travaprost...
 IOP lowered by 13% w/ brimonidine
 IOP lowered by 23% w/ brinzolamide
Brinzolamide as an
Adjunct to Latanoprost
PURPOSE: To evaluate the IOP lowering effect of brinzolamide (1.0%)
as an adjunctive therapy to latanoprost (0.005%) in patients with
open-angle glaucoma or ocular hypertension
METHODS:
• 14 patients with open-angle glaucoma or ocular hypertension who
had been using latanoprost for more than 6 months were initiated
on adjunctive brinzolamide therapy
• IOP values at 1, 2 and 3 months compared with baseline (beginning
of adjunctive therapy)
• Incidence of adverse events examined
Shoji N, et al. Cur Med Res Opin 2005; 21: 503-507.
46
Brinzolamide as an
Adjunct to Latanoprost

Adjunctive therapy lowered IOP by an additional
5.2 mm Hg after 3 months
30
25
IOP (mmHg)
**
20
15
**
21.1 ± 4.8
16.9 ± 4.5
10
16.6 ± 4.0
**
15.9 ± 3.1
5
0
** P < 0.01 (Wilcoxon signed ranked test)
Baseline
1 Month
2 Months 3 Months
Shoji N, et al. Cur Med Res Opin 2005; 21: 503-507.
47
DIURNAL/WAKE
DIURNAL/WAKE
NOCTURNAL/SLEEP
1.30PM
11.30AM
9.30AM
5.30AM
3.30AM
1.30AM
11.30PM
9.30PM
7.30PM
7.30AM
latanoprost
latanoprost + brinzolamide
latanoprost + timolol
N=26
Error bars = SEM
5.30PM
26
24
22
20
18
16
14
12
10
8
6
4
2
0
3.30PM
Habitual IOP (mm Hg)
Brinzolamide or Timolol: Adjunct to
Latanoprost in an Open-Label Study
Clock Time
Liu JH, et al. Ophthalmology 2009; 116(3): 449-54.
48
Prostaglandins
/Prostamides
 Uveal
seleral outflow
 Affects many properties with the
 1955-Ambache described irin which
medicated ocular response to
inflammation
 Naturally synthesized by trabecular
endothelial cells/ciliary muscle cells
 May have only minor inflammatory
 Regulatory effects
Prostaglandins
/Prostamides
 Different
receptor sites DP,EP,IP
 Prostaglandins E and F most effective
in lowering IOP
 They seem to facilitate aqueous
outflow via the uvealscleral pathway
 Latanoprost
0.005%
Xalatan
– Prostaglandin F 2a analogue
– Prodrug
 Travoprost
0.004%
Travatan
– Prostaglandin F 2a analogue
– Prodrug
 Brimatoprost
0.03%
Lumigan
– Synthetic prostamide analog
– Not a prodrug
 Tafluprost
Zioptan
- Non-preserved unit dose
XLT Study – Parrish, Palmberg, et al.
(AJO, May 2003, Vol. 135, No.5)
 Multicenter
study to compare IOP
lowering efficacy of Bimatoprost vs
Latanoprost vs Travaprost
 Also compared safety profiles of the
3 drugs
 Conclusions: All 3 drugs were
comparable in their ability to lower
IOP at all time periods.
– Latanoprost exhibited greater ocular
tolerability
PGAs: IOP-Lowering Effects
PURPOSE: To compare the IOP-lowering effect and
safety of latanoprost, bimatoprost, and travoprost
METHODS:
 12-week, randomized, parallel-group study
conducted at 45
US sites
 Previously treated patients with OAG or OH and an
IOP ≥ 23 mm Hg in one or both eyes after washout
 Received either latanoprost (0.005%), bimatoprost
(0.03%), or travoprost (0.004%) once daily in the
evening
 At baseline and after 6 and 12 weeks of therapy,
masked evaluators measured IOP in triplicate at 8:00
AM, noon, 4:00 PM, and 8:00 PM. The primary
efficacy outcome measure was change between
baseline and week 12 in the 8:00 AM IOP
Parrish et al., Am J Ophthalmol. 2003; 135(5): 688-703.
57
Primary Outcome
8 A.M. IOP reduction (mm Hg) from baseline
to week 12:
 Latanoprost: 8.6 ± 3.7
 Travoprost: 7.9 ± 3.4
 Bimatoprost: 8.7 ± 3.8
Parrish et al., Am J Ophthalmol. 2003; 135(5): 688-703.
58
Adverse Effects
Latanoprost
(n=136)
Bimatoprost
(n=137)
Travoprost
(n=138)
n
No. events
n
No. events
n
No.
events
hyperemia
64
71
94
110
80
90
Eye irritation
9
10
15
16
6
6
Vision blurred
0
0
5
5
2
2
Eye pain
2
2
1
1
4
4
Growth of
lashes
0
0
4
4
1
1
Skin
discoloration
2
2
4
4
4
4
Dry eye
2
2
3
3
2
2
Visual acuity
2
reduced
Parrish et al., Am J Ophthalmol. 2003; 135(5): 688-703.
2
2
3
3
3
Pruritus
0
0
0
3
3
0
59
Look at their failure rate:
 Percent
of pxs who didn’t reach their
target IOP
– Latanoprost – 14%
– Bimatoprost- 6%
– Travaprost – 8%
Adverse Effects

Changes to pigmented tissues
– Iris pigmentation starts at pupil and spreads
concentrically
– Long thick lashes
– Periobital pigment changes
Caution with macular edema, iris/uveitis,
keratitis
 Caution with renal/hepatic dysfunction
 Pregnancy category C

Prostaglandin Side Effects

Iris pigmentation
– Is it reversible?
– Is it pre-cancerous?
Xalatan – 6.7% @ 6mths
16% @ 12mths
 Travatan – 3% @ 12 mths
 Lumigan – 1.9% @ 12mths

Other Prostaglandin side effects
CME
 Uveitis
 Reactivation of HSK
 Hypertrichosis
 Periorbital skin darkening


One must take into consideration the
benefits of low IOP with the risks of the
side effects
Travatan
(Travoprost 0.004%)
 Lowers
IOP 30-33%
 Contraindicated in pregnant woman
 Excellent responder rated in black
pts
 No CME
Responder rates in all patients
 56.3%
for IOP 17 mm Hg for
travatan
 49% for xalatan
 39% for timolol
PGAs: Effects on Circadian
IOP
PURPOSE: To compare 24 hr reduction in IOP with latanoprost,
travoprost and bimatoprost in patients with OAG and ocular
hypertension (OH)
DESIGN: Randomized, double-masked, crossover study
PARTICIPANTS: 24 OAG and 20 OH patients
METHODS:
• Patients treated with randomized cross-over sequence of
latanoprost, travoprost and bimatoprost for 1 month each, with 30
day washout in between
• 24 hr tonometric curves were recorded at baseline (prior to each
treatment) and after each treatment period in seated and supine
positions
• Baseline and post-treatment IOP measured at 3:00, 6:00, 9:00 AM
and noon and 3:00, 6:00, 9:00 PM and midnight
Orzalesi N, et al. Ophthalmology 2006; 113: 239-246.
66
Bimatoprost and Travoprost:
12-Week Study
Mean IOP at Week 12
Mean IOP (mm Hg)
24
20
16
12
Travoprost (n = 138)
Bimatoprost (n = 136)
8
4
0
Baseline mean IOP comparable between groups
Travoprost: 25.5, 23.8, 22.8, 22.0 (8 AM, 12 PM, 4 PM, 8 PM; mm Hg)
Bimatoprost: 25.7, 23.8, 22.8, 22.3 (8 AM, 12 PM, 4 PM, 8 PM; mm Hg)
8 AM
12 PM
4 PM
Time of Day
8 PM
Parrish et al. Am J Ophthalmol. 2003.
% of peak IOP reduction
(@ 12 hr)
Travoprost Appears
Consistent Peak to Trough
100%
95%
90%
85%
80%
75%
70%
65%
60%
Travoprost
Latanoprost
Bimatoprost
9:00
am
3:00
pm
Time
12 hours post dose = peak IOP reduction
9:00
pm
Peak-to-trough
loss:
• Bimatoprost =
38%
• Latanoprost =
26%
• Travoprost =
14%
24 hours post dose = trough IOP reduction
Orzalesi N, et al. Ophthalmology 2006; 113: 239-246.
68
Effect of Travoprost on Diurnal
and Nocturnal IOP
PURPOSE: To assess the diurnal and nocturnal persistence of IOP
reduction after omission of up to two doses of once-daily topical
travoprost in patients with OAG or OH
DESIGN AND METHODS:
• Prospective, open-label study
• 20 patients underwent 24 hr IOP monitoring at baseline prior to
treatment and after 4 weeks or more of travoprost treatment
Sit AJ, et al. Am J Ophthalmol. 2006; 141(6): 1131-1133.
69
28
DIURNAL/WAKE
NOCTURNAL/SLE
EP
DIURNAL/WAKE
26
24
22
20
18
16
Measured in the usual
“habitual position” of the
patients during those time
periods
– Diurnal period – sitting
– Nocturnal period –
supine
1:30 PM
11:30 AM
5:30 AM
3:30 AM
1:30 AM
9:30 PM
11:30 PM
7:30 PM
5:30 PM
3:30 PM
9:30 AM
Error bars = SEM
14
7:30 AM
Habitual IOP (mmHg)
Effect of Travoprost on Diurnal
and Nocturnal IOP
Clock Time
Baseline
“On Treatment”
Sit AJ, et al. Am J Ophthalmol. 2006; 141(6): 1131-1133.
70
Bimatoprost and Travoprost:
6-Month Safety Results


Both medications were well tolerated
Most common adverse event: ocular redness
– 16 patients (20.8%) in the bimatoprost group and 12
patients (14.8%) in the travoprost group (P = .326)


Ocular itching reported for 7.4% of travoprost
patients and 2.3% of bimatoprost patients (P =
.278)
Treatment-related adverse events leading to
patient discontinuations
– 8 patients in the travoprost group exited early: 4 for
lack of efficacy, 2 for ocular redness and lid erythema,
1 for ocular dryness and itching, and 1 for allergic
symptoms
– 2 patients in the bimatoprost group exited early: 1 for
blurry vision
and 1 for ocular redness and lid erythema
Cantor et al. Br J Ophthalmol. In press.
Bimatoprost
(Lumigan 0.03%)
 Lowers
IOP 30-33%
 Favorable lowering of IOP with
lumigan vs xalatan
 Side effects
 15-45% hyperemia
 15% ocular pruritis
 45% Eyelash growth
 CME rare
Percentage of Patients Reaching Target
IOP at 10 AM, Month 12
Bimatoprost and Timolol
12-Month Study
*
90
Target Pressures at Month 12
80
60
69
*
*
47
40
69
61
58
*P < .010 vs timolol
50
*
77
*
Timolol BID (n = 241)
Bimatoprost QD (n = 474)
70
47
37
*
31
30
26
*
21
*
20
10
85
*7
2
12
16
9
5
0
≤ 12
≤ 13
≤ 14
≤ 15 ≤ 16 ≤ 17
Target IOP (mm Hg)
≤ 18
≤ 19
≤ 20
Higginbotham et al. Arch Ophthalmol. 2002.
Additive IOP-Lowering Effect
Additional Intraocular Pressure Lowering (mm Hg)
Alpha Agonist
0
-0.5
-1
-1.5
-2
-2.5
-3
-3.5
-4
-4.5
N=23
Beta-blocker
TCAI
N=25
N=25
-2
-2.5
-3.9
O’Connor DJ, et al. Am J Ophthalmol. 2002; 133(6): 836-7.
74
Nocturnal Efficacy:
Timolol vs. Latanoprost
PURPOSE: To compare the nocturnal effects of oncedaily timolol and latanoprost on IOP
DESIGN: Prospective, open-label, crossover study
METHODS:
 18 patients received topical treatments with timolol
(0.5%), latanoprost (0.005%), and no IOP-lowering
medication, for at least 4 weeks
 At the end of each treatment period, the patient was
housed in a sleep laboratory for 24 hrs and IOP was
measured every 2 hrs using a pneumotonometer
Liu JH, et al. Am J Ophthalmol. 2004; 138: 389-395.
75
Supine
Sitting
No treatment
N=18
Error bars = SEM
1.30PM
9.30AM
7.30AM
11.30AM
Clock Time
5.30AM
3.30AM
1.30AM
11.30PM
9.30PM
Timolol
7.30PM
5.30PM
28
26
24
22
20
18
16
14
12
10
8
6
4
2
0
Sitting
3.30PM
Habitual IOP (mm Hg)
Timolol: Nocturnal IOP
Liu JH, et al. Am J Ophthalmol. 2004; 138: 389-395.
76
Can There be Too much
Prostaglandin?





Alverado, J; Oct 2009 UCSF
Laboratory Analysis of Effect of SLT on Trabecular Outflow
SCE’s were exposed to six different IOP lowering drugs and
SLT/TME’s
The junction assembly/dissassembly was monitored by
confocal flourescent time lapse microscopy
Latanaprost, bimatoprost & Travaprost shared a common
mechanism of action with SLT
– Widening of the paracellular pathways
– Induction of intercellular junction dissassembly
– Decreased transepithelial flow across SCE’s


Clinical impact: TME’s play a critical role in regulating SCE’s
Non-Competing IOP agents may improve IOP spot SLT
Cholinergics
Cholinergics are bound by melanin and
may need a high concentration to affect
darker irides
 Anticholinesterases have similar effects to
cholinergics
 These medications facilitate outflow via
the trabecular meshwork
 Echothiophate iodine may prolong the
effects of succinylcholine

Cholinergics
 Generally
contraindicated in
synechial angle closure, neovascular
glaucoma
 Uveitic glaucoma, retinal detachment
of peripheral breaks
 Pilocarpine pregnancy category C
 Anticholinesterases contraindicated
in pregnant women
Cholingegics

Cholinergics
– Pilocarpine HCL
– Pilocarpine nitrated
– Pilocarpine ocuserts

Cholinesterase Inhibit
– Echothiophate
0.125%
– Demecarium

0.25%-10%
1%, 2%, 4%
20%, 40%
0.03%, 0.06%
0.125%, 0.25%
Mixed
– Carbachol
3.%
0.75%,1.5%, 2.25%,
Pilocarpine
 Low
concentrations deepen chamber
 High concentrations may cause
pupillary block
 Increase axial length of the lens,
shallows AC
 Induce myopia
 Decrease uveosclearl outflow
Pilocarpine
Cilary block (malignant) glaucoma is
worsened with miotis
 Increase permeability of blood aqueous
barrier
 Increase post-op inflammation
 Need higher concentration in pigmented
irides
 Max effect occurs in 2 hours last 8 hours;
12-15 hr still 14-15% reduction in IOP

Pilo toxicity-Wet
Salivation
 Lacrimation
 Sweating
 Vomiting/diarrhea
 Pulmonary edema/death
 Makes Parkinsons disease worse

– (more acetylcholine than dopamine)

10 ml 1% pilocarpine, 100mg is
dangerous
Ocular Side Effects
Conj
hyperemia/follicle
 Miosis
 Brow aches
 Epitheliopathy
 Myopia
 Shallowing of the
AC
 Iritis

Pupillary cysts
Lens opacities
Retinal detachment
Pemphigoid type
reaction
Systemic side effects
 Diarrhea
 Bradycardia
 Tearing
 Salivation
 Nausea
 Diaphoresis
 Cramps