Il controllo circadiano della pressione intraoculare: implicazioni farmacologiche N. ORZALESI, P. FOGAGNOLO Università degli Studi di Milano Ospedale San.

Il controllo circadiano della Il controllo circadiano della pressione intraoculare: pressione intraoculare:

implicazioni farmacologicheimplicazioni farmacologiche

N. ORZALESI, P. FOGAGNOLON. ORZALESI, P. FOGAGNOLOUniversità degli Studi di MilanoUniversità degli Studi di Milano

Ospedale San Paolo - MilanoOspedale San Paolo - Milano

Congresso Nazionale di Farmacologia OculareCongresso Nazionale di Farmacologia OculareCatania, 3 ottobre 2006Catania, 3 ottobre 2006

• IOP represents the main risk factor for glaucoma.

• High IOP is linked to the progression of the disease. • The association between IOP increase and morphological and functional damage is confirmed by experimental glaucoma (photocoagulation or steroid induced, etc.).

Bengtsson B, Heijl A. Diurnal IOP fluctuation: not an independent risk factor for glaucomatous visual field loss in high-risk ocular hypertension. Graefes Arch Clin Exp Ophthalmol. 2005 Jun;243(6):513-8.

When separating effects of mean IOP level and mean IOP fluctuation using Cox multiple regression analysis, only IOP level came out as significant (95% CI 1.09-1.38), and IOP fluctuations did not contribute to the risk (95% CI 0.80-1.60). IOP fluctuation depended linearly on IOP level (p<0.0001), i.e. IOP fluctuation was larger in eyes with higher IOP levels. CONCLUSION: IOP fluctuations were not an independent risk factor for the incidence of glaucomatous visual field loss in subjects with ocular hypertension.

15 21 3

IOP

12

??

From Ritch et al “The Glaucomas, 1996”

Day-type curveDay-type curve

Night-type curveNight-type curve

Liu JH. Circadian rhythm of intraocular pressure.Liu JH. Circadian rhythm of intraocular pressure.

J Glaucoma. 1998 Apr;7(2):141-7. J Glaucoma. 1998 Apr;7(2):141-7.

Nocturnal IOP elevation in rabbitsNocturnal IOP elevation in rabbits

IOVS 2006;47:4050-52.IOVS 2006;47:4050-52.

The presence of The presence of Cry1 Cry1 and and Cry2 Cry2 clock genes clock genes

is essential for the generation of circadianis essential for the generation of circadian

rhythm of IOP in mice.rhythm of IOP in mice.

In the clinical practice:In the clinical practice:•IOP is measured only during office hours, though…

•…a difference of few mmHg within treatments is deemed as clinically significant (EMGTS)

•…similar differences during nighttime are ignored

hsphsp

• Possibility of increased IOP in young adults and

in the aging population (Liu, IOVS 1998, IOVS 1999)

• Possibility of arterial hypotension (Graham,Ophthalmology 1995)

• Significantly greater BP drops in NTG (dippers) (Meyer, BJO 1996)

• Different response to hypotensive drugs

• nondippers: BP < 5% overnight• dippers: BP 5-10% • overdippers: BP > 10% overnight(Choi et al, IOVS 2006)

During the nightDuring the night (…glaucoma does not sleep!!!)(…glaucoma does not sleep!!!) ::

24-hour tonometry: a problem

PositionPosition

Tonometer Tonometer (self?!)(self?!)

SleepSleep (frequency of measurements) (frequency of measurements)

PathologyPathology (healthy/glaucoma)(healthy/glaucoma)

SettingSetting (clinical/lab/home) (clinical/lab/home)

AgeAge (young/old) (young/old)

CCT, R, L eyeCCT, R, L eye

148 untreated Jap POAG IOP < 21 mmHg, office hours (Jap ) Peaks at night 20% > 21 mmHg at night Less nocturnal peaks when sitting

Hara T. et al. Increase of peak IOP during sleep in reproduced diurnal changes by posture. Arch Ophthalmol. 2006;124:165-168.

Remember Remember Sampaolesi!Sampaolesi!

Measuring IOP every Measuring IOP every 30-60 minutes for 30-60 minutes for 24 hours, all NTG 24 hours, all NTG

cases have peaks > cases have peaks > 21 mmHg… 21 mmHg…

NTG = POAG !!!NTG = POAG !!!

SampaolesiSampaolesi

Patient hospitalized

IOP assessment at 3am, 6am, 9am, 12am

3pm, 6pm, 9pm, 12pm

10 mt distance walking

1. Tonopen supine position

3. Tonopen sitting position

4. Goldmann applanation tonometry

2. Blood pressure

Sleep 11 pm-7 am

hsphsp

Orzalesi et al, IOVS 2000

0

2

4

6

8

Midnight

Noon

3 AM

6 AM

9 AM3 PM

6 PM

9 PM

Healthy young

Healthy aged hsphsp

Least-square cos Least-square cos fitting techniquefitting technique Supine (night)Supine (night) Sitting (day)Sitting (day)

0

2

4

6

8Midnight

Noon

3 AM

6 AM

9 AM3 PM

6 PM

9 PM

POAG/OHT

Healthy aged

hsphsp

Orzalesi et al, IOVS 2000

LIU et al, IOVS 2003LIU et al, IOVS 2003

• PARRISH (2003). Latanoprost > bimatoprost (n.s.)

• KONSTAS AG. (2005). Latanoprost < Bimatoprost (0.7 mmHg)

• NOECKER RS (2003). Latanoprost < Bimatoprost (1.5 mmHg)

• DUBINER (2001). Latanoprost < Bimatoprost (decrease of 4.5-8 vs 6-9 mmHg)

• EMGTS (2002). 1 mmHg less = 10% progression less

hsphspFogagnolo P, Rossetti L, Mazzolani F, Orzalesi N.Fogagnolo P, Rossetti L, Mazzolani F, Orzalesi N. Circadian variations in CCT Circadian variations in CCT

and IOP inand IOP in patients with glaucoma. Br patients with glaucoma. Br J Ophthalmol. 2006 Jan;90(1):24-8. J Ophthalmol. 2006 Jan;90(1):24-8.

Max difference: 2.3 mmHg (ns)Max difference: 2.3 mmHg (ns)

n=30n=30Latanoprost x 1Latanoprost x 1Timolol 0.5% x 2Timolol 0.5% x 2

hsphspFogagnolo P, Rossetti L, Mazzolani F, Orzalesi N.Fogagnolo P, Rossetti L, Mazzolani F, Orzalesi N. Circadian variations in CCT Circadian variations in CCT

and IOP inand IOP in patients with glaucoma. Br patients with glaucoma. Br J Ophthalmol. 2006 Jan;90(1):24-8. J Ophthalmol. 2006 Jan;90(1):24-8.

Fluctuations > 5 mmHg in Fluctuations > 5 mmHg in 60%60%

P-value from test of superiorityP-value from test of superiority NOT INFERIORNOT INFERIOR

Konstas Konstas et alet al, Ophthalmology , Ophthalmology 20062006

A well-functioning trabeculectomyprovides a statistically lower

mean, peak, and range of IOP for the 24-hour day than maximum

tolerated medical therapy in advanced glaucoma patients (P <

0,0001)

hsphsp

IOVS 2006;47:2917-2923IOVS 2006;47:2917-2923

Conclusions

• Glaucoma is a “24-hour” disease• Nocturnal IOP measurement difficult but

needed in special cases • Supine/sitting positions• Progression with good office-hour IOP • NTG• Arterial hypotension, dippers (holter)• Associated clinical signs• Adequate medical/surgical management

Università degli Studi di Milano Dipartimento di Medicina, Chirurgia e Odontoiatria

Clinica Oculistica, Ospedale San Paolo