Il controllo circadiano della pressione intraoculare: implicazioni farmacologiche N. ORZALESI, P. FOGAGNOLO Università degli Studi di Milano Ospedale San Paolo - Milano Congresso Nazionale di Farmacologia Oculare Catania, 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 Jun;243(6): 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 ), and IOP fluctuations did not contribute to the risk (95% CI ). 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.

15213 IOP 12 ? From Ritch et al The Glaucomas, 1996 Day-type curve Night-type curve

Liu JH. Circadian rhythm of intraocular pressure. J Glaucoma Apr;7(2): Nocturnal IOP elevation in rabbits Nocturnal IOP elevation in rabbits IOVS 2006;47: IOVS 2006;47: The presence of Cry1 and Cry2 clock genes The presence of Cry1 and Cry2 clock genes is essential for the generation of circadian rhythm of IOP in mice.

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 hsp

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 night (…glaucoma does not sleep!!!): (…glaucoma does not sleep!!!) :

24-hour tonometry: a problem Position Tonometer (self?!) Sleep (frequency of measurements) Pathology (healthy/glaucoma) Setting (clinical/lab/home) Age (young/old) CCT, 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: RememberSampaolesi!

Measuring IOP every minutes for 24 hours, all NTG cases have peaks > 21 mmHg… NTG = POAG !!! Sampaolesi

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 hsp Orzalesi et al, IOVS 2000

Midnight Noon 3 AM 6 AM 9 AM 3 PM 6 PM 9 PM Healthy young Healthy aged hsp Least-square cos fitting technique Supine (night) Supine (night) Sitting (day) Sitting (day)

Midnight Noon 3 AM 6 AM 9 AM 3 PM 6 PM 9 PM POAG/OHT Healthy aged hsp Orzalesi et al, IOVS 2000 LIU 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 vs 6-9 mmHg) EMGTS (2002). 1 mmHg less = 10% progression less

hsp Fogagnolo P, Rossetti L, Mazzolani F, Orzalesi N. Circadian variations in CCT and IOP in patients with glaucoma. Br J Ophthalmol Jan;90(1):24-8. Max difference: 2.3 mmHg (ns) n=30 Latanoprost x 1 Timolol 0.5% x 2

hsp Fogagnolo P, Rossetti L, Mazzolani F, Orzalesi N. Circadian variations in CCT and IOP in patients with glaucoma. Br J Ophthalmol Jan;90(1):24-8. Fluctuations > 5 mmHg in 60%

P-value from test of superiority NOT INFERIOR

Konstas et al, Ophthalmology 2006 A well-functioning trabeculectomy provides 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) hsp

IOVS 2006;47:

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