IGerman journal of Gennan J Ophthalmol (1992) I: 16- 18 Ophthal­ mology

Sp r in~.V~ rl aa 1992

Systemic absorption of ocular cycIopentolate in children *

4 Kimmo Lahdes l , Risto Huupponen 2, Timo Kaila 2, Timo Ali ~ Me lkk i l ii 3, Lotta Salminen , and Matti Saari l

I Department of Ophthalmology, 2 Department or Clinical Pharmacology, and J Department of Anaesthesiology, University of Turku, KiinamyllynkalU 4--8, SF·20S20. Turku, Finlalld, 4 Department of Ophthalmology. Universi ty or Tampcre. Tampcre, Finland

Abstract Cyclopentolate plasma levels were quantita ted clopentolate [I , 4, 13] ; psychotic reactions may also oc­ and heart ra te and pupil size were monitored after ocular cur in adults [12,17]. Besides in the CNS. the systemic application of the drug to juveniles. In all , 12 children toxicity of ocular cyclopentolate may manifest in the were given one 35-~1 eyedrop of either 1% cyclopento­ gastroi ntesti nal tract. Trealmen l with 0.5% cyclopento­ late (n=6) or placebo (n=6) in randomized ordcr in late eyedrops has decreased both the secret ion and the the lower cul-d e-sac of one eye. A se nsi tive radioreceptor volume of gastric acid pre-term infants [9]. Even one assay was used to detcrmine the systemic drug absorp~ fatali lY ha s been observed in a newborn that was given tion. With the exception of o ne child . detectable cyclo­ 1% cyclopenlolate eyed ro ps [3). pentolate concentrations were seen in pl asma at as early Cyclopentolate is rapidly absorbed from cyedrops in as 3 mi n after the ocular drug application. There was adults [11] . We therefore quantitaled cyclopentolate a marked interindividual variation in peak plasma cyclo­ plasma levels after its ocular application to children. A pentolate concentra tions ranging from undetcctably low control group was included for delerminalion of the to 5.8 ng/ml (median. 2.9 ng/ml). In some children a sec­ drug's eITccts on heart rate and pupillary diameter. ond drug concentration peak was detected. Cyclopento­ late increased the pupillary diameter from 4.8 ± 1 mm before drug application to 8±0.9 mm at 30 min after Patients and methods administration. but the children's heart rate did not alter. A total of 12 children (6 boys and 6 girls) hospitali7.ed ror strabis­ mus surgery participated in the study. Written inrormed consent was obtained rrom their parents prior to the study. The study design was approved by the Ethical Committee or the University or Central Hospital of Turku. NolIC or the eyes showed signs of Introd uction conjunctival innammation or excess tearing. The u.pcriment was started at 8 a.m. on the day or surgery. The children received no Cyclopen tolate. a potent synthetic parasympatholytic topical or systemic medication during the 24 h prior to th e trial. drug, causes rapid, intense mydriasis a nd cycloplegia in Arter randomi?.ation, one 3S-111 drop or t "I. cyelopentolate (Or­ the eye. Because of its intense and short duration of tan-Syklo; Leiras Pharmaceutic-otis Co.. Tampere. Finland) or an equal volume of placebo ( Balanced Salt Solution for ophthalm ic action, it is widely used in routine funduscopy and in use; Alcon Laboratories Inc .. Fort Worth. Tex., USA) was instilled testi ng of cycloplegia refraction. The usual concentra­ unilaterotlly into the lower cul-de-sac or the eye. Both the cyclopcn- lions of ocularcyclopentolate solutions range from 0.5% to 1%. When ocula r cyclopentolate was introduced into the Tabte I . Characteristics of the children in the cyc!opentolate group cl inical practice, in the ea rl y 1950s, it seemed to be vi r­ Paticnt s." Ag' Height Weight 8MI 2 tuall y free of the undesi rable systemic side eITC(:ts fre­ number (years) (em) (kg) (kgfm ) quently associated with the use of atropine in children [6]. However, during the past few decades many cases I M 12 IS' 43 of central nervous system (CNS) disturbances have been 2 M 6 126 24 " reported in children following treatment with ocular cy- 3 M 10 142 43 21" 4 M 10 143 36 , 16 • This study was supported by the Eye Foundation. Helsinki. Fin­ F 6 22 " 6 M 7 "'IJ] 17 I"", 3. Mean±SD 9±3 136± IJ JJ±9 18±2 Offprint requeSI$ 10: K. Lahdes 17 tolate and the placebo group consisted of six childrcn. Thc eyc­ (mcdian, 46 ng ml - ( min). Patient 1 failed to show any drops were given with an adjustable Finn pipelle. An antecubital detectable drug concentration in plasma throughout the vei n was cannulated and blood samples we re drawn into tubes study. contai ning etb ylenediaminetetraacctic acid (EDTA ) before admin­ Cyclopcntolate caused mydriasis in all patients, istration of the eyedrops and a\ 3, 5, 8, 15, 30, 45, and 60 min thereafter. The children remained recumbent during the experi­ whereas placebo had no effect (betwecn-group differ­ ment. The body mass index (8M I) was calculated by dividing the ence, P=0.007; ANOVA ror repeated-measures design). weight (i n kilograms) by the height (in mcters) squared. Character­ in the cyclopentolate group the pupillary diameter in­ istics of the ch ildren in the cyelopentolate group are given in Ta· creased rrom 4.8± I mm before drug applica tion to 8± ble I. In the placebo group the mcan age was 10±3 years: the 0.9 at 30 and 60 min thereafter (P ipratropium bromide in plas­ OVA ror repeated-measures design). ma by Ensingcr ct al. [71 was used to determin e the drug concentra­ tions in plasma. The detection limit of the assay was 0.3 ng cyelo­ pentolate in I ml plasma. The area under the curve (A UC) for eyelopcntolate was calculated by the trapezoidal rule. Analysis of Discussion varia nce (ANOVA) for repeated-measures design and student"s paired I- tes\ were used for statistical calculations. The toxic CNS symptoms associated with cyclopentolate eyedrops orten begin within the 1st h after ocular drug application [4]. This clinical finding is in accordance Results with the results or our study. Using a sensitive radiore­ ceptor assay, we found cyclopentolate in plasma within Cyclopentolate concentrations were below the detection a rew minutes arter its ocular application. The time limit in the sa mples taken berore drug application and course or the absorption in children closely resembled in all samples rrom the placebo group. After ocular ap· that previously seen in adults [11]. We have previously plication, cyclopentolate rapidly appeared in blood. shown in adult patients that the systemic absorption or With the exception or one patient, detectable drug con­ two other anticholinergic d rugs, a tropine and scopola­ centrations werc seen in the first sample at 3 min arter minc, is rapid rrom cyedrops [14, 15]. drug administration. At 5 min the cyclopentol ate con­ The exact site of the systemic absorption or topically centrations varied rrom undetectably low to 4.2 ngJ ml applied ocular drugs is not clear. Some absorption ob­ (median, 2. 1 ngJml). In three patients the highest drug viously takes place via the capillaries within the conjunc­ concentration in plasma was recorded at 5 min. In two tiva. In humans, the surface area or the conjunctiva is children the first drug concentration peak in plasma, about 17-fold that of the cornea [18], whic h enhances observed at 5 a nd 8 min arter application (1.2 and the systemic absorption or drug in relation to its ocular 3.9 nglml , respectively), was rollowed by an evcn higher penetration. After drainage through the lacrimal sac and second peak a t 60 and 45 min (2.2 and 5.8 nglml, respec­ nasolacrimal duct, ocular drugs could be absorbed tively ; Table 2). through the nasal mucosa or rrom even lower parts of The amount o r cyclopentolate absorbed systemicall y the gastrointestinal tract. By the o bstructio n or lacrimal varied greatly between the patients. Peak drug concen­ d rainage, the systemic absorption or ocula r timolol, tratio ns in plasma ranged rrom undetectably low to measured as the drug concentration at 60 min after eye­ 5.8 nglml (median, 2.9 nglm!). The AUC (0-60 min) ror drop instillation, could be reduced by > 60% [19] . We plasma cyclopentolate varied rrom 0 to 217 ng ml- I min found a mean reduction or similar magnitude when the calculati on was based on the AUC ror timolol at up Table 2. Cyc1o pentolate concentrations in plasma to 90 min in plasma. In some subjects. however, the ini­ tial absorption of timolol was even enhanced by lacrimal Pati ent Time since eyedrop application (min) drainage obstruction [10). num ber 3 , 8 30 There was a marked inter-individual variation in the " " '" magnitude and time of the peak plasma cyclopentolate 1 UD UD UD UD UD UD UD concentrations. Differences in the amount of drug reach­ 2 1.1 1.' 1.1 1.1 0.8 0.7 0.' ing the nasal mucosa might explain these va riations. Us­ 3 1.8 3. 3. 3. 1.9 1.8 1.3 ing lacrimal scintigraphy, Chavis et al. [5) fou nd thai 4 0 .• 4.2 1.3 0.3 UD UD UD the transi t ti mes or tears thro ugh the lacri mal drainage , 2.1 2.4 3.9 3.' 3. 1 '.8 2 system va ried markedly, even in normal, asymptomatic 0.9 1.2 0.8 0 .• UD 0.8 2.2 • eyes. In one-third of the eyes examined, no tracer was Mea n 1.1 2.2 1.8 1.5 1 1.5 detected in the nose a t 12 min after ocular application ±SD 0.8 1.3 2.2 I.. I.. I.. [5]. The valve or Hasner has been suggested to rorm Cyclopcntolate concentrations arc expressed in nslml. UD, Unde­ a ph ysiological obstruction at the level or the nasolacri­ tec table mal duct, even in many asymptomatic lacrimal drainage 18 systems [2]. This physiological variation in the fun ction 5. Chavis RM, Welham RAN, Maisey MN (1978) Quantitative of the lacrimal drainage system is certainly onc factor lacrimal scintillography. Arch Ophthalmol 96: 2066-2068 explaining the intcrindividual variation of, or even the 6. Gordon OM. Ehrenberg MH (1954) Cyclopentolate hydrochlo­ apparent lack of, systemic absorption of ocular cycla­ ride: a new mydriatic and cycloplegic agent. Am J Ophthalmol 38:831 - 838 pentolate in our patients. The late systemic absorption 7. EnSinger HA, Wahl O. Brantl V (1987) Radioreceptor assay of cyclopentolate in two children suggests the presence for determination of th e antimuscarinic drug ipratropium bro­ of drug, albeit without systemic absorption, in the naso­ mi de in man. Eur J Clin PharmacoI33:459-462 lacrimal duct and its late access to the nose [16]. 8. Isenberg S. Everell S (1984) Cardiovascular effects of mydriat­ One eyedrop of 1% cyclopentolate did not affect the ics in low-birth-weight infants. J Pediatr 105:111 - 112 children's heart ratc. A similar finding was previously 9. Isenberg SI. Abrams C. Hyman PE (1985) EtTects of cyclopcn­ tolate eyedrops on gastric secretory function in pre-term in­ reported in low-birth-weight infants, in whom no heart­ fants. Ophthalmology 92: 698-700 rate change was recorded within 1 h after the administra­ 10. Kaila T, Huupponen R. Salminen L (1986) EtTects of eyelid tion of two drops of 0.5% ocular cyclopentolatc [8). closure and nasolacrimal duct occlusion on the systemic absorp­ Nevertheless, systemic side effects have been reported tion of ocular timolol in human subjects. J Ocul Phannacol in some children following treat ment with ocular cyclo­ 2:365-369 pcntolatc. Our results clearly show that the drug is rapid­ II. Kaila T. Huupponen R, Salminen L. lisalo E (1989) Systemic absorption of ophthalmic cyclopcnlolate. Am J Ophthalmol ly absorbed into the systemic circulation from eyedrops. 107:562- 564 The development of a cyclopentolate fonnu lation whosc 12. Kellner U. Esser J (1989) Akute Psychose durch Intoxikation systcmic absorption is low wou ld increase the safety of mit Cyclopcntolat. Klin Monatsbl Augenheilkd 194:458-461 ocular cyclopentolate therapy in ch ildren. 13. Khurana AK. Ahluwalia BK. Rajan Choudhry, Vohra AK (1988) (letter) Acute psychosis associated with topical cyclopen­ Acknowledgement. The expert technical assistance of Mrs. U. Heik­ tolate hydrochloride. Am J Ophthalmoll05:91 onen is gratefully acknowledged. 14. Lahdes K. Kaila T, Huupponen R. Salminen L. lisalo E (1988) Systemic ahsorption of topically applied ocular atropine. Clin I>harmacol Ther 44: 310-3 14 References 15. Lahdes K. Huupponcn R. Kaila T, Salminen L. lisalo E (1990) Systemic absorption of ocular scopolamine in patients. J Deul I. Adcock EW Ill. Eugene W (1971) Cyclopentolate (Cyclogyl) Phannacol 6:61- 66 toxicity in pediatric patients. 1 Pediatr 79: 127- 129 16. Salminen L (1991) Systemic absorption of topically applied oc­ 2. Amanat LA, Hilditch TE, Kwok CS (1983) Lacrimal scintigra­ ular drugs in humans. J Deul Pharmacol (in press) phy: III. Physiological aspects of lacrimal drainage. Br J Oph­ 17. Shihab ZM (1980) Psychotic reaction in an adult after topical thalmoI67 :729-732 cyc!opentolate. Ophthalmologica 181 :228- 230 3. Bauer CR, Trepanier Trottier MC, Stern L (1973) Systemic 18. Watsky MA, Jablonski MM, Edelhauser HF (1988) Compari. cyclopentolate (Cyclogyl) toxicity in the newborn infant. J Pe­ son of conjunctival and corneal surface areas in rabbit and diatr 82: 501 - 505 human. Curr Eye Res 7 :483-486 4. Binkhorst RD, Weinstein OW, Barell RM, Clahane AC (1963) 19. Zimmennan TJ, Kooner KS, Kandarakis AS, Ziegler LP (1984) Psychotic reaction induced by cyclopcnlolate (Cyclogyl). Am Improving the therapeutic index of topically applied ocular J Ophthalmol 55: 1243- 1245 drugs. Arch Ophthalmol l02 : 551 - 553