Severe systemic Adverse Reactions to Ophthalmic Timolol in a CYP2D6 Homozygous *4 Allele Carrier: A Case Report

References

• Quigley HA . Glaucoma. Lancet377(9774), 1367–1377 (2011).
   PubMed Web of Science ®Google Scholar
• Schuster AK , ErbC , HoffmannEM , DietleinT , PfeifferN. The diagnosis and treatment of glaucoma. Dtsch. Arztebl. Int.117(13), 225–234 (2020).
   PubMed Web of Science ®Google Scholar
• Miglior S , ZeyenT , PfeifferNet al. Results of the European Glaucoma Prevention Study. Ophthalmology112(3), 366–375 (2005).
   PubMed Web of Science ®Google Scholar
• Brubaker RF . Targeting outflow facility in glaucoma management. Surv. Ophthalmol.48(Suppl. 1), S17–S20 (2003).
   PubMed Web of Science ®Google Scholar
• Coca-Prados M , EscribanoJ. New perspectives in aqueous humor secretion and in glaucoma: the ciliary body as a multifunctional neuroendocrine gland. Prog. Retin. Eye Res.26(3), 239–262 (2007).
   PubMed Web of Science ®Google Scholar
• Jonas JB , WangN , WangYX , YouQS , YangD , XuL. Ocular hypertension: general characteristics and estimated cerebrospinal fluid pressure. The Beijing Eye Study 2011. PLOS ONE9(7), e100533 (2014).
   PubMed Web of Science ®Google Scholar
• Casson RJ . Medical therapy for glaucoma: a review. Clin. Exp. Ophthalmol.50(2), 198–212 (2022).
   PubMed Web of Science ®Google Scholar
• Volotinen M , HakkolaJ , PelkonenO , VapaataloH , MäenpääJ. Metabolism of ophthalmic timolol: new aspects of an old drug. Basic Clin. Pharmacol. Toxicol.108(5), 297–303 (2011).
   PubMed Web of Science ®Google Scholar
• Mäenpää J , PelkonenO. Cardiac safety of ophthalmic timolol. Expert Opin. Drug Saf.15(11), 1549–1561 (2016).
   PubMed Web of Science ®Google Scholar
• Coakes RL , BrubakerRF. The mechanism of timolol in lowering intraocular pressure: in the normal eye. Arch. Ophthalmol.96(11), 2045–2048 (1978).
   PubMedGoogle Scholar
• Affrime MB , LowenthalDT , TobertJAet al. Dynamics and kinetics of ophthalmic timolol. Clin. Pharmacol. Ther.27(4), 471–477 (1980).
   PubMed Web of Science ®Google Scholar
• Timoptic®, timolol drug label. Santen SA,Geneva, Switzerland (2022). www.swissmedicinfo.ch/
   Google Scholar
• Nieminen T , UusitaloH , TurjanmaaVet al. Association between low plasma levels of ophthalmic timolol and haemodynamics in glaucoma patients. Eur. J. Clin. Pharmacol.61(5–6), 369–374 (2005).
   PubMed Web of Science ®Google Scholar
• Nieminen T , LehtimäkiT , MäenpääJ , RopoA , UusitaloH , KähönenM. Ophthalmic timolol: plasma concentration and systemic cardiopulmonary effects. Scand. J. Clin. Lab. Invest.67(2), 237–245 (2007).
   PubMed Web of Science ®Google Scholar
• Korte J-M , KailaT , SaariKM. Systemic bioavailability and cardiopulmonary effects of 0.5% timolol eyedrops. Graefes Arch. Clin. Exp. Ophthalmol.240(6), 430–435 (2002).
   PubMed Web of Science ®Google Scholar
• Attar M , ShenJ , LingK-HJ , Tang-LiuD. Ophthalmic drug delivery considerations at the cellular level: drug-metabolising enzymes and transporters. Expert Opin. Drug Deliv.2(5), 891–908 (2005).
   PubMedGoogle Scholar
• Ghate D , EdelhauserHF. Barriers to glaucoma drug delivery. J. Glaucoma17(2), 147–156 (2008).
   PubMed Web of Science ®Google Scholar
• Nelson WL , FraunfelderFT , SillsJM , ArrowsmithJB , KuritskyJN. Adverse respiratory and cardiovascular events attributed to timolol ophthalmic solution, 1978–1985. Am. J. Ophthalmol.102(5), 606–611 (1986).
   PubMed Web of Science ®Google Scholar
• Hayreh SS , PodhajskyP , ZimmermanMB. Beta-blocker eyedrops and nocturnal arterial hypotension. Am. J. Ophthalmol.128(3), 301–309 (1999).
   PubMed Web of Science ®Google Scholar
• Sharifi M , KochJM , SteeleRJ , AdlerD , PompiliVJ , SopkoJ. Third degree AC block due to ophthalmic timilol solution. Int. J. Cardiol.80(2–3), 257–259 (2001).
   PubMed Web of Science ®Google Scholar
• Müller ME , vander Velde N , KrulderJWM , vander Cammen TJM. Syncope and falls due to timolol eye drops. BMJ332(7547), 960–961 (2006).
   PubMedGoogle Scholar
• Volotinen M , KorjamoT , TolonenAet al. Effects of selective serotonin reuptake inhibitors on timolol metabolism in human liver microsomes and cryo-preserved hepatocytes. Basic Clin. Pharmacol. Toxicol.106(4), 302–309 (2010).
   PubMed Web of Science ®Google Scholar
• Volotinen M , TurpeinenM , TolonenA , UusitaloJ , MäenpääJ , PelkonenO. Timolol metabolism in human liver microsomes is mediated principally by CYP2D6. Drug Metab. Dispos.35(7), 1135–1141 (2007).
   PubMed Web of Science ®Google Scholar
• Annotation of EMA Label for Timolol and CYP2D6 . PharmGKB.. www.pharmgkb.org/labelAnnotation/PA166115435 (2019).
   Google Scholar
• Dinai Y , SharirM , NavehN , HalkinH. Bradycardia induced by interaction between quinidine and ophthalmic timolol. Ann. Intern. Med.103(6 Pt 1), 890–891 (1985).
   PubMed Web of Science ®Google Scholar
• Ishii Y , NakamuraK , TsutsumiK , KotegawaT , NakanoS , NakatsukaK. Drug interaction between cimetidine and timolol ophthalmic solution: effect on heart rate and intraocular pressure in healthy Japanese volunteers. J. Clin. Pharmacol.40(2), 193–199 (2000).
   PubMed Web of Science ®Google Scholar
• Committee for Medical Products for Human Use Pharmacovigilance Working Party of the European Medicines Agency . Monthly report, issue no.1106. EMA, London, UK (2011). www.ema.europa.eu/en/documents/report/monthly-report-pharmacovigilance-working-party-phvwp-june-2011-plenary-meeting_en.pdf
   Google Scholar
• CYP2D6 – Drug Label Annotations . PharmGKB (2023). www.pharmgkb.org/gene/PA128/labelAnnotation
   Google Scholar
• Yang Y , BottonMR , ScottER , ScottSA. Sequencing the CYP2D6 gene: from variant allele discovery to clinical pharmacogenetic testing. Pharmacogenomics18(7), 673–685 (2017).
   PubMed Web of Science ®Google Scholar
• Gaedigk A , SangkuhlK , Whirl-CarrilloM , KleinT , LeederJS. Prediction of CYP2D6 phenotype from genotype across world populations. Genet. Med.19(1), 69–76 (2017).
   PubMed Web of Science ®Google Scholar
• Moshetova LK , SoshinaMM , TurkinaKIet al. Effect of CYP2D6*4, CYP2D6*10 polymorphisms on the safety of treatment with timolol maleate in patients with glaucoma. Drug Metab. Pers. Ther.38(2), 143–148 (2022).
   PubMedGoogle Scholar
• Yuan H , YuM , YangY , WuK , LinX , LiJ. Association of CYP2D6 single-nucleotide polymorphism with response to ophthalmic timolol in primary open-angle Glaucoma – a pilot study. J. Ocul. Pharmacol. Ther.26(5), 497–501 (2010).
   PubMed Web of Science ®Google Scholar
• McGourty JC , SilasJH , FlemingJJ , McBurneyA , WardJW. Pharmacokinetics and beta-blocking effects of timolol in poor and extensive metabolizers of debrisoquin. Clin. Pharmacol. Ther.38(4), 409–413 (1985).
   PubMed Web of Science ®Google Scholar
• Edeki TI , HeH , WoodAJ. Pharmacogenetic explanation for excessive beta-blockade following timolol eye drops. Potential for oral-ophthalmic drug interaction. JAMA274(20), 1611–1613 (1995).
   PubMed Web of Science ®Google Scholar
• Nieminen T , UusitaloH , MäenpääJet al. Polymorphisms of genes CYP2D6, ADRB1 and GNAS1 in pharmacokinetics and systemic effects of ophthalmic timolol. A pilot study. Eur. J. Clin. Pharmacol.61(11), 811–819 (2005).
   PubMed Web of Science ®Google Scholar
• Clinical Annotation for CYP2D6*1, CYP2D6*3, CYP2D6*4, CYP2D6*5; Timolol (Level 3). PharmGKB (2021). www.pharmgkb.org/clinicalAnnotation/1183690410
   Google Scholar
• Brodde OE . Beta 1- and beta 2-adrenoceptors in the human heart: properties, function, and alterations in chronic heart failure. Pharmacol. Rev.43(2), 203–242 (1991).
   PubMed Web of Science ®Google Scholar
• Newton GE , AzevedoER , ParkerJD. Inotropic and sympathetic responses to the intracoronary infusion of a beta2-receptor agonist: a human in vivo study. Circulation99(18), 2402–2407 (1999).
   PubMed Web of Science ®Google Scholar
• Clinical Annotation for rs1801252 (ADRB1); Timolol (Level 3 Efficacy) . PharmGKB. www.pharmgkb.org/clinicalAnnotation/1444703187
   Google Scholar
• Clinical Annotation Levels of Evidence . PharmGKB (2023). www.pharmgkb.org/page/clinAnnLevels.
   Google Scholar
• Wettschureck N , OffermannsS. Mammalian G proteins and their cell type specific functions. Physiol. Rev.85(4), 1159–1204 (2005).
   PubMed Web of Science ®Google Scholar
• Nürnberger J , DammerS , MitchellAet al. Effect of the C825T polymorphism of the G protein beta 3 subunit on the systolic blood pressure-lowering effect of clonidine in young, healthy male subjects. Clin. Pharmacol. Ther.74(1), 53–60 (2003).
   PubMed Web of Science ®Google Scholar
• Filigheddu F , ReidJE , TroffaCet al. Genetic polymorphisms of the beta-adrenergic system: association with essential hypertension and response to beta-blockade. Pharmacogenomics J.4(3), 154–160 (2004).
   PubMed Web of Science ®Google Scholar
• Dörr M , CoSchmidtCO , SpielhagenTet al. β-blocker therapy and heart rate control during exercise testing in the general population: role of a common G-protein β-3 subunit variant. Pharmacogenomics11(9), 1209–1221 (2010).
   PubMed Web of Science ®Google Scholar
• Alvan G , CalissendorffB , SeidemanP , WidmarkK , WidmarkG. Absorption of ocular timolol. Clin. Pharmacokinet.5(1), 95–100 (1980).
   PubMed Web of Science ®Google Scholar
• Uusitalo H , NiñoJ , TahvanainenKet al. Efficacy and systemic side-effects of topical 0.5% timolol aqueous solution and 0.1% timolol hydrogel. Acta Ophthalmol. Scand.83(6), 723–728 (2005).
   PubMedGoogle Scholar
• Uusitalo H , KähönenM , RopoAet al. Improved systemic safety and risk-benefit ratio of topical 0.1% timolol hydrogel compared with 0.5% timolol aqueous solution in the treatment of glaucoma. Graefes Arch. Clin. Exp. Ophthalmol.244(11), 1491–1496 (2006).
   PubMed Web of Science ®Google Scholar
• Mancia G , RoseiEA , AziziMet al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur. Heart J.39(33), 3021–3104 (2018).
   Google Scholar
• Prioritization of CPIC Guidelines. CPIC (2023). https://cpicpgx.org/prioritization-of-cpic-guidelines/
   Google Scholar