Intraoperative Floppy Iris Syndrome Induced by Tamsulosin: The Risk and Preventive Strategies.

Tamsulosin is an antagonist of a subtype-specific alpha-1A- and alpha-1D-adrenoceptor (AR) that is expressed in the prostate gland, urethra, and bladder. Several reports have shown a possible relationship between ophthalmologic adverse effects and the use of alpha-1-receptor medicines, including tamsulosin. This descriptive review evaluates the intraoperative floppy iris syndrome (IFIS) associated with tamsulosin. A search of the Medline and PubMed databases was conducted to identify control trials, case reports, and observational examinations published in English. The publication dates were restricted (January 1, 2000, to January 1, 2020). Keywords (tamsulosin, alpha-blocker, ocular, eye, adverse reaction, and IFIS) were used in the searches. The searches identified 66 studies including in vitro or in vivo studies, trials, and observational studies. Twenty-two (33.33%) studies were articles citing tamsulosin and IFIS as having confirmed potential risk to ocular safety. The results of this review, including a comprehensive summary of published research on tamsulosin use in different populations, have identified several articles showing associations between tamsulosin and IFIS that merit further investigation. Suspending of potential causative pharmacological treatment of IFIS before ocular surgery including tamsulosin, proper identification of at-risk patients, preoperative prophylaxis treatments, and surgical technique modifications clearly can mitigate the anticipated risk of IFIS induced by tamsulosin. Copyright:

Introduction

Tamsulosin is an antagonist of a subtype-specific alpha-1A- and alpha-1D-adrenoceptor (AR) that is expressed in the prostate gland, urethra, and bladder. It can elicit a relaxation of the prostate gland and bladder smooth muscles, thereby ensuring a maximal urine flow (Qmax), while moderating the lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH).[1] Men with enlarged prostate glands experience reduced urinary streams because of bladder outlet obstruction.[1] This promotes bladder dysfunction and lower urinary tract side effects, disabled bladder draining, and urinary tract contamination. Whenever BPH is disregarded, it can lead to intense urinary retention, urosepsis, constant renal deficiency, and death auxiliary to BPH. BPH has a histological predominance of 8%, 50%, and 80% in the fourth, sixth, and ninth decades of life, respectively.[2]

Three distinctive alpha-1-AR subtypes – the alpha-1A-, alpha-1B-, and alpha-1D-ARs[3] – are dispersed generally in the prostate muscle, lower urinary tract, heart, liver, vascular tissue, and ocular muscles.[3]

The entire class of alpha-AR antagonists (ARA - 1A) can also induce intraoperative floppy iris syndrome (IFIS),[1] an adverse effect that was first reported by Chang and Campbell 15 years ago in 2005.[4] Several other therapeutics and pharmacological groups can adversely affect eye function and lead to the development of ocular adverse effects, summarized in Li et al. 2008 review, these effects including angle-closure glaucoma with certain β2-adrenergic agonists, intraocular pressure and subcapsular cataract with glucocorticoids, open-angle glaucoma in vulnerable patients with the use of the anticancer agent docetaxel, and bull's-eye maculopathy induced by aminoglycosides.[5]

Alfuzosin, terazosin, and doxazosin are also ARA α1A, but they lack the specificity of tamsulosin to α1A.[1] Each of the four medications is similarly effective in treating LUTS, but alfuzosin and tamsulosin are less likely to lead to hypotension than are the less particular alpha-blockers terazosin and doxazosin.[167] The prostate enlargement rate expands by 2.0%–2.5% every year in adult men,[78] and this enlargement can lead to clinical BPH development, urine retention, and a requirement for prostate medical procedures, including the use of AR antagonists therapeutics to improve patient's clinical condition and quality of life.[91011]

There are reports in the literature that demonstrates a likely relationship between alpha-AR antagonists, including tamsulosin and ocular adverse effects “IFIS.”[56] Therefore, the aim of this literature review was to evaluate the incidence of IFIS associated with tamsulosin. Furthermore, the study will discuss the potential preoperative and intraoperative strategies for the management of IFIS.

Methods

The search strategy looked for randomized control trials (RCTs), case reports, observational studies, and other peer-reviewed full articles published in the English language between January 1, 2000, and August 1, 2020. Research articles on quantitative observational investigations, case reports, and RCTs were mainly focused on tamsulosin, alpha-blocker, ocular, eye, adverse drug reactions (ADRs), antagonistic medication incidents, poisonous effects, IFIS, one-sided choroidal detachment, chemosis, and acute-onset myopia. The primary outcome was the prevalence of any unfavorable visual adverse effects in patients treated with tamsulosin. The secondary outcomes were dose-associated toxicity and comorbidities with tamsulosin. Up-to-date information is presented on tamsulosin and its impedance of various eye illnesses, such as IFIS. In addition, the relationship is explored between the iris smooth muscle or the prostate and the effect of possible structural changes due to persistent dosing with α-blockers. Basic clinical rules can be introduced to assist physicians in recognizing patients who would benefit from early reference for an ophthalmological assessment before initiating alpha-1-antagonist treatment.

Results

The search identified 66 articles, including in vivo or in vitro studies, clinical trials, and observational descriptive studies. Of these, one-third referred specifically to tamsulosin and IFIS (n = 22, 33.33%).

In vitro studies

Animal studies have established that alpha-1A-ARs are also the most widely distributed ocular subtype and are found in the iris dilator muscle in rats[12] and rabbits.[13] The antagonism of alpha-1A-ARs by tamsulosin in the iris dilator muscle resulted in poor muscle tone and flaccid iris stroma, thus leading to fluttering and sluggish of the iris.[1314] In vitro studies on rabbits have demonstrated that tamsulosin can bind to iris melanin to inhibit the dilator muscle and promote IFIS.[1516]

Alpha-1-receptors have been recognized in the lower urinary tract and the heart, liver, and vascular and visual smooth muscle.[12] The alpha-1A-AR is known to intervene in pupil expansion in rodents and rabbits; however, no human examinations have been carried out.[11] The iris dilator smooth muscle blockade causes iris tone deterioration by the parasympathetically innervated iris effect that promotes clinical IFIS.[16]

The studies have shown that tamsulosin has a greater affinity for the alpha-1A-AR than for the alpha-1B-AR and the alpha-1D-AR. Tamsulosin is highly bound to plasma proteins (94% to 99%), primarily alpha1 acid glycoprotein (AGP), the pharmacological activity of a drug directly relates to the unbound concentration. The unbound (therapeutic) concentration of tamsulosin following multiple dosing in men with BPH, were much greater in prostate than in blood plasma, suggesting a continued binding of tamsulosin with the target tissues. Based on this, in the iris, tamsulosin is proposed to bind for long period to the postsynaptic 1AAR of the iris-enlarging muscle.[1718]

Tamsulosin has also been shown to have a ten times greater potency in blocking phenylephrine-induced prostatic compression in dogs[19] and a hundred-fold greater potency in relaxation of smooth muscles in rabbits when compared with the nonselective adrenergic antagonists.[20]

The iris and alpha-1-adrenergic receptor antagonists

The iris is an intact tissue with many different layers, and its innervation directs the iris muscle tone.[21] The role of the iris smooth muscle includes an organization of competing pathways including sympathetic and parasympathetic, peptidergic, serotonergic, dopaminergic, and prostaglandin-related pathways[17] and controlling pupil size both dilation and constrictions. Dilated pupil diameter preoperatively has been considered an independent risk factor for the development of IFIS; a dilated pupil of 7.0 mm or smaller had 95% specificity for predicting IFIS in patients who have been treated with alpha-1A-AR antagonists, where pupil dilation was mostly inhibited by tamsulosin among other alpha-1A-AR antagonists.[22]

According to Friedman,[23] vascular dysfunction of the iris is related to the blockade of alpha-1A-ARs in the blood vessel walls in patients taking tamsulosin. The vasculature of the iris serves as a skeletal structure for the iris, so any weakness promotes an intense dysfunction of the related muscle.[2223] The constrictive effect of tamsulosin on iris dilator contraction and vascular dysfunction can add to the IFIS effects seen in patients. Along these lines, patients who are taking tamsulosin could encounter a risk of IFIS during cataract medical procedures.[42425] The chronic use of tamsulosin promotes atrophy of the macular plate and subsequent pupil expansion; this could explain the flaccid nature of this tissue discovered during cataract medical procedures.[26] Pärssinen et al. revealed that tamsulosin showed a delayed presence in the aqueous humor, suggesting a broadened activity on the ciliary body and iris.[26] This delayed activity of tamsulosin can cause lasting changes in the iris function by irreversibly inhibits alpha-1-ARs, causing permeant iris atrophy that may not revert upon discontinuation of the drug.[14]

It has been suggested by some ophthalmologists to discontinue tamsulosin for 2 weeks before cataract surgery and to commence treatment immediately after surgery;[27] nevertheless, it has been reported that IFIS can still occur in patients who discontinued treatment even a year before the surgery.[4] Another study was not in favor of discontinuing tamsulosin before cataract surgery; considering the absence of conclusive evidence, they had recommended the use of iris hooks to avoid the need for altering current treatment.[28]

Tamsulosin induces intraoperative floppy iris syndrome

IFIS was first reported in 2002 in association with tamsulosin use, but the principal report of this disorder was not published until mid-2005.[4] Apart from alpha-AR antagonists, different other contributory risk factors were identified to be associated with IFIS, including decreased preoperative dilated pupil diameter,[22] increasing age,[29] male sex (attributed to the use of alpha-AR antagonists for BHP),[2930] certain medications such as antipsychotics and tranquilizers such as benzodiazepines,[2931] the use of angiotensin receptor inhibitors in females,[32] and the use of finasteride as an adjunct to alpha-1A-AR antagonists.[31] Notably, diabetes mellitus and hypertension were not found to be associated with IFIS.[3334]

The mechanism of tamsulosin induces IFIS has been reported by Prata et al.,[35] who showed a localized decline in the thickness of the iris dilator muscle in patients treated with tamsulosin because of irreversible muscle atrophy. This change increases the risk of adverse events, such as capsule rupture, vitreous misfortune, iris prolapse, iris stromal atrophy, and chamber bleeding,[14] and these complexities may cause a loss of corneal endothelial cells.[3637]

In a large cohort study conducted in Canada, 3550 patients (3.7%) had recent exposure to tamsulosin, of whom 284 (0.3%) had an adverse event. The study concluded that exposure to tamsulosin within 2 weeks of cataract surgery was significantly associated with serious postoperative eye adverse events.[38]

Lim et al.[39] detailed a lower rate of IFIS in Asian populations than in Western societies due to the darker iris color. Shah et al.[40] found an association between the billowing and flabby character of the iris and iris prolapse during phacoemulsification in patients taking tamsulosin 2 days before the day of the medical procedure.

The American Society of Cataract and Refractive Surgery issued a warning to all ophthalmologists regarding the relationship of tamsulosin with IFIS and expanded complexity rates and suggested the use of a nonselective alpha-blocker for treatment of BPH or commencing tamsulosin after phacoemulsification.[41]

Strategies to manage intraoperative adverse effects induced by tamsulosin

The authors suggested suspending tamsulosin treatment at 1–14 days before any cataract medical procedure.[414] Others proposed that urologists should not change the recommended doses for alpha-blockers; however, they should suspend the administration of tamsulosin 7 days before any scheduled intraoperative medical procedure.[442] Other strategies included:

Preoperative prophylaxis measures

Patients associated with a high risk to developing IFIS and those suffering BPH who are planning to undergo cataract surgery should be avoided the use of selective alpha-blockers and must inform their ophthalmologists about the intake of tamsulosin;[4] the disclosure of use before cataract surgery is highly important.[1442] As a precautionary measure, the urologist treating the patient can inform the ophthalmologist about tamsulosin treatment and other causative medications described earlier; if cataract surgery is under consideration, the ophthalmologists can then inform the patient to discontinue tamsulosin 7 days before an intraocular surgery.[4243]

Pharmacologic prophylactic strategies have demonstrated value in the prevention of IFIS; intracameral alpha-1-AR agonists effects, such as phenylephrine or epinephrine, can directly stimulate the iris dilator smooth muscle receptors, thereby diminishing the propensity toward iris prolapse and billowing.[44454647] The use of preoperative topical atropine sulfate and intracameral nonpreserved epinephrine hydrochloride has been proven as an effective method to reduce the incidence of IFIS;[44454647] the outcome is closely related to choice of surgical technique under the care of a senior ophthamologist.[4849]

A recent study to compare the prophylactic strategy in at-risk groups of IFIS receiving mydriatic treatments before phacoemulsification surgery showed a significant reduction of mild IFIS incidence, from 86.05% (n = 37/n = 43 patients) of atropine sulfate 1% treated group to 60.53% (n = 23/n = 38 patients) in adrenaline 1 mg/ml treated group. The analysis failed to show positive results in a reduction of severe forms, reconsidering ARA α1A withdrawal and a rational interruption of causative pharmacological treatment in some patients.[50]

Preoperative atropine drops (e.g., 1% three times/day for 1 to 2 days preoperatively) can augment cycloplegia. Due to the risk of intense urinary maintenance, systemic alpha-blockers should not be halted in general if atropine is utilized.[51]

Recently, the US Food and Drug Administration has approved a combination of phenylephrine 1% and ketorolac 0.3% intraocular use during cataract surgery to reduce the incidence of miosis, iris prolapse, and postoperative pain.[52]

Topical instillation of a lidocaine (2%) jelly, blended with cyclopentolate, phenylephrine, and ketorolac as a standard widening routine, can be utilized before the medical procedure.[4445464750]

Intraoperative measures

Several methodologies have been proposed to deal with the iris in IFIS; these incorporate the utilization of highly viscous or visco-versatile ophthalmic viscosurgical devices and placement of mechanical widening gadgets.[437]

All-around application of specific general surgical standards is recommended to maintain adequate pupil dilation at the time of routine cataract surgery for high-risk male patients on tamsulosin. It is critical for the optimal visualization, particularly if preoperative assessment concluded that IFIS is suspected to occur. The use of intracameral epinephrine was associated with lower incidence of IFIS. However, poorly dilated pupil after an intracameral epinephrine injection at the commencement of the surgery can be considered an early sign of potential incidence of IFIS.[43753]

Strengths, limitations, and future research

The review has added more evidences from clinical trials and prospective observational studies to the evidence base regarding the ocular safety of tamsulosin and its interference with eye diseases, particularly IFIS.

The data presented here should be interpreted with caution, as this is not a systematic review. It is a simple descriptive literature review, where the design may not have identified all relevant studies. Several confounding morbidity factors and causative medicines were reported to be linked to IFIS. Most of the reviewed literature did not clearly define the adverse effects that were reported as an “ADR;” hence, the information provided is insufficient to assess the causality, severity, and preventability of ocular adverse reactions to tamsulosin. However, this review provided a considerable number of researches that linked IFIS to tamsulosin use that cannot be ignored.

Future studies on tamsulosin should use systematic review and meta-analysis designs to provide information about the incidence of ADRs that are relevant to alpha-blocker use and to develop intervention tools to improve alpha-blocker prescription and monitoring in different populations.

Conclusion

This review provides a comprehensive summary of published research on tamsulosin use in different populations and its results have identified several articles that link tamsulosin and IFIS, an association that merits further investigation. However, the study design may not have identified all relevant studies, and the data do not provide sufficient information to assess the causality, severity, and preventability of ocular events related to tamsulosin. For this reason, inferences regarding the findings must be made prudently. Currently, there is no conclusive preventive strategy for the development of IFIS in high-risk patients. However, suspending of potential causative pharmacological treatment of IFIS before ocular surgery including tamsulosin, proper identification of at-risk patients, preoperative prophylaxis treatments, and surgical technique modifications clearly can mitigate the anticipated risk of IFIS induced by tamsulosin.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.