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Tamsulosin HCL (Flomax) and Cataract Surgery
Author Response: Tamsulosin HCL (Flomax) and Cataract Surgery
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Bruce I. Gaynes, bgaynes@rush.edu
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bgaynes{at}rush.edu Bruce I. Gaynes
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I have read with interest the recent article by Pärssinen et al.1 describing complications of intraoperative floppy iris syndrome (IFIS) with use of systemic tamsulosin for benign prostatic hypertrophy (BPH). I would, however, like to point out several observations pertinent to the discussion. The integration of data regarding serum drug concentration and pharmacodynamic consequence is a realm of applied pharmacokinetics that is typically employed in the appraisal of drugs with either narrow therapeutic indices or concentration-dependent pharmacodynamic properties, such as antibiotics. The utility of such "random" measures of serum drug concentration is validated by exploiting known facets of drug kinetics and dosing to transform an otherwise empiric finding to a reasonably predictable observation that can be interpreted with sound theoretic rationale. Unfortunately, depiction of concentration-dependent consequences of drug action as demonstrated by Päarssinen et al., without an adequate précis of known factors that influence drug disposition, results in a coincidental portrayal of concentration-dependent drug response that is at best of verisimilitudinal significance. In the case of Flomax capsules (tamsulosin HCL extended release) for example, it has been previously demonstrated that bioavailability and consequent peak serum concentration varies from 40% to 70% depending on whether the drug was taken with or without food.2 By providing an explanation of the relationship between time of drug dosing, propinquity to meals and time of blood draw, in conjunction with use of known pharmacokinetic parameters of tamsulosin disposition, the resultant serum concentration data would have been clearly more instructive and certainly more relevant in terms of comparative data assessment. One aspect of drug concentration data demonstrated in Tables 1 and 2 by Pärssinen et al.1 that is notable, however, is the conspicuous lack of correlation between serum and aqueous humor tamsulosin drug concentration, the latter remaining remarkably flat despite marked relative spikes in concomitant serum drug concentration. Of further interest, it should be noted that heterocyclic, basic compounds such as chlorpromazine and chloroquine as well as tamsulosin demonstrate a pronounced affinity for alpha 1 acid glycoprotein (AAG), a plasma protein constituent that in addition to albumin plays a broad role in drug-protein binding.3 The attractive character that defines AAG-drug binding phenomena has been shown to be based on a combination of hydrophobic–electrostatic interactions, which may be predicted to mechanistically parallel iterative forces involved in binding affinity between drugs such as chloroquine and chlorpromazine and the indolequinone polymer melanin.3,4,5 Inasmuch as tamsulosin demonstrates a particularly strong affinity for AAG, one may hypothesize the chemical character of tamsulosin would be such that tamsulosin binding affinity for melanin would be substantial. Binding affinity to melanin has been shown to be strongly related to cationic charge distribution found in basic molecules.6,7,8 Chloroquine for example is a 4-aminoquinoline compound composed of both a secondary amine and substituted amino group (pKa of 8.1 and 10.2, respectively) that exists as a doubly protonated entity at physiologic pH and which has a marked affinity for melanin.7 Interestingly, molecular comparisons of tamsulosin and chloroquine demonstrate remarkable similarities in that that tamsulosin displays both a secondary amine and sulfonyl amino group with pKa of 8.4 and 10.2, respectively, (Boehringer Ingelheim Pharmaceuticals Inc., Technical Support Service, personal communication, December 2006) findings strikingly similar to chloroquine. One may predict therefore that, similar to chloroquine, tamsulosin exists in the doubly protonated highly cationic form at physiologic pH, qualities that define binding affinity for melanin.8 One may predict therefore that uveal binding tendencies for tamsulosin closely parallel that of chloroquine, and accumulation of tamsulosin in pigmented structures would certainly not be unexpected. If in fact tamsulosin does bind to uveal melanin in a reversible manner as would be predicted based on the chemical character of the molecule, one could rationalize many facets of tamsulosin-related IFIS despite prolonged periods of drug discontinuation. Although previous authors9 have suggested that in general, drug binding to iridal melanin is at best transient of the order of several days, there is compelling data to argue that drug-melanin binding relationships are indeed more than fleeting. For example, radio-labeled timolol maleate, a compound with established melanin affinity, has been detected in aqueous humor for up to 42 days following drug discontinuation.10 The observations outlined in this communication may in part explain findings described by Pärssinen et al. that demonstrate relatively flat tamsulosin aqueous drug concentration despite fluctuating serum concentration (Table 1) and up to 28 days of drug discontinuation (Table 2) and which may relate to the sink- reservoir properties of uveal melanin acting to dampen temporal fluctuations and prolong aqueous tamsulosin concentration, respectively. Although Pärssinen et al.1 suggest that tamsulosin imparts "permanent changes in iris function," it is my belief that drug depot effects of melanin, in conjunction with the anatomic proximity of the iridal pigment and dilator myoepithelium, act in concert to prolong alpha receptor blockade related to tamsulosin use. Summarily, the predicted cationic features of tamsulosin and remarkable ionization similarities to chloroquine certainly suggest that tamsulosin has high melanin affinity, which may indeed contribute to the occurrence of IFIS-related tamsulosin toxicity. In my opinion, the delineation of tamsulosin ionization characteristics and melanin binding affinity will provide enlightening rewards in terms of facets of tamsulosin-related IFIS and, perhaps, additional forms of ocular toxicity. Furthermore, relevance of random measures of drug concentration as described by Pärssinen et al.1 without appropriate exploitation of known pharmacokinetic parameters provides at best a static and marginally tangential appraisal of tamsulosin-related pharmacodynamic circumstance and toxicity. Bruce I. Gaynes Ophthalmology and Pharmacology, Rush University College of Medicine, Chicago, Illinois References 1. Pärssinen O, Leppänen E, Keski-Rahkonen P, Mauriala T, Dugué B, Lehtonen M. Influence of tamsulosin on the iris and its implications for cataract surgery. Invest Ophthalmol Vis Sci. 2006;47:3766-3771. |
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Olavi Parssinen
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olavi.parssinen{at}top.fimnet.fi Olavi Parssinen
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We appreciate the attention Gaynes has paid to our article "Influence of tamsulosin on the iris and its implications for cataract surgery."1 The main purpose of our article was primarily to present different characteristics of intraoperative floppy iris syndrome (IFIS) than to clarify the molecular basis of this phenomenon. Gaynes pointed out the great variation of tamsulosin concentration depending on, for example, whether the drug was taken with or without food. That is true, but the time of drug intake also causes significant variation in the serum concentration of tamsulosin. Sato and co-workers2 found that the plasma concentration of tamsulosin in dogs was close to the limit of detection at 240 minutes after intake, while concentrations in the prostate and urethra remained 13-44 times higher. Consequently, these two factors may cause significant daily variation in the serum concentrations of tamsulosin. However, our investigations of the blood specimen taken just before the operation enables us to conclude that the concentration of tamsulosin in serum at the time of surgery did not correlate with the severity of IFIS. The further pharmacodynamics of tamsulosin in serum was beyond the scope of our study. Nevertheless, we were able to detect a measurable amount of tamsulosin in the aqueous humor as long as 1 to 4 weeks after its use. This indicates that tamsulosin obviously binds to some intraocular tissues, probably in the iris and perhaps in the ciliary body. It would be interesting to know the changes in the concentration of tamsulosin in the aqueous humor, but this is difficult to investigate without animal experiments. Gaynes supposed that the effects of a drug attached to melanin together with the anatomic proximity of the iridal pigment and dilator myoepithelium prolongs alpha receptor blockade related to the use of tamsulosin. IFIS was found after the discontinuation of tamsulosin three years earlier,3 which is difficult to explain without any anatomical changes in the structure of iris muscles. The transmission electron microscopy study of Terry et al.4 showing a lack of identifiable myofibrils in the iris dilator muscle in patients using tamsulosin leads one to suppose that the anatomical reason for IFIS is some kind of atrophy in the iris dilator muscles. Many structurally and pharmacologically unrelated drugs from different therapeutic classes can bind to melanin in the uveal tract and in the retinal pigment epithelium. Examples include numerous drugs acting on the central nervous system, beta-blockers, beta-agonists, antimalarial drugs, sympathomimetic amines, and antibiotics. The critical factors are the acid/base status and the lipophilicity of the molecule.5 However, melanin binding and toxicity are two separate entities, the latter being related to the intrinsic toxicity of the compound rather than its ability to bind. Chloroquine and phenothiazines are often used as examples of drugs with retinal toxicity linked to melanin binding. Gaynes compared the molecular structure of tamsulosin and chloroquine and found remarkable similarities. Further studies are needed to investigate the hypothesis of tamsulosin binding to uveal melanin, as well as the tamsulosin toxicity on the iris dilator muscle, and also whether melanin acts as a reservoir of tamsulosin. The most serious form of irreversible ocular damage caused by chloroquine, is pigmentary retinopathy.6 Phenothiazine, on the contrary, causes retinopathy which is reversible.6 If tamsulosin is binding to melanin as Gaynes hypothesized, its possible accumulation in the retinal pigment epithelium and its toxicity should also be studied. Olavi Pärssinen1 1Ophthalmic Department of Central Hospital of Central Finland, Jyväskylä, Finland References 1. Pärssinen O, Leppänen E, Keski-Rahkonen P, Mauriala T, Dugué B, Lehtonen M. Influence of tamsulosin on the iris and its implications for cataract surgery. Invest Ophthalmol Vis Sci. 2006;47:3766-3771. |
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