Supplement to EyeWorld July 2013
Inflammation and success inrefractive cataract surgeryNew anti-inflammatory therapeutics“There are factors that we know have helpedimprove outcomes in patients who are re-ceiving advanced technology IOLs,” saidTerry Kim, MD, professor of ophthalmol-ogy, Duke University School of Medicine,Durham, N.C. Among the more familiar factors are patient selection, improved biometry and keratometry, OCT imaging,and femtosecond laser technology.
One variable tends to be overlooked interms of how important it is to the out-comes of refractive cataract procedures: inflammation. The goal with these proce-dures, said Dr. Kim, should be to eliminatepost-cataract inflammation.
Accreditation StatementThis activity has been planned and imple-mented in accordance with the EssentialAreas and policies of the AccreditationCouncil for Continuing Medical Educationthrough the joint sponsorship of the Ameri-can Society of Cataract and Refractive Sur-gery (ASCRS) and EyeWorld. ASCRS isaccredited by the ACCME to provide contin-uing medical education for physicians.
Educational ObjectivesOphthalmologists who participate in thiscourse will:• Identify the impact of ocular inflammationon outcomes in refractive cataract surgery;
“A lot of us are not aware of some ofthe recent advances in therapeutic agents,”said Dr. Kim. “We’ve had some new and ex-citing developments in terms of our choicesfor anti-inflammatory therapy with regardto both topical corticosteroids and non-steroidal agents,” he said.
In terms of nonsteroidal anti-inflam-matory drugs (NSAIDs), there have beensome notable reformulations of familiaragents. Prolensa (bromfenac 0.07%), whichreceived FDA approval in April, provides alower concentration of the active ingredientthan Bromday (bromfenac 0.09%). The newdrug is approved for once-a-day daily dosing1 day preop, the day of surgery, and 14 dayspostoperatively.
David F. Chang, MD, has received a retainer, ad hoc fees, or other consulting income from: Abbott Medical Optics, Clarity Medical Systems, LensAR, and Transcend. He is a member of the speakersbureaus of:Allergan and Zeiss Certified. He has received researchfunding from Glaukos. Dr. Chang has investment interests in Calhourn Vision, ICON Bioscience, PowerVision, and Revital Vision. He receives a royalty or other financial gain from Eyemaginationsand SLACK Inc.
Uday Devgan, MD, has received a retainer, ad hoc fees, or otherconsulting income from: Aaren Scientific, Bausch & Lomb, GersonLehman Group, Hoya Vision Care, and ISTA. He is a member of thespeakers bureau for Alcon. Dr. Devgan has an investment interest inSpecialty Surgical and receives a royalty or other financial gain fromAccutome.
Terry Kim, MD, has received a retainer, ad hoc fees, or other consulting income from: Alcon, Bausch & Lomb, ISTA, Ocular Systems, Ocular Therapeutix, PowerVision, and SARCode Bioscience.
Dr. Kim joined a faculty of experts tolook at “Knocking Down Inflammatory Barriers to Success in Refractive Cataract Surgery” at an EyeWorld CME Educationsymposium held at the 2013 ASCRS•ASOASymposium & Congress. Their objectiveswere to recognize the impact of ocular inflammation on outcomes in refractivecataract surgery, understand the role of anti-inflammatory therapies in mediating andpreventing anterior and posterior segmentocular tissue response throughout the in-flammatory cascade, and identify strategiesto prevent edema and relieve pain by maxi-mizing the formulation of anti-inflamma-tory agents to enhance their penetrationinto target tissues.
This CME supplement is supported by an unrestrictededucational grant from Bausch + Lomb.
• Understand the role of anti-inflammatorytherapies in mediating or preventing oculartissue response throughout the inflammatorycascade; and• Identify strategies to prevent edema and relieve pain by maximizing the penetration vehicle of anti-inflammatory agents into targettissues.
Designation StatementThe American Society of Cataract and Refrac-tive Surgery designates this live educationalactivity for a maximum of 0.5 AMA PRA Cate-gory 1 Credits.™ Physicians should claim onlycredit commensurate with the extent of theirparticipation in the activity.
Financial Interest DisclosuresThe faculty have disclosed the following financial interest relationships within the last 12 months:
Francis S. Mah, MD, has received a retainer, ad hoc fees, or otherconsulting income from: Alcon, ForSight Labs, and ISTA. He is amember of the speakers bureau of Allergan and Bausch & Lomb.
Keith A. Warren, MD, has received a retainer, ad hoc fees, or otherconsulting income and is a member of the speakers bureau of:Alcon, Dutch Ophthalmic USA, and Genentech.
Staff member Laura Johnson has no financial interests to disclose.
Claiming CreditTo claim credit, participants must visitwww.CMESupplement.eyeworld.org to review educational content and downloadthe post-activity test and credit claim. Allparticipants must pass the post-activity testwith a score of 75% or higher to earn credit.Standard internet access is required. AdobeAcrobat Reader is needed to view the mate-rials. CME credit is valid through January30, 2014. CME credit will not be awardedafter that date.
Notice of Off-Label UsePresentationsThis activity may include presentations on
drugs or devices or uses of drugs or devicesthat may not have been approved by theFood and Drug Administration (FDA) or havebeen approved by the FDA for specific usesonly.
ADA/Special AccommodationsASCRS and EyeWorld fully comply with thelegal requirements of the Americans withDisabilities Act (ADA) and the rules and reg-ulations thereof. Any participant in this edu-cational program who requires specialaccommodations or services should contactLaura Johnson at [email protected] or703-591-2220.
ASCRS
“The optimized pH represents an ad-vanced formulation designed to facilitatepenetration into the eye,” said Dr. Kim,adding that it will be available as 1.6 mLand 3 mL in a 7.5-mL bottle.
Nepafenac, on the other hand, is nowavailable in a higher concentration of 0.3%,Ilevro. Originally available at a concentra-tion of 0.1% (Nevanac), the new formula-tion is also approved for once-a-day dosing1 day preop, on the day of surgery, and 2weeks postoperatively, and will be availableas 1.7 mL in a 4-mL bottle.
In terms of corticosteroids, Durezol (difluprednate emulsion 0.05%) is not new,having been launched in 2008. However,said Dr. Kim, “The launch of difluprednaterepresented a new class of corticosteroidmedication that we had not seen in quite afew years. It is indicated for the treatment of inflammation and pain associated withocular surgery and anterior uveitis with QIDdosing.”
More recently approved for the sameindications is Lotemax gel (loteprednol ophthalmic gel 0.5%), which uses a uniqueand innovative mucoadhesive technology toensure adherence to the ocular surface andenhance penetration into the eye.
Impact of inflammation on the posterior segment and the role of anti-inflammatory therapy“As a retinal surgeon dealing with patientswho have posterior segment disease, manytimes I’m the person that’s bringing a gunto a knife fight,” said Keith A. Warren, MD,professor of ophthalmology, University of Kansas, and founder, Warren Retina Associates, Overland Park, Kan. “For these patients, you really don’t want any inflam-mation so it becomes very important to tryto stem that.”
Dr. Warren offered a retina specialist’sperspective on the effects of inflammationduring refractive cataract surgery, highlight-ing its impact on the posterior segment andthe role of anti-inflammatory therapy.
Dr. Warren believes that patients un-dergoing refractive cataract surgery “havelittle or no tolerance” for any intraocular inflammation. Advanced technology IOLs,such as multifocal IOLs in particular, don’twork if inflammation is present.
“Basically, [patients] want to get theirmoney’s worth,” he said. “Inflammatorycontrol in refractive cataract surgery pa-tients is tantamount to any successful out-come.”
Common pathophysiologyMany retinal diseases share a common in-flammatory pathophysiology. In particular,surgeons performing refractive cataract sur-gery should remember that pseudophakiccystoid macular edema (CME) occurs bysimilar mechanisms.
During surgery, inflammation is causedby the release of cytokines and other signalsmeant to induce protection against insultsto the body. In the uveal tract, inflamma-tion thus occurs by a number of mecha-
nisms, but is ultimately characterized by abreakdown in the blood–retina barrier. Thisin turn leads to leakage of proteinaceousfluid, leading to swelling in the retina andin the ocular media.
This inflammation, with its resultingprostaglandin-mediated breach of theblood–retina barrier, puts any patient under-going refractive cataract surgery at high riskfor CME.
CME is a late onset complication, usually occurring 4-6 weeks after surgery.Studies have shown that increased retinalthickening occurs in a staggering 12% ofcases following uncomplicated cataract sur-gery,1 appearing 4-6 weeks after surgery.2
A full evaluation of each patient shouldbe conducted prior to surgery. This includesidentifying risk factors in the clinical historyby examining factors such as duration ofsystemic disease, length of surgery, compli-cations that may have occurred during sur-gery, and co-morbidities such as diabetes, aswell as conducting a thorough preop examto look for any signs of pre-existingretinopathy (Figure 1).
Dr. Warren also recommended perform-ing optical coherence tomography (OCT)during preop evaluation. The precise meas-urement of the retinal thickness provided byOCT allows surgeons to evaluate risk, helpsthem educate patients regarding their pre-and postop outcomes, and provides an ob-jective way to monitor response to therapy.
Steroids, NSAIDs, anti-VEGFWhen approaching the patient at risk, corti-costeroids are the drug of choice for treatinginflammatory diseases including CME andshould be used at maximum strength pre-and postop to control inflammation. Theyare the best agents because their mechanismof action is very broad and non-specific:They regulate VEGF production and expression as well as inhibit the release
of cytokines and other inflammatory mediators; in short, they influence multiplepathways in the inflammatory cascade.
Prednisolone acetate 1% has been the“standard of care” in the U.S.,3 having beenused as a comparator in clinical trials formore than 20 years, but newer formulationssuch as difluprednate and loteprednol gelare certainly worth considering.
For instance, being a prodrug allows di-fluprednate to rapidly penetrate the cornealepithelium and maintain a consistent con-centration of a high level of drug in the target tissue. The drug is formulated as anemulsion to further improve dose unifor-mity—without requiring shaking—com-pared with prednisolone suspension.
Meanwhile, the mucoadhesive technol-ogy used in loteprednol gel facilitates betteradherence to the ocular surface, thus also allowing for better penetration of the drugand higher concentrations in the target tis-sue.
In addition to corticosteroids, NSAIDscan be used as indicated for postoperativepain and inflammation. It should be notedthat while none are indicated for CME,studies have shown that newer NSAIDs havesome efficacy in both prophylaxis and treat-ment of the condition.4,5
NSAIDs have a narrower, more specificmechanism of action. They are believed towork by cyclooxygenase (COX) enzyme inhibition, thereby reducing prostaglandinproduction. Of the two COX isoforms,COX-2 is induced by trauma—i.e., surgery—and so is the primary target for inhibitionwith NSAIDs. Newer NSAIDs may addressmore COX-2-mediated prostaglandin synthesis.
The use of NSAIDs has other benefits,including the induction of a larger pupil fora longer duration of time, as well as reduc-tions in both postoperative pain and photo-phobia.5,6
Figure 1. Risk factors for CME
A third modality for treating inflamma-tion comes from the retinal surgeon’s arena.Anti-VEGF therapy uses molecules designedto competitively inhibit the VEGF molecule—which is known to induce endothelial cellvasodilation and promote vascular perme-ability, leading to vascular leakage and theformation of secondary CME. Indicated forexudative macular degeneration and usedoff-label to treat a variety of ocular condi-tions, anti-VEGF therapy is particularly use-ful in eyes that have had longstanding CMEthat is unresponsive to other treatmentmodalities.
In cases where first-line treatment witha single agent fails, combination therapy isuseful. By combining different modalities—corticosteroids with NSAIDs and/or anti-VEGF therapy—pharmacological intervention occurs at multiple, separate sitesof action, allowing for a synergistic effect.
Treatment stratificationDr. Warren stratifies his approach to CMEtreatment according to the duration of thedisease. For acute CME occurring 4-6 weekspostop, he uses a combination of a topicalsteroid and NSAID. For persistent or resist-ant CME (around 8 weeks postop), he uses atopical steroid or sub-Tenon’s injection andan NSAID. For chronic/resistant CME(around 12 weeks postop), he uses an in-traocular steroid injection combined withan NSAID. For recalcitrant CME (4-6 monthsor greater), he would combine an intraocu-lar steroid, an anti-VEGF agent and anNSAID, and may consider vitrectomy and/ora steroid implant.
Surgeons should keep in mind that upto 20% of patients treated for CME may re-bound after discontinuation of treatment.For such cases, Dr. Warren uses a steroid andan NSAID, with the steroid tapered over 6-8weeks.
But what’s really important to keep inmind, said Dr. Warren, is that once CME occurs, the patient will have persistent reduction in contrast sensitivity and colordesaturation. “The goal here is to preventthis with prophylaxis,” he said.
Impact of inflammation on the anterior segment and the role of anti-inflammatory therapy“Inflammation affects the entire eye, frontto back,” said Uday Devgan, MD, chief ofophthalmology, Olive View UCLA MedicalCenter, and associate clinical professor,UCLA School of Medicine, Los Angeles. Itaffects the cornea, the anterior chamber andangle, the iris and ciliary body, the lens capsule, as well as the posterior segment and retina.
In the anterior segment, inflammationmanifests clinically as hyperemia, miosis,impaired vision, and pain; in the posteriorsegment, diminished visual acuity may beseen secondary to CME. Postop inflamma-tion typically consists of mild iritis, withclinical signs of ocular inflammation, including cells and flare in the anterior
chamber; more severe cases may also in-clude significant reduction in vision, as wellas pain, redness, and periocular swelling.
Postop inflammation, said Dr. Devgan,is “certainly something that we need totreat, especially with premium lenses thatrequire a really quiet eye, good tear film,and no inflammation for the best visual re-sults.”
“Inflammation slows visual recovery,”he added. Fighting inflammation withNSAIDs and steroids together can thereforenot only reduce postop inflammation andpain, but also improve visual recovery.
Inflammation cascadeSeveral factors influence inflammation afterrefractive cataract surgery—inherent patientfactors such as cataract density, iris color,and the patient’s age, as well as surgical factors such as the volume of balanced saltsolution run through the eye during surgeryand total surgical time. The surgery itself isassociated with physical trauma that in-duces the inflammatory response.
Inflammation is the endpoint of thearachidonic acid cascade, which, physiologi-cally, follows the conversion of arachidonicacids into prostaglandins. The cascade thus
provides targets for pharmaceutical therapy:Anti-inflammatory medication can blockdifferent portions of the pathway, withsteroids interfering with the activity ofphospholipase A2, thus inhibiting the re-lease of arachidonic acid and arachidonicacid metabolites early in the cascade, andNSAIDs interfering with the activity ofCOX-1 and COX-2 receptors to inhibitprostaglandin synthesis.
Together, steroids and NSAIDs can beused to resolve the anterior chamber cellsand flare of inflammation and increase patient comfort. NSAIDs are also used routinely in prophylaxis, administered toprevent inflammation, and while steroidsare not used routinely, they can be, said Dr.Devgan. In fact, in his routine preop dosingregimen, Dr. Devgan starts both steroids andNSAIDs together.
“If you’re going to start with NSAIDs,you may as well start with steroids too,” saidDr. Devgan.
A logical approachSince inflammation starts immediately, it islogical to get both steroids and NSAIDs intothe eye before the first incision. Starting thedrugs before the surgery allows the drug to
Figure 2. CME treatment, stratified by duration of disease
• Acute CME: 4-6 weeks post-op – Treat with topical steroid and NSAID
• Persistent or resistant CME (8 weeks or greater) – Treat with topicalsteroid or sub-Tenon’s injection + NSAID
• Chronic/resistant CME (12 weeks or greater) – Treat with intraocularsteroid injection + NSAID
• Recalcitrant CME (4-6 months or greater) – Treat with intraocularsteroid + anti-VEGF + NSAID, vitrectomy or perhaps steroid implant
• Rebound CME, recurring after discontinuation of topical therapy –Treat with steroid + NSAID, with the steroid tapered over 6-8 weeks
Figure 3. Achieving therapeutic steady state: 1 day vs. 3 days preop
achieve tissue levels before surgery, since ittakes about three to five doses on average toachieve steady state (Figure 3). Preop dosingalso attenuates the inflammatory responseand gets patients in the habit of usingdrops.
After surgery, both steroids and NSAIDsare indicated for use out to 14 days postop.Steroids in particular should be used to“hammer the inflammation”—hit inflam-mation hard with more frequent dosing initially, taking advantage of the immediatepostop period when compliance is at itsbest. When the steroids are no longerneeded, they should be tapered off, unlikeNSAIDs, which are simply discontinued.
Dr. Devgan’s routine is to begin topicalNSAIDs, steroids, and an antibiotic 3 daysbefore surgery, continuing the NSAID out to6 weeks, the steroid BID for 1 week followedby once a day for another week, and the antibiotic TID for 1 week after surgery.
The bottom line, said Dr. Devgan, is“use your clinical judgment. Determinewhen the inflammation is resolved, and tailor the treatment to the patient.”
Postop recovery, he added, is as impor-tant as surgical technique.
Risk factors for steroid responseamong cataract patientsIn his own private practice, David F.Chang, MD, clinical professor of ophthal-mology, University of California, Los Altos,Calif., had noticed how an occasional patient would present with an alarming in-crease in IOP shortly after cataract surgery.
“The IOP would be up to 50 or 60 mmHg, and the patients had called becausetheir vision was blacking out when theywould bend over,” he said. “They alwaysseemed to be young, really high myopes,and they might present less than one weekfollowing uncomplicated surgery.”
Dr. Chang diagnosed these patients assteroid responders because these were pres-sure spikes following normal postop day 1tonometry, and the pressure would normal-ize after stopping the topical steroid.
Dr. Chang described the results of a retrospective study he conducted to identifythe risk factors in these cases, presentingdata recently published in the Journal ofCataract & Refractive Surgery.7 “If you reviewthe literature, the only published risk factorfor a steroid response is open-angle glau-coma,” he said.
In a chart review covering a 2-year pe-riod, Dr. Chang and his colleagues gathereddata on 1,642 consecutive patients. All thepatients underwent phacoemulsificationwith IOL implantation and had received auniform treatment regimen of 1% pred-nisolone acetate three times a day for 2weeks, then twice a day for 2-3 weeks. Eachpatient also received a topical NSAID and anantibiotic.
Dr. Chang analyzed age and axiallength measurements using the IOLMaster,always taking the first eye in a bilateralcataract surgical patient. IOP measurementswere recorded preop, at postop day 1, and at
least one additional time between 2 and 4weeks after surgery.
He defined steroid responders as patients who underwent uncomplicated surgery but had an IOP measurement of atleast 28 mm Hg beyond the first 72 hoursafter surgery, to exclude surgical factors suchas retained OVD or corneal edema. Exclu-sion criteria included any hyphema, endophthalmitis, or TASS. “We decided touse 28 mm Hg as our threshold becausemany of us would alter or initiate treatmentat this IOP level,” Dr. Chang explained.
To be sure that it was drug induced, anIOP elevation of ≥25% on steroid and anIOP drop of ≥25% off steroid was requiredfor the patient to be classified as a steroid responder.
After excluding patients who were notprescribed steroids (e.g., known responders,herpetic eye disease), a total number of1,613 consecutive patients had uncompli-cated surgeries and were taking topicalsteroids postoperatively. Of these patients,39 (2.4%) had IOPs of ≥28 mm Hg, 15(0.9%) had IOPs of ≥35 mm Hg, and 7(0.4%) had IOPs in the range of 40-68 mmHg. Of the 7 patients with alarmingly highIOPs, 6 were <65 years old, 4 were high my-opes, and 6 were diagnosed early—between5 and 14 days after surgery. Of the 39 patients exceeding the threshold 28 mm HgIOP for steroid response, only 6 had aknown risk factor—open-angle glaucoma.
This left 85% without any known riskfactors. By analyzing the 39 steroid respon-
Figure 4. Cumulative % steroid responders by age and axial length
Figure 5. Steroid responder odds ratios, with treatment stratification by risk
Improving drug deliveryThe basic challenge, said Dr. Mah, is thattypically out of an average of 50 microlitersof medication dropped onto the eye andthrough various mechanisms includingspillage, lacrimation and blinking, tear filmturnover, and conjunctival and scleral absorption, only about 5% of the total dose actually enters the eye to work as intended10,11,12 (Figure 6).
Attaining an optimal drug concentra-tion at the site of action thus presents amajor problem in ocular therapeutics.
Strategies to improve drug deliveryfocus on overcoming two basic challenges:minimizing precorneal drug loss and maxi-mizing corneal drug absorption. This isachieved by increasing the effective dose,utilizing molecular design, and/or utilizingformulation science (Figure 7).
The first strategy, increasing the effec-tive dose, may mean increasing the concen-tration of the active drug, such as with thelatest formulation of nepafenac (0.3% from0.1%), and/or decreasing the size of the suspension particles such as the 40% reduc-tion of the new nepafenac formulation. Although increasing the dosing frequencymay also increase the effective dose, Dr.Mah said, increasing the dosing frequency isnot a very favorable approach since it alsodecreases patient compliance. Reducingdrug concentrations may seem counter toincreasing the effective dose, if the efficacycan be optimized using other methods, the advantage is the potential to reduce unwanted side effects. This was the strategyfor the new formulation of bromfenac(0.07% from 0.09%).
The second strategy uses molecular de-sign to increase lipophilicity and solubility.
ders, Dr. Chang and his colleagues were ableto identify two factors significantly associ-ated with IOP response.
First was age. The mean age of thesteroid responders was significantly lowerthan the mean age of the non-responders,61.3±11.8 years vs. 71.8±11.7 years, respec-tively (p<0.01).
Second was axial length. The respon-ders had significantly longer eyes than thenon-responders, 25.59±3.0 mm vs.24.33±1.75 mm, respectively (p<0.01).
The significance of these risk factors becomes even clearer when the data is strati-fied (Figures 4 and 5). In terms of age, pa-tients 40-54 years old are four times morelikely to be steroid responders than patients≥65 years old. In terms of myopia, the riskof steroid response rose with increasingaxial length. Compared to eyes <25.0 mmlong, eyes longer than 27 mm had a morethan 5-fold increase in risk and those longerthan 29.0 mm had more than a 14-fold in-crease in risk (Figures 4 and 5).
Taken together, the youngest patients(40-54 years old) with the longest eyes(≥29.0 mm) have a markedly greater 46-foldincrease in steroid response risk comparedto older patients (≥65 years old) with nor-mal axial length (<25.0 mm)—35.7% vs.0.7%, respectively.
Interestingly, these ratios were thesame across the spectrum of steroid respon-ders regardless of the severity of IOP in-crease—meaning these risk factors do notappear to influence the severity of the re-sponse.
This risk stratification has given Dr.Chang the opportunity to customize his ap-proach to postoperative steroid use follow-ing cataract surgery, particularly in light of published studies that suggest steroid responders may be more tolerant ofloteprednol etabonate 0.5% than of othercorticosteroids.8,9 Where patients have a sig-nificantly higher odds ratio of a steroid re-sponse —i.e., patients less than 65 years oldwith an axial length of 25.0-29.0 mm (redbox in Figure 5)—he uses loteprednol,avoids difluprednate, and monitors the IOPmore closely. For patients at highest risk—i.e., patients of all ages with axial lengths>29.0 mm (green box in Figure 5)—he usestopical NSAIDs only, opting to add lotepred-nol only if necessitated by factors such asgreater inflammation, with the addition ofprophylactic topical glaucoma medicationto prevent an IOP spike.
This study is the first to correlatesteroid response to high myopia and thefirst to tie steroid response to younger age interms of topical as opposed to intravitrealmedication.
The two risk factors combined result ina very high percentage of steroid respon-ders. For these eyes, loteprednol etabonate0.5% offers a possibly safer alternative, andDr. Chang’s subsequent clinical experiencebears this out.
Medication vehicles: Strategies to prevent edema and relieve pain“Medications, as we all know, are a little bitmore than just the active ingredients,” saidFrancis S. Mah, MD, director, cornea andexternal disease, and co-director, refractivesurgery, Scripps Clinic, La Jolla, Calif. Everybottle of medication includes other compo-nents, such as preservatives, drug deliverysystems, viscosity increasing agents, buffers,stabilizers, and carrier vehicles.
“It’s a very special scenario that wehave with the eye because we put these eyedrops directly onto the place of therapy,”said Dr. Mah. The medication vehicle thus“plays a huge role in terms not only of effi-cacy, but of safety and tolerability as well.”
In fact, safety is a major part of the de-sign of newer formulations of steroids andNSAIDs, particularly in terms of medicationvehicles. “We want to reduce as much aspossible the baggage that comes along withmedications,” he said. “In general, we try tohave the lowest concentrations that willprovide the efficacy of the drug, and we tryto optimize the preservatives so that we re-duce any potential for toxicity.”
In addition to safety, medication vehi-cles provide opportunities to enhance effi-cacy through increased penetration andtissue concentrations. Medication vehiclescan, for instance, increase the solubility ofdrugs. The cornea, said Dr. Mah, provides astrong barrier to the entry of these drugsinto the eye due to its biphasic structure,with lipophilic epithelial and endotheliallayers combined with a hydrophilic stroma.Medication vehicles provide ways to over-come that barrier, thus helping to optimizedosing, ideally reducing dose frequency, resulting in improved patient compliance.
Figure 6. Topical ocular drug deposition
Lipophilicity can be increased by usingunique chemical structures. The chemicalnature of bromfenac is hydrophilic, thusformulation pH and vehicle are key to facili-tating rapid penetration to produce earlyand sustained drug levels, which has beenaccomplished in the new formulation.Meanwhile, nepafenac is a prodrug, a prop-erty that allows it to rapidly and safely crossthe cornea.
Lowering the pH can decrease thecharge, increasing lipophilicity, and facili-tate corneal penetration of NSAIDs. Thenewer bromfenac formulation lowers the pHof the original bromfenac formulation, from8.3 to 7.8 (closer to the 7.4 pH of tear fluid).This decreases the charge, increases thelipophilicity, and so increases the drug delivery into the eye. This strategy has alsobeen used by the new nepafenac formula-tion showing the importance of this prop-erty for topical NSAIDs.
A third strategy is to use formulationscience to increase viscosity. An example ofthis is to use a mucoadhesive matrix such aspolycarbophil USP, which stays in contactwith the conjunctiva and delivers the drugto the surface of the eye over a period ofhours, thus increasing the bioavailability ofthe drug. This is the vehicle used inloteprednol gel. Other medications such asthe new nepafenac formulation use guargum, which acts as a stabilizer, emulsifier,thickening, and suspending agent, or lipidemulsion technology such as the diflupred-nate formulation to increase viscosity,corneal penetration, and residence time,and so bioavailability.
These technologies also mean that thenewer drugs do not need shaking—the drug
remains suspended evenly. This improvesdrug delivery so that drop-to-drop varianceof drug does not occur. This is especially important considering prednisolone acetate1%, for example, may vary from 0% drug to700% depending on shaking or not and bot-tle inversion.
Preservatives – a necessary evilRecent years have seen some controversyover another component of modern drugs—preservatives. However, Dr. Mah called thema “necessary evil,” used to prevent microbialactivity and prolong the shelf life of drugs.Two primary preservatives are used in anti-inflammatory agents: sorbic acid and benza-lkonium chloride (BAK).
Sorbic acid has long been used in artifi-cial tears because it causes only minimal irri-tation or damage to the ocular tissues and isthus recommended for sensitive eyes. Mean-while, according to Dr. Mah, 72% of oph-thalmic medications are preserved withBAK. One of the benefits of using this sub-stance with its mild toxicity is that it en-hances drug penetration through the corneaby breaking epithelial bonds. This toxicity isdose dependent, and newer anti-inflamma-tory formulations contain lower concentra-tions.
Not all the sameIt is important to note that not all medica-tion vehicles are the same. The distinction isparticularly important when consideringgeneric drugs. Unlike branded drugs, gener-ics can be approved without clinical studiesto show efficacy or safety; rather, they onlyneed to show 80% bioequivalence in thebottle.
“I personally recommend brandedmedications to all my patients,” said Dr.Mah.
An additional issue surroundinggeneric drugs is the Supreme Court rulingthat states that companies that manufacturegeneric medication are not responsible forthe product insert and the label, and aretherefore not liable if a patient has a compli-cation with these drugs. This may shift theliability to the prescribing surgeons andtheir offices, hospitals, and surgical centers.Dr. Mah suggested that it may be necessaryto provide written consent or acknowledge-ment stating that patients prescribed withgeneric drugs have been informed of and accept the risks of taking medication notbacked by efficacy and safety studies.
The issues of liability aside, it is a significant comfort to know that there are excellent quality products available, de-signed to deliver the optimum therapeuticeffect with the fewest unwanted side effects, rigorously studied in clinical trials to showefficacy and safety.
References1. McColgin AZ, Raizman MB. Invest OphthalmolVis Sci. 1999;40(S289).2. Mishima H, Masuda K, et al. Prog Clin Res.1989;31:251-264.3. Raizman MB et al. Curr Med Res Opin.2007;23:2325-31.4. Heier JS, Topping TM, Baumann W, et al. Ophthalmology 2000;107:2034-8. 5. Warren KA, Fox JE. Retina 2008;28:1427-1434.6. Hariprasad SM et al. Clin Ophthalmol2009;3:147-154.7. Chang DF, Tan JJ, Tripodis Y. Risk factors forsteroid response among cataract patients. JCataract Refract Surg. 2011 Apr;37(4):675-81.8. Bartlett JD, Horwitz B, Laibovits R, Howes JF.Intraocular pressure response to loteprednoletabonate in known steroid responders. J OculPharmacol. 1993;9:157-165. 9. Holland EJ, Djalilian AR, Sanderson JP. Attenua-tion of ocular hypertension with the use of topicalloteprednol etabonate 0.5% in steroid respondersafter corneal transplantation. Cornea2009;28:1139-1143.10. Ghate D and Edelhauser HF. Expert Opin DrugDeliv. 2006;3:275-287.11. Gaudana R. et al. AAPS J. 2010;12:340-360.12. Coffey MJ et al. Manuscript in preparation.
Contact informationChang: [email protected]: [email protected]: [email protected]: [email protected]: [email protected]
Figure 7. Strategies to improve ocular drug delivery
At the 2013 ASCRS•ASOA Symposium & Congress, morethan 1,000 physicians respondedto an important new clinicaltrends survey that will continue
to be assessed each year. The survey askedASCRS members more than 85 key ques-tions relating to current issues they face ona regular basis. The goal is to obtain opin-ion from a significant percentage of themembership and to have the results re-viewed and interpreted by the ASCRS Clini-cal Committees. If the Committeesdetermine there exists a gap between cur-rent programming and membership view-points, understanding or practice patterns,the information will be used to address fu-ture education efforts, both in the mainprogram and through ASCRS’ CME educa-tional grants. Data collected from the an-nual survey will provide a solid basis fortracking ASCRS’ progress in resolving theseeducation gaps.
Many topics related to post cataractsurgery inflammation were a part of thissurvey. These included topics on the level of inflammation currently seen by ASCRSmembers, the impact of low to moderate inflammation on outcomes, current thera-peutic trends, and perspectives on genericsubstitutions.
When asked the normal levels of in-flammation they would expect aftercataract surgery, most responded that theywould consider between trace to 1+ celland flare at day 1 postop after cataract sur-gery as normal. Specifically, 56% view thislevel as normal, while 30% of members ex-pect between zero and trace cell and flarepostop on an average basis. Only 15% ex-pect to see 1+ cell and flare in postop “nor-mal” cataract patients.
In another question, survey respon-dents were asked to move from their ex-pected inflammation levels to the actualpercentage of cataract patients they seewho have 1+ cell and flare postopera-tively. Sixteen percent have under 1% ofpatients at this 1+ cell/flare level, while32% have under 2% at this level. On theother hand, 29% of respondents have 20%or more of their patients with 1+cell/flare. So there seems to be a relativelywide variation in the incidence of moder-ate inflammation among survey respon-dents.
The clinical impact of low to moder-ate ocular inflammation is often de-bated. When survey respondents wereasked about the clinical impact of this levelof inflammation, most agreed that it had asignificant impact on variability in visualacuity and quality results (71%), visual re-covery time (81%), or patient comfort andsatisfaction (83%).
What percentage of your cataract patients has 1+ cells/flare or greater postoperatively?
Percentage of survey respondents using the following pharmaceuticalsat the following timeframes before and after cataract surgery:
How important do you believe that it is to use BOTHNSAIDs and corticosteroids to block the inflammatorycascade after cataract surgery, when indicated?
Steroids NSAIDs Antibiotics
3 days preop 19% 43% 43%
1 day preop 16% 32% 33%
Intraop 27% 16% 40%
1 day postop 67% 42% 51%
Do not use 5% 14% 3%
Key inflammation practice patterns and clinical opinions of ASCRS members
CME Questions (Circle the correct answer)
Copyright 2013 ASCRS Ophthalmic Corporation. All rights reserved. The views expressed here do not necessarily reflect those of the editor, editorial board, or the publisher, and in no way imply endorsement by EyeWorld or ASCRS.
1. According to Dr. Devgan, how many days after cataract surgery are steroids and NSAIDs indicated for?
a. 1 dayb. 7 daysc. 14 daysd. 28 days
2. According to Dr. Chang, which of the following factors were associated with“steroid responders” or patients who presented with an elevated IOP after cataract surgery?
a. High myopia and younger ageb. Low myopia and younger agec. High myopia and older aged. Low myopia and older age
3. According to Dr. Mah, of the 50 microlitersof medication dropped into the eye, whatpercentage of the total dose actually entersthe eye to work as intended?
a. 50%b. 25%c. 10%d. 5%
4. Which of the following is NOT a strategyidentified by Dr. Mah on how to improvedrug delivery to the eye?
a. Increase effective doseb. Increase lipophilicity and solubility
with molecular designc. Increase viscosity with formulation scienced. Combine with other drugs
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