Matthew Cantrell

Intraoperative Floppy Iris Syndrome Associated with α1-Adrenergic Receptor Antagonists

OBJECTIVE: To describe intraoperative floppy iris syndrome (IFIS) in association with α1-adrenergic receptor (α1AR) antagonists by conducting a thorough literature review. DATA SYNTHESIS: Literature retrieval was accomplished by searching MEDLINE (2000–December 2007) using the terms intraoperative floppy iris syndrome (IFIS), adrenergic α-antagonist(s), tamsulosin, doxazosin, terazosin, and/or alfuzosin. In addition, reference lists from identified publications were reviewed to identify additional reports and studies of interest. STUDY SELECTION AND DATA EXTRACTION: All articles in English identified from data sources were reviewed for relevance and uniqueness prior to inclusion. DATA SYNTHESIS: IFIS was first described in 2005 as a clinical triad observed during cataract surgery that includes fluttering and billowing of the iris stroma, propensity for iris prolapse, and constriction of the pupil. IFIS increases the risk of complications during cataract surgery. Numerous reports have linked IFIS to use of α1AR antagonists, most notably tamsulosin, which is prescribed for benign prostatic hyperplasia. Tamsulosin blocks prostatic α1AARs but may also selectively block α1AARs in the iris dilator muscle, preventing mydriasis during cataract surgery. Other α1AR antagonists, including terazosin, doxazosin, and alfuzosin, have also been linked to IFIS; however, their relationship to the syndrome is not as definitive. When ophthalmologists are aware of a patients previous α1AR antagonist exposure, specific steps can be taken to reduce the risk of surgical complications. Corrective measures used during surgery have included iris expansion hooks, intracameral phenylephrine, and preoperative atropine. CONCLUSIONS: IFIS is a clinical syndrome observed during cataract surgery reported in patients taking systemic α1AR antagonists. It has been most strongly linked to use of tamsulosin. Medication washout periods of up to 2 weeks and specific surgical procedures have been attempted to reduce risk of complications from α1AR antagonists in the setting of cataract surgery. Patients should be educated regarding potential risks of this drug class so that they can discuss them with their healthcare providers, specifically ophthalmologists, prior to cataract surgery.

Alvimopan for postoperative ileus

PURPOSE The efficacy, safety, pharmacology, pharmacokinetics, drug-drug interactions, and administration of alvimopan for postoperative ileus are reviewed. SUMMARY Alvimopan is a selective mu-opioid receptor antagonist with no central nervous system activity. When orally administered after partial small- or large-bowel resection in patients with primary anastomosis, alvimopan shortened the return of bowel function and time to discharge by approximately one day without compromising analgesia. Alvimopan was not shown to be beneficial on these same outcomes after hysterectomy and has not been studied in other surgical populations. Alvimopan is generally well tolerated, with the frequency of adverse events being similar to placebo when used postoperatively for one week or less. Long-term studies of alvimopan in opioid-induced bowel dysfunction have shown an association with adverse cardiovascular outcomes, neoplasms, and fractures. Because of these concerns, the Entereg Access Support and Education program was developed. The recommended dosage of alvimopan is 12 mg administered with a sip of water 30 minutes to five hours before surgery, followed by 12 mg twice daily beginning the day after surgery for a maximum of seven days, 15 total doses, or until discharge. There is a limited amount of pharmacoeconomic analysis concerning alvimopan. CONCLUSION Alvimopan, a peripherally acting mu-opioid receptor antagonist, is a novel agent for the treatment of postoperative ileus. It appears to decrease the duration of postoperative ileus and hospitalization by approximately one day, theoretically offsetting its acquisition costs. Unresolved long-term safety issues, a limited indication, and its restricted-access program are likely to hinder its widespread use in the surgical population.

Silodosin for Benign Prostatic Hyperplasia

Objective: To review the pharmacology, pharmacokinetics, clinical trials, and safety of silodosin, a recently approved α1A-adrenergic receptor (AR) antagonist for benign prostatic hyperplasia (BPH). Data Sources: English-only articles obtained from MEDLINE (1966–October 2009) using the search terms silodosin and KMD-3213 were reviewed. In addition, a search of International Pharmaceutical Abstracts (1970–October 2009) was conducted. Study Selection and Data Extraction: Available English-language articles were reviewed, as well as abstracts from available non-English articles. Data Synthesis: Silodosin reduces urinary symptoms associated with BPH in as little as 1 day after initiation. The largest clinical trial conducted to date demonstrated a decrease in International Prostate Symptom Score of –6.4 ± 6.63 points compared to –3.5 ± 5.84 in patients receiving placebo (p < 0.0001). Silodosin also improved urinary flow rates by approximately 2.8 ± 3.44 mL/sec, which is comparable to other α1-AR antagonists. The usual dose of silodosin is 8 mg once daily and should be reduced to 4 mg for patients with moderate renal dysfunction. Use is contra indicated in patients with severe renal and hepatic impairment or taking strong CYP3A4 inhibitors. In clinical trials, the most prevalent adverse effects were ejaculatory disturbances, occurring in approximately 28% of patients, although only 2.8% of patients discontinued treatment due to this adverse effect. Preliminary data suggest that, similar to other third-generation α1A-AR antagonists, silodosin has little potential to cause significant cardiovascular adverse effects such as orthostatic hypotension or syncope. To confirm these findings, long-term studies are still needed, especially in patients taking antihypertensive agents and in those with a history of intolerance to other α1-AR antagonists. Conclusions: Silodosin was approved by the Food and Drug Administration in 2008. Long-term studies demonstrating improvement in clinically Important outcomes of BPH have yet to be published. In addition, pharmacoeconomic analyses would assist in defining its current place in therapy. Until this information is available, silodosin may be best reserved as an alternative to other second- and third-generation α1-AR antagonists.

Factors Associated With Students’ Perception of Preceptor Excellence

Objectives. To identify factors associated with preceptor excellence as rated by student pharmacists and to assess the correlation of excellent ratings with years as pharmacist, specialty certification, and faculty appointment status. Methods. A retrospective analysis of student pharmacist evaluations of preceptors from May 2009 to May 2012 was completed to determine factors associated with preceptor excellence. Results. Preceptors who showed an interest in teaching, related to the student as an individual, encouraged discussion, were accessible, provided feedback, served as a role model, were organized, and/or spent increased time with students were more likely to be rated excellent. Conclusion. Serving as role models and showing an interest in teaching demonstrated the strongest association with being an excellent preceptor. Identifying factors students associate with preceptor excellence may result in enhanced preceptor recruitment, development, and training.

Tadalafil: A Phosphodiesterase-5 Inhibitor for Benign Prostatic Hyperplasia

Tadalafil is a phosphodisesterase (PDE)‐5 inhibitor recently approved by the United States Food and Drug Administration for lower urinary tracts symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). The mechanism for improved LUTS is thought to be related to three principal theories: alterations in nitric oxide levels, Rho‐associated protein kinase deactivation, and reductions in pelvic atherosclerosis. The efficacy of PDE‐5 inhibitors for the treatment of LUTS associated with BPH has been demonstrated in several randomized placebo‐controlled trials. Tadalafil is thought to be superior based on an extended half‐life; however, other PDE‐5 inhibitors have positive results in BPH and have not been proved to be inferior to tadalafil. Before administration, concomitant use of medications such as nonselective α‐adrenergic antagonists, nitrates, and cytochrome P450 inhibitors should be assessed for possible drug interactions. Potential adverse drug events seen in Food and Drug Administration–approved tadalafil include back pain, dyspepsia, headache, and dizziness. Given the efficacy and safety data currently available, the PDE‐5 inhibitor tadalafil represents a reasonable alternative for selected male patients with LUTS associated with BPH, especially with concomitant erectile dysfunction.

Adverse Neuropsychiatric Events Associated with Varenicline Use in Veterans: A Case Series

Varenicline represents a major advance in the treatment of nicotine addiction and has been shown to be safe and effective to promote abstinence. However, in a small number of patients, neuropsychiatric adverse events and worsening of underlying psychiatric conditions have been reported. As the veteran population has higher rates of co-morbid psychiatric conditions and nicotine dependence this population may be at higher risk for serious adverse effects to varenicline warranting close monitoring. Herein we report seven cases of varenicline associated neuropsychiatric adverse events and describe an institutional response to adequately monitor patients to ensure safety and efficacy.

Association Between Topiramate Use and Serum Bicarbonate Levels in a Veteran Population

Background: Topiramate has been associated with metabolic acidosis secondary to decreased serum bicarbonate. Product labeling recommends serum bicarbonate monitoring at baseline and periodically thereafter. Objective: The study objective was to assess changes in serum bicarbonate within the first year of topiramate use in an outpatient veteran population. Methods: This was a single-center, retrospective study conducted at the Iowa City Veterans Affairs Health Care System. Inclusion criteria required a minimum of 1 topiramate outpatient prescription between October 1, 1999, and August 31, 2012, and at least 1 serum bicarbonate level within 12 months prior to topiramate initiation. Patients with topiramate nonadherence, concurrent use of sodium bicarbonate or oral carbonic anhydrase inhibitors, and individual serum bicarbonate values obtained during inpatient hospitalizations were excluded. Change in bicarbonate was evaluated using a paired t test. Decreases in bicarbonate of ≥5 mEq/L, values <20 mEq/L, days to lowest value, and correlation between adverse drug reactions (ADRs) and topiramate discontinuation were evaluated. Results: Of 546 patients reviewed, 350 were included in the analysis. There was a statistically significant decrease of 2.7 mEq/L in bicarbonate following initiation of topiramate. Only 1 patient had a bicarbonate value <17 mEq/L. There was no association between bicarbonate decrease ≥5 mEq/L and ADRs. Conclusions: A statistically significant reduction in bicarbonate levels occurred with topiramate, which was clinically insignificant. ADR occurrence did not correlate with bicarbonate levels <17 mEq/L or a decrease ≥5 mEq/L. Our results indicate that serum bicarbonate levels should only be monitored before topiramate initiation and in patients presenting with symptoms suggestive of acidosis.

Comparative Effectiveness of Anticholinergic Agents for Lower Urinary Tract Symptoms

BACKGROUND Limited data from short-term clinical trials suggest efficacy advantages of solifenacin and fesoterodine over other anticholinergic agents in the treatment of lower urinary tract symptoms. OBJECTIVES To (a) determine the real-world comparative effectiveness of newer anticholinergic agents for lower urinary tract symptoms, as assessed by 1-year persistence, and (b) identify patient factors independently associated with persistence. METHODS We conducted a retrospective cohort study of U.S. veterans initiating newer anticholinergic therapy between October 2007 and August 2015. Multiple log-binomial regression was used to contrast 1-year persistence rates across anticholinergic agents while adjusting for measured confounders. Persistence was selected as a measure of effectiveness because nonpersistence is a common pathway encompassing inefficacy and intolerability, particularly in symptom-driven conditions. RESULTS A total of 26,775 patients were included, of which 10,386 (38.8%) persisted with anticholinergic therapy at 1 year. Using long-acting tolterodine as the reference agent, superior persistence rates were observed for solifenacin (RR = 1.08, 95% CI = 1.03-1.13) and fesoterodine (RR = 1.25, 95% CI = 1.09-1.43), and a lower rate for short-acting tolterodine (RR = 0.90, 95% CI = 0.85-0.94). Patient factors associated with higher persistence rates included older age, male sex, and comorbidities such as multiple sclerosis, Parkinsons disease, and diabetes. CONCLUSIONS Consistent with clinical trial reports, we found evidence for superior effectiveness of solifenacin and fesoterodine relative to other anti-cholinergics and for long-acting formulations over short-acting formulations. DISCLOSURES This work was supported by the Iowa City VA Health Care System and by the Department of Veterans Affairs, Office of Research and Development, Health Services Research and Development Service (CDA 10-017). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the U.S. government. The authors have no conflicts of interest. Study concept and design were contributed by all the authors. Shaw took the lead in data collection, along with Lund, and data interpretation was performed by Lund, Goodson, and Cantrell. The manuscript was written by Goodson, Cantrell, Lund, and Shaw and revised by Lund, Goodson, Cantrell, and Shaw.

Pathophysiology and Pre-Operative Evaluation of Patients at Risk for Intraoperative Floppy Iris Syndrome (IFIS)

Intraoperative Floppy Iris Syndrome (IFIS) has received a significant amount of attention and subsequent research since it was first reported in 2005 (Bell et al., 2009; Blouin et al., 2007; Chang & Campbell, 2005; Chang et al., 2007; Oshika et al., 2007; Srinivasan et al., 2007; Takmaz & Can, 2007). Current and former uses of alpha-1 adrenergic receptor (α1AR) antagonists—most notably tamsulosin—appear to be at the highest risk for this surgical complication (Chang & Campbell, 2005). IFIS is characterized by loss of muscle tone in the iris, thereby preventing mydriasis and involves a triad of pupil constriction, fluttering and billowing of the iris stroma, and propensity for iris prolapse during cataract surgery (Chang & Campbell, 2005). While α1AR antagonists are often used for various urological conditions, they also block α1AR receptors in the iris dilator muscle and may worsen muscle tone and lead to the iris billowing sometimes seen in cataract surgery. Without adequate pupil dilation, IFIS reduces visualization of the surgical field, including the cataract itself. This impairs removal and can lead to other complications including rupture of the posterior capsule, which further increases the risk of other vision-threatening complications of cataract surgery (Schwinn & Afshari, 2006).

Estrogen Therapy: An Approach to Treatment-Resistant Aggressive Behaviors in Patients with Dementia

One of the most challenging aspects in the care of patients with dementing illnesses is management of the neuropsychiatric symptoms, which may include aggression. Aggressive behaviors in elderly patients with dementia may include verbal abuse to caregivers or other patients, inappropriate sexual behaviors, or acts of physical violence (Guay, 2008; Shelton & Brooks, 1999). These behaviors often lead to resistance in activities of daily living for the patient and are distressing to patients, family members, and caregivers alike. Medications currently used to treat neuropsychiatric symptoms, including aggression, include selective serotonin reuptake inhibitors (SSRIs) and antipsychotic agents (Kverno, Rabins, Blass, Hicks, & Black, 2008). However, atypical antipsychotic agents have been associated with an increased risk of cerebrovascular events in patients with dementia, and now include a black box warning regarding this risk (Schneider, Dagerman, & Insel, 2005; Schneider et al., 2006). Other agents used in the management of aggressive symptoms in patients with dementia include benzodiazepines, lipophilic beta blockers, and mood stabilizing agents. (Kverno et al., 2008; Shelton & Brooks, 1999) Treatment responses are variable, and tolerability issues can lead to discontinuation of treatment. Estrogen therapy has been studied as a potential option for the treatment-refractory patient. The mechanism of action of