Role of Phenazopyridine in Urinary Tract Infections Op Gupta*, Kk Aggarwal**

drug review Role of Phenazopyridine in Urinary Tract Infections op gupta*, kk aggarwal**

Abstract Irritative voiding symptoms, urinary urgency, frequency, nocturia, painful voiding, bladder discomfort or stranguria, are to the urinary tract much as a cough is to the pulmonary system, i.e., they are a nonspecific manifestation of multiple potential underlying causes. Urinary tract infections (UTIs) are usually associated with irritative voiding symptoms, such as painful urination (dysuria), urinary urgency and frequency. Anticholinergic drugs like flavoxate, oxybutynin provide beneficial symptomatic relief. However, they have associated adverse anticholinergic effects, such as dry mouth, which hinders patient compliance. Phenazopyridine hydrochloride acts as a topical analgesic on the mucosal lining of the urinary tract and thus relieves the irritative symptoms associated with UTI. It is compatible with antibiotics and relieves pain during the interval before the antibiotic begins to control the infection. It is well-tolerated as it lacks the anticholinergic side effects of other anticholinergics.

Keywords: Irritative voiding symptoms, anticholinergics, UTI, patient compliance, phenazopyridine hydrochloride

rritative voiding symptoms are to the urinary tract a ureteral stent after ureteroscopy is a common practice much as a cough is to the pulmonary system, i.e., in urology. It has been reported that 38-80% of patients Ia nonspecific manifestation of multiple potential experience stent-related symptoms such as flank pain, underlying causes. Similar to the lungs, the urinary lower abdominal discomfort, urinary urgency, urinary bladder responds to a spectrum of pathologic processes frequency, infection.5 with a limited repertoire of symptoms. Irritative Anticholinergic medications provide useful beneficial symptoms of the lower urinary tract generally refer to symptomatic management in these patients.1 urinary urgency, frequency, nocturia, painful voiding, 1 bladder discomfort or stranguria. An Internet-based Anticholinergics questionnaire found that 20-30% of adults >40 years reported symptoms of urgency, frequency, nocturia The anticholinergic/antispasmodic drugs are used to 6 or urge incontinence. The study also noted that 5% of relieve cramps or spasms of the bladder and to reduce 7 men and 8% of women reported bladder pain; painful irritative voiding symptoms. urination was found in 3% of adults. In addition, Anticholinergic drugs reduce detrusor contractions patients with the most severe lower urinary tract by blocking antimuscarinic receptors in the detrusor. symptoms (LUTS) had the greatest degree of bother, Since, muscarinic receptors are found in many highest rates of clinical anxiety or depression, and the different organs, urinary antispasmodics are associated lowest quality-of-life.2 with adverse anticholinergic effects, such as blurred vision, dry mouth, constipation, urinary retention, LUTS are associated with lower urinary tract and central nervous system effects such as dizziness, dysfunction. They can also indicate pathologies other somnolence and headaches.8 The elderly, so also the than lower urinary tract dysfunction, such as urinary 3 children, are usually more sensitive to these effects of tract infection (UTI). Many patients with indwelling anticholinergics.6 catheter experience catheter cramp. Irritation of the trigone causes detrusor contractions, known as bladder Flavoxate: A tertiary-amine antimuscarinic, flavoxate spasms, in these patients. Bladder spasms are a is used for its antispasmodic properties in the distressing complication for the patient.4 Placement of symptomatic treatment of many urological conditions including overactive bladder and incontinence. Randomized studies9,10 and one Cochrane review7 *Professor, Dept. of Medicine have found flavoxate to be no better than placebo for MGIMS, Sevagram, Wardha **Senior Physician and Cardiologist urge incontinence. Given the lack of demonstrated Moolchand Medcity, New Delhi effect of flavoxate in placebo-controlled studies itis

Indian Journal of Clinical Practice, Vol. 22, No. 9, February 2012 437 Drug Review difficult to recommend its use and it is definitely not Table 1. Pharmacokinetics: Salient Features a first-line treatment. Bilateral acute angle closure 22  Half-life: 7.35 hours. glaucoma following flavoxate administration has 23  Metabolism: Mainly metabolized by hydroxylation; the 11 been reported. extent of azo bond cleavage is low. 5-hydroxyl PAP is the 24 Briggs and associates reported essentially no effect major metabolite (48.3% of the dose).  Excretion: Rapidly excreted by the kidneys directly into of flavoxate in elderly patients with detrusor the urine (65% of the drug is excreted unchanged into the 12 hyperreflexia. urine); about 40% is excreted in the bile.23 Major urinary Oxybutynin: Oxybutynin is a tertiary-amine with metabolites: 4-acetylaminophenol (NAPA) followed in order by 5,4’-dihydroxy-PAP, 5-hydroxy-PAP, 4’-hydroxy-PAP and anticholinergic, antispasmodic and local anesthetic 2’-hydroxy-PAP.24 properties.13 Its usefulness is however limited by classic antimuscarinic side effects. Dry mouth is the of the mechanosensitive Aδ fibers as demonstrated by most common and bothersome complaint, followed by Aizawa et al in their study. They evaluated the effect constipation, blurred vision, dry eyes, urinary retention of phenazopyridine on afferent nerve activity by direct and drowsiness. These adverse effects, particularly measurement of both Aδ- and C-fibers, and compared dry mouth, are often severe enough to cause poor the outcome with the effects of a local anesthetic patient compliance, suboptimal dosing and even drug (lidocaine) and of an analgesic (acetaminophen). discontinuation.14 Intravenous administration of phenazopyridine was The mean pharmacokinetic parameters (i.e., Cmax found to significantly decrease dose-dependently only and AUC) of oxybutynin may be altered when the Aδ-fiber but not the C-fiber activity. Acetaminophen co-administered with antibiotics like macrolides significantly decreased only Aδ-fiber activity, but (erythromycin, clarithromycin). These drugs should it was not dose-dependently completely. Lidocaine 15 therefore be used together with caution. inhibited both the Aδ- and C-fiber activities.21 Oxybutynin was no better than placebo in patients Table 1 describes the salient pharmacokinetic with bladder spasm after transurethral surgery16 or properties of phenazopyridine. for the treatment of incontinence in the presence of Phenazopyridine Efficacy: Clinical Evidence detrusor instability in elderly institutionalized people.17 Clinically, oxybutynin appears more potent in causing Phenazopyridine hydrochloride acts as a topical dry mouth than in inhibiting detrusor instability.14 analgesic on the mucosal lining of the urinary tract and thus relieves pain, burning, urgency and Role of phenazopyridine frequency.19 Phenazopyridine hydrochloride is an azo dye with local  Phenazopyridine relieves symptoms of urogenital 18 analgesic and anesthetic effects on the urinary tract. infections: A study was done on 118 cases of Chemically, phenazopyridine is 2,6-Pyridinediamine, urogenital infections with symptoms of pain 19 3-(phenylazo), monohydrochloride. on urination, burning, frequency and nocturia. It is used as a urinary tract antiseptic and analgesic The patients were administered phenazopyridine as brief adjuvant therapy for treatment of UTI. 500 mg in dose of two tablets thrice-daily. In 65 Additionally, the drug is used for many urologic (55.1%) cases, all the characteristic symptoms problems involving dysuria.20 of urogenital infections were relieved: Pain on urination was alleviated or abolished in 95.3%; Clinical Pharmacology burning on urination was relieved in 93.6%; The exact mechanism of action of phenazopyridine frequency decreased in 85%, nocturia was hydrochloride is not known. It is excreted in the urine, eliminated or reduced in 83.7%, with reduction where it exerts a topical analgesic effect on the mucosa the organized sediment. In the remaining 53 cases, of the urinary tract. This action helps to relieve pain, symptomatic relief was also observed in all but a burning, urgency and frequency. Phenazopyridine has few, although, there was no concomitant reduction no antimicrobial actions. in the organized urinary sediment. No toxic effects Phenazopyridine exerts its clinical effect in conditions from phenazopyridine were observed during the of urinary bladder hypersensitivity by direct inhibition two weeks of its administration.25

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 Phenazopyridine is very useful as adjuvant to person’s quality-of-life. A catheter is a foreign body antimicrobial therapy in uncomplicated UTIs: and its presence may trigger bladder spasm and Phenazopyridine when administered along with pain.29 Phenazopyridine helps to relieve the pain antibiotics is efficacious as short-term analgesic caused by catheters.4 in the treatment of uncomplicated UTIs (uUTIs)  Phenazopyridine relieves postoperative ureteral as shown in a randomized, open label study. stent discomfort: Stent placement after uretero- Phenazopyridine, when given with antibiotics such scopy results in considerable morbidity in the as ciprofloxacin, doxycycline within 48 hours of form of irritative lower urinary tract symptoms.30 diagnosis, resulted in marked reduction in urinary Norris et al published their findings of a small but symptoms of burning micturition (91%) and pain well-conducted double-blind, placebo-controlled 23 during voiding of urine (89%). study comparing ER oxybutynin, phenazopyridine  Phenazopyridine co-administration enhances and placebo in patients who had a stent place ciprofloxacin bioavailability: A study compared after ureteroscopy. Each of 60 patients who the pharmacokinetic behavior of ciprofloxacin received a unilateral stent after ureteroscopy administered alone versus ciprofloxacin plus was given a blister pack containing 21 unmarked phenazopyridine. While there were no differences capsules of either extended-release oxybutynin between the two treatments in terms of peak plasma 10 mg, phenazopyridine 200 mg or placebo in a

concentration (Cmax) and elimination constant prospective, randomized and double-blinded (ke), area under the concentration-time curve to fashion. Patients were instructed to take 1 capsule

last measurable concentration (AUCt) and area 3 times daily immediately after the procedure. under the concentration-time curve extrapolated Patients were given 50 tablets of oral narcotic

to infinity (AUC∞) were 35% and 29% higher, to be taken as needed. Assessment tools respectively, in the combined treatment arm. included a questionnaire for stent symptoms,

In addition, a significant delay in tmax (from visual analog scale scores and requirement of 1 to 1.5 hours) and a statistical increase of 29% in narcotic medications. Results did not show mean residence time (MRT) were also observed differences for flank pain, suprapubic pain, in the combination group. The study concluded urinary frequency, urgency and dysuria. that phenazopyridine, when given together The phenazopyridine group reported less with antibiotic (ciprofloxacin) enhances its bio- hematuria on postoperative Day 1 when compared availability with regard to the amount absorbed with placebo, which was statistically significant.5 and MRT in the body, which is beneficial during  Phenazopyridine relieves autonomic dysreflexia treatment.26 associated with cystitis: Autonomic dysreflexia  Phenazopyridine does not alter efficacy of (AD) in individuals with spinal cord injury and sulfonamides against uropathogenic bacteria: other neurologic disorders is due to a genitourinary Phenazopyridine is widely used as an adjunct to cause 81-87% of the time. Urinary bladder sulfonamides in the treatment of bacterial UTIs distension due to urinary retention, blocked and has been shown not to alter the effectiveness catheters or of defective catheter tubing or of sulfonamides (sulfacytine, sulfisoxazole drainage bags is the commonest precipitant. UTIs and sulfamethoxazole) against uropathogenic can also induce AD, albeit not as commonly as 27 bacteria. The combined bacteriostatic activity of bladder distension.31 Phenazopyridine is useful in sulfonamide compounds and phenazopyridine the management of AD associated with cystitis as upon Balantidium coli has also been demonstrated documented by Paola and coauthors.32 earlier by Neter and Loomis.27,28 When used along with an antibiotic for the Conclusion treatment of a UTI, phenazopyridine should not be  Irritative voiding symptoms occur with a high given for more than two days as there is insufficient prevalence in the general population1 and can data to support benefits of administration beyond greatly affect patients’ quality-of-life. These 19 this time period. symptoms can be a source of great discomfort,  Phenazopyridine relieves pain due to bladder embarrassment and loss of confidence, causing spasms: Indwelling urinary catheters can cause withdrawal from social life and affecting physical severe pain and discomfort and can impair a and mental health.33 UTIs are usually associated

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