Role of Phenazopyridine in Urinary ...

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
I
rritative voiding symptoms are to the urinary tract
much as a cough is to the pulmonary system, i.e.,
a nonspecific manifestation of multiple potential
underlying causes. Similar to the lungs, the urinary
bladder responds to a spectrum of pathologic processes
with a limited repertoire of symptoms. Irritative
symptoms of the lower urinary tract generally refer to
urinary urgency, frequency, nocturia, painful voiding,
bladder discomfort or stranguria.1 An Internet-based
questionnaire found that 20-30% of adults >40 years
reported symptoms of urgency, frequency, nocturia
or urge incontinence. The study also noted that 5% of
men and 8% of women reported bladder pain; painful
urination was found in 3% of adults. In addition,
patients with the most severe lower urinary tract
symptoms (LUTS) had the greatest degree of bother,
highest rates of clinical anxiety or depression, and the
lowest quality-of-life.2
LUTS are associated with lower urinary tract
dysfunction. They can also indicate pathologies other
than lower urinary tract dysfunction, such as urinary
tract infection (UTI).3 Many patients with indwelling
catheter experience catheter cramp. Irritation of the
trigone causes detrusor contractions, known as bladder
spasms, in these patients. Bladder spasms are a
distressing complication for the patient.4 Placement of
*Professor, Dept. of Medicine
MGIMS, Sevagram, Wardha
**Senior Physician and Cardiologist
Moolchand Medcity, New Delhi
a ureteral stent after ureteroscopy is a common practice
in urology. It has been reported that 38-80% of patients
experience stent-related symptoms such as flank pain,
lower abdominal discomfort, urinary urgency, urinary
frequency, infection.5
Anticholinergic medications provide useful beneficial
symptomatic management in these patients.1
Anticholinergics
The anticholinergic/antispasmodic drugs are used to
relieve cramps or spasms of the bladder6 and to reduce
irritative voiding symptoms.7
Anticholinergic drugs reduce detrusor contractions
by blocking antimuscarinic receptors in the detrusor.
Since, muscarinic receptors are found in many
different organs, urinary antispasmodics are associated
with adverse anticholinergic effects, such as blurred
vision, dry mouth, constipation, urinary retention,
and central nervous system effects such as dizziness,
somnolence and headaches.8 The elderly, so also the
children, are usually more sensitive to these effects of
anticholinergics.6
Flavoxate: A tertiary-amine antimuscarinic, flavoxate
is used for its antispasmodic properties in the
symptomatic treatment of many urological conditions
including overactive bladder and incontinence.
Randomized studies9,10 and one Cochrane review7
have found flavoxate to be no better than placebo for
urge incontinence. Given the lack of demonstrated
effect of flavoxate in placebo-controlled studies it is
Indian Journal of Clinical Practice, Vol. 22, No. 9, February 2012
437
Drug Review
difficult to recommend its use and it is definitely not
a first-line treatment. Bilateral acute angle closure
glaucoma following flavoxate administration has
been reported.11
Briggs and associates reported essentially no effect
of flavoxate in elderly patients with detrusor
hyperreflexia.12
Oxybutynin: Oxybutynin is a tertiary-amine with
anticholinergic, antispasmodic and local anesthetic
properties.13 Its usefulness is however limited by
classic antimuscarinic side effects. Dry mouth is the
most common and bothersome complaint, followed by
constipation, blurred vision, dry eyes, urinary retention
and drowsiness. These adverse effects, particularly
dry mouth, are often severe enough to cause poor
patient compliance, suboptimal dosing and even drug
discontinuation.14
The mean pharmacokinetic parameters (i.e., Cmax
and AUC) of oxybutynin may be altered when
co-administered with antibiotics like macrolides
(erythromycin, clarithromycin). These drugs should
therefore be used together with caution.15
Oxybutynin was no better than placebo in patients
with bladder spasm after transurethral surgery16 or
for the treatment of incontinence in the presence of
detrusor instability in elderly institutionalized people.17
Clinically, oxybutynin appears more potent in causing
dry mouth than in inhibiting detrusor instability.14
Role of phenazopyridine
Phenazopyridine hydrochloride is an azo dye with local
analgesic and anesthetic effects on the urinary tract.18
Chemically, phenazopyridine is 2,6-Pyridinediamine,
3-(phenylazo), monohydrochloride.19
It is used as a urinary tract antiseptic and analgesic
as brief adjuvant therapy for treatment of UTI.
Additionally, the drug is used for many urologic
problems involving dysuria.20
Clinical Pharmacology
The exact mechanism of action of phenazopyridine
hydrochloride is not known. It is excreted in the urine,
where it exerts a topical analgesic effect on the mucosa
of the urinary tract. This action helps to relieve pain,
burning, urgency and frequency. Phenazopyridine has
no antimicrobial actions.
Phenazopyridine exerts its clinical effect in conditions
of urinary bladder hypersensitivity by direct inhibition
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Indian Journal of Clinical Practice, Vol. 22, No. 9, February 2012
Table 1. Pharmacokinetics: Salient Features
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Half-life: 7.35 hours.22
Metabolism: Mainly metabolized by hydroxylation;23 the
extent of azo bond cleavage is low. 5-hydroxyl PAP is the
major metabolite (48.3% of the dose).24
Excretion: Rapidly excreted by the kidneys directly into
the urine (65% of the drug is excreted unchanged into the
urine); about 40% is excreted in the bile.23 Major urinary
metabolites: 4-acetylaminophenol (NAPA) followed in order
by 5,4’-dihydroxy-PAP, 5-hydroxy-PAP, 4’-hydroxy-PAP and
2’-hydroxy-PAP.24
of the mechanosensitive Aδ fibers as demonstrated by
Aizawa et al in their study. They evaluated the effect
of phenazopyridine on afferent nerve activity by direct
measurement of both Aδ- and C-fibers, and compared
the outcome with the effects of a local anesthetic
(lidocaine) and of an analgesic (acetaminophen).
Intravenous administration of phenazopyridine was
found to significantly decrease dose-dependently only
the Aδ-fiber but not the C-fiber activity. Acetaminophen
significantly decreased only Aδ-fiber activity, but
it was not dose-dependently completely. Lidocaine
inhibited both the Aδ- and C-fiber activities.21
Table 1 describes the salient pharmacokinetic
properties of phenazopyridine.
Phenazopyridine Efficacy: Clinical Evidence
Phenazopyridine hydrochloride acts as a topical
analgesic on the mucosal lining of the urinary tract
and thus relieves pain, burning, urgency and
frequency.19
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Phenazopyridine relieves symptoms of urogenital
infections: A study was done on 118 cases of
urogenital infections with symptoms of pain
on urination, burning, frequency and nocturia.
The patients were administered phenazopyridine
500 mg in dose of two tablets thrice-daily. In 65
(55.1%) cases, all the characteristic symptoms
of urogenital infections were relieved: Pain on
urination was alleviated or abolished in 95.3%;
burning on urination was relieved in 93.6%;
frequency decreased in 85%, nocturia was
eliminated or reduced in 83.7%, with reduction
the organized sediment. In the remaining 53 cases,
symptomatic relief was also observed in all but a
few, although, there was no concomitant reduction
in the organized urinary sediment. No toxic effects
from phenazopyridine were observed during the
two weeks of its administration.25
Drug Review
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Phenazopyridine is very useful as adjuvant to
antimicrobial therapy in uncomplicated UTIs:
Phenazopyridine when administered along with
antibiotics is efficacious as short-term analgesic
in the treatment of uncomplicated UTIs (uUTIs)
as shown in a randomized, open label study.
Phenazopyridine, when given with antibiotics such
as ciprofloxacin, doxycycline within 48 hours of
diagnosis, resulted in marked reduction in urinary
symptoms of burning micturition (91%) and pain
during voiding of urine (89%).23
Phenazopyridine co-administration enhances
ciprofloxacin bioavailability: A study compared
the pharmacokinetic behavior of ciprofloxacin
administered alone versus ciprofloxacin plus
phenazopyridine. While there were no differences
between the two treatments in terms of peak plasma
concentration (Cmax) and elimination constant
(ke), area under the concentration-time curve to
last measurable concentration (AUCt) and area
under the concentration-time curve extrapolated
to infinity (AUC∞) were 35% and 29% higher,
respectively, in the combined treatment arm.
In addition, a significant delay in tmax (from
1 to 1.5 hours) and a statistical increase of 29% in
mean residence time (MRT) were also observed
in the combination group. The study concluded
that phenazopyridine, when given together
with antibiotic (ciprofloxacin) enhances its bioavailability with regard to the amount absorbed
and MRT in the body, which is beneficial during
treatment.26
Phenazopyridine does not alter efficacy of
sulfonamides against uropathogenic bacteria:
Phenazopyridine is widely used as an adjunct to
sulfonamides in the treatment of bacterial UTIs
and has been shown not to alter the effectiveness
of
sulfonamides
(sulfacytine,
sulfisoxazole
and sulfamethoxazole) against uropathogenic
bacteria.27 The combined bacteriostatic activity of
sulfonamide compounds and phenazopyridine
upon Balantidium coli has also been demonstrated
earlier by Neter and Loomis.27,28
When used along with an antibiotic for the
treatment of a UTI, phenazopyridine should not be
given for more than two days as there is insufficient
data to support benefits of administration beyond
this time period.19
Phenazopyridine relieves pain due to bladder
spasms: Indwelling urinary catheters can cause
severe pain and discomfort and can impair a
person’s quality-of-life. A catheter is a foreign body
and its presence may trigger bladder spasm and
pain.29 Phenazopyridine helps to relieve the pain
caused by catheters.4
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Phenazopyridine relieves postoperative ureteral
stent discomfort: Stent placement after ureteroscopy results in considerable morbidity in the
form of irritative lower urinary tract symptoms.30
Norris et al published their findings of a small but
well-conducted double-blind, placebo-controlled
study comparing ER oxybutynin, phenazopyridine
and placebo in patients who had a stent place
after ureteroscopy. Each of 60 patients who
received a unilateral stent after ureteroscopy
was given a blister pack containing 21 unmarked
capsules of either extended-release oxybutynin
10 mg, phenazopyridine 200 mg or placebo in a
prospective, randomized and double-blinded
fashion. Patients were instructed to take 1 capsule
3 times daily immediately after the procedure.
Patients were given 50 tablets of oral narcotic
to be taken as needed. Assessment tools
included a questionnaire for stent symptoms,
visual analog scale scores and requirement of
narcotic medications. Results did not show
differences for flank pain, suprapubic pain,
urinary frequency, urgency and dysuria.
The phenazopyridine group reported less
hematuria on postoperative Day 1 when compared
with placebo, which was statistically significant.5
Phenazopyridine relieves autonomic dysreflexia
associated with cystitis: Autonomic dysreflexia
(AD) in individuals with spinal cord injury and
other neurologic disorders is due to a genitourinary
cause 81-87% of the time. Urinary bladder
distension due to urinary retention, blocked
catheters or of defective catheter tubing or
drainage bags is the commonest precipitant. UTIs
can also induce AD, albeit not as commonly as
bladder distension.31 Phenazopyridine is useful in
the management of AD associated with cystitis as
documented by Paola and coauthors.32
Conclusion

Irritative voiding symptoms occur with a high
prevalence in the general population1 and can
greatly affect patients’ quality-of-life. These
symptoms can be a source of great discomfort,
embarrassment and loss of confidence, causing
withdrawal from social life and affecting physical
and mental health.33 UTIs are usually associated
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439
Drug Review
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with irritative voiding symptoms, such as
painful urination (dysuria), urinary urgency and
frequency.
3.
Takeda M, Araki I, Kamiyama M, Takihana Y, Komuro M,
Furuya Y. Diagnosis and treatment of voiding symptoms.
Urology 2003;62(5 Suppl 2):11-9.
Anticholinergic drugs are widely used in clinical
practice to reduce irritative voiding symptoms.7
4.
Sulzbach LM. Ask the experts. Crit Care Nurse
2002;22(3):84-7.
5.
Norris RD, Sur RL, Springhart WP, Marguet CG, Mathias
BJ, Pietrow PK, et al. A prospective, randomized, doubleblinded placebo-controlled comparison of extended
release oxybutynin versus phenazopyridine for the
management of postoperative ureteral stent discomfort.
Urology 2008;71(5):792-5.
6.
Kulkarni SK. Antispasmodics – A new perspective.
JAMA India 2001;4(8):119-21.
7.
Roxburgh C, Cook J, Dublin N. Anticholinergic drugs
versus other medications for overactive bladder
syndrome in adults. Cochrane Database Syst Rev 2007;(3):
CD003190.
8.
Therapeutic Class Review Urinary Antispasmodics
http://ovha.vermont.gov/advisory-boards/urinaryantispasmodics.3.09.pdf.
9.
Chapple CR, Parkhouse H, Gardener C, Milroy EJ.
Double-blind, placebo-controlled cross-over study
of flavoxate in the treatment of idiopathic detrusor
instability. Br J Urol 1990;66(5):491-4.
Anticholinergics/Antispasmodics help relieve
dysuria and provide relief from bladder spasms.
Optimal control is obtained if both infection and
bladder spasms are treated simultaneously.34
Urinary antispasmodics such as oxybutynin and
flavoxate are muscarinic receptor antagonists
and exert beneficial direct relaxant effect on
smooth muscle of the urinary tract. But they have
high incidence of side effects, predominantly
dry mouth, which is a major disadvantage leading
to poor patient compliance and discontinuation
of treatment.
The lack of demonstrated effect of flavoxate in
placebo-controlled studies makes it difficult to
recommend the use of flavoxate and it is definitely
not a first-line treatment.11
Clinically, oxybutynin appears more potent in
causing dry mouth than in inhibiting detrusor
instability, which precludes its use.14 Also,
drug interactions are known to occur when
co-administered with antibiotics like macrolides.
Phenazopyridine is a urinary tract analgesic, which
is used to treat symptoms of dysuria,34 while
the patient is awaiting medical evaluation and
treatment.35
When taken orally, majority of the drug enters
the urine unchanged, where it acts as a topical
analgesic within the bladder.34
Phenazopyridine is also frequently used for
adjunctive treatment of pain associated with UTIs
in addition to antibiotics aimed at the underlying
microbial infection.35 It relieves pain and discomfort during the interval before antibiotic therapy
begins to control the infection.19
Most doctors prefer to use phenazopyridine as a
first choice drug in dysuria.
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