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BIO Magazine - Clinical evidence on the efficacy and safety of uroanalgesics. Δεκέμβριος 2015
Δεκέμβριος 2015 No38

BIO Health

Clinical evidence on the efficacy and safety of uroanalgesics.
Clinical evidence on the efficacy and safety of uroanalgesics.

ABSTRACT: Urinary tract infections are an increasingly common problem. Acute uncomplicated cystitis is observed chiefly in women and its diagnosis and management is rather straightforward. The initial therapy includes antibiotics very often combined with analgesics such as phenazopyridine, cranberry juice capsules and potassium citrate. These medicines can be purchased without prescription and are called over the counter drugs. Little is known to the consumers how these drugs should be used regarding their efficacy, mechanism of action and side effects. The aim of this study is to evaluate the effectiveness and safety of these drugs by retrieving information from PubMed, Cochrane and Scopus databases. We concluded that over the counter uroanalgesics despite their effectiveness, present toxicity and side effects that render necessary the need for better advising and informing of the consumers.

KEY WORDS: cystitis, urinary tract infections, over the counter, phenazopyridine, potassium citrate, cranberry juice.

 

Introduction

Urinary tract infections is a term that is applied to a variety of clinical conditions varying from the asymptomatic presence of bacteria in the urine to severe infection of the kidney resulting in sepsis1-3. Acute cystitis refers to urinary infection of the lower urinary tract, mainly the bladder and is more commonly observed in women than in men. More specifically it occurs 20 times more frequently in women than men, with approximately 50-60% of adult women reporting a UTI at some time during their lives. The diagnosis is based on clinical symptoms while in case of acute cystitis there is usually no need for extensive radiologic investigation.

Management of acute cystitis includes a short course of oral antibiotics4. Appropriate antibiotic use is of great significance given the potential risk of upper UTI and urosepsis in case of untreated UTI. TMP-SMX, nitrofurantoin and fluoroquinolones, have an efficient activity against most pathogens that cause cystitis. In adults and children the duration of treatment is usually limited to 3-5 days while longer therapy is proved to be not indicated. In premenopausal, non pregnant women, single dose antimicrobial therapy is less effective than the same antibiotic used for longer duration.

In addition to antimicrobial agent therapy, there can be added a short term use of urinary analgesics which belong to the group of over the counter products. There is no much evidence on how the public uses formally prescription medications that are available over the counter. In this study we aimed to review the available published evidence regarding the use, effectiveness and safety of all the available over the counter uroanalgesic products.

Materials and methods

The studies and case reports included in this review were retrieved from search performed in Pubmed, Cochrane, and Scopus databases. Bibliographies of relevant articles were also hand searched. The search strategy applied on Pubmed was (cystitis, urinary tract infections, over the counter, phenazopyridine, potassium citrate, cranberry juice).

Results

1. Cranberry Juice

American Cranberry (Vaccinium macrocarpon) is found in Eastern North America and Northern Europe. Its traditional use as a medicine was mainly for the relief of urinary symptoms. The scientific research of its therapeutic efficacy dates from 19th century5,6,7. The original and primary theory was that cranberry had the ability to acidify urine. More specifically Kinney and Bount found that certain amount of cranberry juice (450-720 ml) daily lowered urinary PH. This study was in total agreement with the studies conducted by Jackson and Hicks showing that 710 ml of cranberry juice lowered the urine PH of 21 elderly men. This theory was quickly debunked by the researches of Bodel et al. Consumption of large amounts of cranberry juice can only slightly reduce urine PH and modestly increase hippuric acid excretion.

There is no clinical evidence that cranberry consumption is effective and can be used to treat UTIs once an infection is present8,9. On the other hand the currently accepted mechanism of its action suggests that cranberry juice has the ability to disable E.Coli capacity to adhere the urethra10-11-12. The fruit consists of two compounds, fructose and proanthocyanidine whose effectiveness in adhering to proteins on the fimbriae of E.coli can prevent the bacteria from sticking to the epithelial cell lining of the urethra. This inhibition of adherence broadens the way to facilitate the infection’s attenuation or prevention.

The previous suggestions were in agreement with the studies conducted by J.P.Lavigne et al which evaluated the antibacterial efficacy of consumption of commercial Vaccinium Macrocarpon (cranberry capsules)10. The in vitro model in this study proved that 108 mg of cranberry induced a significant reduction in bacterial adherence of T24 cells in comparison to placebo. In accordance to in vitro, the in vivo model also confirmed that E.Coli strains have reduced ability to kill C.Elegans after growth in the urine of patients who consumed cranberry capsules. Cranberry juice has also antibacterial activity against S.Aureus, K. Pneumoniae, P. Aeraginosa and P. Mirabilis.

Toxicity and adverse effects

Cranberries as food have a long term history and are considered to be totally safe for consumption. However the previous statement does not suggest that cranberries can always be safe and more specifically in all populations or at high levels of consumption11. Overconsumption of cranberry is correlated with a risk of kidney stones. In healthy individuals consumption of up to 4L/day of cranberry juice is considered to be safe, in contrast to people with nephrolithiasis who may be at increased risk for stone formation12. In children and infants who have consumed more than 3L/day has been reported gastrointestinal distress and diarrhea.

Drug interactions

Cranberry has been implicated to interact with CYP2C9, the enzyme responsible for metabolizing warfarin and to inhibit CYP3A4 whose substrate is cyclosporine11-12. However 2 recent clinical studies confirmed no evidence of interaction due to cranberry juice consumption.

2.Potassium citrate

Potassium citrate mixture BP is a common pain reliever to acute bacterial cystitis13. Its action is based on alkalinizing urine which leads to discomfort relief of cystitis caused by infections of the lower urinary tract. The recommended dosage is 10 ml three or four times a day and each 10 ml dose contains 28mmol potassium.

 Since potassium citrate mixture has a bad taste, sodium citrate granules were created under the commercial brand name “Cymalon”, in order to be distributed as an over the counter product14. In the study conducted by Munday et al. women with cystitis who agreed to participate were evaluated. All women had full screening for gonorrhea, trichomoniasis, candidiasis and chlamydial cervical infection and where excluded if a genital tract pathogen was identified. The results of various symptoms of urinary tract infection before and after treatment with Cymalon are shown in Fig.A.  

The British National Formulary has recommended as contra indications patients with glomerural filtration rates less than 20 ml/minute because of the risk of hyperkalaemia. Despite these warnings, the mixture is still available and can also be purchased without prescription. 2 case reports from Broadgreen Hospital in Liverpool indicate that there might be high risk in using potassium citrate mixture BP both in hospitals and in the community even when renal function is normal13. In order to avoid this toxicity it is suggested that serum electrolyte concentration is monitored when the mixture is used in hospital and that it shouldn’t be purchased without prescription from any retail pharmacist.

3.Phenazopyridine

Pyridium is a bladder analgesic used all over the world. Urinary analgesics such as phenazopyridine 200mg tds, is a therapeutic option for patients with severe dysuria. Phenazopyridine has a potential analgesic effect on the mucosa of the urinary bladder18.It is usually prescribed in combination with sulfonamides as it is considered to enhance its antibacterial activity16,17.  It can be administered to patients with urgency, frequency and all the acute cystitis symptoms as it usually leads to resolution or improvement. Because no experimental data on combination with antibacterial therapy were available, Heifeld et al conducted a study which evaluated the possible influence of phenazopyridine on the in vivo antibacterial efficacy of three sulphonamides. The results clearly indicated that phenazopyridine did not have an effect on the effectiveness in the tests.

Side effects-Toxicity

Phenazopyridine is an over the counter product. It is available without prescription, a fact that makes it one of the most popular choices for suicidal attempts. It is primarily excreted by the kidneys 90%17. Approximately 40% of the excreted drug is a metabolized phenazopyridine while the remaining substance consists of potential toxic metabolites such as aniline. The previous information suggests that even therapeutic doses of this drug and its metabolites can cause toxicity and side effects especially if the renal function is poor. An early study by Walton and Lawson evaluated the effect of large doses of pyridium in rats and dogs. The results were transparent: Liver damage with central necrosis and toxic degeneration of the renal collecting tubules was a frequent observation. In addition single megadoses leaded to central nervous system depression, methemoglobinemia, hemolytic anemia and up to 50%  mortality.

The most common side effect is a mild gastrointestinal discomfort following methemoglobinemia, Heinz body hemolytic anemia, liver toxicity, skin pigmentation as well as acute renal failure 17. More precisely there is in the literature an evidence based syndrome-like in Pyridium toxicity. The symptoms are: gastrointestinal irritation, abdominal cramps, nausea, vomiting, and sometimes diarrhea. Skin symptoms are yellow discoloration with normal liver enzymes and without sclera icterus due to the deposition of the azo dye in the skin in addition to brown orange color of the urine. The acute renal failure is a late observation especially with underlying kidney disease.

Discussion

In response to demands for more alternative consumer choice and in order to decrease health care costs, the last 20 years  there has been made an effort to make prescription drugs available as over the counter products. Recently the Food and Drug Administration uses 3 regulatory criteria in order to determine whether a prescription medication should be available as an OTC drug. The drug 1) should have low potential for misuse 2) treat an easily self diagnosed condition 3) contain a package label with easily understood indications, contra indications and instruction of use. Unfortunately data based on several studies suggest that consumer choice to purchase an OTC drug is simply based on advertisements without having knowledge of the side effects, of the cause of the symptoms and the mechanism of action of the drugs. While the indication of these drugs are only for temporary use in combination with further medical care, their ability to cover the symptoms creates the false impression that they provide a cure, leading the patients to use them as the initial treatment and to under treat the existing disease.

Over the counter products such as uroanalgesics despite the limited clinical evidence on their effectiveness and safety could potentially cause without contestation serious health problems. Correct knowledge, better patient education and post OTC marketing surveillance are the only ways for proper usage of over the counter medication and decrease of substitution policies.    

References

  1. Christine A. Heisler, John B. Gebhart. Urinary tract infection in the adult female. J. Pelvic Med Surg 2008;14:1-14
  2. Walters MD, Karram MM. Urogynecology and reconstructive surgery 3d ed. Philadelphia : Mosby Elsevier
  3. Hooton TM, Scholes D, Hughes JP et al. A prospective study of risk factors for symptomatic urinary tract infections in young women. N. Engl J Med. 1996; 335: 468-474 
  4. David E Rahn. Urinary tract infections contemporary management. Urologic Nursing October 2008;Vol 28 (no5) 
  5. Jean Jacques Dugoua , Dugald Seely , Daniel Perri, Edward Mills, Gideon Koren. Safety and efficacy of cranberry (Vaccinium Macrocarpon) during pregnancy and lactation. Can J Clin Pharmacol Winter, January 18, 2008;Vol 15(1): e80-e86. 
  6. Boon H, Smith M. The complete natural medicine guide to the 50 most common   medicinal herbs. 2004 Toronto Robert Rose
  7. Raz R., Chazan B, Dan M. Cranberry juice and urinary and urinary tract infection. Clin. Infect Dis 2004; 38(10):1413-19
  8. Ofek I, Goldhar J, Zafriri D, Lis H, Adar R, Sharon N. anti Escherichia Coli a dhesing activity of cranberry and blueberry juices.N Engl J Med 1991; 324:1599
  9. Foo LY, Lu Y, Howell AB, Vorsa N. The structure of cranberry proanthocyanidins   which inhibit adherence pathogenic P.Fimbriated Escherichia in vitro. Phytochemistry 2000;5:173-81
  10. J.P.Lavigne,C. Bourg,C Combescure, H.Botto,A.Sotto.In vitro and in vivo evidence of dose dependent decrease of uropathogenic Escherichia Coli virulence after consumption of commercial Vaccinum macrocarpon capsules. European Society of Clinical Microbiology and Infectious diseases CMI 2007;14:350-355 
  11. Anonymous. Possible interactions between warfarin and cranberry juice. Current problems in Pharmacovigilance 2003:29-8
  12. Grenier J et al. Pomelo juice but not cranberry juice affects the pharmacokinetics of cyclosporine in humans. Clin. Pharmacol Ther 2006;79(3): 255-262
  13. JE Elisabeth, NJ Carter. Potassium citrate mixture soothing but not harmless. Broadgreen Hospital Liverpool 
  14. PE Munday. Cymalon in the management of urinary tract symtoms.
  15. C.L.Heifetz, M.W.Fischer. Phenazopyridine-Sulphonamide combination antibacterial therapy in mice. Antimicrobial Agents and Chemotherapy Jan 1973; p134-175
  16. Neter E, T A Loomis. The combined bacteriostatic activity of sulphonamide compound and pyridium upon E.Coli in vitro. Urol Cutaneous Rev 1941;45:295-297
  17. Ali Mirza , Onder et al. Acute renal failure due to phenazopyridine overdose.Case report and review to the literature. Pediatr. Nephrol 2006; 21:1760-1764  

Athanasios-Marios Voulgaris MD,   Ioannis Boutas MD.

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