The Malignant Couple: Phenacetin Nephropathy-urothelial Tumors

THE MALIGNANT COUPLE: PHENACETIN NEPHROPATHYUROTHELIAL TUMORS Scientific coordinators: MITITIUC IRINA,PhD HOGAS SIMONA,MD

Author: Pricop Mariana Coauthors: Pricop Daniela Biru Diana -Madalina

PHENACETIN • Phenacetin, introduced in

1887, was used principally as an analgesic, and was one of the first synthetic fever reducers to go on the market.

• It is also known

historically to be the first analgesic without antiinflammatory properties.

PHENACETIN • Phenacetin was widely used until the third quarter of the twentieth century, but was then largely replaced by non-carcinogenic drugs.

• Some branded phenacetin-based preparations continued to be sold, but with the phenacetin replaced by safer alternatives.

• A popular brand of phenacetin was Roche's Saridon, which was reformulated in 1983 to contain propyphenazone, paracetamol and caffeine.

• Paracetamol is a metabolite of phenacetin with

similar analgesic and antipyretic effects, but the new formulation has not been found to have phenacetin's carcinogenicity.

PHENACETIN NEPHROPATHYUROTHELIAL TUMORS

• Analgesic nephropathy occurs in about 4 out of

100,000 people, mostly women over 30. The rate has decreased significantly since phenacetin is no longer widely available in OTC preparations.

• Risk factors include: * Use of OTC analgesics containing more than one active ingredient * Chronic headache * Chronic backache or musculoskeletal pain * Emotional or behavioral changes * History of dependent behaviors including smoking, alcoholism, and excessive use of tranquilizers * Pain with menstrual periods

PHENACETIN NEPHROPATHYUROTHELIAL TUMORS The cardinal features of the Analgesic Syndrome:

PHENACETIN NEPHROPATHYUROTHELIAL TUMORS • In general, phenacetin is metabolized by

acetaminophen after dehydration in the liver and thereafter it undergoes either sulfate acid or glutamic conjugation in the kidneys;

• The remaining free phenacetin is then excreted into the urine. Excessive acetaminophen results in the depletion of glutathione and the accumulation of acetaminophen oxides and an activated reaction may thus occur.

PHENACETIN NEPHROPATHYUROTHELIAL TUMORS • The reflux of acetaminophen into the kidneys and its

concentration in the renal medulla contribute to the inhibition of prostaglandin synthesis, thus leading to renal medullary ischemia and renal papillary necrosis.

• The resulting tubular obstruction promotes an

enlargement of the renal cortex and the formation of a histological background of interstitinal nephritis.

PHENACETIN NEPHROPATHYUROTHELIAL TUMORS • Regarding the development of urotherial tumor

associated with phenacetin abuse, N-hydroxylation products, the intermediate metabolite of phenacetin such as N-hydroxy-p-phenetidine and 2hydroxyphetidine, seemed to be potential carcinogens.

• The process of carcinogenesis in urotherium by

exposure of the potential carcinogens in phenacetin metabolic products are considered to take at least 10 years under excessive .

• Therefore, almost all reported cases of urotherial

tumor associated with phenacetin abuse had a history of excessive phenacetin use for more than 10

PHENACETIN NEPHROPATHYUROTHELIAL TUMORS

PHENACETIN NEPHROPATHYUROTHELIAL TUMORS

PHENACETIN ABUSE Double target on reno-urinary system

PHENACETIN NEPHROPATHYUROTHELIAL TUMORS • Specific kidney injuries

– renal papillary necrosis - chronic interstitial nephritis (the neprhopathy is a result from decreased blood flow to the kidney rapid consumption of antioxidants subsequent oxidative damage )

• This damage may lead to progressive chronic renal

failure, abnormal urinalysis results high blood pressure and anemia. A proportion of individuals with phenacetin nephropathy may develop end-stage kidney disease.

• Also the phenacetin abuse is directly related to the •

urothelial tumors. Phenacetin abuse-daily consume for at least 5 years(minimum total dose=2-7kg)

PHENACETIN NEPHROPATHYUROTHELIAL TUMORS

Drug-induced acute interstitial nephritis

PHENACETIN NEPHROPATHYUROTHELIAL TUMORS

Papillary necrosis

PHENACETIN NEPHROPATHYUROTHELIAL TUMORS

PHENACETIN NEPHROPATHYUROTHELIAL TUMORS

PHENACETIN NEPHROPATHYUROTHELIAL TUMORS B.I.,male,65years old,Pascani

• 1978-amputation left leg • Pain in the amputated leg -> chronical abuse of

phenacetin -3-60 tablets/day for 19 years (30 kg)

• Microscopic hematury-high suspicion of vesical tumors

• 1997-phenacetin nephropathy

PHENACETIN NEPHROPATHYUROTHELIAL TUMORS S.F.,female,75years old,Iasi

• Abuse of phenacetin-headaches->3-6 tablets/day for 20 years(4-8kg)

• 2000-CRF stage 5,peritoneal dialysis • 2001-after 5 episode of peritonitis->hemodialysis • 2007-multiple vesical tumors ->endoscopic resection • 2009-fever with unknown etiology-suspicion of metastasis

Conclusions “in memoriam phenacetin

nephropathy”

 The asociation between phenacetin and urothelial tumors is a reality .

 Every patient with phenacetin nephropathy needs to be closely observed for urothelial tumors

 The cases of phenacetin nephropathy are among

the last ones because products containing phenacetin the drug was withdrawn from the market in Western countries in the 1980s and also in Japan in 2001.

 The evolution is slowly progression to chronic renal failure

 Stoping the phenacetin ingestion can stabilize the

Stop to the consumption of over the counter pain medications! It could affect permanently and irreversible your reno-urinary system!

THANK YOU!