Altieri P

Barracca A

Ledda O

Manca O

Michittu B

Pani A

Pili GF

English

Archivio istituzionale della ricerca - Università di Cagliari

Renal Failure, 20(3), 533-537 (1998) CASE REPORT Acute Renal Failure After Massive Ingestion of Gliclazide in a Suicide Attempt A. Barracca, 0. Ledtla, B. Michittu, G.F. Pili, 0. Manca, A. Pani, and P. Altieri Department of Renal Disease Azienda Ospedaliera Brottu Cagl iari, Itnl y ABSTRACT Gliclazide, a suI$onlyurea class molecule, is  used to control glycaemic levels in non insulin-dependent diabetes mellitus. Acute and chronic lox- icity studies, conducted in various animal species, have demonstrated a very low toxicity. We report a patient who developed acute renal failure due lo acute tubular necrosis following a massive ingestion of gliclazide in an suicide attenipl. The patient ingested 28 grams of gliclazide; the normal dose of gliclazide is  80 mg one or hvice a day. A1 admi-vsion the patient was h.ypog1ycaemia and in a few days became oliguric with an increase in the serum creatinine concentration, hut with a normal blood urea nitrogen level. He underwent dialysis and ten days after ingestion of gliclazide, his renal function improved rapidly. Key It brds; Gliclazide; Acute Renal Failure; Hemodlalysis. INTRODUCTION Gliclazide. a sulfonylurea class molecule, is used to control glycaemic levels in pa- tients with non-insulin-dependent dlabetes mellitus (NIDDM). Gliclazide has a molecu- Address correspondence to: Dr. Antonio Barracca, D~ivisione di Nefrologid e Dialisi, Ospedale San Michele, Via Peretli, 09134 Cagliari, Italy. Tcl: 39-70-539.4911496 :533 Copyright 0 1998 by Marcel Dekker, Inc. Ren Fail Downloaded from informahealthcare.com by The University of Manchester on 10/31/14For personal use only.534 Barracca et al. lar weight of 324.4. Administration of a single dose of 40-120 mg of gliclazide results in a peak plasma concentration (C-), at steady state, ranging from 0.3 to 8 pg/mL in patients with NDDM and from 0.7 to 4.9 pg/mL in healthy volunteers (1-4). Steady state concentrations are obtained in W D M  patients after 2 days of an oral administra- tion of 40 to 120 mg of gliclazide. Gm values tend to increase after repeated admini- strations but drug accumulation does not occur (5) .  Gliclazide, like other sulfonylureas, is highly bound to plasma proteins (94%, range 85-99Y0). The mean apparent volume of distribution in healthy volunteers and in pa- tients with NIDDM is 19 L ranging from 13 to 24 L with an age-related increase (6). Gliclazide is extensively metabolized in humans to at least seven metabolites: the two major metabolites are oxidued while the remaining are hydroxylated. The metabolites have no hypoglycaemic activity. In the urine, only low levels of unchanged drug are present, whereas in the plasma more than 90% of the drug is in the parent form. The major route of elimination of gliclazide and its metabolites is via the urine. Studies us- ing radiolabelled gliclazide have shown that 60-70% of the rahoactivity is excreted in the urine and 10 to 20% in the feces. The plasma half life (t1/2) of gliclazide is ap- proximately 11 hours, thus allowing once or twice dosing to maintain 24 hour blood glucose control (7). Toxicity Acute toxicity studtes on gliclazide have been conducted by oral adrmnistration to four animal species of both sexes: rat, mouse, gwnea pig, and dog. Toxicity was extremely low, the gunea pig being the more sensitive species. The overall LDso was calculated to be greater than 1500 m a g  and so 330 to 1300 times greater than the dose adrmnistered to humans. Subacute stuclles were conducted after oral administration in two animal species: the gunea pig and the dog. In the guinea pig after adrmnistration of 25, 50 or 100 mgkg 6 days out 7 for 8 weeks, neither change in body weight nor in organ weight occurred during the treatment. Histologcal stuQes Qd not reveal any lesions that could be asso- ciated with the treatment. Similar results were observed in studtes on chronic toxicity where doses of 25, 100 or 200 m&g were gwen orally 6 days out 7 for 26 weeks. These studies were conducted in three animal species the rat, the dog and the monkey. No target organs were detected. Doses without adverse effect OIJOAEZL) of 100 mgkgld for the rat and 180 m a g d  for the monkey were determined. A safety margin of 15-22 was calculated, based on drug plasma concentration. A fall in blood urea was seen in all treated animals and a sigmficant fall in blood glu- cose was observed in animals treated with 10 mgkg/d. Fhstological stuclles did not re- veal any lesion that could be associated with the treatment. CASE REPORT A 42 year old male was admitted to our hospital because he ingested 350 tablets (roughly 28 grams) of Gliclazide in a suicide attempt. The patient was not dabetic. At admission, the patient was hypoglycaemic (blood glucose < 20 mg/dL) and a 10% i.v. Ren Fail Downloaded from informahealthcare.com by The University of Manchester on 10/31/14For personal use only.Acute Renal Failure After Gliclazide Overdose 535 glucose solution was administered. The patient was otherwise well. Blood urea nitrogen (BUN) and creatinine values were 18 mg/dL and 0.8 mg/dL. respectively. The tempera- ture was 36.8 "C and the blood pressure was 130/80 mmHg. Table 1 shows blood chemi- cals findlngs. On the second hospital day, glucose infusion was continued (glycaemia 60 mg/dL) and the renal function appeared normal. On the thrd  hospital day. the patient was olig- uric and dluretic agents were started (Forosemide 3-4 mg/kg/h and Dopamine 2-3 &kg/min) but on the fourth hospital day the patient had become anuric. Table 1 shows blood chemicals findmgs. The kidneys were normal at echografk scanning. A TC99m DTPA scan showed a good pefision. BUN was within normal range values (20 mg/dL), but creatinine levels were high (8 mg/dL) while low levels of scAwn and potassium were noted. Renal failure was dagnosed and heniodialysis started on the sixth day of hospitaliza- tion, to correct fluid overload and hyponatraemia. Blood samples were collected before and after the first and the second hemodlalysis treatment to determine gliclazide levels. Figure 1 shows the results of these determinations. With the first dlalysis, the pre- and post-dlalysis gliclazide levels were 1444 and 1251 pg/mL, respectively. With the second dialysis. the pre-and post-dialysis levels w'ere 439 and 335  pg/mL., respectively. Hemo- dialysis was repeated on the eight and ninth hospital day. On the tenth hospital day renal function improved rapidly, the patient became polyunc, hemodlalysis was stopped. The urinalysis showed the presence of glucose; hyaline and granular casts were also preseint. The patient was Qscharged on the twenti- eth hospital day. At the time of Ischarge, the BUN was 10 mg/& and the serum cre- atinine concentration was 2.4 mg/dL) (Table 1). DISCUSSION The present case confirms the low toxicity of gliclazide already demonstrated in ani- mal studles and above all the absence of target organs seen in toxicity studles. The overall LDso was calculated to be greater than 1500 mgKg and so 330 to 1300 times greater than the dose administered for clinical use. T h s  man has taken a dose of 400 mglKg. This dose is 400 time!; greater than the dose used in humans. Couturier (8) presented a case of ingestion of an unknown dose of gli- clazide in an suicide attempt. In his work;, Couturier documents the procedure for the detection of gliclazide in plasma, several days after ingestion of the drug. The author shows how the peak concentration, after intake 80 mg in normal subjects averaged 4.76 k 0.63 pg/mL and was reached 1.17 k 0.615 h after ingestion of the drug. In our case the h g h  drug plasma levels are consequent on. the large dose taken by the patient. Based on a mean half life of 10 hours and assuming that no saturation of absorption and hepatic metabolism occurred (which is unlikely), 'we can estimate that plasma levels have been as high as 1.800 pg/mL. on day 1. This is consistent with the calculation we can make from the levels obtained at the therapeutic doses (2.2 to 8 pg/mL after 160 mg). Assum- ing that kinetics is linear, levels would have been raised up to 350 to 1400 &mL after 28.000 mg. In chronic studies, hyponatraemia is frequently found. This situation is present in dia- betic patients treated with sulphonamides. These drugs have an antidluretic action. For Ren Fail Downloaded from informahealthcare.com by The University of Manchester on 10/31/14For personal use only.536 Barracca et al. Table 1 Values Obtained after Gliclazide Overdose 1st HD 4th IID Discharge BUN, mg/& Cratinine, mg/dL AST, U L  AL,T, U/L Na, mEq/L K, mEq5 CPK, UL Rl3c x lo6 WC x 103 18 0.8 234 267 130 3 164 4.14 8.91 20 10 8 2.4 230 23 210 42 105 135 2.1 3 180 75 3.88 7.26 Removal of gliclazide by dialiysis concentration 1600 1400 1200 lo00 800 600 400 200 0 lodialysis 2"dia lysis 1 Pre dialysis 2 Post dialysis Figure 1. Removal of gliclazide by dialysis. example, chloropropamide was the most important drug for the treatment of diabetes insipidus. The same drugs have a little diuretic action. In diabetic patients treated with sulphonamides, we can find low levels of sodium in 33% of patients treated with gliclazide; in those treated with chloropropamide, the fre- quency of hyponatraemia is of 23%, and only in 6% of patients treated with glibencla- mide is there hyponatraemia (9). Also in our patient hyponatraemia was observed during hospitalization. In conclusion, our patient had cellular damage expressed by an elevation of the liver enzymes, and acute renal failure due to acute tubular necrosis. The high protein binding Ren Fail Downloaded from informahealthcare.com by The University of Manchester on 10/31/14For personal use only.Acute Renal Failure After Gliclazide Overdose 537 of Gliclazide in the plasma (94%) could account for the inability of cfialysis to remove excess Gliclazide in spite of a low molecular weight and an apparent clearance of 24 mL/min in humans (Figure 1). REFlZRENCES 1. 2. 3. 4. 5 .  6. 7. 8. 9. Caqbe l  DB, Adrianssens P, Hopkins YW, Gordon B, Willams JRB: Pharmacokmelics and metabolism of gliclazide: a review. In: Keen ET, (4); Gliclazide and the Trearment ofDiabetes, International Congress and Symposium Series "29. F ' r d i g s  of International Symposium, London, April 5-6, 1979; London, Acadanic Press and Royal Society of Medicine, 1980, pp 71-82. Kobayashi K, Kimura M, Sakoguchi T, Kitani Y, Hata M ti al.: Influence of blood prdeins on biomedical analysis. 111. Pharmacokinetics and protein biriding of gliclazide. J Pharmacobio-Dynamics 4:436-442, 1981. Oida T, Yoshida K, Kagemcto A, Sekme Y: This metabolism of gliclazide in man. Xenobiotica 15:  87-96, 1985. Shiba J, Kajinuma H, Sumki K, Hagura R, Kawai A, d al.: Serum gliclazidc arncentration in diabetic pa- tients. Relationship between gliclazide and serum concentration. Diab Res Clrn Prachce 2: 301-306, 1986. Kobayashi K, Kimura M, Sakoguchi T, Hase A, Matsuoka A, Kaneko S: F'harmacokinetics of gliclazide in healthy and diabetic subjects. JPharm Sci 73:1684-3687, 1984. Forette B, Rolland A, Hopkins Y, Gordon B, Campbell DB: Gliclazide pharmacokinetics in the elderly. llth Congress of rhe International Diabetes Federation Abstracts; Amsterdam:Exqta Media, 1982 Arcfiambeaud-Monveroux F ,  Novaille Y, Nadallon S, Treves R. Merle L: Intaadion between gliclazide and &metidine. Eur JClin Pharmacol91:631, 1985'. Couturier E. Roman A, Jahjah L, Sener A, Malaisse J: Plasma gliclazide measurement 5 days afler ingestion ofthe hypoglyaemic sulfonylurea in an attempted suicide. Diabetes Research 3 1 :41- 44, 1966. GIN H ti Coll.: Hyponatrernie induite par le sulfamides Hypoglycemisants: etude chez 70 patients. Ann Meo' Int 139:455, 1966. Ren Fail Downloaded from informahealthcare.com by The University of Manchester on 10/31/14For personal use only.

Acute renal failure after massive ingestion of gliclazide in a suicide attempt

https://iris.unica.it/bitstream/11584/271326/1/Acute%20Renal%20Failure%20After%20Massive%20ingestion%20of%20Gliclazide%20in%20a%20suicide%20attempt.pdf

Acute renal failure after massive ingestion of gliclazide in a suicide attempt

Abstract

Similar works

Full text

Available Versions

Archivio istituzionale della ricerca - Università di Cagliari