Metformin Associated Lactic Acidosis. Jun-Ki Park 9/6/11

Transcription

1 Metformin Associated Lactic Acidosis Jun-Ki Park 9/6/11

2 Probably the most common mechanism by which metformin elevates blood lactate is by inducing catecholamine release in those who regulate or prescribe it Peter W Stacpoole, Editorial, Diabetes Care 1998

3 Incidence: estimated 2-10 patients per 100,000 patients receiving metformin per year. MALA accounts for approximately 0.1-1% of total patients admitted to ICU. Life-threatening condition with mortality rate of 30-50%.

4 Nearly all of the reported cases of MALA have occurred in individuals with both hemodynamic (e.g. hypotension) and metabolic (e.g. liver or renal disease) underlying causes of impaired lactate metabolism. Controversy remains whether the use of metformin is a cause or a coincidence in lactic acidosis of DM patients.

5 LA Rates in T2DM Before Introduction of Metformin Brown et al. Diabetes Care 1998

6 Biguinides

7 Pharmacokinetic Aspects of Metformin Bioavailability percent; absorbed mainly from the small intestine; estimated absorption half-life, 0.9 to 2.6 hours Plasma concentration Maximal, 1 to 2mg per milliliter (approximately105m) 1 to 2 hours after an oral dose of 500 to 1000 mg; negligible binding to plasma proteins Plasma half-life Metabolism Elimination Estimated at 1.5 to 4.9 hours Not measurably metabolized About 90 percent is eliminated in urine in 12 hours; multiexponential pattern involving glomerular filtration and tubular secretion

8 Metformin has acid dissociation constant values (pka) of 2.8 and 11.5 and, therefore, exists very largely as the hydrophilic cationic species at physiological ph. The pka of 11.5 makes metformin a stronger base than most other basic drugs with less than 0.01% unionized in blood

9 The volume of distribution (Vd) has been reported to range from 63 to 276 L after IV administration. During dosage with 2000 mg metformin daily, Vd is approximately 600 L. As approximately 50% is absorbed the actual Vd during multiple dosage is about 300 L. This large Vd indicates that there is considerable tissue uptake of metformin.

10 Excretion of unchanged drug in urine is the major mode of elimination of metformin. No metabolites of metformin have been found in urine. Metformin is a small molecule (165Da) which is not bound to plasma proteins and, therefore, is readily filtered at the glomerulus. The low lipid solubility of metformin should lead to negligible passive resorption. Metformin is a substrate for several transporters in the kidney

11 Graham et al. Clin Pharmacokinet 2011

12 Pathomechanism of MALA Metformin promotes the conversion of glucose to lactate in the splanchnic bed of small intestine Intracellular redox potential shifts from aerobic to anaerobic metabolism Metformin inhibits hepatic gluconeogenesis from lactate, pyruvate, alanine, resulting in additional lactate and substrate for lactate production. (mainly by decreased pyruvate carboxylase activity, a rate limiting enzyme in the formation of glucose from lactate)

13

14

15

16 Owen et al. Biochem J 2000

17 Owen et al. Biochem J 2000

18

19 X

20 Does plasma metformin level predict lactate level / mortality? Lalau et al. Diabetes Care 1998

21 Seidowsky et al. Crit Care Med 2009

22 Highest arterial levels of lactate were not consistently a/w high plasma concentrations of metformin in this series of patients. Patient s underlying hemodynamic condition, not the degree of metformin accumulation, is the main determinant of marked hyperlactatemia.

23 Multivariate analysis performed to determine the factors independently associated with mortality, with the following variables: - age, arterial blood lactate, ph, LODS score and PT activity. The only variable significantly associated with mortality in this multivariate model was PT activity at admission (p < )

24 Treatment Optimal treatment modality for MALA is controversial and relies on nonspecific supportive measures: - Gastrointestinal decontamination for acute ingestions; active charcoal. - Securing airway, breathing and circulation - For patients with profound acidosis (ph <7.10), consider sodium bicarbonate infusion; e.g. 1-2meq/kg IVP, then 3 amps bicarb in 1L D5W at 250cc/hr) - For pt with profound acidosis, renal disease, or critical illness, HD/CRRT. Hemodialysis will correct metformin-associated acidbase disturbance and increase metformin clearance.

25 Hemodialysis In the Seidowsky study, of all patients, 31 were treated by HD, always initiated in the first 12 hours after admission in the ICU. Sequential measurements of plasma metformin levels during HD showed that in 85% of patients, a cumulative HD duration of 15 hours was a/w the return of metformin level to normal therapeutic values.

26 Seidowsky et al. Crit Care Med 2009

27 Seidowsky et al. Crit Care Med 2009

28 Exclusion Criteria for the Use of Metformin Renal impairment: plasma creatinine values 1.5 mg per deciliter (132 mmol per liter) for men and 1.4 mg per deciliter (124 mmol per liter) for women Cardiac or respiratory insufficiency that is likely to cause central hypoxia or reduced peripheral perfusion History of lactic acidosis Severe infection that could lead to decreased tissue perfusion Liver disease, including alcoholic liver disease, as demonstrated by abnormal liver-function tests Alcohol abuse with binge drinking sufficient to cause acute hepatic toxicity Use of intravenous radiographic contrast agents

29 THANK YOU!