CHAPTER 2-102: METFORMIN

INTRODUCTION

Metformin is a biguanide antihyperglycemic agent that is recommended as the initial drug treatment in patients with type II diabetes. Metformin toxicity can occur after acute overdose or in the setting of chronic use in patients with renal impairment.

MECHANISM OF TOXICITY

1. Metformin acts by inhibiting gluconeogenesis and glycogen breakdown, decreasing glucose absorption and improving peripheral insulin sensitivity.

2. Other pharmacologic actions include inhibition of fatty acid oxidation and oxidative phosphorylation, and increased intestinal lactate production.

3. Pharmacokinetics. Peak absorption occurs 2–6 hours after ingestion but may be delayed after ingestion of sustained-release formulations. The volume of distribution (Vd) has been reported as high as several hundred liters but is probably closer to 80 L in an adult. Elimination is entirely renal, with a half-life of 2.5–6 hours.

TOXIC DOSE

1. Adults. Lactic acidosis occurred 9 hours after ingestion of 25 g of metformin by an 83-year-old, and fatal lactic acidosis and cardiovascular collapse occurred 4 hours after ingestion of 35 g by a 33-year-old.

2. Children. Based on a multicenter pediatric case series, unintentional ingestion of less than 1, 700 mg is unlikely to cause significant toxicity.

CLINICAL PRESENTATION

1. The most common effects after acute metformin overdose are nausea, vomiting, lethargy, and abdominal pain. More serious poisoning is associated with coma, seizures, and cardiovascular collapse.

2. Lactic acidosis is common with serious intoxication and may be fatal. The risk increases in the presence of renal dysfunction.

3. Pancreatitis has been reported in both therapeutic use and overdose of metformin.

4. Hypoglycemia is not common (metformin does not increase insulin release) but has been reported, even in the absence of other hypoglycemic drugs such as sulfonylureas or insulin.

DIAGNOSIS

Metformin toxicity should be suspected in any patient with severe lactic acidosis.

1. Specific levels. Serum metformin levels can be measured in specialty laboratories but are not readily available in most hospitals. The therapeutic plasma concentration is 0.5–2.5 mg/L. Levels greater than 50 mg/L were associated with serious toxicity and high mortality.

2. Other useful laboratory studies. Arterial blood gases, renal function tests, electrolytes, glucose, and lactate level.

TREATMENT

1. Emergency and supportive measures

   1. Maintain an open airway and assist ventilation if necessary.

   2. Treat hypotension, coma, seizures, or hypoglycemia if they occur.

   3. Closely monitor lactate levels, renal function, and glucose.

2. Specific drugs and antidotes. No specific antidotes are available. Lactic acidosis can be treated with sodium bicarbonate; however, bicarbonate infusions alone are often ineffective and patients with severe acidosis may require hemodialysis.

3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I–38).

4. Enhanced elimination.

   1. Hemodialysis is recommended for correction of severe acidosis and also enhances the clearance of metformin (170 mL/min).

   2. Continuous venovenous hemofiltration (CVVH) has been used successfully in hemodynamically unstable patients, ...