Metformin

Class

• • Biguanide class anti-diabetic

Indications

• diabetes mellitus type 2

  • • especially in overweight people

• • polycystic ovary syndrome (PCOS) associated with insulin resistance

  • gestational diabetes?

Administration/Absorption

• • Oral

  • Absorbed over 6 hours

  • Bioavailability is 50 to 60% under fasting conditions.

  • Administration with food decreases and delays absorption

  • Peak action occurs 3 hours after oral administration.

Dosage

Distribution

• • VOD is 654 L for metformin 850 mg administered as a single dose

  • Negligibly bound to plasma proteins

Mechanism

• • suppression of hepatic gluconeogenesis

  • activates AMP-activated protein kinase (AMPK)

    • => increase in the expression of SHP, which in turn inhibits the expression of the hepatic gluconeogenic genes PEPCK and Glc-6-Pase

  • Other effects:

    • increases insulin sensitivity

    • enhances peripheral glucose uptake by phosphorylating GLUT-4 enhancer factor

    • increases fatty acid oxidation

    • decreases absorption of glucose from the gastrointestinal tract

    • causes GLUT4 deployment to the plasma membrane

  • Duration of action is 8-12 hours

  • The rare side effect, lactic acidosis, is thought to be caused by decreased liver uptake of serum lactate, one of the substrates of gluconeogenesis

Excretion

• • Half-life 6.2 hours

  • Metformin is not metabolized and is excreted unchanged in the urine

  • Approximately 90% of the drug is eliminated in 24 hours in those with healthy renal function

  • Renal clearance of metformin is approximately 3.5 times that of creatinine clearance

    • Indicates that tubular secretion is the primary mode of metformin elimination.

Side effects

• • Its main side effects are dyspepsia, nausea and diarrhea

    • Dose titration and/or use of smaller divided doses may decrease side effects

Interactions

Contraindications

• • Risk of lactic acidosis means metformin should be avoided in:

    • severely compromised renal function (creatinine clearance < 30 ml/min)

    • acute/decompensated heart failure

    • severe liver disease

    • for 48 hours after the use of iodinated contrast dyes