DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Nateglinide is metabolized primarily by hepatic CYPs [2C9,
70%; 3A4, 30%] and thus should be used cautiously in patients with
hepatic insufficiency. About 16% of an administered dose is excreted
by the kidney as unchanged drug. Dosage adjustment is unnecessary
in renal failure. Some drugs reduce the glucose-lowering effect of
nateglinide (corticosteroids, rifamycins, sympathomimetics, thiazide
diuretics, thyroid products); others (alcohol, NSAIDs, salicylates,
MAOIs, and nonselective β blockers) may increase the risk of hypoglycemia
with nateglinide. Nateglinide therapy may produce fewer
episodes of hypoglycemia than other currently available oral insulin
secretagogues including repaglinide. As with sulfonylureas and
repaglinide, secondary failure occurs.
A MPK
and PPAR γ activators
Metformin
NATEGLINIDE
METFORMIN
Mechanism of Action. Metformin (GLUCOPHAGE, others)
is the only member of the biguanide class of oral hypoglycemic
drugs available for use today (Bailey and
Turner, 1996). Metformin increases the activity of the
AMP-dependent protein kinase (AMPK) (Zhou et al.,
2001). AMPK is activated by phosphorylation when cellular
energy stores are reduced (i.e., lower concentrations
of ATP and phosphocreatine). Activated AMPK
stimulates fatty acid oxidation, glucose uptake, and
nonoxidative metabolism, and it reduces lipogenesis and
gluconeogenesis. The net result of these actions is
increased glycogen storage in skeletal muscle, lower
rates of hepatic glucose production, increased insulin
sensitivity, and lower blood glucose levels.
Metformin causes a similar profile of effects and
is dependent on AMPK activation (Shaw et al., 2005).
Although the molecular mechanism by which metformin
activates AMPK is not known, it is thought to be
indirect, possibly by reducing intracellular energy
stores. Consistent with this, metformin has been shown
to inhibit cellular respiration by specific actions on mitochondrial
complex I. Metformin has little effect on
blood glucose in normoglycemic states and does not
affect the release of insulin or other islet hormones and
rarely causes hypoglycemia. However, even in persons
with only mild hyperglycemia, metformin lowers blood
glucose by reducing hepatic glucose production and
increasing peripheral glucose uptake. This effect is at
least partially mediated by reducing insulin resistance
at key target tissues. The hepatic effect is probably the
dominant mode of action and involves primarily suppression
of gluconeogenesis. Table 43–8 compares metformin
and thiazolidinediones (glitazones).
Table 43–8
Comparison of Metformin and Thiazolidinediones
PARAMETER METFORMIN THIAZOLIDINEDIONES
Molecular target AMPK PPARγ
Pharmacologic action Suppression of HGP Enhanced insulin sensitivity
a
Reduction of HbA 1c
1.0-1.25 0.5-1.4
Reduction of FFA Minimal Moderate
Stimulation of adiponectin Minimal Significant
Effect on body weight Minimal Increased
Peripheral edema Minimal Moderate
Fracture risk None Increased
Lactic Acidosis Rare b None
a
Magnitude of absolute reduction dependent on starting A1C value
b
In renal insufficiency
HGP = hepatic glucose production