Metformin, marketed
under the tradename Glucophage among others, is the first-line medication for
the treatment of type 2 diabetes.[] This is particularly true in people who are
overweight.] It is also used in the treatment of polycystic ovary syndrome.]
Limited evidence suggests metformin may prevent the cardiovascular disease and
cancer complications of diabetes.[] It is not associated with weight gain. It
is taken by mouth.
MEACHINSM OF ACTION
Metformin, marketed
under the tradename Glucophage among others, is the first-line medication for
the treatment of type 2 diabetes. This is particularly true in people who are
overweight.] It is also used in the treatment of polycystic ovary syndrome] Limited
evidence suggests metformin may prevent the cardiovascular disease and cancer
complications of diabetes.[] It is not associated with weight gain It is taken
by mouth.[
Activation of AMPK,
an enzyme that plays an important role in insulin signaling, whole body energy
balance, and the metabolism of glucose and fats,[86] was required for
metformin's inhibitory effect on the production of glucose by liver cells.[87]
Activation of AMPK was required for an increase in the expression of small
heterodimer partner, which in turn inhibited the expression of the hepatic
gluconeogenic genes Phosphoenolpyruvate carboxykinase and glucose
6-phosphatase.[88] Metformin is frequently used in research along with AICA
ribonucleotide as an AMPK agonist. More recent studies using mouse models in
which the genes for AMPKα1 and α2 catalytic subunits (Prkaa1/2) or LKB1, an
upstream kinase of AMPK, had been knocked out in hepatocytes, have raised
doubts over the obligatory role of AMPK, since the effect of metformin was not
abolished by loss of AMPK function.]The mechanism by which biguanides increase
the activity of AMPK remains uncertain; however, metformin increases the
concentration of cytosolic adenosine monophosphate (AMP) (as opposed to a
change in total AMP or total AMP/adenosine triphosphate). Increased cellular
AMP has also been proposed to explain the inhibition of glucagon-induced
increase in cAMP and activation of PKA.[83] Metformin and other biguanides may
antagonize the action of glucagon, thus reducing fasting glucose
levels.Metformin also induces a profound shift in the faecal microbial
community profile in diabetic mice and this may contribute to its mode of
action possibly through an effect on glucagon- like peptide-1 secretion.
PHARMACOKINETICS
Metformin has an
oral bioavailability of 50–60% under fasting conditions, and is absorbed
slowly.[80][100] Peak plasma concentrations (Cmax) are reached within one to
three hours of taking immediate-release metformin and four to eight hours with
extended-release formulations.[80][100] The plasma protein binding of metformin
is negligible, as reflected by its very high apparent volume of distribution
(300–1000 l after a single dose). Steady state is usually reached in one or two
days.
Metformin has acid
dissociation constant values (pKa) of 2.8 and 11.5, so exists very largely as
the hydrophilic cationic species at physiological pH values. The metformin pKa
values make metformin a stronger base than most other basic drugs with less
than 0.01% nonionized in blood. Furthermore, the lipid solubility of the
nonionized species is slight as shown by its low logP value [log(10) of the
distribution coefficient of the nonionized form between octanol and water] of
-1.43. These chemical parameters indicate low lipophilicity
CONTRAINDICTION
Metformin is
contraindicated in people with any condition that could increase the risk of
lactic acidosis, including kidney disorders (arbitrarily defined as creatinine
levels over 150 μmol/l (1.7 mg/dl),), lung disease and liver disease. According
to the prescribing information, heart failure (in particular, unstable or acute
congestive heart failure) increases the risk of lactic acidosis with
metformin.A 2007 systematic review of controlled trials, however, suggested
metforn is the only antidiabetic drug not associated with any measurable harm
in people with heart failure, and it may reduce mortality in comparison with
other antidiabetic agents.
ADVERSE EFFECT
Metformin is
contraindicated in people with any condition that could increase the risk of
lactic acidosis, including kidney disorders (arbitrarily defined as creatinine
levels over 150 μmol/l (1.7 mg/dl),), lung disease and liver disease. According
to the prescribing information, heart failure (in particular, unstable or acute
congestive heart failure) increases the risk of lactic acidosis with metformin.
A 2007 systematic review of controlled trials, however, suggested metformin is
the only antidiabetic drug not associated with any measurable harm in people
with heart failure, and it may reduce mortality in comparison with other
antidiabetic agent
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