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

Absorption, Distribution, and Elimination. Metformin is absorbed
primarily from the small intestine. The drug is stable, does not bind
to plasma proteins, and is excreted unchanged in the urine. It has a
t 1/2
in the circulation of ~2 hours. The transport of metformin into
cells is mediated in part by organic cation transporters (see
Chapter 5). Organic cation transporter 1 (OCT 1) is believed to carry
the drug into cells such as hepatocytes and myocytes where it is
pharmacologically active. Organic cation transporter 2 (OCT 2) is
thought to transport metformin into renal tubules for excretion. There
is recent evidence suggesting that genetic variation in OCT 1 among
humans may affect the response to metformin.
Therapeutic Uses and Dosage. Metformin is currently
the most commonly used oral agent to treat type 2 diabetes
and is generally accepted as the first-line treatment
for this condition. Metformin is effective as
monotherapy and in combination with nearly every
other therapy for type 2 diabetes, and its utility is supported
by data from a large number of clinical trials.
Fixed-dose combinations of metformin in conjunction
with glipizide, glyburide, pioglitazone, repaglinide,
rosiglitazone, and sitagliptin are available. Metformin is
available as an immediate-release form, and treatment
is best started with low doses and titrated over days to
weeks to minimize side effects. The currently recommended
dosing is 0.5-1.0 g twice daily, with a maximum
dose of 2550 mg; there is no advantage of
thrice-daily administration. A sustained-release preparation
is available that is effective for once-daily dosing;
the maximum dose for this compound is 2 g.
Metformin has superior or equivalent efficacy of glucose lowering
compared to other oral agents used to treat diabetes, and
reduces diabetes-related complications in patients with type 2 diabetes.
Unlike many of the other oral agents, metformin does not typically
cause weight gain and in some cases causes weight reduction.
Metformin is not effective in the treatment of type 1 diabetes. Several
observational studies suggest that diabetic patients treated with metformin
may have lower rates of cardiovascular disease and mortality,
compared to individuals treated with alternative therapies ( Evans
et al., 2006; Johnson et al., 2005). The results of the Diabetes
Prevention Program indicate that in persons with impaired glucose
tolerance, treatment with metformin delays the progression to diabetes.
Metformin has been used as a treatment for infertility in
women with the polycystic ovarian syndrome. Although not formally
approved for this purpose, metformin has demonstrable effects to
improve ovulation and menstrual cyclicity and reduce circulating
androgens and hirsutism.
Adverse Effects and Drug Interactions. The most common side
effects of metformin are gastrointestinal. Approximately 10-25% of
patients starting this medication report nausea, indigestion, abdominal
cramps or bloating, diarrhea, or some combination of these.
Metformin has direct effects on GI function including glucose and
bile salt absorption. Use of metformin is associated with 20-30%
lower blood levels of vitamin B 12
(DeFronzo et al., 1995), probably
due to malabsorption, but neurological or hematological consequences
of this have not been reported. Most GI adverse effects of
metformin abate over time with continued use of the drug, and can be
minimized by starting at low doses and gradually titrating to a target
dose over several weeks, and by having patients take it with meals.
Like phenformin, metformin has been associated with lactic
acidosis. The most concrete evidence of this is from cases of metformin
overdose where very high circulating levels of the drug were
associated with high plasma lactate and acidemia. However, the estimated
incidence of lactic acidosis attributable to metformin use is
3-6 per 100,000 patient-years of treatment (Lalau and Race, 2001;
Scarpello and Howlett, 2008), which is comparable to rates in type 2
diabetic patients not using metformin. Moreover, several recent
analyses of this association have raised doubts as to whether the
association of lactic acidosis with metformin is causal (Kamber et al.,
2008). Many cases of lactic acidosis associated with the use of metformin
have been reported in patients with concurrent conditions
that can cause poor tissue perfusion such as sepsis, myocardial
infarction, and congestive heart failure. Renal failure is another common
comorbidity reported in patients having lactic acidosis associated
with metformin use, and decreased glomerular filtration rates
are thought to increase plasma metformin levels by reducing clearance
of drug from the circulation. There are no consensus guidelines
for renal contraindications for metformin use; because clearance of
the drug is not altered significantly until the creatinine clearance
drops below 50 mL/minute, metformin is probably safe in patients
with this level of renal function (Herrington and Levy, 2008). It is
important to assess renal function before starting metformin and to
monitor function at least annually. Metformin should be discontinued
preemptively in situations where renal function could decline
precipitously, such as before radiographic procedures that use contrast
dyes and during admission to hospital for severe illness.
Metformin should not be used in severe pulmonary disease, decompensated
heart failure, severe liver disease, or chronic alcohol abuse.
Cationic drugs that are eliminated by renal tubular secretion
have the potential for interaction with metformin by competing
for common renal tubular transport systems. Careful patient
monitoring and dose adjustment of metformin is recommended in
patients who are taking cationic medications such as cimetidine,
furosemide, and nifedipine, excreted via the proximal renal tubular
secretory system.
Thiazolidinediones
Chemistry and Mechanism of Action. Thiazolidinediones
are ligands for the peroxisome proliferation activating
receptor γ (PPARγ) receptors, a group of nuclear hormone
receptors that are involved in the regulation of genes
related to glucose and lipid metabolism (Yki-Jarvinen,
2004). Two thiazolidinediones are currently available to
treat patients with type 2 diabetes, rosiglitazone (AVANDIA)
and pioglitazone (ACTOS). These compounds are generally
similar but have several important differences.
Although much is understood about the molecular mechanisms
of action of the thiazolidinediones, they have complex
effects on a wide variety of tissues, and much
remains to be learned about their overall clinical impact
1259
CHAPTER 43
ENDOCRINE PANCREAS AND PHARMACOTHERAPY OF DIABETES MELLITUS AND HYPOGLYCEMIA