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

may be more frequent in patients taking a sulfonylurea and one of
these agents: androgens, anticoagulants, azole antifungals, chloramphenicol,
fenfluramine, fluconazole, gemfibrozil, histamine H 2
antagonists,
magnesium salts, methyldopa, monoamine oxidase inhibitors
(MAOIs), probenecid, sulfinpyrazone, sulfonamides, tricyclic antidepressants,
and urinary acidifiers. Other drugs may decrease the glucose-lowering
effect of sulfonylureas by increased hepatic
metabolism, increased renal excretion, or inhibiting insulin secretion
(β-blockers, Ca 2+ channel blockers, cholestyramine, diazoxide, estrogens,
hydantoins, isoniazid, nicotinic acid, phenothiazines, rifampin,
sympathomimetics, thiazide diuretics, and urinary alkalinizers).
Dosage Forms Available. Treatment is initiated at lower end of the
dose range and titrated upward based on the patient’s glycemic
response. Some have a longer duration of action and can be prescribed
in a single daily dose (glimepiride), whereas others are formulated
as extended-release or micronized formulations to extend
their duration of action (Table 43–7). The dose for the extendedrelease
glipizide or micronized glyburide is lower. Glyburide is not
recommended when the creatinine clearance is < 50 mL/minute or
in elderly individuals because reduced drug and metabolite clearance
greatly increases the risk of hypoglycemia. Other sulfonylureas
such as glipizide or glimepiride appear safer in elderly individuals
with type 2 diabetes.
Therapeutic Uses. Sulfonylureas are used to treat
hyperglycemia in type 2 diabetes. Between 50% and
80% of properly selected patients respond to this
class of agents. All members of the class appear be
equally efficacious. A significant number of patients
who respond initially later cease to respond to the sulfonylurea
and develop unacceptable hyperglycemia
(secondary failure). This may occur as a result of a
change in drug metabolism or more likely from a progression
of β-cell failure. A recent randomized trial
found that the initial improvement in glycemic control
was less durable with glyburide monotherapy
(compared to metformin or rosiglitazone monotherapy),
suggesting that the secondary failure rate is
higher with this class of drugs (Kahn et al., 2006).
Some individuals with neonatal diabetes or MODY-3
respond to these agents (this is an off-label use).
Combinations of insulin and sulfonylureas and other
oral agents are discussed later. Contraindications to
the use of these drugs include type 1 diabetes, pregnancy,
lactation, and, for the older preparations, significant
hepatic or renal insufficiency.
K ATP
Channel Modulators:
Non-Sulfonylureas
Repaglinide. Repaglinide (PRANDIN) is an oral insulin
secretagogue of the meglitinide class (Table 43–6). It
is a benzoic acid derivative structurally unrelated to the
sulfonylureas, but like sulfonylureas, it stimulates
insulin release by closing K ATP
channels in pancreatic β
cells. The drug is absorbed rapidly from the GI tract,
and peak blood levels are obtained within 1 hour. The
t 1/2
is ~1 hour. These features allow for multiple
preprandial use as compared with the classical once- or
twice-daily dosing of sulfonylureas.
Repaglinide is metabolized primarily by the liver
(CYP3A4) to inactive derivatives. Repaglinide should
be used cautiously in patients with hepatic insufficiency.
Because a small proportion (~10%) is metabolized
by the kidney, dosing of the drug in patients with
renal insufficiency also should be performed cautiously.
As with sulfonylureas, the major side effect of repaglinide
is hypoglycemia. Like sulfonylureas, repaglinide is
associated with a decline in efficacy (secondary failure)
after initially improving glycemic control. Certain
drugs may potentiate the action of repaglinide by displacing
it from plasma protein binding sites (β-blockers,
chloramphenicol, coumarins, MAOIs, nonsteroidal
anti-inflammatory drugs [NSAIDs], probenecid, salicylates,
and sulfonamide) or altering its metabolism
(gemfibrozil, itraconazole, trimethoprim, cyclosporine,
simvastatin, clarithromycin).
Nateglinide. Nateglinide (STARLIX) is an orally effective
insulin secretagogue derived from d-phenylalanine.
Like sulfonylureas and repaglinide, nateglinide stimulates
insulin secretion by blocking K ATP
channels in pancreatic
β cells (Rosenstock et al., 2004). Nateglinide
promotes a more rapid but less sustained secretion of
insulin than other available oral antidiabetic agents. The
drug’s major therapeutic effect is reducing postprandial
glycemic elevations in type 2 diabetes patients.
Nateglinide is approved by the FDA for use in type 2
diabetes. It is most effective when administered in a
dose of 120 mg, 1-10 minutes before a meal.
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CHAPTER 43
ENDOCRINE PANCREAS AND PHARMACOTHERAPY OF DIABETES MELLITUS AND HYPOGLYCEMIA