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

INSULIN SECRETAGOGUES AND ORAL
HYPOGLYCEMIC AGENTS
A variety of sufonylureas, meglitinides, GLP-1 agonists,
and inhibitors of dipeptidyl peptidase-4 (DPP-4)
are used as secretagogues to stimulate insulin release
(Table 43–6).
K ATP
Channel Modulators:Sulfonylureas
Chemistry. All members of this class of drugs are substituted
arylsulfonylureas. They differ by substitutions
at the para position on the benzene ring and at one nitrogen
residue of the urea moiety. The sulfonylureas are
divided into two groups or generations of agents. The
first generation sulfonylureas (tolbutamide, tolazamide,
and chlorpropamide) are rarely used now in the
treatment of type 2 diabetes and are not discussed
(information is available in prior editions of this book).
The second, more potent generation of hypoglycemic
sulfonylureas includes glyburide (glibenclamide; DIA-
BETA, others), glipizide (GLUCOTROL, others), and
glimepiride (AMARYL, others) (Table 43–7). Some are
Table 43–6
Properties of Insulin Secretagogues
available in an extended-release (glipizide) or a
micronized (glyburide) formulation.
Mechanism of Action. Sulfonylureas stimulate insulin
release by binding to a specific site on the β cell K ATP
channel complex (the sulfonylurea receptor, SUR) and
inhibiting its activity. K ATP
channel inhibition causes
cell membrane depolarization and the cascade of events
leading to insulin secretion (Figure 43–3). The acute
administration of sulfonylureas to type 2 diabetes
patients increases insulin release from the pancreas.
Sulfonylureas may also reduce hepatic clearance of
insulin, further increasing plasma insulin levels. In the
initial months of sulfonylurea treatment, fasting plasma
insulin levels and insulin responses to oral glucose challenges
are increased. With chronic administration, circulating
insulin levels decline to those that existed
before treatment, but despite this reduction in insulin
levels, reduced plasma glucose levels are maintained.
The explanation for this is not clear, but it may relate to
the fact that chronic hyperglycemia per se impairs
insulin secretion (glucose toxicity), and with the initial
CLASS/GENERIC NAME DAILY DOSAGE a , mg DURATION OF ACTION, h
Sulfonylureas - first generation
Chlorpropamide 100-500 >48
Tolazamide 100-1000 12-24
Tolbutamide 1000-3000 6-12
Sulfonylureas - second generation
Glimepiride 1-8 24
Glipizide 5-40 12-18
Glipizide (extended release) 5-20 24
Glyburide 1.25-20 12-24
Glyburide (micronized) 0.75-12 12-24
Nonsulfonylureas (Meglitinides)
Repaglinide 0.5-16 2-6
Nateglinide 180-360 2-4
GLP-1 agonist
Exenatide 0.01-0.02 4-6
Dipeptidyl Peptidase-4 Inhibitors
Saxagliptin 2.5-5
Sitagliptin 100 12-16
Vildagliptin 50-100 12-24
a
Dose may be lower in some patients
1255
CHAPTER 43
ENDOCRINE PANCREAS AND PHARMACOTHERAPY OF DIABETES MELLITUS AND HYPOGLYCEMIA