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

Therapeutic Uses. α-Glucosidase inhibitors are indicated
as adjuncts to diet and exercise in type 2 diabetic
patients not reaching glycemic targets. They can also
be used in combination with other oral antidiabetic
agents and/or insulin. In clinical studies α-glucosidase
inhibitors reduce A1C by 0.5-0.8%, fasting glucose by
~1 mM and postprandial glucose by 2.0-2.5 mM. These
agents do not cause weight gain or have significant
effects on plasma lipids. α-Glucosidase inhibitors have
been demonstrated to reduce the progression from
impaired glucose tolerance to type 2 diabetes.
Pramlintide
Mechanism of Action. Islet amyloid polypeptide
(amylin), is a 37–amino acid peptide produced in the
pancreatic β cell and secreted with insulin. A synthetic
form of amylin with several amino acid modifications
to improve bioavailability, pramlintide (SYMLIN), has
been developed as a drug for the treatment of diabetes
(Hoogwerf et al., 2008). It is thought to mediate its
actions through specific binding to the amylin receptor
in specific regions of the hindbrain. Activation of the
amylin receptor cause reductions in glucagon release,
delayed gastric emptying, and satiety.
Absorption, Distribution, Metabolism, Excretion, and Dosing.
Pramlintide is administered as a subcutaneous injection prior to
meals. Pramlintide is not extensively bound by plasma proteins and
has a t 1/2
of 50 minutes. Metabolism and clearance is primarily by the
kidney. The doses in patients with type 1 diabetes start at 15 μg and
are titrated upward to a maximum of 60 μg; in type 2 diabetes the
starting dose is 60 μg and the maximum is 120 μg. Because of
differences in the pH of the solution, pramlintide should not be
administered in the same syringe as insulin.
Adverse Effects and Drug Interactions. The most common adverse
events associated with pramlintide therapy are nausea and hypoglycemia.
Although pramlintide alone does not lower blood glucose,
addition to insulin at mealtimes has been noted to cause increased
rates of hypoglycemia, occasionally severe. It is currently recommended
that prandial insulin doses by reduced 30-50% at the time of
pramlintide initiation and then retitrated. Because of its effects on
GI motility, pramlintide is contraindicated in patients with gastroparesis
or other disorders of motility. Because pramlintide can delay
gastric emptying, it should be used with caution when combined
with other compounds that affect GI motility. Moreover, the pharmacokinetics
of drugs that require rapid GI absorption may be altered.
Pramlintide is a pregnancyCategory C drug. Pramlintide can be
used in persons with moderaterenal disease (creatinine clearance
>20 mL/minute).
Therapeutic Uses. Pramlintide is approved for treatment
of types 1 and 2 diabetes as an adjunct in patients who
take insulin with meals. In clinical trials of type 2 diabetic
subjects, pramlintide reduced A1C by 0.5%, lowered
insulin requirements, and caused weight loss of
1.0-2.5 kg over 3-6 months. Results in studies of type
1 diabetic subjects were similar, with reductions in A1C
of 0.3-0.5%, weight loss of 1-2 kg, and insulin sparing.
Pramlintide is now being evaluated as a drug for weight
loss in nondiabetic persons.
Bile Acid Binding Resins
Mechanism of Action. Bile acid metabolism is abnormal
in patients with type 2 diabetes, and there have
been intermittent reports that bile acid binding resins
lower plasma glucose in diabetic patients. The mechanism
by which bile acid binding and removal from
enterohepatic circulation lowers blood glucose has not
been established. Bile acid sequestrants could reduce
intestinal glucose absorption, although there is no direct
evidence of this. Bile acids also act as signaling molecules
through nuclear receptors, some of which may act
as glucose sensors. The only bile acid sequestrant
specifically approved for the treatment of type 2 diabetes
is colesevelam (WELCHOL); other bile acid sequestrants
likely are also effective.
Absorption, Distribution, Metabolism and Excretion. Colesevelam
is provided as a powder for oral solution and as 625-mg tablets; typical
usage is three tablets twice a day before lunch and dinner or six
tablets prior to the patient’s largest meal. The drug is absorbed from
the intestinal tract only in trace amounts, so that its distribution is limited
to the GI tract.
Adverse Effects and Drug Interactions. The most common side
effects of colesevelam are gastrointestinal, with constipation, dyspepsia,
abdominal pain, and nausea affecting up to 10% of treated
patients. Intestinal obstruction has been reported in persons with previous
intestinal surgery or obstruction. Like other bile acid binding
resins, colesevelam can increase plasma triglycerides in persons with
an inherent tendency to hypertriglyceridemia. In ~400 patient-year
exposures in clinical trials, plasma triglycerides in treated patients
did not exceed 1000 mg/dL, and no associated pancreatitis was documented;
nonetheless, colesevelam should be used cautiously in
patients with plasma triglycerides >200 mg/dL. Colesevelam has no
effects on systemic drug metabolism but can interfere with the
absorption of commonly used drugs like phenytoin, warfarin, verapamil,
glyburide, L-thyroxine, and ethinyl estradiol; these medications
should be given 4 hours prior to colesevelam. The drug may
also interfere with the absorption of fat-soluble vitamins.
Colesevelam is a pregnancy Category B drug that has no contraindications
in patients with renal or liver disease.
Therapeutic Uses. The bile acid binding resin colesevelam,
approved for treatment of hypercholesterolemia, may be used for
treatment of type 2 diabetes as an adjunct to diet and exercise
(Sonnett et al., 2009). In clinical trials, colesevelam reduced A1C
by 0.5% when added to metformin, sulfonylurea, or insulin treatment
in type 2 diabetic patients. A new bile acid binding resin, col-
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CHAPTER 43
ENDOCRINE PANCREAS AND PHARMACOTHERAPY OF DIABETES MELLITUS AND HYPOGLYCEMIA