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

abdomen currently is the preferred site of injection in the morning
because insulin is absorbed 20-30% faster from that site than from the
arm. If the patient refuses to inject into the abdominal area, it is
preferable to select a consistent injection site for each component of
insulin treatment (e.g., before-breakfast dose into the thigh, evening
dose into the arm). Rotation of insulin injection sites traditionally has
been advocated to avoid lipohypertrophy or lipoatrophy, although
these conditions are infrequent with current preparations of insulin.
In a small group of patients, subcutaneous degradation of insulin has
been observed, and this has necessitated the injection of large
amounts of insulin for adequate metabolic control.
Insulin Dosing and Regimens. In most patients, insulin-replacement
therapy includes long-acting insulin (basal) and a short-acting
insulin to provide postprandial needs. In a mixed population of type
1 diabetes patients, the average dose of insulin is usually 0.6-0.7
units/kg body weight per day, with a range of 0.2-1 units/kg per
day. Obese patients generally and pubertal adolescents require more
(~1-2 units/kg per day) because of resistance of peripheral tissues
to insulin. Patients who require less insulin than 0.5 units/kg per
day may have some endogenous production of insulin or may be
more sensitive to the hormone because of good physical conditioning.
The basal dose suppresses lipolysis, proteolysis, and hepatic
glucose production; it is usually 40-50% of the total daily dose with
the remainder as prandial or pre-meal insulin. The insulin dose at
meal time should reflect the anticipated carbohydrate intake (many
patients with type 1 diabetes calculate a ratio of the insulin dose to
the number of grams of carbohydrate). A supplemental scale of
short-acting insulin is added to the prandial insulin dose to allow
correction of the BG. With all insulin dosing, the provider should
consider the insulin sensitivity of the patient and adjust the insulin
dosing accordingly. Insulin administered as a single daily dose of
long-acting insulin, alone or in combination with short-acting
insulin, is rarely sufficient to achieve euglycemia. More complex
regimens that include multiple injections of long-acting or shortacting
insulin are needed to reach this goal. In all patients, careful
monitoring of therapeutic end points directs the insulin dose used.
This approach is facilitated by self-glucose monitoring and measurements
of A1C.
A number of commonly used dosage regimens that include
mixtures of insulin given in two or more daily injections are depicted
in Figure 43–8. An effective regimen involving multiple daily injections
consisting of basal administration of long-acting insulin (e.g.,
insulin glargine or determir) either before breakfast or at bedtime
and preprandial injections of a short-acting insulin (Weng et al.,
2008). This method is called basal/bolus and is very similar to the
pattern of insulin administration achieved with a subcutaneous infusion
pump. Another regimen used is the split-mixed regimen involving
the pre-breakfast and pre-supper injection of a mixture of shortand
long-acting insulins. When the pre-supper NPH insulin is not
sufficient to control hyperglycemia throughout the night, the evening
dose may be divided into a pre-supper dose of regular insulin followed
by NPH insulin at bedtime.
Individuals with diabetes may sometimes consume smaller
amounts of food than originally planned. This, in the presence of a
previously injected dose of insulin that was based on anticipation of
a larger meal, could result in postprandial hypoglycemia. Thus, in
patients who have gastroparesis or loss of appetite, injection of a
short-acting analog postprandially, based on the amount of food
actually consumed, may provide smoother glycemic control.
Adverse Events. The most common adverse reaction during insulin
therapy is hypoglycemia. Hypoglycemia is the major risk that must
be weighed against benefits of efforts to normalize glucose control.
Additional information about hypoglycemia and its treatment is provided
later in this chapter. Insulin is an anabolic hormone, and
insulin treatment of both type 1 and type 2 diabetes is associated
with modest weight gain. Paradoxically, improved glycemic control
may initially lead to the deterioration of retinopathy in rare patients,
but this is followed by a long-term reduction in diabetes-related complications.
There has been a dramatic decrease in the incidence of
allergic reactions to insulin with the transition to recombinant human
insulin; these may still occur as a result of reaction to the small
amounts of aggregated or denatured insulin in preparations, to minor
contaminants, or because of sensitivity to one of the components
added to insulin in its formulation (protamine, Zn 2+ , etc.). Human
insulin, as delivered to patients with diabetes, is immunogenic as
reflected by the observation that many patients have circulating antiinsulin
antibodies, but these do not alter insulin pharmacokinetics
or action. Atrophy of subcutaneous fat at the site of insulin injection
(lipoatrophy) was a rare side effect of older insulin preparations.
Lipohypertrophy (enlargement of subcutaneous fat depots) has been
ascribed to the lipogenic action of high local concentrations of
insulin.
Insulin Treatment of Ketoacidosis and Other Special Situations.
Acutely ill diabetic patients may have metabolic disturbances that
are sufficiently severe or labile to justify intravenous administration
of insulin (Kitabchi et al., 2009). Such treatment is most appropriate
in patients with ketoacidosis or severe hyperglycemia with a
hyperosmolar state. Insulin infusion inhibits lipolysis and gluconeogenesis
completely and produces near-maximal stimulation of glucose
uptake. In most patients with diabetic ketoacidosis, blood
glucose concentrations will fall by ~10% per hour; the acidosis is
corrected more slowly. As treatment proceeds, it often is necessary
to administer glucose along with the insulin to prevent hypoglycemia
but to allow clearance of all ketones. Some physicians prefer to initiate
therapy with a loading dose of insulin, but this tactic appears
unnecessary because steady-state concentrations of the hormone are
achieved within 30 minutes with a constant infusion. Patients with
nonketotic hyperglycemic hyperosmolar state may be more sensitive
to insulin than are those with ketoacidosis. Appropriate replacement
of fluid and electrolytes is an integral part of the therapy in
both situations because there is always a major deficit. Regardless of
the insulin regimen, the key to effective therapy is careful and frequent
monitoring of the patient’s clinical status, glucose, and electrolytes.
A frequent error in the management of such patients is the
failure to administer long-acting insulin subcutaneously before the
insulin infusion is discontinued.
Treatment of Diabetes in Children or Adolescents. Diabetes is
one of the most common chronic diseases of childhood, and rates of
type 1 diabetes in American youth are estimated at 1 in 300, with an
increasing incidence over the past 20 years. One of the unfortunate
corollaries of the growing rates of obesity over the past three decades
is an increase in the numbers of children and adolescents with nonautoimmune,
or type 2, diabetes. Current estimates are that 15-20% of
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CHAPTER 43
ENDOCRINE PANCREAS AND PHARMACOTHERAPY OF DIABETES MELLITUS AND HYPOGLYCEMIA