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

1 S
Asp
Lys
S
A chain
Gly
21
Asn
S
S
Arg Arg
1 3 S
S 28 29 30 31 32
B chain
Pro Lys Thr
Lys Pro
Asp
dissociates into monomers almost instantaneously following injection.
This property results in the characteristic rapid absorption and
shorter duration of action compared with regular insulin. Two therapeutic
advantages have emerged with lispro as compared with regular
insulin. First, the prevalence of hypoglycemia is reduced with
Glu
Lys
ε N-myristoyl
Insulin glargine
Insulin
Insulin lispro
Insulin glulisine
Insulin aspart
Insulin detemir
Figure 43–7. Insulin analogs. Modifications of native insulin
can alter its pharmacokinetic profile. Reversing amino acids 28
and 29 in the B chain (lispro) or substituting Asp for Pro 28B
(aspart) gives analogs with reduced tendencies for molecular
self-association that are faster acting. Altering Asp 3B to Lys and
Lys 29B to Glu produces an insulin (glulisine) with a more rapid
onset and a shorter duration of action. Substituting Gly for
Asn 21A and lengthening the B chain by adding Arg 31 and Arg 32
produces a derivative (glargine) with reduced solubility at pH
7.4 that is, consequently, absorbed more slowly and acts over a
longer period of time. Deleting Thr 30B and adding a myristoyl
group to the ε-amino group of Lys 29B (detemir) enhances
reversible binding to albumin, thereby slowing transport across
vascular endothelium to tissues and providing prolonged action.
B
Insulin analog
Glargine (or detemir)
Regular
NPH
lispro; second, glucose control, as assessed by A1C, is modestly but
significantly improved (0.3-0.5%).
Insulin aspart (NOVOLOG) is formed by the replacement of
proline at B28 with aspartic acid. This reduces self-association to a
degree similar to lispro. Like lispro, insulin aspart dissociates rapidly
into monomers following injection. Comparison of a single subcutaneous
dose of aspart and lispro in a group of type 1 diabetes
patients revealed similar plasma insulin profiles. In clinical trials,
insulin aspart and insulin lispro have had similar effects on glucose
control and hypoglycemia frequency, with lower rates of nocturnal
hypoglycemia as compared with regular insulin.
Insulin glulisine (APIDRA) is formed when glutamic acid
replaces lysine at B29, and lysine replaces asparagine at B23; these
substitutions result in a reduction in self-association and rapid dissociation
into active monomers. The time–action profile of insulin
glulisine is similar to that of insulin aspart and insulin lispro. Similar
to insulin aspart, insulin glulisine has been approved in the U.S. for
continuous subcutaneous insulin infusion (CSII) pump use.
Long-Acting Insulins. Neutral protamine hagedorn (NPH; insulin
isophane) is a suspension of native insulin complexed with zinc and
protamine in a phosphate buffer. This produces a cloudy or whitish
solution in contrast to the clear appearance of other insulin solutions.
Because of this formulation, the insulin dissolves more gradually
when injected subcutaneously and thus its duration of action is prolonged.
NPH insulin is usually given either once a day (at bedtime)
or twice a day in combination with short-acting insulin. In patients
with type 2 diabetes, long-acting insulin is often given at bedtime to
help normalize fasting blood glucose. It should be noted that the use
of long-acting basal insulin alone will not control postprandial glucose
elevation in insulin-deficient type 1 or type 2 diabetes.
Insulin glargine (LANTUS) is a long-acting analog of human
insulin that is produced following two alterations of human insulin.
Two arginine residues are added to the C terminus of the B chain,
and an asparagine molecule in position 21 on the A chain is replaced
with glycine. Insulin glargine is a clear solution with a pH of 4.0,
A B C
Morning Afternoon Evening Night Morning Afternoon Evening Night Morning Afternoon Evening Night
Insulin effect
Glargine
L S HS B
Insulin effect
B
L S HS
B
Bolus Bolus
Bolus
Basal infusion
B L S HS B
Figure 43–8. Commonly used insulin regimens. Panel A shows administration of a long-acting insulin like glargine (detemir could also
be used but often requires twice-daily administration) to provide basal insulin and a pre-meal short-acting insulin analog (Table 43–5).
Panel B shows a less intensive insulin regimen with BID injection of NPH insulin providing basal insulin and regular insulin or an
insulin analog providing meal-time insulin coverage. Only one type of shorting-acting insulin would be used. Panel C shows the
insulin level attained following subcutaneous insulin (short-acting insulin analog) by an insulin pump programmed to deliver different
basal rates. At each meal, an insulin bolus is delivered. B=breakfast; L=lunch; S=supper; HS=bedtime. Upward arrow shows
insulin administration at mealtime. (Copyright 2008 American Diabetes Association. From Kaufman FR (ed), Medical Management
of Type 1 Diabetes, Fifth Edition. Modified with permission from the American Diabetes Association.)
Insulin effect
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CHAPTER 43
ENDOCRINE PANCREAS AND PHARMACOTHERAPY OF DIABETES MELLITUS AND HYPOGLYCEMIA