Page 769 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 41 Pancreatic Hormones & Antidiabetic Drugs 755

B. Long-Acting Insulin Preparations (Tables 41–5, 41–6) with less immunogenicity than human insulin in animal studies.
1. NPH (neutral protamine Hagedorn, or isophane) Glargine’s interaction with the insulin receptor is similar to that of
insulin—NPH insulin is an intermediate-acting insulin whose native insulin and shows no increase in mitogenic activity in vitro.
absorption and onset of action are delayed by combining appropri- It has sixfold to sevenfold greater binding than native insulin to
ate amounts of insulin and protamine so that neither is present the insulin-like growth factor 1 (IGF-1) receptor, but the clinical
in an uncomplexed form (“isophane”). After subcutaneous injec- significance of this is unclear.
tion, proteolytic tissue enzymes degrade the protamine to permit
absorption of insulin. NPH insulin has an onset of approximately 3. Insulin detemir—In this insulin the terminal threonine is
2–5 hours and duration of 4–12 hours (Figure 41–5); it is usually dropped from the B30 position and myristic acid (a C-14 fatty
mixed with regular, lispro, aspart, or glulisine insulin and given two acid chain) is attached to the B29 lysine. These modifications
to four times daily for insulin replacement. The dose regulates the prolong the availability of the injected analog by increasing both
action profile; specifically, small doses have lower, earlier peaks and self-aggregation in subcutaneous tissue and reversible albumin
a short duration of action with the converse true for large doses. binding. The affinity of insulin detemir is four- to fivefold lower
than that of human soluble insulin and, therefore, the U100 for-
2. Insulin glargine—Insulin glargine is a soluble, “peakless” mulation of insulin detemir has a concentration of 2400 nmol/mL
(ie, having a broad plasma concentration plateau), long-acting compared with 600 nmol/mL for NPH. The duration of action
insulin analog. The attachment of two arginine molecules to for insulin detemir is about 17 hours at therapeutically relevant
the B-chain carboxyl terminal and substitution of a glycine for doses. It is recommended that the insulin be injected once or
asparagine at the A21 position created an analog that is soluble twice a day to achieve a stable basal coverage. This insulin has been
in an acidic solution but precipitates in the more neutral body reported to have lower within-subject pharmacodynamic variabil-
pH after subcutaneous injection. Individual insulin molecules ity compared with NPH insulin and insulin glargine.
slowly dissolve away from the crystalline depot and provide a low,
continuous level of circulating insulin. Insulin glargine has a slow 4. Insulin Degludec—In this insulin analog, the threonine at
onset of action (1–1.5 hours) and achieves a maximum effect after position B30 has been removed and the lysine at position B29 is
4–6 hours. This maximum activity is maintained for 11–24 hours conjugated to hexadecanoic acid via a gamma-l-glutamyl spacer.
or longer. Glargine is usually given once daily, although some In the vial, in the presence of phenol and zinc, the insulin is
very insulin-sensitive or insulin-resistant individuals benefit from in the form of dihexamers but, when injected subcutaneously,
split (twice a day) dosing. To maintain solubility, the formulation it self-associates into large multihexameric chains consisting of
is unusually acidic (pH 4.0), and insulin glargine should not be thousands of dihexamers. The chains slowly dissolve in the sub-
mixed with other insulins. Separate syringes must be used to mini- cutaneous tissue, and insulin monomers are steadily released into
mize the risk of contamination and subsequent loss of efficacy. the systemic circulation. The half-life of the insulin is 25 hours.
The absorption pattern of insulin glargine appears to be indepen- Its onset of action is in 30–90 minutes, and its duration of action
dent of the anatomic site of injection, and this drug is associated is more than 42 hours. It is recommended that the insulin be

8
Insulin lispro, aspart, glulisine
7
Glucose infusion rate (mg/kg/min) 5 4 3 2 NPH Insulin degludec
6
Regular

Insulin glargine
Insulin detemir
1

1 2 3 4 5 6 7 8 9101112131415161718192021222324
Time (h)
FIGURE 41–5 Extent and duration of action of various types of insulin as indicated by the glucose infusion rates (mg/kg/min) required to
maintain a constant glucose concentration. The durations of action shown are typical of an average dose of 0.2–0.3 U/kg. The durations of regu-
lar and NPH insulin increase considerably when dosage is increased.