Page 771 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 41 Pancreatic Hormones & Antidiabetic Drugs 757

A mechanical patch pump (V-Go, Valeritas) designed spe- 2. Immune insulin resistance—A low titer of circulating IgG
cifically for patients with type 2 diabetes is available on a basal- anti-insulin antibodies that neutralize the action of insulin to a
plus-bolus insulin regimen. The device is preset to deliver one of negligible extent develops in most insulin-treated patients. Rarely,
three fixed and flat basal rates (20, 30, or 40 units) for 24 hours the titer of insulin antibodies leads to insulin resistance and may
(at which point it must be replaced), and there is a button that be associated with other systemic autoimmune processes such as
delivers two units per press to help cover meals. lupus erythematosus.

D. Inhaled Insulin Lipodystrophy at Injection Sites
A dry powder formulation of recombinant regular insulin (techno- Injection of animal insulin preparations sometimes led to atrophy
sphere insulin, Afrezza) is now approved for use in adults with dia- of subcutaneous fatty tissue at the site of injection. Since the
betes. It consists of 2- to 2.5-μm crystals of the excipient, fumaryl development of human and analog insulin preparations of neutral
diketopiperazine, that provide a large surface area for adsorption pH, this type of immune complication is almost never seen. Injec-
of proteins like insulin. After inhalation from the small, single-use tion of these newer preparations directly into the atrophic area
device, pharmacokinetic studies show that peak levels are reached often results in restoration of normal contours.
in 12–15 minutes and decline to baseline in 3 hours, significantly Hypertrophy of subcutaneous fatty tissue remains a problem
faster in onset and shorter in duration than subcutaneous insulin. if injected repeatedly at the same site. However, this may be cor-
Pharmacodynamic studies show that median time to maximum rected by avoiding the specific injection site.
effect with inhaled insulin is approximately 1 hour and declines to
baseline by about 3 hours. In contrast, the median time to maxi-
mum effect with subcutaneous insulin lispro is about 2 hours and
declines to baseline by 4 hours. In trials, inhaled insulin combined ■ MEDICATIONS FOR
with injected basal insulin was as effective in lowering glucose TREATMENT OF TYPE 2 DIABETES
as injected rapid-acting insulin combined with basal insulin. It
is formulated as a single-use color coded cartridge delivering 4, Several categories of glucose-lowering agents are available for
8 or 12 units immediately before the meal. The manufacturer patients with type 2 diabetes: (1) agents that bind to the sulfo-
provides a dose conversion table; patients injecting up to 4 units nylurea receptor and stimulate insulin secretion (sulfonylureas,
of rapid-acting insulin analog should use the 4-unit cartridge. meglitinides, d-phenylalanine derivatives); (2) agents that lower
Those injecting 5–8 units should use the 8-unit cartridge. If the glucose levels by their actions on liver, muscle, and adipose tissue
dose is 9–12 units of rapid-acting insulin pre-meal then one 4-unit (biguanides, thiazolidinediones); (3) agents that principally slow
cartridge and one 8-unit cartridge or one 12-unit cartridge should the intestinal absorption of glucose (α-glucosidase inhibitors);
be used. The inhaler is about the size of a referee’s whistle. The (4) agents that mimic incretin effect or prolong incretin action
most common adverse effect of inhaled insulin was cough, affect- (GLP-1 receptor agonists, dipeptidyl peptidase 4 [DPP-4] inhibi-
ing 27% of trial patients. A small decrease in pulmonary function tors), (5) agents that inhibit the reabsorption of glucose in the
(forced expiratory volume in 1 second [FEV ]) was seen in the first kidney (sodium-glucose co-transporter inhibitors [SGLTs]), and
1
3 months of use, which persisted over 2 years of follow-up. Inhaled (6) agents that act by other or ill-defined mechanisms (pramlint-
insulin is contraindicated in smokers and patients with chronic ide, bromocriptine, colesevelam).
lung disease, such as asthma and chronic obstructive pulmonary
disease. Spirometry should be performed to identify potential lung
disease prior to initiating therapy. During the clinical trials, there DRUGS THAT PRIMARILY
were two cases of lung cancer in patients who were taking inhaled STIMULATE INSULIN RELEASE BY
insulin and none in the comparator-treated patients.
BINDING TO THE SULFONYLUREA
Immunopathology of Insulin Therapy RECEPTOR
At least five molecular classes of insulin antibodies may be pro- SULFONYLUREAS
duced in diabetics during the course of insulin therapy: IgA, IgD,
IgE, IgG, and IgM. There are two major types of immune disor- Mechanism of Action
ders in these patients:
The major action of sulfonylureas is to increase insulin release
1. Insulin allergy—Insulin allergy, an immediate type hyper- from the pancreas (Table 41–7). They bind to a 140-kDa high-
sensitivity, is a rare condition in which local or systemic urticaria affinity sulfonylurea receptor that is associated with a beta-cell
results from histamine release from tissue mast cells sensitized by inward rectifier ATP-sensitive potassium channel (Figure 41–2).
anti-insulin IgE antibodies. In severe cases, anaphylaxis results. Binding of a sulfonylurea inhibits the efflux of potassium ions
Because sensitivity is often to non-insulin protein contaminants, through the channel and results in depolarization. Depolariza-
the human and analog insulins have markedly reduced the inci- tion opens a voltage-gated calcium channel and results in calcium
dence of insulin allergy, especially local reactions. influx and the release of preformed insulin.