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

Glucose, mmol/L
13
12
11
10
9
8
7
6
5
4
3
Glucose
10 g
20 g
Glucagon
1.0 mg
Insulin
R x
0 1 2 3 4 5 6 7 8
Time (hours)
240
220
200
180
160
140
120
100
Figure 43–12. Treatment of hypoglycemia with glucose or
glucagon. The blood glucose falls following administration of
insulin (at time = 0). Following administration of oral glucose
(10 or 20 g) or subcutaneous glucagon (at arrow marked “R x
”),
the blood glucose rises. The blue band shows the recovery when
glucose or glucagon was not administered. (Copyright 1993
American Diabetes Association. From Wiethop and Cryer.
Diabetes Care, Vol. 16, 1993; 1131–1136. Reprinted with permission
from The American Diabetes Association.)
results primarily from inhibition of insulin secretion.
Diazoxide interacts with the K ATP
channel on the β cell
membrane and either prevents its closing or prolongs
the open time; this effect is opposite to that of the sulfonylureas
(Figure 43–3). Diazoxide has been used to
treat patients with various forms of chronic or recurring
hypoglycemia.
The usual oral dose is 3-8 mg/kg per day in adults and children
and 8 to 15 mg/kg per day in infants and neonates. The drug can
cause nausea and vomiting and thus usually is given in divided doses
with meals. Diazoxide circulates largely bound to plasma proteins
and has a t 1/2
of ~48 hours. Thus the patient should be maintained at
the chosen dosage for several days before evaluating the therapeutic
result. Diazoxide has a number of adverse effects, including retention
of Na + and fluid, hyperuricemia, hypertrichosis (especially in
children), thrombocytopenia, and leucopenia, which sometimes limit
its use. Despite these side effects, the drug may be useful in patients
with inoperable insulinomas and in children with neonatal hyperinsulinism
(leucine sensitivity, islet cell hyperplasia, nesidioblastosis,
extrapancreatic malignancy, or islet cell adenoma).
OTHER PANCREATIC ISLET HORMONES
Somatostatin was identified as an inhibitor of GH secretion
from the pituitary. Somatostatin (SST) is produced
80
60
40
Glucose, mg/dL
by δ cells of the pancreatic islet, cells of the GI tract, and
in the CNS. Somatostatin, produced as a 14–amino acid or
a 28–aminoacid peptide molecule, acts through a family of
five GPCRs, SSTR 1-5.
SST inhibits a wide variety of
endocrine and exocrine secretions, including TSH and GH
from the pituitary, gastrin, motilin, VIP, glicentin, and
insulin, glucagon, and pancreatic polypeptide from the
pancreatic islet. The physiological role of somatostatin has
not been defined precisely, but its short t 1/2
(3-6 minutes)
prevents its use therapeutically. Longer-acting analogs
such as octreotide (SANDOSTATIN) and lanreotide (SOMAT-
ULINE) are useful for treatment of carcinoid tumors,
glucagonomas, VIPomas, and acromegaly (Chapter 38).
A depot form of octreotide or lanreotide can be administered
intramuscularly every 4 weeks. Octreotide or lanreotide successfully
controls excess secretion of growth hormone in most patients, and
both have been reported to reduce the size of pituitary tumors in
about one-third of cases. Octreotide has been used to treat severe
hypoglycemia related to sulfonylurea ingestion (Cryer et al., 2009).
Because octreotide also can decrease blood flow to the GI tract, it has
been used to treat bleeding esophageal varices, peptic ulcers, and
postprandial orthostatic hypotension. Gallbladder abnormalities
(stones and biliary sludge) occur frequently with chronic use of the
somatostatin analogs, as do GI symptoms. Hypoglycemia, hyperglycemia,
hypothyroidism, and goiter have been reported in patients
being treated with somatostatin analogs for acromegaly.
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CHAPTER 43
ENDOCRINE PANCREAS AND PHARMACOTHERAPY OF DIABETES MELLITUS AND HYPOGLYCEMIA