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

CH 2 OH
21
CH 2 OH
CH 2 OH
CH 2 OH
1219
C O
H 3 C 20
18
HO 12 17 OH
H 3 C 11 13
16
19
1 9 C D
2
14 15
10 8
3 A B
O 4
5 6 7
Hydrocortisone
O
C
H 3 C
HO
H 3 C
F
Fludrocortisone
O
OH
O
C
H 3 C
HO
H 3 C
F
Triamcinolone
O
OH
OH
O
C
H 3 C
HO
H 3 C
F
Dexamethasone
O
OH
CH 3
HO
H 3 C
CH 2 OH
H 3 C
C O
OH
O
H 3 C
CH 2 OH
H 3 C
C O
OH
O
H 3 C
CH 2 OH
OH
C O
CH
HO
H 3 C
CH 2 OH
H 3 C
C O
OH
CH 3
CHAPTER 42
F
O
O
O
O
Prednisolone
Cortisone
Aldosterone,
Betamethasone
hemiacetal derivative
Figure 42–7. Structure and nomenclature of corticosteroid products and selected synthetic derivatives. The structure of hydrocortisone
is represented in two dimensions. Note that the steroid ring system is not completely planar and the orientation of the groups
attached to the steroid rings is an important determinant of the biological activity. The methyl groups at C18 and C19 and the hydroxyl
group at C11 project upward (forward in the two-dimensional representation and shown by a solid line connecting the atoms) and are
designated β. The hydroxyl at C17 projects below the plane (behind in the two-dimensional representation, and represented by the
dashed line connecting the atoms) and is designated α.
with glycyrrhizic acid, a component of licorice implicated in
licorice-induced hypertension.
Carbohydrate and Protein Metabolism. Corticosteroids
profoundly affect carbohydrate and protein metabolism,
which can be viewed as protecting glucose-dependent
tissues (e.g., the brain and heart) from starvation. They
stimulate the liver to form glucose from amino acids
and glycerol and to store glucose as liver glycogen. In
the periphery, glucocorticoids diminish glucose utilization,
increase protein breakdown and the synthesis of
glutamine, and activate lipolysis, thereby providing
amino acids and glycerol for gluconeogenesis. The net
result is to increase blood glucose levels. Because of
their effects on glucose metabolism, glucocorticoids
can worsen glycemic control in patients with overt diabetes
and can precipitate the onset of hyperglycemia in
susceptible patients.
The mechanisms whereby glucocorticoids inhibit glucose utilization
in peripheral tissues are not fully understood. Glucocorticoids
decrease glucose uptake in adipose tissue, skin, fibroblasts, thymocytes,
and polymorphonuclear leukocytes; these effects are postulated to
result from translocation of the glucose transporters from the plasma
membrane to an intracellular location. These peripheral effects are
associated with a number of catabolic actions, including atrophy of
lymphoid tissue, decreased muscle mass, negative nitrogen balance,
and thinning of the skin.
Similarly, the mechanisms by which the glucocorticoids promote
gluconeogenesis are not fully defined. Amino acids mobilized
from a number of tissues in response to glucocorticoids reach the
liver and provide substrate for the production of glucose and
glycogen. In the liver, glucocorticoids induce the transcription of a
number of enzymes involved in gluconeogenesis and amino acid
metabolism, including phosphoenolpyruvate carboxykinase
(PEPCK), glucose-6-phosphatase, and the bifunctional enzyme
fructose-2,6-bisphosphatase. Analyses of the molecular basis for regulation
of PEPCK gene expression have identified complex regulatory
influences involving an interplay among glucocorticoids,
insulin, glucagon, and catecholamines. The effects of these hormones
and amines on PEPCK gene expression mirror the complex
regulation of gluconeogenesis in the intact organism.
Lipid Metabolism. Two effects of corticosteroids on
lipid metabolism are firmly established. The first is the
dramatic redistribution of body fat that occurs in settings
of endogenous or pharmacologically induced
hypercorticism, such as Cushing’s syndrome. In this
setting, there is increased fat in the back of the neck
(“buffalo hump”), face (“moon facies”), and supraclavicular
area, coupled with a loss of fat in the extremities.
The other is the permissive facilitation of the lipolytic
ACTH, ADRENAL STEROIDS, AND PHARMACOLOGY OF THE ADRENAL CORTEX