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Color Atlas of Pharmacology
Bearbeitet von
Detlef Bieger, Geraldine O'Sullivan, Heinz Luellmann, Heinz Lüllmann, Klaus Mohr, Albrecht Ziegler, Lutz
Hein, Jürgen Wirth
Neuausgabe 2005. Taschenbuch. 416 S. Paperback
ISBN 978 3 13 781703 1
Format (B x L): 12,5 x 19 cm
Zu Inhaltsverzeichnis
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330
p
Therapy of Selected Diseases
Osteoporosis
Osteoporosis is defined as a generalized decrease in bone mass (osteopenia) that
equally affects bone matrix and mineral content and is associated with a change in spongiosal architecture. This condition predisposes to collapse of vertebral bodies and
bone fractures with trivial trauma (e. g., hip
fractures).
Bone substance is subject to continual remodeling. The equilibrium between bone
formation and bone resorption is regulated
in a complex manner: a remodeling cycle is
initiated by osteoblasts when these stimulate uninucleated osteoclast precursor cells
to fuse into large multinucleated cells. Stimulation occurs by direct cell-to-cell contact
between osteoblasts and osteoclast precursor cells and is mediated by the RANK ligand
on the surface of osteoblasts and its receptor
on the osteoclasts (or their precursors), as
well as cytokines secreted by osteoblasts.
These processes are inhibited by estrogens
and a protein secreted by osteoblasts (osteoprotegerin). The osteoclast creates an acidic
milieu, enabling minerals to be solubilized,
and then phagocytoses the organic matrix.
Hormones regulate these events.
In hypocalcemia, the parathyroid increases its secretion of parathormone, resulting in enhanced liberation of Ca2+. Calcitonin transfers active osteoclasts into a resting state. Calcitonin given therapeutically
relieves pain associated with neoplastic
bone metastases and vertebral body collapse. Estrogens diminish bone resorption
by (a) inhibiting activation of osteoclasts by
osteoblasts and (b) promoting apoptosis of
osteoclasts.
Idiopathic osteoporosis cannot be prevented by prophylactic therapy, but its development can be delayed. This requires: a
healthy lifestyle with plenty of physical exercise (sports, hiking), daily intake of calcium (1000 mg/day Ca2+) and of vitamin D
(1000 IU/day). The same principle holds for
postmenopausal osteoporosis. Hormone
replacement therapy in postmenopausal
women has not been successful because of
an increased incidence of breast cancers,
thromboembolism, and other adverse effects
(p. 250). Long-term hormone replacement
therapy should no longer be carried out.
If osteoporosis has become clinically
manifest, attempts can be made at improving the condition by means of drugs, or at
least slowing down further deterioration.
Besides administration of calcium and vitamin D, the following options are available.
Bisphosphonates (N-containing) structurally mimic endogenous pyrophosphate
(see formulae), and like the latter are incorporated into the mineral substance of bone.
During phagocytosis of the bone matrix, they
are taken up by osteoclasts. There, the Ncontaining bisphosphonates inhibit prenylation of G-proteins and thus damage the cells.
Accordingly, osteoclast activity levels are
lowered by alendronate and risedronate,
while osteoclast apoptosis is promoted. The
result is a reduction in bone resorption and a
decreased risk of bone fractures.
Raloxifene exerts an estrogen-like effect
on bone, while acting as an estrogen antagonist in the uterus and breast tissue (p. 254).
In terms of fracture prophylaxis, its effectiveness appears inferior to that of bisphosphonates. Thromboembolism and edema are reported as adverse effects.
It should also be mentioned that intermittent slight elevation in the plasma concentration of parathormone leads to increased
formation of bone substance. The likely explanation is that, under this condition, stimulation of osteoblasts is sufficient to induce
synthesis of bone matrix but not strong
enough to activate osteoclasts. This strategy
is applied therapeutically by administration
of a fragment (amino acids 1–34) of recombinant human parathormone (teriparatide, s.c.).
Lüllmann u. a., Color Atlas of Pharmacology (ISBN 3-13-781703-X) © 2005 Georg Thieme Verlag
Osteoporosis
331
A. Bone: normal state and osteoporosis
Normal state
Osteoporosis
Organic bone matrix
Bone mineral: hydroxyapatite
B. Regulation of bone remodeling
Progenitor
cells
Parathyroid hormone
Biphosphonates
Fusion
Estrogens
Estrogens
RANKL
Apoptosis
O
PG
RANKL
Activation
G
OP
(Pre)Osteoblasts
Osteoclasts
Calcitonin
OH
HO
P
O
OH
O
P
O
Pyrophosphate
OH OH OH
RANK = receptor activating NF-Κ-B
OH
RANKL = RANK-Ligand
OPG = Osteoprotegerin
Bone resorption
Stimulation
Inhibition
HO
P
C
P
O
CH2 O
OH
(CH2 )2
Alendronate
NH2
Lüllmann u. a., Color Atlas of Pharmacology (ISBN 3-13-781703-X) © 2005 Georg Thieme Verlag