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Pharmacology > Drugs acting on bone metabolism > Flashcards

Drugs acting on bone metabolism Flashcards

1
Q

What are the main minerals in bone?

A

Calcium and phosphates

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2
Q

What are the main cells in bone homeostasis?

A

osteoblasts,

osteoclasts and osteocytes.

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3
Q

What are osteoblasts?

A

Osteoblasts are bone-forming
cells: they secrete important
components of the extracellular
matrix-the osteoid.

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4
Q

What are Osteoclasts?

A

Osteoclasts are multinucleated

bone-resorbing cells.

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5
Q

What are osteocytes?

A 
Osteocytes are derived from the
osteoblasts, which, during the
formation of new bone, become
embedded in the bony matrix
and differentiate into
osteocytes. These cells form a connected cellular network that,
along with the nerve fibers in
bone has a role in the response
to mechanical loading.
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6
Q

What is osteoid?

A

Osteoid is the organic
matrix of bone and its
principal component is
collagen.

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7
Q

What is bone remodeling?

A 
 The process of remodelling involves:
• Two main cell types: osteoblasts and osteoclasts
• Variety of cytokines
• Bone minerals-particularly calcium and phosphate
• The actions of several hormones:
 Parathyroid hormone (PTH)
 Calcitonin
 The vitamin D family
 Estrogens
 Growth hormone
 Steroids
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8
Q

What is the action of cells and cytokines?

A

The osteoblast expresses a surface ligand, the RANK ligand (RANKL):
• Expression is stimulated by calcitriol, parathyroid hormone (PTH), cytokines
and glucocorticoids

RANKL interacts with a receptor on the
osteoclast termed RANK (receptor
activator of nuclear factor kappa B). The
result is:
• Differentiation and activation of the
osteoclast progenitors to form mature
osteoclasts;
• Fusion of osteoclasts occurs to give giant
multinucleated bone-resorbing cells.

The osteoblast also releases ‘decoy’ molecules of osteoprotegerin (OPG),
which can bind RANKL and prevent activation of the RANK receptor.

 Bisphosphonates inhibit bone resorption
by osteoclasts.

 Anti-RANKL antibodies (e.g.
denosumab) bind RANKL and prevent
the RANK-RANKL interaction.

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9
Q

What are the hormones involved in bone metabolism?

A 
The actions of several hormones:
 Parathyroid hormone (PTH)
 Calcitonin
 The vitamin D family
 Estrogens
 Growth hormone
 Steroids
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10
Q

What is the function of Parathyroid hormone?

A

 Mobilises Ca2+ from bone
 Promotes its reabsorption by the
kidney
 Stimulates the synthesis of calcitriol,
which in turn increases Ca2+
absorption from the intestine and synergises with PTH in mobilizing bone Ca2+
 Promotes phosphate excretion

• Net effect – to increase the concentration of Ca2+ in the
plasma and lower that of
phosphate

 But given therapeutically in a low intermittent dose, PTH and
fragments of PTH
paradoxically stimulate
osteoblast activity and
enhance bone formation.
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11
Q

What is calcitonin and what is its function?

A

 Calcitonin is a peptide
hormone secreted by
the specialized ‘C’ cells
in the thyroid follicles.

 The main action of
calcitonin is on bone:
• Inhibits osteoclasts
• In the kidney:
 Decreases of the
reabsorption of both Ca2+
and phosphate
• Its overall effect:
 Decrease of the plasma
Ca2+ concentration
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12
Q

What are the sources of vitamin D?

A

Two sources of vitamin D:
 Dietary ergocalciferol (D2)
 Cholecalciferol (D3) is generated in the skin by the action of ultraviolet irradiation.

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13
Q

What occurs in the conversion of cholecalciferol?

A

 In the liver to calcifediol (25-hydroxy-vitamin D3)
 Further in the kidney to calcitriol (1,25-
dihydroxy-vitamin D3) – the active form

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14
Q

What is the function of calcitriol?

A

Calcitriol
 Stimulates the absorption of Ca2+ and phosphate
in the intestine
 Mobilizes Ca2+ from bone
 Increases Ca2+ reabsorption in the kidney
tubules
 Promotes the maturation of osteoclasts and
stimulates their activity
 Decreases collagen synthesis by osteoblasts

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15
Q

What function does estrogen have on bone metabolism?

A

• Inhibit the cytokines that
recruit osteoclasts

• Oppose the bone resorbing, Ca2+-
mobilizing action of PTH

• Increase osteoblast
proliferation and inhibit
apoptosis

• Withdrawal of estrogen,
as happens at the
menopause, can (and
usually does) lead to
osteoporosis.
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16
Q

How do glucocorticoids play a role in bone metabolism?

A 
Glucocorticoids
• Physiological
concentrations are
required for osteoblast
differentiation.
• Excessive
pharmacological
concentrations:
 Inhibit osteoblast
differentiation and activity
 Stimulate osteoclast action
 Result:
 Osteoporosis
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17
Q

What are some examples of bone diseases?

A

Rickets
osteoporosis
paget’s disease of bone

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18
Q

How are the drugs used in bone disorders classified?

A 
1. Bisphosphonates
а. I generation
Clodronic acid
b. II generation
Alendronic acid
Ibandronic acid
Zoledronic acid
  1. Estrogens, SERM
    Raloxifene
  2. Parathormone analogs
    Teriparatide
  3. Monoclonal antibodies
    against RANKL
    Denosumab
  4. Strontium
    Strontium ranelate
  5. Calcitonin
    Calcitonin
  6. Vit. D and analogs
    Calcitriol
    Cholecalciferol
    Calcipotriol
  7. Calcimimetics
    Cinacalcet
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19
Q

What is the PK of bisphosphonates?

A 
 PK
• Applied orally or i.v.
• Poorly absorbed
• Accumulate at the sites of bone mineralisation (50% of the dose)
• Remain in bone potentially for
months or years
• The free drug is excreted
unchanged by the kidney.
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20
Q

What is the PD of Bisphosphonates?

A

 PD
• They inhibit bone resorption by
an action mainly on the
osteoclasts
• They form tight complexes with calcium in the bone matrix
• Osteoclasts are exposed to high concentrations of the drugs during bone resorption

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21
Q

What are the unwanted effects of bisphosphonates?

A 
 Unwanted effects
• Oesophagitis (alendronate)
• Bone pain – occasionally
• Given intravenously –
osteonecrosis of the jaw
(zoledronate)
22
Q

What are the clinical uses of bisphosphonates?

A 
 Clinical uses of
bisphosphonates
• Osteoporosis
 Prevention of fractures in
high-risk individuals
 Alendronate – by mouth,
daily or once weekly in
addition to calcium with
vitamin D3.
 Zoledronate – annually by
intravenous infusion,
expensive
• Malignant disease involving
bone (e.g. metastatic breast
cancer, multiple myeloma)
 To reduce bone damage, pain
and hypercalcaemia

• Paget’s disease of bone
 Intermittent administration

23
Q

What is the mechanism of action, clinical use, and ADRs of Estrogens and SERM?

A

Raloxifene

 Mechanism of action – SERM
• Agonist activity on bone, stimulating osteoblasts and
inhibiting osteoclasts
• Agonist actions on the cardiovascular system
• Antagonist activity on mammary tissue and the uterus

 Clinical use
• An alternative to a bisphosphonate for secondary
prevention in postmenopausal women who cannot
tolerate a bisphosphonate

 Adverse drug reactions
• Hot flushes, leg cramps, and peripheral edema
• Less common are thrombophlebitis and
thromboembolism

24
Q

What are PTH and teriparatide?

A 
 Teriparatide – the
peptide fragment (1-
34) of recombinant
PTH:
• Given in small doses
subcutaneously once
daily
• Paradoxically stimulates
osteoblast activity and
enhances bone
formation
• Used to treat selected
patients with
osteoporosis
• Well tolerated
25
Q

What is the mechanism of action of Monoclonal antibodies against RANKL (Denosumab)?

A 
 Mechanism of action
• Monoclonal antibody (IgG2
), which
targets and binds with high
affinity with RANKL
• Inhibits osteoclastogenesis and
activity
26
Q

What is the clinical use of Monoclonal antibodies against RANKL (Denosumab)?

A

Clinical use
• Treatment of postmenopausal
osteoporosis and some cancers
(prostate and breast)

27
Q

What is the administration of Monoclonal antibodies against RANKL (Denosumab)?

A

Administration
• S.c. once every 6 months together
with Calcium and vitamin D

28
Q

What is the ADR of Monoclonal antibodies against RANKL (Denosumab)?

A 
ADR: 
• Infections (airways and urinary
tract) because a number of cells
in the immune system also
express RANKL
• Rarely – osteonecrosis of the jaw
29
Q

What is strontium rantelate?

A

Strontium ranelate

• Inhibits bone resorption and also stimulates bone
formation

• An alternative to a bisphosphonate in prevention of
osteoporotic fractures, when a bisphosphonate is not
tolerated

• The precise mechanism of action is not clear
 Strontium atoms are adsorbed onto the hydroxyapatite
crystals
 Remain in the bone for many years
 Eventually they exchange for calcium in the bone minerals

• The drug is well tolerated.

30
Q

What are cholecalciferol and calcitriol used for?

A

 Given orally
 Deficiency states: prevention and treatment of
rickets and osteomalacia (cholecalciferol).
 Osteodystrophy of chronic renal failure
(calcitriol).

31
Q

What is calcipotriol used for?

A

Calcipotriol
 Ointment
 Psoriasis (inhibits cell proliferation; has effects
on immunologic markers that are thought to play
a role in the etiology of the disease)

32
Q

What is calcitonin used for?

A

Synthetic salmon calcitonin
Given by subcutaneous or intramuscular
injection.
Clinical use:
• Hypercalcaemia (e.g. associated with neoplasia)
• Paget’s disease of bone (to relieve pain and
reduce neurological complications)

33
Q

What is cinacalet?

A

 A calcimimetic agent – mimics the action of
calcium in the body by:
• Mimics the stimulatory effect of Ca2+ on the calcium-sensing receptor to inhibit PTH secretion by the
parathyroid glands.
• The reduction in PTH levels also leads to a decrease
in blood calcium levels.

34
Q

what are the clinical uses of cinalcet?

A

 Clinical uses:

• In secondary hyperparathyroidism in patients with
serious kidney disease who need dialysis

• To reduce hypercalcemia in patients with
parathyroid carcinoma or with primary
hyperparathyroidism who cannot have their
parathyroid glands removed

35
Q

Which are the hormones secreted by the thyroid gland?

A
  • Thyroxine (T4)
  • Tri-iodothyronine (T3)
  • Calcitonin
36
Q

Which hormone regulates hormone synthesis and secretion?

A 
Hormone synthesis
and secretion are
regulated by thyroid-stimulating hormone
(thyrotrophin) and
influenced by plasma
iodide.
37
Q

What is the functional unit of the thyroid?

A 
 The functional
unit of the
thyroid is the
follicle.
 The follicle:
• A single layer of
epithelial cells
(1)
• A cavity (*)
filled with a
thick colloid
containing
thyroglobulin.
38
Q

How are thyroid hormones synthesized?

A

• Uptake of plasma iodide by the
follicle cells

• Oxidation of iodide and
iodination of tyrosine residues of
thyroglobulin to MIT and DIT
(thyroperoxidase)

• Coupling in pairs: either MIT with DIT to form T3, or two DIT
molecules to form T4.

• Endocytosis of the thyroglobulin
molecule into the follicle cell

• Proteolysis of thyroglobulin and releasing T4 and T3

• Secretion of T4 and T3
into the
plasma.

39
Q

What are the actions of thyroid hormones?

A

Two categories:

• Affecting metabolism:
 General increase in the metabolism of carbohydrates,
fats and proteins, T3 being three to five times more
active than T4

• Affecting growth and development – a critical
effect on growth:
 Partly by a direct action on cells
 Indirectly by influencing growth hormone production
and potentiating its effects on its target tissues

40
Q

What is the mechanism of action of thyroid hormones?

A

 Genomic actions – a
specific nuclear
receptor, TR

• T4 may be regarded as a
prohormone, because
when it enters the cell, it
is converted to T3
• T3
then binds with high
affinity to a member of
the TR family
• Activation of
transcription, resulting in
generation of mRNA and
protein synthesis

 Non-genomic actions

41
Q

What are some abnormalities of thyroid function?

A

 Hyperthyroidism
(thyrotoxicosis); either
diffuse toxic goiter or
toxic nodular goiter

 Hypothyroidism; in
adults this causes
myxoedema, in infants
cretinism

 Simple non-toxic goitre
caused by dietary
iodine deficiency,
usually with normal
thyroid function
42
Q

Which are the drugs used for thyroid and thyroid activity?

A
  1. Drugs with the activity of thyroid hormones
    Levothyroxine
  2. Thyreostatic agents
    Thiamazol Propylthiouracil
  3. Iodides
    Potassium iodide
43
Q

What is levothyroxine?

A

Levothyroxine:

Synthetic compound
Given orally
Unwanted effects may occur with
overdose:

• Severe overdose:
 Signs and symptoms of hyperthyroidism
 Precipitating of angina pectoris, cardiac dysrhythmias
or even heart failure

• Less severe overdose
 Increased bone resorption leading to osteoporosis

44
Q

What is the action of thyreostatic agents? (Thiamzol, Propylthiouracil)

A

Mechanism of action:
• Inhibition of the iodination of tyrosil residues in thyroglobulin
• Inhibition of the thyroperoxidase-catalysed oxidation reactions
• Reduction of the deiodination of T4
to T3
in peripheral tissues (Propylthiouracil)

45
Q

What is the clinical response of thyreostatic agents? (Thiamzol, Propylthiouracil)

A

The clinical response:
• After several weeks (the thyroid may have large stores of hormone)
• Propylthiouracil is thought to act somewhat more rapidly because of the
reduction of the deiodination of T4
to T3

46
Q

What is the ADR of thyreostatic agents? (Thiamzol, Propylthiouracil)

A

Adverse drug reactions:
• Neutropenia and agranulocytosis (the most dangerous unwanted effect with an
incidence of about 1%, reversible on cessation of treatment}
• Rashes (more common up to 25%)

47
Q

What are the indications of thyreostatic agents? (Thiamzol, Propylthiouracil)

A

 Indications:
• Hyperthyroidism (diffuse toxic goitre) – long treatment (at least 1 year)
• In very severe hyperthyroidism (thyroid storm) – propylthiouracil is preferred.
The β-adrenoceptor antagonists (e.g. propranolol) are also used.

48
Q

What is the mechanism of action of Potassium iodide?

A

Mechanism of action – not entirely clear:
• It may inhibit iodination of thyroglobulin, possibly by reducing
the H2O2 generation that is necessary for this process

49
Q

What are the effects of potassium iodide?

A

Effects:
• Temporary inhibition of the release of thyroid hormones (10-14
days)
• Reduction in vascularity of the gland

50
Q

What are the clinical uses of potassium iodide?

A

Clinical use:
• For the preparation of hyperthyroid subjects for surgical
resection of the gland
• As part of the treatment of thyroid storm

51
Q

What are the ADRs of potassium iodide?

A

Adverse drug reactions (iodide in tears and saliva):
• Lacrimation, conjunctivitis
• Pain in the salivary glands

Pharmacology (35 decks)

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