Download Sheet#4,Dr.Alia,Sura Khrisat

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pharmacology- #4
Sura H.khraisat
Today’s lecture we going to talk about a new topic in endocrine system and to be specific we going
to talk about factors that affect bone minerals homeostasis.
**At the first what are the main component of bones?
_calcium and phosphate.
We going to focus more about calcium but their regulation much tight together
**what are the hormones that govern calcium concentration?
-Parathyroid hormone: which is secreted from parathyroid glands which are four small glands found
on the surface of thyroid gland.
-calcetonin: which is secreted from thyroid gland
-vitamin D : which is made in the body through different tissues and organs starting from skin , liver
then the active component is made in the kidneys.
There another hormones that affect and control bone composition and structure such as:
- estrogen : mainly excessive estrogen cause bone reabsorption but to be more specific androgens
have “ biphasic effect” which is meaning its according to the time and concentration of these
hormone it can affect the bone that’s why the female patients after menopause they take what we
called it “hormone replacing therapy which can increase the risk of having “ osteoporosis”.
- Growth hormone: it affects bone formation because it helps up the linear body growth.
-thyroid hormone: increases bone make up or deposition of the minerals because it affect linear
body growth.
One of our colleagues asked about the aldosterone…so the aldosterone that is secreted from
adrenal gland which is a member of glucocorticoids hormone which are affecting the bone in
negative way so we going to have bone reabsorption and that we going to cover next lectures.
But the factors that we going to talk about are mainly 1) parathyroid hormone 2) calcetonin 3)
Vitamin D.
Now, let’s take a close up view about calcium.
Calcium is very important to our body 98% of it is presented in our skeleton in form “Hydroxyaptite
crystals” in form of mineral salts they are deposited in the bone and other tissues such as teeth
which form the immobilized portion.
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We have also the ionic form which is critical component of different tissue and processes in the
body:
- We have muscle contraction.
- signaling neuronal conduction many of signaled cascades “kinnases” they need calcium for
activation and also for neurotransmitters release.
- And we cannot forget the blood clotting cascade.
So when we have Hypocalcaemia
We go to have problems with these processes.
As we see in this figure:
Smooth muscle contraction calcium usually binds to calmodulin “protein that carry calcium and
facilitate its binding to enzymes” so the enzymes get activated.
Neurotransmitters release as we see the terminals neuron so we need calcium to bind to the
vesicles to go bind to the plasma membrane at cause exocytose.
And about this figure:
Another example we have talked about which is the eNOS “ endothelial nitric oxide synthase” that
necessary for production of NO (vasodilator) which is important for maintenance of blood flow for
different organs, so as we see we need calcium-calmodulin complex to bind to the eNOS .
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CaM kinases II which is important signaling transduction enzymes and also need calcium for their
function.
** We don’t have to worry about the structure of eNOS
As we said before 98% are in the bone and teeth and the remaining “in plasma” is also distributed
as:
50% in ionized form where the parathyroid and calcetonin play role in their regulation.
46% bounded to proteins “albumin”
2-4% Complexed to organic ions (phosphate and citrate).
The concentration in normal adult should be kept 2-2.5mmol/L, with differences in patients’
situation the recruitment to maintain this concentration is changed according to age, gender,
prolactation and pregnancy.
When we have hypocalcaemia that’s doesn’t mean the only cause is deficiency in calcium but there
are another factors that play role in that problem such as vitamin D which aids on absorption of
calcium in our body for example. Absorption, deposition and excretion of vitamin D can be the main
causative in hypocalcaemia.
In our country, unfortunately we have a high number –especially in females- that have Vitamin D
deficiency because they don’t like to be subjected to the sunlight for enough periods so e must go
and check our Vitamin D level.
In markets usually we have calcium supplementation with Vitamin D, but this amount is not enough
to whom having vitamin D deficiency.
So how these hormones – PTH, calcetonin, Vitamin D- regulate the hypocalcaemia when it occurs.
If we have low calcium concentration level in our body, the body is going to correct that through
bone, intestine and kidneys.
In hypocalcaemia we have mainly the Parathyroid hormone functioning , it will mobilize the source
of calcium from the bone to the blood ,in the kidney it will increase the production of vitamin D3”
the active form of Vitamin D” and increase calcium reabsorption .in the intestine it increases the
absorption of calcium.
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** Problems related to Hypocalcaemia:
Patient with hypocalcaemia will develop what we called “ tetani /paraspasm” ,because when we
have hypocalcaemia the ions concentration inside and outside the cell will change so the sodium
channels which is responsible for depolarization will be affected too -the equilibrium of ions at
resting membrane will change – and because some of sodium channels are activated by calcium .
The threshold of depolarization will be lower than the normal so we will have titanic muscle
contraction and layrngyospasm which can affect breathing.
In relation to the clotting and role of calcium in this process this patient will have what called
“Puperia “ which is a hematoma under the skin and small pink points under skin.
And according to neurology we are going to have paraesthesia.
In Hypocalcaemia the main role is for calcetonin which is going to inhibit osteocalstic activity of the
bone, inhibit the parathyroid release and inhibit one step of vitamin D production and increase the
excretion of calcium finally decrease the calcium absorption from the intestine.
** Both hormones “parathyroid and calcetonin” are decrease phosphate concentration –increase its
excretion- but they are opposite to each other according to calcium.
**there is a factor which similar to the effect of parathyroid hormone which called “parathyroid
hormone releasing peptide (PTHrP) “which has the segments of amino acid which responsible for
releasing the hormone, these peptide are synthesized and secretion in certain tissue in the body
and it is also secretion in certain carcinoma “tumors” and this is the explanation for those patients
to have hypocalcaemia
Related to dentistry this hormone play a major role in tooth eruption process ; we know that to
have an erupted tooth we need the bone to be reabsorbed around the tooth socket and that what
the (PTHrP) does, it is secreted from cells in the oral cavity called ( reduced enamel epithelium) .
There is a drug related to parathyroid hormone “Teriparatide”
Is a recombinant form of parathyroid hormone (amino acids 1-34), used in the treatment of severe
osteoporosis, which doesn’t make sense!!
This drug will activate the osteoclastic activity but studies on animals show that when we give this
drug in Intermittent way “ once a day” it will enhanced the osteoplastic activity and build up the
bone. But on other hand it has risk of developing osteosarcoma.
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In the slides there is an article which is not included in our exam but its related to dentistry which
said that if we enhanced the periodontitis in experimental rats by putting a cord in their gingival
sulcus then they get treated by intermittent dosing of PTH it will be helpful to recover these rats, so
it likes what the drug does for osteoporosis.
Then the dr summary and read what in the slides about calcetonin and vitamin D.
In this figure:
Vitamin D again as we said it’s a pro hormone which is
Need to be metabolized to active form in the body.
Vitamin D is made from cholesterol in the skin and in the slides
there is a figure shows the steps of activating the Vitamin D but
we don’t have to memorize them.
Vitamin D it’s a transcription factor which is going inside the cell
to the nucleus, binds to the DNA there
The activation needs the receptor and the Vitamin D complex
and together initiate the transcription – translation process for certain genes, then we have proteins
and these protein facilitate the entry of the calcium into the blood stream.
Now we are going to talk about drugs:
Bisphosphonates
Is used to treat osteoporosis and its structure similar to a group in the hydroxyapetite “bone” which
called pyrophosphate so this drug goes to the bone and binds to that group .another thing about
this drug that it can stop osteoclastic activity when it is stimulated.
Another uses for this drug: Hypocalcaemia and Paget’s disease.
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Examples on bisphosphonate : Pamidronate(Aredia)
Zoledronicacid (Zometa)
- AdministredIV for rapid relief of Hypercalcemia.
(Most Effective)
Calcitonin: SC (not as rapid)
Plicamycin (Mithracin): inhibitor of RNA synthesis in osteoclasts.
Disadvantage: bone marrow suppressant.
Paget’s disease:
Deposition of abnormal bone , reabsorption in places and deposition in others and as we see in the
x-ray looks like Cotton patch appearance fosse that have more mineralization process and another
areas that have desorption of bones.
So we have uncontrolled osteoclastic bone resorption with secondary bone formation, so we have
bone reabsorption in somewhere and bone formation in somewhere else.
These patients are more subjected to have bone fractures like osteoporosis .to treat them we give
them factor that sops the osteoclastic activity such as bisphosphnate or calcetonin.
The osteoplastic and osteoclastic activity are very active and the bone is always in remodeling
manner so by giving these drugs we can correct the situation to some extent and we help building
up the bone not as much as what we going to correct in extra bone formation.
Osteoporosis:
We treat this patient by the analogue of PTH “Teriparatide” and we have other factors which are
estrogen replacement therapy; which is predisposing factors but if I give it to the patient in low
dose they enhanced the bone formation “biphasic effect” with calcium supplementation with
Vitamin D.
*denosumab:
This is anew drug for treat osteoporosis “Prolia” is the commercial name not the opposite like in the
slides it is RANK-ligand inhibitor “RANK it’s a receptor for protein called nuclear factor kappa B it
activates the osteoclastic activity of the bone so by these drug we block or inhibit this receptor”.
The nice thing about this drug that it’s given twice a year
.
Good luck.
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