Download Sheet#3,Dr.Alia , Sereen Alshawish

24/2/2013
pharmacology #3.
Sereen al shaweesh
Today lecture is talking about Thyroid and anti thyroid drugs , but to understand these drug
we must review the anatomy and histology of the gland , and how do these drug synthesize in
order to know how it affect our body .
 Thyroid gland is located in the neck
adjacent to the 5th cervical vertebrae &
it's composed of specialized epithelium
cells which have capability to synthesize
the different thyroid hormones .
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 You can see follicles surrounded by colloid material where protein called thyroglobulin
which it's a substrate for the thyroid hormone synthesis
& also after the synthesis these hormones stored there
until later on we need them for release . you can see
around the colloid material a specialized epithelium cell
called follicular cell.
There are 3 hormones that are secreted from thyroid gland; T3 ,T4, calcitonin . today we will
focus mainly about T3 & T4 , calcitonin we will talk about it when talking about parathyroid
hormone because they regulate Ca level in the blood .
T3 also called : tri-iodothyronine ,T4 (tetra iodothyronine) .
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you can notice that iodine is a very important substrate for the synthesis of these
hormones .
these two hormones are different from each other :
chemically : the number of iodine atoms .Physiologically T3 is almost 4 times more potent
than T4, also have more affinity for it's receptor than T4 .
-
T4 ratio to T3 is 5:1 ; so in the body we try to convert T4 to more active T3 through
enzymes we will talk about it .
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We need supplements for iodine such as : fish , vegetables and salt .
Usually we need 150 microgram\day to keep up the normal level of synthesis of T3 & T4, 60
microgram from these 150 goes to thyroid gland for the synthesis of the hormones, but it's
not the case in all situation ; in pregnancy the women need 200 MG , and who have low
thyroid hormone need more…
Function of the thyroid hormone :
1- maintenance of growth of the children into adults and developments , so deficiencies
in T3 &T4 during childhood due to critinisim (actually I didn't hear it well !) , mental
retardation and retardation in growth .
2- carbohydrates and protein metabolism controlled by thyroid hormones that’s why
every tissue affected by thyroid hormones , the major tissue affected : heart ,liver ,
kidney, skeletal muscle , pituitary gland and intestine because they have more
receptors than other like spleen –not that much affected by these hormones -.
3- Control body temperature and the energy levels , how?
Thyroid hormone receptors it's protein that bound to the DNA , so the thyroid hormone
go and fuses to the cell membrane through certain proteins that help in transportation ,
then it goes inside the nucleus and bind to certain protein , this complex (thyroid
hormone and it's receptor ) act as transcription factor , it's initiate transcription and
translation of certain gene that have to do with metabolism and mitochondria , ETC , so
we enhance the energy production in the body .
We need constant concentration of T3 &T4 in our blood in order to do there proper
function unlike pituitary (pulsatile manner) .

How this concentration regulated?
We have more than one axis :
1- hypothalamus – pituitary –target tissue axis .
2- hypothalamus – pituitary – thyroid axis : controls the level of T3 and T4 that secreted
from the thyroid ; hypothalamus secret hormone called TRH (thyrotropien releasing
hormone) , stimulate the release of TSH from anterior pituitary .. this is +ve stimuli to
release thyroid hormone .
if T3 and T4 level increase in large amount there will be –ve feed back mechanism , goes
back to hypothalamus and pituitary to stop the synthesis of TSH & TRH .
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pharmacology #3.
Sereen al shaweesh
The other factor that regulate thyroid hormones : acute psychosis or prolonged
exposure to cold may activate the axis.
-In this lecture we will talk about a lot of drugs that affect thyroid gland in many ways :
* some factor that inhibit the release of these hormones; drugs such as glucocorticoids ,
cortisone & dopamine they inhibit anterior pituitary to release TSH .
* Thyroid agents : drug that are similar to thyroid hormone , these are given to substitute
a deficiency Ex: hypothyrodisim ( T3 or T4 or combination of them).
* Or if the patients have excessive T3 & T4 releasing we give them drugs to counter act
these effect .. ( anti thyroid drug) .
* drugs that affect the distribution effect and reabsorption of thyroid gland hormone .
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Iodide ( the ionic form) in our body it will be oxidized to ( iodine) , so iodide is ingested
in our body by food & then converted to iodine by enzymes.
Iodide also controls the secretion or the synthesis of thyroid hormone ; so if we have too
little of iodine, too much substrate , less synthesis so it has –ve effect here .
Wolff–Chaikoff effect : which is a reduction in the thyroid hormone level caused by
ingestion of large amount of iodide ,excessive amount of iodine stops the enzyme that
convert iodide to iodine.
It's an autoregulatory mechanism , it inhibits mainly oxidation of iodide or organification
by enzyme called thyroperoxidase ( TPO ) which is an essential enzyme and a key step in
synthesis of the thyroid hormone .
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*The synthesis of thyroid hormones :
the iodide in the blood stream will get absorbed from the intestine to get into follicular
cell of the thyroid gland through NA-I symporter ( NIS) .
in the basement membrane we have NIS , and another protein called pendrin takes the
iodide to the lumen of the cell where the synthesis happen.
Note : some drugs & ions that present in excessive amount in our body like : thiocyanate
(by product in the respiration and ETC) inhibit the function of the NIS, so the iodide can't
enter the cell .
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Also ; we need a protein called (thyroglobulin ) which is synthesize in ER and gets
transported to the lumen of the follicles through exocytosis.
So now we have iodide and thyroglobulin :
- iodide get oxidized by a protein called TPO to iodine.
- thyroglobulin contains tyrosine residue which is usually active & easily hydroxlyzed ,
oxidized & iodinated .
Now the iodine ion will interact with tyrosine residue , so thyroglobulin iodinated to
make T3 & T4 , so when we need to secrete the hormones ,the iodinated form of
thyroglobulin go through proteolysis in order to carry it in parts .
After proteolysis we end up with either mono iodotyrosine when we have only 1 iodine
or di iodotyrosine ( 2 iodine ion ) .
- If 2 molecules of di iodotyrosine bind to each other T4 will be formed.
- If 1 mono iodotyrosine and 1 di iodotyrosine bind to each other T3 will be formed.
T4 is more abundant inside the follicles than T3 , but T3 is more active , so in our body
we can convert T4 into T3 through reaction called : de iodination ( remove one iodide).
Deiodination reaction :
T4 have 2 rings ; and these rings have 4 iodide , there is an outer & inner ring , if the
deiodination reaction occur in the outer ring iodide this will form active T3 ,but if the
reaction cleaves one of the inner ring iodide we get
adverse T3 which is inactive .
*There are certain drugs , that can inhibit
deiodenization some of them are anti arrhythmatic
and some of them are anti convulsion , so if we
stop the conversion of T4 to T3 we lose some of the activity of the thyroid hormone.
EX: Amiodarone which is anti anti arrhythmatic drug & beta blocker and these 2 drugs
can inhibit deiodination and the conversion of T4 to active T3 .
NOTE : also certain situation can stop deiodenation like starvation ,severe stress and
illness .
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*Thyroid agents :
There are certain situation where we need to give the pt. drugs to substitute for
deficiencies in thyroid hormones. We have 4 forms of the thyroid hormones:
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pharmacology #3.
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Levothyroxine (T4) .
Liothyronine (T3) .
Liotrix : which is a combination between T4 & T3 with ratio 4:1 .
Thyroid desiccated : they took the thyroid glands from certain animals like pigs dry it ,
grind it & finally they get powder which is a combination of T3 & T4 .
How do we decide which of these drugs can be used ?
It depends on the pt. status , for older pt. we usually give them T4 , WHY ?
One of the function of the T3 is increasing the sensitivity to catecholamines which can
lead to heart rate increase , so because of that we don't give T3 to older pt. to prevents
the harmeful increase in the heart rate.
*Some people have problem in metabolism ( slow metabolizer) , it's better to give them a
combination of T3 & T4 (Liotrix).
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Anti thyroid agents :
These are given in situation where we have excessive production of the thyroid hormone
so we can use the radioactive iodine and this can stop the enzyme TPO from it's function.
EX:
 (131I) sodium (Iodotope)
• Methimazole (Tapazole)
• Potassium iodide : high concentration of iodide can stop the enzyme.
• Propylthiouracil [PTU]
• Thyrotropin, recombinant human TSH
 (Thyrogen)
……………………………………………………..
We will talk about certain deficiencies and how to treat them with the drugs we
mention :
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1- Hypothyrodisim :
In children : thyroid hormone is important for the development of the children so
hypothyrodisim it's a syndrome resulting from deficiency of thyroid hormone and it's
manifested by retardation in growth & dwarfisim in these children , later on they can
develop mental retardation , so it's very important to treat this condition as early as
possible , and the treatment is easy which is by supplement of thyroid hormone .
-
-
In adult : if the deficiency happen later on in life , symptoms will appear ; fatigue
,weight gain , and intolerance to heal .
*Why they have hypothyrodisim?
some people have already hyperthyrodisim because of tumor and this tumor was
restricted so now the gland won't be able to synthesize sufficient amount of the
hormones , the pt. must take supplements of thyroid hormones , because they might
suffer from hypothyrodisim .
An autoimmune disease Hashimoto's thyroiditis ( antibody that attack our thyroid
gland and destruct it which leads to inability to synthesize the hormones).
If the hypothalamus or pituitary doesn't produce TSH because of tumor .
Plz refer to the table in the slides .
2- Goiter :
Is a symptoms of enlargement of thyroid gland -can be functional or dysfunctional gland- ,
it caused by certain genetic deficiency in the enzymes such as TPO so they aren't able to
synthesis T4, these pt. have a condition called thyroiddisformonogenesis , usually they have
deficiencies in T3 & T4 , as a +ve feedback mechanism; pituitary secrete more TSH so the
gland will grow BUT it can't make hormones !
* another cause of goiter ;the body is absorbing iodide but the gland doesn't synthesize the
hormones , so in order to rescue my self, the thyroid gland enlarge but it's not producing
functional hormone.
*Also certain drugs can cause it .
Radiation & certain congenital condition can cause deficiencies of the thyroid hormone such
as : critnism in early childhood & they usually have mental retardation if they aren't treated
correctly in time.
*It can be secondary to TSH deficiency because of problem in the hypothalamus or anterior
pituitary .
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TSH receptor blocking antibody :
Sometimes in certain people lymphocyte produce an antibody that blocks the receptor for
TSH , so it prevents TSH from binding and functioning as well.
* goiter can be associated with hypothyrodisim or hyperthyrodisim ;If there is a tumor in
the thyroid and it's secreting a large amount of the thyroid hormones ,this enlargement can
be associated with hyperthyrodisim which could be a compensatory mechanism of
decreasing the synthesis of hormones when we have block in the thyroid enzymes.
*Iodine defecincy : gland enlarge trying to increase surface area which absorb as much
iodine as it can in order to make up enough T3 & T4 .
How do we detect this disease?
By measuring the amount of T3 , T4 & TSH ; if the TSH are high ( more than 5 mg/ml)
we know there is something wrong with the synthesis of T3 & T4 ( because it's a
feedback mechanism).
3-Hyperthyrodism:
The over production of the thyroid hormones , it's have opposite symptoms of
hypothyrodisim & usually these pt. will have fatigue , weight loss, rapid heart beat &
anxiety , why they lose their weight ?
Because thyroid hormone correlate to the metabolism of glucose ..
The causes : gravis disease ( the lymphocyte produces TSH receptor antibody that
blocks TSH receptor but sometimes the antibody can stimulate the receptor and cause
activation of secretion it depend on the condition of the pt).
Very special characteristics of gravis pt. opthalmopathy (a protrusion of one or both
eyes, caused by inflammation of the eye muscles by attacking autoantibodies) : TSH
receptors present in orbital fibroblast when TSH antibody bind to these receptors they
cause stimulation & over growth in their eyes .
Thyrotropin:
Tumors of the hypothalamus or pituitary gland can cause the uncontrolled release of
TSH, which accumulates in the thyroid and can cause subsequent follicular or papillary
cancer of the thyroid so TSH replacement therapy (thyrotropin) used to treat pt. who
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have thyroid cancer and under surgical removal of the cancer , after removing the
tumor the pt. lives with supplements of T3 & T4 to substitute the missing .
More TSH production goes to the remaining tissue of thyroid and stimulate the cancer
regrowth, in order to prevent this regrwoth we give the pt. exogenous TSH which is the
recombinant form ( thyrotropin alpha ) following thyroidectomy to suppress the release of
endogenous TSH which can stimulate the tumor growth .
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How the degredation of thyroid hormones occur ?
1- The iodination mechanism .
2- Degredation reaction by the liver ( which is the major site for metabolism).
We have some drugs that interfere with this pathway , and others enhance it .
 Drugs that increase the metabolism of thyroxine:
– Rifampin (Rifadin) : which is an antibiotic
– Phenobarbital : anti convulsions
– Carbamazepine (Tegretol)
– Warfarin (Coumadin) anti coagulant
– Oral hypoglycemic agents
The pt. who take these drugs may not have enough dose because they clear quickly.
 Some drugs reduce thyroid hormone production (Amiodarone, Lithium ,Iodinecontaining medications) because of the effect of iodine in inhibiting the synthesis .
 Drugs that displace thyroid hormone from protein binding .
After synthesis and secreting of thyroid hormones in the blood it will bind to protein
called thyroid binding globulin TBG instead of binding to it's receptor, these drugs
increase the amount of TBG such as : estrogen ,temoxifin (breast cancer drug).
And there are some drugs decrease the amount of the globulin synthesis such as
(androgen or glucocorticoids) but some drugs displace the thyroid hormone from
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protein itself ( take the thyroid place) so we will end up with more concentration of
thyroid hormone .
these drugs are : furosamide (duritics ) , Mefenamic acid (non steroidal anti
inflammotry drug like ibuprofen) , Salicylates like asprin .
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Many thanks to Aseel Majali :D
Your colleague : Sereen al shaweesh 
Best of luck
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