pharma sheet # 5 - Tara Elias

Thyroid gland
We will start with the axis (regulation by hypothalamus and anterior pituitary) in order to understand the system.
Starting with the hypothalamus  regulation is through TRH ((which is tripeptide “3 a. a” that mainly regulates the synthesis and release of TSH))
While TSH  contains alpha and beta subunits, so TRH regulate transcription, translation, glycosylation and storage of TSH.
T3, T4 negative feedback mainly at the level of anterior pituitary and little negative feed back is exerted at the level of hypothalamus.

**Remember: - the first step to be affected is the RELEASE.

TSH interacts with specific receptor present on the thyroid follicles resulting in regulating T3, T4 synthesis and release by the thyroid follicles.
We mentioned that certain cases of hypothyroidism could be successfully managed by TRH administration provided that anterior pituitary and thyroid gland are fine.
• TRH orally as well as I.V effective.
• TRH is a maybe used to asses the function of anterior pituitary.


**T3 (tri- iodotyrosine), T4 (thyroxin, tetra- iodotyrosine).
So they are iodinated tyrosine, amino acid administration.
**in the slides you can see the structure of T3 contain 3 iodine groups, and T4 contain 4 iodine groups.

Now, regarding synthesis of thyroid hormones, many of the steps are under regulation by TRH, TSH and we can target these steps by drugs. (Anti-thyroid drugs)

**iodide is necessary for T3, T4 synthesis however; iodide deficiency with hypothyroidism is not present nowadays because we added iodide to the salt. So hypothyroidism due to iodide deficiency is very rare nowadays.
Going back…… iodide has to be taken by thyroid follicles so:
1. Up take of iodide by thyroid follicles.
2. Oxidation and activation of iodide into iodine.( before iodinating thyroglobulin). Then we have storage proteins known as thyroglobulin which contains many tyrosine residues.
3. Iodination reaction  addition of iodine to tyrosine while tyrosine is still connected to thyroglobulin forming:
a) Mono- iodotyrosine.
b) Di-iodotyrosine
4. coupling reaction (combination) of:
1 mono + 1 di = T3 (tri- iodotyrosine).
1 di + 1 di = T4 (tetra- iodotyrosine).
Please note that tyrosine is still bound to thyroglobulin.
5. Hydrolyze thyroglobulin to release T# and T4.



**Mono & di- iodotyrosine are not secreted or released from thyroid follicles what is released is T3, T4. Then T3 & T4 are stored and whenever they are needed they are released to blood stream quickly because thyroid gland is ductless gland.


**Any of these steps could be site of action of different anti-thyroid drugs.
**We have already talked about TSH mechanism.

 Regarding iodide: iodide is essential for the formation of T3, T4 however; iodide is used as anti-thyroid drug.
The first proposed mechanism of how iodide produce its anti-thyroid effect: is by inhibition its uptake (a sort of auto regulatory mechanism) if iodide is increased in the thyroid follicle it negatively feedback on it’s uptake (inhibiting further uptake & synthesis). Later on they found that the MAJOR mechanism of action of iodide as anti-thyroid drug is by inhibition release.
{So it inhibits its uptake only in large doses…. While the Major mechanism is release inhibition}.also Iodide is needed for synthesis of thyroid hormones.
 Source is salt (major source) but it’s also found in bread, dairy products... etc
 The daily requirement is 10 gms per day.

 Thyroid hormones following its release binds to specific globulin in
The blood which is the mean of transfer of T3, T4 to target cell and reservoir for T3, T4.

What are the differences between T3 & T4??
A- Thyroid content: (thyroid gland contains more T4) in a ratio of 4:1 {major source of T4 is thyroid gland} whereas the major source of T3 is peripheral deiodination ((loss of 1 iodide from T4 resulting in T3)) most of the released T4 is deiodinized by peripheral tissues to T3.
** AS if we are saying that the action of thyroid hormones is these that belong to T3.
B-Potency:
T3 > T4
C-Protein binding:
T3< T4
((T4 more strongly binds to the globulin ))
D- Half life:
T4 1 week {longer half life}
T3 1Day.

** A question: which hormone is released more from thyroid??
T4 because thyroid content in T4 is higher than T3 {so it’s released in excess as compared to T3} but most of T4 will be converted to T3. {More combination of di- iodotyrosine}.







General effects:
1) Essential for growth and development particularly the CNS. In the past there where so many cases of mental retardation due to T3 & T4 deficiency , but nowadays its not present  because deficiency of T3 & T4 in the first year of life is not obvious and the manifestations is not clear [ the infant seems to be completely normal] so there is no observational manifestations in the infant whatsoever following delivery. ((nowadays it’s a routine in many hospitals, to asses their levels in the blood)).

 Congenital hypothyroidism (critinism):
Could be for many reasons:
• Absence of thyroid gland.
• Production of certain antibodies by the female during pregnancy.
• The use of anti-thyroid drugs by the pregnant lady that has developed hyperthyroidism.
Whatever the cause is this is known as CRITINSM. In the first year of life the infant looks completely normal, if we don’t pay attention to this fact the CNS development will be affected and hence mental retardation will be the result.
So measuring T3, T4 is very simple and by this test we can prevent such condition because the treatment is very easy ((will be by HRT … T3 or T4)).

2) Increase: BMR, O2 consumption, metabolism.
3) Increase lipolysis.
4) Decrease cholesterol blood level.
5) Increase Beta adrenergic receptor particularly in cardiovascular system in the heart.
** So over activity of symp. System is a major manifestation of hyperthyroidism and the first manifestations that appear on a patient with excess production of T3, T4 is over activity of symp. And its manifestation includes:
Tachycardia, sweating, nervousness, anxiety … etc


Disorders:
I. Hypothyroidism:
Congenital……. cretinism
Adults………. myxedema
Symptoms are not that difficult to diagnose  you can reach to the diagnoses of hypothyroidism by its symptoms such as non pitting edema, dull looking patient…etc

{Plz refer to the slides since the Dr. read them very quickly and its not clear }

Treatment: HRT with T3 or T4 preparations.

Thyroid preparations:
 Animal source: they take the gland of animals (bovine…..) because T3, T4 structure in humans are not different from that in animals. {Tyrosine derivatives}.

A) Thyroid USP: they take thyroid glands, desiccates them, dry them and make tablets out of them.
There is some regulations about this tablets that the iodine should not exceed a specific %  the tablet should not contain more than 0.23% of iodine {iodine is Not an easy element}.

 iodine could lead to frequent allergic reactions.( allergy is common with iodine, even when they need to take x-ray that require contrast media ,before giving iodine to the patient they do allergic test, because it has been associated with many deaths preceded by anaphylactic shock).


USP …. (United state pharmacopeial)
 BP …. (British pharmacopeial)
**So allergy reactions with those tablets are frequent since it contains the whole gland (it contains many things, proteins whatever…!) that could lead to allergy however, they are:
* Very effective * cheap


B) Thyroid extract: they extract thyroglobulin, which contains T3,T4 and made tablets out of thyroglobulin.
Its cleaner preparation!!!! Associated with less frequent side effects compared to thyroid USP.
• Highly effective in management of hypothyroidism.
• Cheap  more expensive as compared to USP & less expensive than synthetic.
But allergies are still frequent  you take thyroglobulin, hydrolyze it in the intestine. Mono & di-iodo will not be absorbed {highly water soluble}. What is absorbed is T3, T4  interact with specific nuclear receptors (highly lipid soluble). So it’s quickly absorbed from GI and reach target cell.

 Synthetic preparation:
Synthetic T4 (L-thyroxine) …. Check the slides plz
They synthesized T3 also.
*the Dr. doesn’t find any advantage of synthesis of T3 (liothyronine sodium) . It maybe used in crises and acute hypothyroidism I.V, because it’s more potent and short acting.
*T4 once taken it will be converted to T3 very quickly, that’s why T3 has no over advantages.
Combination of T3 & T4 is known as (liotrix) in the same ratio that is found in the thyroid gland ….. 4:1 (T4:T3)
*All of them are orally effective.
*half life 1 week with the exception of synthetic T3  its half life is 1 day (same as natural hormones).




Clinical uses:
1) Hypothyroidism
2) Thyroid cancer… whatever preparation you want to use, but how does it works??
answer: through negative feedback mechanism.
So, we will be making negative feedback at the level of anterior pituitary. {TSH dependant cancer} because these cancers depend on their development and metastasis on TSH  we inhibit TSH by T3, T4.
-Note: not necessary that all cancers will be associated with excess production of T3, T4.
3) Weight reduction (abuse)
** Both T# & T4 lower blood cholesterol level … in the past they used such preparation to reduce cholesterol level blood and hence weight.
**Weight reduction programs {give a lot of drugs such as T3, T4 and androgens for the muscles) along with exercise.

**T3, T4 cause over activity of the symp. Causing increase burden on the heart.
**A lot of deaths have been reported following the use of even the D-isomer which has ¼ potency of L-isomer, With respect to its calorgenic effect, BMR on the heart. But they are equipotent in lowering blood cholesterol level. [D & L isomer]

Side effects:
• Hyperthyroidism
• Allergic reactions.

II. Hyperthyroidism:
Excess production of T3, T4 (thyrotoxicosis). But in grave’s disease the patient must have:
 Hyperthyroidism
 Hyperplasia of the thyroid.
 Exophalmus { bulging of the eye anteriorly out of the orbit}…source Wikipedia
Very severe condition  surgery is preferred to other alternatives of treatments.

**Hyperthyroidism manifestations:
1. Intolerance.
2. nervousness
3. irritability
4. motion instability
5. Over activity of symp.
6. tachycardia, arrhythmia atrial fibrillation is common))

**Diagnoses is easy  patient comes to the hospital with irritability, nervousness, sweating and tachycardia {we don’t want to reach to atrial fibrillation}.






To control these manifestations:
a) Propanolol { Beta blocker} :
REMEMBER: prpanolol is not an anti-thyroid drug. Anti-thyroid dug by definition  those agents which hit the synthetic machinery of thyroid preparation (starting with iodide uptake and ending up with release) any of these steps are inhibited by a specific agent known as anti-thyroid agent. Prpanolol has no effect on thyroid, it only corrects the over activity of the symp.
** Some references say that it has some effect on release  But the Dr. does not believe in that.
b) Anti- thyroid drugs are used in the treatment of hyperthyroidism.
c) Surgery if dug therapy fails.

But in surgery, we have to be careful because we have 4 parathyroid imbedded on the posterior wall of the thyroid; therefore, a good surgeon will do subtotal thyroidectomy in which he leaves some tissue and at least one parathyroid.

The advantage of this subtotal thyroidectomy is preserving the parathyroid but it has a major disadvantage which is recurrent hyperthyroidism because the tissue that is left by this procedure can grow again leading to hyperthyroidism.
• Many surgeons prefer to remove the entire thyroid. Along with this removal, parathyroid will be removed too and the resulting hyperparathyroidism can be easily treated by vit.D administration. (this will be mentioned next lecture).

• Available thyroid drugs:
1-THIOAMIDES:
A-propylthiouracil (least potent)
B-curbimazole (more potent)
C-methimazole (most potent
→Mechanism of action:
by inhibiting or interfering with oxidation, iodination and coupling reactions. in addition to the inhibition of these reactions, propylthyouracil has the ability to decrease the peripheral iodination of T4 to T3.
→Side effects and disadvantages:
1. Allergy.
2. Hepatic dysfunction.
3. Agranulocytosis.
4. Continuous treatment for at least 2 years (as if we are saying that this treatment is for life because if we stop it high relapse and hyperthyroidism will occur and that is the major disadvantage of this group of drugs.
5. Late onset of action: these drugs target the synthetic machinery; therefore, their action will be delayed until all the stored amounts are depleted then it will start acting and this will take about 1 day to happen.





2-IODIDE:
Has anti-thyroid effect
→ Mechanism of action is by decreasing the oxidation reaction and mainly by decreasing the release of T3 and T4.
As we said, the theory regarding inhibition its own uptake has become controversial.
→ Side effects:
Allergy (major)
This drug is widely used by thyroid surgeons to decrease the vascularity of thyroid gland.

Q\WHEN WE WANT TO GIVE IODIDE WILL IT CAUSE –VE FEED BACK OR IT WILL INHIBITE RELEASE?
A\the DR. said to forget about –ve feed back theory so the answer is that it will inhibits the release
→Side effects are more because its uptake takes time, therefore large doses are needed.
→Iodide action is fast.
• Radioactive iodide:
The only tissue that uptakes iodine is the thyroid gland.
Iodine is only needed for the synthesis of T3 and T4 (it has no other function on the body).
So we add radioactive material to the iodine since it is taken up only by the thyroid (selective).
→Remember radioactivity is always damaging to the tissue.

→As you know, cancer is treated by either by:
1. chemotherapy
2. radiotherapy
3. surgery
So radiation kills tissue therefore it is used to cause damage to the thyroid gland only without sever side effects. And the one that is used is (iodine 131) which is available orally as solutions and capsules.
Small doses are used mainly to asses the function of the gland: by giving the tablet to a normal individual, after a while we put thyroid counter on the gland, a sound will be heard and this means that this radioactive iodine has been taken by the thyroid (diagnostic uses).
→Intermediate doses are mainly used in the management of hyperthyroidism.
→Massive doses side effects causes damage to the cells and mainly used in the management of thyroid cancer.
→We have alpha and bête radiation. The damaging effect is mainly by beta radiation.
→Side effects:
1. pulmonary fibrosis
2. Contraindicated during pregnancy tetragenic effect and carcinoma.








→Lithium carbonate:
Acts in a similar mechanism to iodine, it mainly inhibits the release of T3 and T4 from the thyroid.
→Considered as the drug of choice in the management of a psychiatric condition known as “manis depressive psychosis”.

→Side effect:
1. nausea
2. diarrhoea
3. blurred vision
4. diabetes insipidus

The end


Done by: Tara Elias
Date of lecture: 22-2-2011