ENDOCRINE drugs

1. THE THYROID HORMONES
AND DRUGS USED IN
THYROID ABNORMALITIES
Dr. Ruth Namyalo

2. Thyroid hormones
• Thyroid hormones accelerate metabolism. Their release
is regulated by the hypophyseal glycoprotein TSH,
whose release, in turn, is controlled by the hypothalamic
tripeptide TRH.
• Secretion of TSH declines as the blood level of thyroid
hormones rises; by means of this negative feedback
mechanism, hormone production is “automatically”
adjusted to demand.

3. Thyroid hormones
• The thyroid releases predominantly thyroxine (T4).
However, the active form appears to be triiodothyronine
(T3);
• T4 is converted in part to T3, receptor affinity in target
organs being 10-fold higher for T3. The effect of T3
develops more rapidly and has a shorter duration than
does that of T4.
• Plasma elimination t1/2 for T4 is about 7 d; that for T3,
however, is only 1.5 d.

5. Synthesis and release of thyroid
hormones

7. Thyroid hormone synthesis and
release
• Release involves the proteolytic breakdown of the
peptide bonds between iodinated compounds and
thyroglobulin.
• T4 and T3 pass out of the thyroid cells into the
circulation.
• 99% of the plasma thyroid hormones are protein
bound, particularly to an alpha-globulin called
thyroxine-binding globulin.
• 90% of the circulating hormone is T4, the remainder is
T3.

8. Effects of thyroid hormone
• In general thyroid hormones increase the oxygen
consumption of most metabolically active tissues
[exceptions: brain, testes, uterus, spleen and anterior
pituitary].
• They stimulate lipid catabolism, protein synthesis and
intestinal carbohydrate absorption.

11. Diseases of the thyroid gland
• There are several causes of hyperthyroidism.
• Graves' disease (diffuse toxic goiter) the most common
• Thyroiditis—acute phase of Hashimoto's thyroiditis.
• Subacute thyroiditis
• Toxic multinodular goiter (Plummer's disease)
• Drug induced—amiodarone, iodine=Factitious
(iatrogenic) thyrotoxicosis“.
• TSH-secreting pituitary adenoma (toxic adenoma)

12. Hyperthyroidism continued…
• Grave's disease represents 60-90% of cases.
• Prevalence: 2.7% in female, 0.25% in male.
Grave's disease is an autoimmune disease in which
autoantibodies act on TSH receptor on thyroid gland
and lead to its activation and release of T3 and T4.

13. Signs and symptoms of
hyperthyroidism
 Nervousness, palpitation, goiter, heat intolerance,
weight loss & ophthalmopathy.
Ophthalmopathy is a group of symptoms and signs but it is
not present in all cases of grave's disease).
 Symptoms & signs of hyperthyroidism are similar to
those of anxiety. So, we need to differentiate between
them by measuring T4 & TSH levels.

14. Diagnosis of hyperthyroidism
• serum free T4 and TSH
• Note that T3 level increases after a long time. This is due
to the conversion of T3 to T4 in the circulation.

15. Thyroid releasing hormone
stimulation test
• Protirelin is used as a diagnostic aid because of its ability
to stimulate the anterior pituitary gland and influence the
output of TSH.
• A patient with normal thyroid function will respond to an
I/V injection of Protirelin with an increased output of
TSH.
• In thyrotoxicosis this increased output is prevented by
negative feedback excerted by the elevated
concentration of thyroid hormone.

16. • TSH concentration may also fail to rise in hypothyroidism
due to pituitary failure.

17. Thyroid stimulation hormone
stimulation
test
• The ability of the thyroid to respond to stimulation by
TSH is determined as increased uptake of radioactive
iodine.
• Lack of response in a hypothyroid patient indicates a
primary fault at pituitary level.

19. Drugs used in Hyperthyroidism
1. Radioactive iodine (131I)
• The drug of 1st choice in many countries.
• The most widely used radioactive type, because it has
both ß and γ radiations, while others have only γ
• Route of administration: orally.
• Maximal uptake by the thyroid cells within 8 hours.
• t½ : 8 days.
• Maximal effect is reached after 2 months.

20. Radioactive iodine (131I)
• Suitable for patients above the age of 45 years.
• Contraindicated in pregnancy, lactation & young age; cuz
it will cause growth retardation due to hypothyroidism
effect of the drug.

21. Radioactive iodine
• Is treated exactly as un-labelled Iodine by the body and
is rapidly and efficiently trapped by the thyroid gland.
• Incorporated into the Iodo-amino acid and deposited into
the colloid of the follicles.
• Several isotopes of iodine are available I131 is the one
normally used in the treatment of hyperthyroidism.
• The dose needed is large compared with that used in
diagnostic tests.

22. Radioactive iodine
• The radioactive iodine is deposited in the colloid of
follicles from where the destructive beta particles
originate.
• The depth of penetration of particles is 0.5mm which
means radiation damage occurs to the parenchymal
cells; little or no damage to the surrounding tissue.

23. Radioactive iodine
• The response is slow [this is overcome by administration
of anti-thyroid drug post dosing] and there is a high
incidence of myxoedema [up to 50 % of cases in 8 years
after dosing ] due to difficulty in estimating the effective
dose.
• There is a late increase in incidence of thyroid cancer.
• Also used in testing of thyroid function.

24. Medically useful isotopes of iodine
ISOTOPE PLASMA
HALF LIFE
RADIATION
EMITTED
APPLICATIO
N
I125 57 days Gamma rays Diagnostic
aid
I131 8days Beta particles
Gamma rays
Diagnostic&
Treatment
I132 2.3 hours Beta particles
Gammarays
Diagnostic
aid

25. 2. Thioamides
Mechanism of action
• Block the action of thyroid peroxidase enzyme and
hence:
a) No oxidation of iodide to iodine
b) No iodination
Examples:
• Carbimazole:
• A prodrug converted to methimazole when it is taken
orally .

26. Thioamides
Methimazole:
• Is 10 times more potent than propylthiouracil.
Propylthiouracil:
• Is the safest drug to use in pregnancy.
• Also has additional actions differing from the other
thioamides. It will block the effect of deiodinase II (i.e.
prevent the conversion of T4 to T3 intracellularly). So, it
produces an earlier effect. Hence, used in emergency.
• The drugs are well absorbed from the intestine and
widely distributed in tissues

27. Thioamides
• The duration of action is brief and dosage of 3 times
daily is required.
• Response to treatment takes several weeks with
euthyroid state produced in 1-2 months.

28. Thioamides
• To avoid relapse treatment should be prolonged [ 1.5-
2 years ] and even then relapse is common- up to 50%
may within 3 months of stopping treatment.
• Thioamides may also be used before thyroid surgery
and to hasten euthyroidism after radiation therapy.
• Side-effects include – skin rashes, lymphadenopathy
and fever [3-5 % of patients treated] and
agranulocytosis [ 0.5 %].

29. Thioamides
• If the dosage is too high and a hypothyroid state is
produced, enlargement of the gland [goitre] may result;
TSH being released from the anterior pituitary in
response to the low circulating concentration of thyroid
hormones and stimulating glands causing hyperplasia.

30. • Prophylthiouracil is useful when rashes develop to
carbimazole as there is usually no cross sensitivity.
• When used during pregnancy or lactation there is a
danger of neonatal goitre and hypothyroidism as the
drugs can enter the foetus from the placenta and
newborn from milk.

31. Monovalent ions
• Potassium Perchlorate compete with I- for active uptake
process and blocks I- access to the gland.
• This ability is attributed to the perchlorate ion being
monovalent, hydrated and of similar size to I-.
• Because it has caused fatal aplastic anaemia on rare
occasion- It is used only infreguently when toxic
reactions prevent the use of the Thioamides.

32. Iodide
• The daily intake of I- in amounts considerably above the
normal requirement of 100-200 nanograms is able to
control hyperthyroidism (Wolff-Chaikoff effect).
• The mechanism action is unclear but I- promotes
involution of hypertrophied tissue with an increased
colloid storage and decreased release of thyroid
hormones.
• A possible explanation for this action is that I- reduces
the effect of TSH on cyclic AMP concentration in thyroid
cells.

33. Iodide
The effects are rapid in onset [0-15 days for maximal effect]
but not sustained.
is useful before surgery to prepare the gland for sub-
total thyroidectomy, but only after prior treatment with
anti-thyroid drugs and together with other anti-thyroid
drugs supportive measures in thyrotoxic crisis.
It is prescribed as iodine aqueous solution. Iodine in
Potassium iodide [Lugol’s solution ].

34. Lugol’s solution
• The effect of the drug is loose after 2 weeks (escape
phenomenon-decreased inorganic iodine concentration inside the
thyroid follicle below a critical threshold)
• if we use this drug, we can`t do this surgery before 2 days or
after 2weeks-It is best to do the surgery after one week.
We use this drug for surgery because :
a) when the patient is thyrotoxic, he may die from the
surgery .
b) when the vascularity of the thyroid is high , he may bleed
profusely.

35. Antagonistic at beta adrenoceptors
• Propranolol and others reduce many of the signs and
symptoms of thyrotoxicosis- Nervousness, Atrial
fibrillation and increased myocardial contractility and
cardiac output.
• Propranolol is valuable before thyroidectomy, after
irridation and thyrotoxic crisis [in conjunction with anti-
thyroid drugs and supportive measures].

36. Thyroid storm(thyrotoxic crisis)
• Is an acute, life-threatening syndrome characterized by
hypermetabolism &excessive adrenergic discharge.
• So, the patient will suffer from hyperthermia &severe
tachycardia & may end up with heart failure & agitation.

37. Treatment of thyrotoxicosis
1- propranolol: B- adrenoceptor blocker I.V. (administered
slowly) or oral.
• If the patient ends up with heart failure, we give
Diltiazem( orally or I.V. infusion).
2- Sodium Ipodate: is a contrast media.
• In high doses (10g daily), it blocks the conversion of T4
to T3 (immediate).
• It is administered orally .
3- Methimazole: oral or rectal (the latter is better)

38. Hypothyroidism
• Prevalence: 1.5% (female ratio is higher [5 female: 1
male]).
• Most common type: Hashimoto thyroiditis.
• TSH-receptor blocking antibodies.
Sign & symptoms:
• Cold intolerance, dry skin, coarse edema, bradycardia,
cognitive impairment, depression, sleepiness.
• This may be mistaken with depression
Lab diagnosis:
• Subnormal free T4 & elevated TSH.

39. Use of thyroid hormones
• Thyroxine Sodium and Liothyroxine Sodium are only
used as replacement therapy to treat hypothyroid
states [adult myxoedema, childhood cretinism].
• Thyroxine Sodium is normally the drug of choice for
maintenance therapy but-
• Liothyronine Sodium may be preferred when a rapid
onset of action [hypothyroid coma] or shorter duration
of action [hypothyroidism with ischemic heart disease]
is required.

40. Thyroid hormones
• Thyroid hormones may enhance the effect of the oral
anti-coagulants although the mechanism is not clear.
• The hormones can be shown to inhibit metabolism of
anticoagulants and to displace them from protein binding
sites.

41. Myxedema coma
• Hypothermia, hypoglycemia, hypoventilation,
hyponatremia, stupor (marked diminution to
environmental stimuli), shock & death.
Treatment:
1- restore body temperature.
2- body fluids & electrolyte replacement.
3- levothyroxine : I.V./ we could also use liothyronine.
4- hydrocortisone: I.V.

42. EFFECTS HYPOTHYROID STATE HYPERTHYROID STATE[
THYROTOXICOSIS
Body weight Gain Loss
Oxygen Consumption Decreased Increased
CNS Impaired mentality,poor
memory and concentration –
also drowsiness.
Excitability
Restlessness
Apprehension
Insomnia
Somatic, Motor Nervous
system
Decreased activity Increased activity
Sympathetic Nervous System Decreased activity Increased activity
Cardiovascular system Bradycardia
Fall in cardiac output and BP.
Tachycardia
Increased cardiac output and
BP.
Gastrointestinal tract Activity diminished
Constipation
Activity increased
Diarrhoea.
Sensitivity to catecholamines Decreased Increased.

43. The End