1. Thyroid and Anti thyroid drugs

2. Role of the Thyroid gland
participates in normalizing growth and development and energy levels and the proper functioning and maintenance of tissues / organs
critical for the nervous, skeletal and reproductive tissues
it affects secretion and degradation rates of all hormones

3. Function of the Thyroid Gland
secretion of the following hormones:
triiodothyronine (T3) ; 59% iodine
tetraiodothyronine (T4; also known as thyroxine); 65% iodine
calcitonin

4. THYROID PHYSIOLOGY Iodide Metabolism Biosynthesis of Thyroid Hormones
The recommended daily adult iodide (I-) intake is 150 mcg
Biosynthesis of Thyroid Hormones
Transport of Thyroid Hormones
thyroxine-binding globulin (TBG)
about 0.04% of total T4 and 0.4% of T3 exist in the free form.

5. Biosynthesis of thyroid hormones
Figure Biosynthesis of thyroid hormones. The sites of action of various drugs that interfere with thyroid hormone biosynthesis are shown.

6. Biosynthesis of thyroid hormones

7. Steps in Biosynthesis Iodide trapping Oxidation of iodide to iodine
Iodide Organification
Formation of T4 and T3
Release of T4 and T3

8. Peripheral metabolism of thyroid hormones
The primary pathway for the peripheral metabolism of thyroxine (T4) is deiodination  deiodination of T4 may occur by monodeiodination of the outer ring, producing 3,5,3'-triiodothyronine (T3), which is three to four times more potent than T4

10. Basic pharmacology of thyroid & antithyroid drugs Thyroid hormones
A model of thyroid hormone action is depicted in Figure 38-4
T3 and T4 are triiodothyronine and thyroxine, respectively.
PB, plasma binding protein;
F, transcription factor; R, receptor; PP, proteins that bind at the proximal promoter.
Figure Regulation of transcription by thyroid hormones

11. Hypothyroidism
A syndrome resulting from a deficiency of thyroid hormones and is manifested largely by a reversible slowing down of all body functions.
There is a striking retardation of growth and development.
In children, manifested as dwarfism and severe MR.

12. Synthetic Thyroid Hormone
synthetic levothyroxine (synthetic T4)
Brand names: Eltroxin , Euthyrox,Levoxyl, Levothroid, Synthroid
for hormone replacement therapy in hypothyroidism
DOSE
Infants and Children require more T4/Kg body weight than adults
Average dose for an infant micrograms/kg/d
Average dose for an adult – 1.7micrograms/kg/d
Once daily
Pharmacokinetics
should be taken 30min before or 1 hour after meals (delayed absorption for soy, other foods and drugs)
takes 6-8 weeks to reach steady state levels
Labs should be repeated after 2 months

13. Synthetic Thyroid Hormone
reasons for its use:
stability
content uniformity
low cost
lack of allergenic foreign protein
easy laboratory measurements of serum levels
long half-life (7days)
once a day dosing

14. Synthetic Thyroid Hormone
Uses
Hormone replacement therapy
In young patients or those with mild disease- full replacement therapy started
In older patients and in patients with cardiac disease -start treatment with reduced dosage
Myxedema Coma – medical emergency
Loading dose – of T4 – micrograms I/V initially f/by `50micrograms daily
I/V T3 – more cardiotoxic and difficult to moniter
Hypothyroidism and Pregnancy – daily dose –adequate

15. Synthetic Thyroid Hormone
synthetic liothyronine (synthetic T3) is 3-4x more potent
(Cytomel,Triostat)
not used alone for long term treatment secondary to short half life and large peaks in serum T3 levels
increase risk for cardiac side effects secondary to hyperthyroid states during treatment

16. Hyperthyroidism
A thyroid disorder caused by an antibody- mediated auto-immune reaction, but the trigger for this reaction is still unknown
most common cause of hyperthyroidism

17. Anti-thyroid Drugs Thioamides Iodides radioactive iodine
Beta adrenoceptor blocking agents

18. Mechanism of action of anti thyroid drugs

19. Biosynthesis of thyroid hormones
Figure Biosynthesis of thyroid hormones. The sites of action of various drugs that interfere with thyroid hormone biosynthesis are shown.

20. Thioamides Methimazole Propylthiouracil (PTU) Carbimazole MOA:
inhibit synthesis by acting against iodide organification (both)
coupling of iodotyrosines (both)
Blocks peripheral conversion of T4 to T3 (PTU)

21. Thioamides Pharmacokinetics: almost completely absorbed in the GIT
serum half life: 90mins(PTU) ; 6 hours (methimazole)
excretion: kidney – 24 hours (PTU) ; 48 hours (Methimazole)
can cross placental barrier (lesser with PTU)
Methimazole 10x more potent than PTU
PTU more protein-bound

22. Thioamide uses Definitive therapy Preoperatively Along with RAI
Graves disease
Toxic nodular goitre
Preoperatively
In thyrotoxic patients
Along with RAI

23. Thioamides Adverse Effects: maculopapular rash
benign transient leukopenia
agranulocytosis
hepatitis (PTU) ; cholestatic jaundice (Methimazole)
vasculitis
lupus-like syndrome

24. Iodine131 preparations: sodium iodide 131
MOA: trapped within the gland and enter intracellularly and delivers strong beta radiations destroying follicular cells
Penetration range µm
Clinical uses: Grave’s, primary inoperable thyroid CA
Contraindication: pregnancy

25. Iodine131 Advantages Easy administration Effectiveness Low expense
Absence of pain

26. Iodine131
Thioamides should be given initially and stop 5-7 days before radioactive iodine administration
131I dosage generally ranges between uCi/g of estimated thyroid wt. corrected for uptake. May be repeated after 6 months
Adverse effects
permanent hypothyroidism
potential for genetic damage
may precipitate thyroid crisis

27. Anion Inhibitors
Monovalent anions such as perchlorates, pertechnetate and thiocyanate can block uptake of iodide by the gland by competitive inhibition
can be overcome by large doses of iodides
useful for iodide-induced hyperthyroidism (amiodarone-induced hyperthyroidism)
rarely used due to its association with aplastic anemia

28. Biosynthesis of thyroid hormones
Figure Biosynthesis of thyroid hormones. The sites of action of various drugs that interfere with thyroid hormone biosynthesis are shown.

29. Inorganic Iodines
major anti-thyroids before the introduction of thioamides (1950s)
preparations:
strong iodine solution (Lugol’s)
potassium iodide
iodone

30. Inorganic Iodines MOA: inhibit iodide organification Uses: Caution:
acutely blocks release of thyroid hormone from the gland by inhibiting thyroglobulin proteolysis
inhibit iodide organification
Uses:
useful in thyroid storms: 2-7 days
Preoperatively - iodides decrease vascularity, size and fragility of hyperplastic gland
Caution:
it may delay onset of thioamide effects; should be given after initiation of thioamides
The gland will escape from inhibition after 2-8 weeks.

31. Iodinated Contrast Media
Ipodate (oral)
Iopanoic acid (oral)
Diatrizoate (intravenous)
valuable in hyperthyroidism (but is not labeled for this indication)
MOA: inhibits conversion of T4 to T3 in the liver, kidney, brain and pituitary
Another MOA is due to inhibition of hormone release secondary to iodide levels in blood
Useful in thyroid storms (adjunctive therapy)

32. Beta Blockers Drugs: Propranolol, Metoprolol, Atenolol MOA:
Membrane-stabilizing action: inhibits T4 to T3
Ameliorate many disturbing s/sxs of hyperthyroidism secondary to increased circulating catecholamines by blocking beta receptors
Indications: Grave’s, Thyroid storm

33. Corticosteroids
Prednisone is given for patients with Grave’s ophthalmopathy
1mg/kg/day (60mg/day 3 divided doses); if it should be given for more than 4 weeks, taper to decrease risk of adrenal crisis

34. Thyroid storm Sudden exacerbation of throtoxic symptoms
Life threatening condition
Vigorous management
Propanalol 1-2mg i/v or 40-80mg PO Q6h
Diltiazem mg Po Q8-6 hrs or 5-10mgs intravenous infusion/hour

35. Thyroid storm Supportive therapy Plasmapheresis/peritoneal dialysis
Potassium iodide
Propylthiouracil
Hydrocortisone
Supportive therapy
Plasmapheresis/peritoneal dialysis

36. Hyperthyroidism and Pregnancy
Ideal situation- treat before pregnancy
Pregnancy-Radioactive iodine CI
Propylthiouracil
Dose limitation≤ 300mgs/day
Methimazole alternative- fetal scalp defects