The thyroid gland produces thyroid hormones that regulate metabolic processes throughout the body. It traps iodine from the diet and uses it to synthesize the hormones thyroxine (T4) and triiodothyronine (T3). These hormones control growth, development, metabolism, and other functions. The thyroid requires adequate iodine intake, an efficient gland, and appropriate control by thyroid stimulating hormone from the pituitary gland to effectively produce hormones. Thyroid hormones act through nuclear receptors in tissues to increase protein synthesis and metabolic activity. Hyperthyroidism and hypothyroidism can be treated with synthetic thyroid hormones or drugs that interfere with thyroid hormone production and action.

1. Thyroid hormones
GM 2018/19

2. References
• https://www.ncbi.nlm.nih.gov/books/NBK285550/

3. Thyroid gland (TG)
Function: traps iodine, makes hormones, T4/ T3, essential for the
regulation of metabolic processes throughout the body
• synthesis & secretion of:
L-thyroxine (tetraiodothyronine, T4) and L-triiodothyronine (T3)
• normal growth and development; body temperature; metabolism
• contain 59%/65% (respectively) iodine as an essential part of the
molecule
• normal thyroid maintains a concentration of free iodide 20-50 times
higher than plasma
• Calcitonin /second type of thyroid hormone/:
regulation of Ca+2

5. TG Function
• Effective production has 3 key elements:
– adequate suppy/material (iodine)
• ingested iodine absorbed in small intestine and carried in the
circulation as iodide (I-)
• concentrated and stored in thyroid, oxidized, and
incorporated into thyroglobulin (Tg) to form T4/T3. After a
variable period of storage in thyroid follicles, Tg undergoes
proteolysis and the released hormones are secreted into the
circulation, where specific binding proteins carry them to
target tissues
– efficient machin (TG)
– appropriate controls (Pituitary TSH; TSH receptors)

6. Iodine
• European daily dietary intake of iodine is ~150
μg: ~125 μg taken up by the TG for hormone
synthesis, unused excreted via kidneys
• Too much iodine increases the incidence of
iodine-induced hyperthyroidism, autoimmune
thyroid disease or perhaps thyroid cancer
• Too little causes goiter, hypothyroidism and
their consequences (features of the so-called
iodine deficiency disorders)

7. TG MOA
• Once taken up by TG, iodide undergoes
enzymatic reactions incorporating it into a
thyroid hormone
• Ratio T4:T3 within thyroglobulin is ~5:1 (most of the
hormone released is thyroxine)
• Most of T3 circulating in the blood is derived from
peripheral metabolism of thyroxine (ie, conversion)

8. BASIC PHARMACOLOGY OF
THYROID & ANTITHYROID DRUGS
Pharmacokinetics: Thyroxine absorption best in
duodenum and ileum;
• absorption modified by food, drugs, pH,
intestinal flora
• oral bioavailability - L-thyroxine avg 80%
• T3 almost completely absorbed (95%)

9. Iodothyronines
• Water insoluble, when released from
thyroglobulin, rapidly bind to the plasma
proteins, transthyretin (aka thyroxine-binding
prealbumin), thyroxine-binding globulin (TBG)
and albumin.
• Vary in capacity and affinity for T3/T4; ~70% of
circulating thyroid hormones are bound to TBG;
fraction (<0.5%) exists in a free form in the
circulation, in equilibrium with the bound forms

10. MOA
• Most of the effects of thyroid on metabolic
processes appear to be mediated by
activation of nuclear receptors that lead to
increased formation of RNA and subsequent
protein synthesis (eg., increased formation
of Na+/K + -ATPase).

11. MOA
• Large numbers of thyroid hormone receptors:
pituitary, liver, kidney, heart, skeletal muscle,
lung, intestine
• Few receptor: spleen, testes
• Brain lacks anabolic response to T3, contains
intermediate number of receptors
• Receptor affinity: T3 ten x greater than T4

12. Effects of Thyroid Hormones
• optimal growth, development, function, and
maintenance of all body tissues
• critical for the development and functioning
of nervous, skeletal, reproductive tissues
• effects depend on protein synthesis and
potentiation of secretion/action of GH

13. Effects
• widespread influence on metabolism of drugs
and carbohydrates, fats, proteins, vitamins (many
of these changes dependent on or modified by
activity of other hormones)
• Secretion/degradation rates of catecholamines,
cortisol, estrogens, testosterone, insulin directly
affected by thyroid status
– (Many of the manifestations of thyroid hyperactivity resemble sympathetic nervous system
overactivity (esp. cardiovascular system)
• Changes in catecholamine-stimulated cAMP
paralel thyroid activity changes

14. Thyroid formulations
• Synthetic: levothyroxine (T4), liothyronine, liotrix;
Animal origin - desiccated thyroid
• Synthetic levothyroxine: DOC
– replacement/suppression: stability, content uniformity, low
cost, lack of allergenic foreign protein,ease of lab
determinations (serum levels), 7 day t1/2 (allows qD
administration)
– T 4  T 3 (intracellularly); giving T4 produces both
hormones
– Generic levothyroxine provide comparable efficacy and
cost-effectiveness vs. branded products

15. Levothyroxine
Recommended form of thyroid hormone in
routine treatment of primary hypothyroidism
because of: (1) its efficacy in resolving the
symptoms of hypothyroidism; (2) favorable side-
effect profile; (3) ease of administration; (4)
good intestinal absorption; (5) long serum half-
life; (5) cost; (6) experience of its benefits

16. • Liothyronine (T 3 ) is 4 x more potent than
levothyroxine
– not for routine replacement therapy because of
t1/2 - 24 hrs requires multiple daily doses; higher
cost; TDM not by a conventional lab. tests and due
to greater activity and consequent greater risk of
cardiotoxicity: avoid in patients with cardiac
disease
– used for short term TSH suppression

17. • use of desiccated thyroid unjustified due to:
– protein antigenicity
– product instability
– variable hormone concentrations
– difficulty in laboratory monitoring

18. ANTITHYROID AGENTS
– interfere with production of thyroid hormones
– modify tissue response to thyroid hormones
– glandular destruction
– Goitrogens: suppress secretion of T3/T4 and
thereby increase TSH, which in turn produces
glandular enlargement (goiter)
• Clinical use: thioamides, iodides, radioactive
iodine

19. Thioamides Thiocarbamides
Anti-thyroid drugs: external compounds influencing thyroid hormone
synthesis; inhibitory drugs: thionamides: propylthiouracil and
methimazole.
In the thyroid they act by competing with tyrosyl residues of Tg for
oxidized iodine
MOA: multiple
• prevent hormone synthesis
– inhibit thyroid peroxidase-catalyzed reactions and block iodine
organification
– block coupling of iodotyrosines
• PTU, methimazole(some) inhibit periphera deiodination of T4/T3
• Delayed onset of action (need to deplete T4 stores
(3–4 wks)

20. Thioamides
Methimazole, propylthiouracil (PTU),
carbimazole, (converted to methimazole):
treatment of thyrotoxicosis
• Methimazole: 10 x more potent than PTU,
– DOC (adults/children)
• PTU: ADR: severe hepatitis! reserved for use
during the 1st. trimester of pregnancy in
thyroid storm, and pts. with ADR to
methimazole (other than agranulocytosis or hepatitis)

21. Pharmacokinetics
• Methimazole:
– completely absorbed but at variable rates
– readily accumulated by thyroid gland
• Excretion slower than PTU; 65–70% of a dose
is recovered in the urine in 48 hrs.
• T1/2 6 h

22. PTU
• rapid absorption, reaches Cmax (peak serum
levels) within 1 hr
• Bioavailability 50–80% (due to incomplete
absorption or a large first-pass effect)
• VD approximates total body water; accumulates
in the thyroid gland
• Mostly excreted by kidney as inactive metabolite
within 24 hrs
• t1/2 1.5 h (DOC for pregnant/lactating women -
binds to plasma proteins and less crosses the
placenta/enters the breast milk.

23. T1/2
• Short plasma half-life has minimal influence
on the duration of antithyroid action or the
dosing interval because of accumulation by
the thyroid gland
– PTU give q6–8 hrs, a single 100 mg dose inhibits
iodine organification by 60% for 7 hrs.
Methimazole a 30 mg dose exerts an antithyroid
effect for > 24 hrs - qD dosing

24. • thioamides pass placenta barrier, are
concentrated by the fetal thyroid - risk of fetal
hypothyroidism!
• propylthiouracil preferable in 1st trimester of
pregnancy because it is strongly protein-bound
and does not cross placenta readily
• methimazole rarely implicated in congenital
malformations
• Both are secreted in low concentrations in breast
milk - safe for nursing infant

25. ADRs
• Agranulocytosis: infrequent (0.1–0.5%) can be
deadly
• Rash (4–6%), urticarial rash infrequent
• Hepatitis; lethal reported cases (with PTU)

26. IODIDES
• rarely used as monotherapy (should be
initiated after onset of thioamide therapy)
• and avoided if treatment with radioactive
iodine seems likely.
• inhibit organification/hormone release and
decrease size/vascularity of hyperplastic gland
• Improvement in thyrotoxic symptoms
• Use in thyroid storm: rapid action (2–7 days)

27. ADRENOCEPTOR-BLOCKING AGENTS
metoprolol, propranolol, atenolol adjunct in
thyrotoxicosis - many symptoms mimic those
associated with sympathetic stimulation.
• clinical improvement of hyperthyroid
symptoms without any effect on (usually)
thyroid hormone levels
• Propranolol >160 mg/d may  T 3 levels by
inhibiting peripheral conversion of T4 to T3
(20% drop)

28. Calcitonin
• Polypeptide secreted by TG C cells
• Homeostasis of Ca+2
• Decreases rate of bone resorption
• Inhibitor of osteoclastic activity
• Preparations: 1) calcitonin-human: synthetic polypeptide with
a.a. sequence of human calcitonin 2) calcitonin-salmon; from
salmon or synthetic polypeptide with a.a. sequence of salmon
calcitonin
• Formulation: nasal spray; Inj. (SC, IM)
• Indications: treatment of severe hypercalcemia, PAGET'S dz.,
postmenopausal osteoporosis. Called also thyrocalcitonin.