The document discusses thyroid and antithyroid drugs, covering the synthesis, transport, and mechanisms of thyroid hormones (T3 and T4), as well as their physiological effects and roles in various diseases. It details the actions of these hormones on metabolism, growth, and the nervous system, as well as pharmacotherapeutic approaches to treat conditions like hypothyroidism and hyperthyroidism. Additionally, it outlines various treatment options, their mechanisms, pharmacokinetics, and potential adverse reactions.

1. Thyroid TTThhhyyyrrroooiiiddd aaaannnndddd AAAAnnnnttttiiii----tttthhhhyyyyrrrrooooiiiidddd ddddrrrruuuussss
By: A.M.NASEEFA
JSS COLLEGE OF
PHARMACY, MYSORE

2. Thyroid & Antithyroid
drug Introduction:
@ Thyroid releases T3 & T4
@ The ratio of T4 to T3 is 5:1, so most of the hormone released is
thyroxine
@ Most of the T3 in the blood is derived from thyroxine
@ T3 is three to four times more potent than T4
@ The affinity of the receptor site for T3 is about ten times higher than
that for T4
Thyroid gland secretes thyroid hormones—
* Triiodothyronine (T3)
* Tetraiodothyronine (T4, thyroxine)
* Calcitonin
Although the thyroid gland is not essential for life, inadequate secretion
of thyroid hormone (hypothyroidism) results in bradycardia, poor
resistance to cold, and mental and physical slowing (in children, this can
cause mental retardation and dwarfism).
•If, however, an excess of thyroid hormones is secreted
(hyperthyroidism), then tachycardia and cardiac arrhythmias, body
wasting, nervousness, tremor, and excess heat production can occur.
•The thyroid gland also secretes the hormone “calcitonin” a serum
calcium-lowering hormone.

3. Synthesis of thyroid hormones
Steps:
1. Uptake of Iodide ion by thyroid gland(NaI-symporter).
2. Oxidation of iodide and the iodination of tyrosyl groups.
3. Coupling of iodotyrosine residues.
4. Resorption of the thyroglobulin colloid from the lumen into
the cell.
5. Proteolysis of thyroglobulin and the release of T4 and T3
into the blood.
6. Recycling of the iodine within the thyroid cell via de-iodination
of mono/diiodotyrosines and reuse of the I‾
7. Peripheral conversion of T4 to T3
Transport of Thyroid Hormones:
T4 and T3 in plasma - bound to protein - thyroxine-binding
globulin (TBG) – Reversibly
Only about 0.04% of total T4 & 0.4% of T3 exist in the free
form.

4. Mechanism of action:
 Thyroid hormones have effects on virtually every cell
of the body
 Both T4 and T3 must dissociate from thyroxine-binding
plasma proteins prior to entry into cells,
either by diffusion or by active transport.
 In the cell, T4 is enzymatically deiodinated
(iodothyronine5’-deiodinase) to T3, which enters the
nucleus and attaches to thyroid (TR) receptors.
 TRs are proteins containing thyroid hormone-binding,
DNA-binding, and dimerization domains
 The activation of these receptors promotes the
formation of RNA and subsequent protein synthesis,
which is responsible for the effects of T4.

5. Disease of Thyroid gland:
Hyperthyroidism/Thyrotoxicosis/Grave’s
disease
Hypothyroidism –
# Cretinism (in children)
# Myxoedema (in adult)

7. PHARMACOLOGICAL ACTION
the actions of T4 &T3 are qualitativelysimilar &
are nicely depicted in the features of hypo and
hyperthyroidism. They affect the function of
practically all body cells.
Growth and development: T4 and T3 are
essential for normal growth and development.
• In adults, hypothyroidism results in intelligence
impairment and slow movements.
▲Insufficiency→ cretinism (infant & child), and myxedema
(adult);
▲Excess→hyperthyroid

8. Metabolic function:
CHO metabolism:
• increase glycogenolysis & gluconeogensis in liver
• increase glucose absorption from GIT
• Enhance glycolysis – rapid uptake of glucose by the cell.
• Net result – increse in blood glucose level. Hyperglycaemia and
diabetic-like state with insulin resistance occur in hyperthyroidism.
On protein metabolism:
• increase protein catabolism
• prolong action results in negative nitrogen balance and tissue
wasting.
• Weight loss is a feature of hyperthyroidism.
• T3/T4 in low concentration inhibits mucoprotien synthesis which is
so characteristically accumulates in myoedema (hypothyrodism).
On lipids:
• T3/T4 indirectly enhance lipolysis by potentiating the action of
catecholamines & other lipolytic harmones probably by
suppressing a phophodiesterases.
• Lipogenesisis also stimulated.
• Plasma free fatty acid levels are elevated,
• All phases of cholesterol metabolism are accelerated but its
conversion to bile acids dominates.
Thus, Hyperthyroidism is characterized by hypocholestrolemia.LDL
levels in blood are reduced.

9. Calorigenesis:
• T3/T4 increase BMR by stimulation of cellular metabolism. this is
important for maintaining body temperature.
• The mechanism of calorigenesis was believed to be uncoupling of
oxidative phosporylation : excess energy being released as heat.
However this occurs only at high doses and is not involved in
mediating the physiological actions of T3/T4.
Nervous system:
T3/T4 have profound functional effect on CNS. Mental retardation is the
hallmark of cretinism, sluggishness & other behavioral
features are seen myxoedema.Hyperthyroid individuals are anxious ,
nervous,excitable, exhibit tremours and hyperreflexia.
Skeletal muscle:
muscles are flabby & weak in myxoedema while thyrotoxicosis
produces increased muscle tone , tremors & weakness due to
myopathy.

10. CVS :
• T3 and T4 cause a hyperdynamicstate of circulation
which is partly secondary to increased peripheral
demand and partly due to direct cardiac actions.
• Heart rate, contractility and output are increased
resulting in a fast pulse.
• T3 and T4 stimulate heart by direct action on
contractile elements (increasing the myosin fraction
having greater Ca2+ATPase activity) and
probably by up regulation of β1 adrenergic receptors.
• Atrial fibrillation and other irregularities are common in
hyperthyroidism.
• Thyroid hormones can also precipitate CHF and
angina. BP, specially systolic, is often raised.

11. GIT:
• Propulsive activity is increased by T3/T4. Hypothyroid
patients often constipated while diarrhoea is common on
hyperthyroidism.
Kidney:
• T3/T4 donot cause diuresis in euthyroid individuals but the
rate of urine flow often increased when myxoedematous
patients are treated with it.
Haemopoiesis:
• hypothyroid patients suffer from some degreeof anaemia
which is restored only by T4 treatment. Thus T4 appears to
be facilitatory to erythropoiesis.
Reproduction:
• thyroid has indirect effect on reproduction. Fertility is
impaired in hypothyroidism & women suffer from
oligomenorrhoea. Normal thyroid function is required for
maintainence of pregnancy and lactation.

12. Pharmacokinetics:
easily absorbed Orally ; the bioavalibility of T4 is 80% and
T3 is 95%. Drugs that induce hepatic microsomal
enzymes
(e.g.,rifampin, phenbarbital, phenytoin, and etc) improve
their metabolism.
USES: The most important uses of thyroid hormone are
as replacement therapy in deficiency states
–Cretinism: Levothyroxine (T4) (8-12 pg/kg)
–Adult hypothyroidism: T4 50pg daily
–Nontoxic goiter
–Myxoedemacoma
–Thyroid nodules
–Papillary carcinoma of thyroid

13. Thyroid drugs
 levothyroxine (L-T4)
 liothyronine (T3)
 liotrix (T4 plus T3)

14. Synthetic levothyroxine
--thyroid replacement and suppression therapy.
Adv:
-high stability
-uniform
-low cost
-lack of allergenic foreign protein
-easy laboratory measurement of serum levels
-long half-life -7 days (once-daily administration)
-In addition, T4 is converted to T3 intracellularly; thus,
administration of T4 produces both hormones.
-Generic levothyroxine preparations provide comparable efficacy
and are more cost-effective than branded preparations.
liothyronine (T3) is 3 to 4 times more potent than levothyroxine.
Use: short-term suppression of TSH.
Disadv: - Shorter half-life -24 hours (not recommended for routine
replacement therapy which requires multiple daily doses)
- Higher cost
- Difficulty of monitoring.
- Its greater hormone activity and consequent greater risk of
cardiotoxicity
- avoided in patients with cardiac disease. It is best.

15. Liotrix
Mixture of thyroxine and liothyronine .
- Expensive
- Oral administration of T3 is unnecessary ,so
combination is not required ( levothyroxine
preferable)
Adverse reactions
* Overmuch leads to thyrotoxicosis
* Angina or myocardial infarction usually
appears in aged
Clinical use
* Hypothyroidism: cretinism & myxedema;
* simple goiter: for pathogeny remaining
unclear (endemic goiter directly supply
iodine) &Others:

16. Treatment of hyperthyroidism
(thyrotoxicosis):
•Excessive amounts of thyroid hormones in the
circulation are associated with a number of disease
states, including Graves' disease, toxic adenoma
and goiter.
• In these situations, TSH levels are reduced.
• The goal of therapy is to decrease synthesis and/or
release of additional hormone.
• This can be accomplished by removing part or all of
the thyroid gland, by inhibiting synthesis of the
hormones, or by blocking release of the hormones
from the follicle.

17. Classification
1. Inhibitors of iodine uptake (lonicinhibitors)
eg: –Thiocyanates(-SCN), Perchlorates (-ClO4), Nitrates
(-NO3,).
2.Inhibitors of thyroid hormones synthesis
(antithyroiddrugs)eg: –Propylthiouracil, Methimazole,
Carbimazole.
3.Inhibit hormone release
eg: –Iodine, Iodides of Na and K, Organic iodide.
4.Destroy thyroid tissue
eg:–Radioactive iodine (131I, 125I, 123I)
5.Inhibitors of peripheral conversion of T4 to T3
eg:–Propylthiouracil, beta blockers and ipodate

18. 1. Inhibitors of iodine uptake
 Thiocyanates(-SCN), Perchlorates (-ClO4), Nitrates (-NO3,).
 These monovalent anions inhibit iodide trapping by the thyroid probably because
of similar hydrated ionic size as a result T3/T4 cannot be synthesized.
 They are toxic and not used now
2. ANTITHYROID DRUGS (Inhibitors of thyroid hormone synthesis)
 The thioamines such as propylthiouracil, methimazole and carbimazole, compete
with thyroglobulin for oxidized iodide and thereby prevent the organification
process catalyzed by thyroid peroxidase.
 In addition, they also inhibit the coupling of thyroid hormone precursors, and
thereby inhibits thyroid hormone synthesis
 They do not interfere with trapping of iodide and do not modify the action of T3
and T4 on peripheral tissues or on pituitary.
 Propylthiouracil also inhibits peripheral conversion of T4 to T3
Pharmacokinetics: quikly absorbed orally , widely distributed in body, enters milk,
cross placenta.Metabolized in liver and excreated in urine as primary metabolite.
Adverse effects: Hypothyroidism due to overtreatment is common but reversible on
stopping the drug. G.I intolerence, skin rashes , joint pain,Loss/graying of hair, fever
and liver damage are rare.
Uses: anti-thyroid drugs control thyrotoxicosis in both Grave’s disease and toxic
nodular goiter.

19. 3. Inhibitors of hormone release
•  Iodine, Iodides of Na and K, organic iodide.
•  Though iodine is a constituent of thyroid hormones, it is
the fastest acting thyroid inhibitor.
•  A pharmacologic dose of iodide inhibits the iodination of
tyrosines, but this effect lasts only a few days. What is more
important, iodide inhibits the release of thyroid hormones from
thyroglobulin by mechanisms not yet understood.
•  Today, iodide is rarely used as the sole therapy.
•  However, it is employed to treat potentially fatal
thyrotoxiccrisis (thyroid storm) or prior to surgery, because it
decreases the vascularity of the thyroid gland.
•  Iodide is not useful for long-term therapy, because the
thyroid ceases to respond to the drug after a few weeks.
•  Iodide is administered orally.

20. 4. Destroy thyroid tissue
 This can be accomplished either surgically or by destruction of the
gland by beta particles emitted by radioactive iodine (131I), which is
selectively taken up by the thyroid follicular cells.
 Radioactive iodine (131I, 125I, 123I)
131I - t1/2 8days (most commonly used)
125I - t1/2 13hours (rarely used diagnostically)
123I - t1/2 60days
Uses: in thyrotoxicosis in both Grave’s disease and toxic nodular goiter.
Average therapeutic dose 3-6m curie.
Advantage:
Treatment is simple, inexpensive.
No surgical risk,
once hyperthyroidism is controlled ,cure is permanent
Disadvantage:
May cause hypothyroidism
Long latent period of response
Contraindicated during pregnancy- foetal thyroid will be destroyed-cretinism
other abnormallities occur if given in first trimester
Not suitable for young patients

21. 5. Inhibitors of peripheral
conversion of T4 to T3
• –Propylthiouracil, beta blockers and ipodate
• –beta-adrenergic blockers such as esmolol, decrease
the clinical features of hyperthyroidism such as
sweating, tremor, tachycardia.
• –It has also been demonstrated that beta blockers can
reduce peripheral conversion of T4 to T3.
• –Ipodateis a radiocontrastagent. It significantly inhibits
conversion of T4 to T3 by inhibiting the enzyme 5’-
deiodinase.

22. Thyroid storm
is a life-threatening health condition that is associated with untreated or
undertreated hyperthyroidism. During thyroid storm, an individual's heart
rate,blood pressure, and body temperature can soar to dangerously high
levels.
 β-Blockers that lack sympathomimetic activity, such as propranolol,
are effective in blunting the widespread sympathetic stimulation that
occurs in hyperthyroidism.
 Intravenous administration is effective in treating thyroid storm.
 An alternative in patients suffering from severe heart failure or
asthma is the calcium-channel blocker, diltiazem
 Other agents used in the treatment of thyroid storm include
Propylthiouracil(because it inhibits the peripheral conversion of T4to
T3 but methimazole does not), iodides, and glucocorticoids (to
protect against shock).