Pharmacology of thyroidal and antithyroidal drugs

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THYROID HORMONES AND
ANTI THYROID DRUGS
Prepared by: Mirza Anwar Baig
M.Pharm (Pharmacology)
Anjuman I Islam's Kalsekar Technical Campus,
School of Pharmacy.
New Panvel,Navi Mumbai

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CONTENTS:
1. Introduction to thyroid gland,thyroid
hormones
2.Process of production and storage of
thyroid hormones
3.Effects of thyoid hormones
4.Diseases related to thyroid hormones
5.Therapeutic uses of thyroidal drugs
6.Anti thyroidal drugs

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What are thyroid hormones?
• The thyroid gland secretes 3 hormones-
thyroxine (T4), triiodothyronine (T3) and
calcitonin.
• The former two are produced by thyroid
follicles, have similar biological activity.
• Calcitonin produced by interfollicular 'C' cells is
chemically and biologically entirely different. It
is considered regulates calcium metabolism.

4. 1.Introduction to thyroid gland,
thyroid hormones.

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Bried histroy of invention:
The physiological significance of thyroid gland was
recognized only after Graves and Basedow (1835, 1840)
associated the clinical features of the 'Graves' disease'
with swelling of thyroid gland and Gull (1874) correlated
myxoedema with its atrophy.
Kendall (1915) obtained crystalline thyroxine and suggested
its chemical formula which was confirmed in 1926.
Thyroxine was the first hormone to be synthesized in the
laboratory.
Later, as T4 could not account for all the biological activity of
thyroid extract, search was made and more potent T3 was
discovered in 1952

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THE THYROID GLAND

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FEEDBACK REGULATION
THE HYPOTHALAMIC-PITUITARY-THYROID AXIS

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THYROID GLAND HISTOLOGY
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

9. 2. Process of production and
storage of thyroid hormones

10. 10Co

11. 11Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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THYROID HORMONES
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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T4 and T3 hormones
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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PITUITARY-THYROID AXIS
– –
+
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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3.Effects of thyoid hormones

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• TSH binds to specific cell surface
receptors that stimulate adenylate
cyclase to produce cAMP.
• TSH increases metabolic activity that is
required to synthesize Thyroglobulin
(Tg) and generate peroxide.
• TSH stimulates both I- uptake and
iodination of tyrosine resides on Tg.
4. Mechanism of actions of
thyroidal hormones:
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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THYROID HORMONES IN THE
BLOOD
• Approximately 99.98% of T4 is bound to
3 serum proteins: Thyroid binding
globulin (TBG) ~75%; Thyroid binding
prealbumin (TBPA or transthyretin) 15-
20%; albumin ~5-10%
• Only ~0.02% of the total T4 in blood is
unbound or free.
• Only ~0.4% of total T3 in blood is free.
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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THYROID HORMONE
DEIODINASES
• Three deiodinases (D1, D2 & D3) catalyze
the generation and/disposal of bioactive
thyroid hormone.
• D1 & D2 “bioactivate” thyroid hormone by
removing a single “outer-ring” iodine atom.
• D3 “inactivates” thyroid hormone by
removing a single “inner-ring”iodine atom.
• All family members contain the novel
amino acid selenocysteine (SeC) in their
catalytic center.
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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BASICS OF THYROID HORMONE
ACTION IN THE CELL
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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Hypothyroidism and
Hyperthyroidism
5. Diseases related to thyroid
hormones
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

21. 21Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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EXAMPLES OF THYROID DISEASES
1° Hypothyroidism Hyperthyroidism
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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EXAMPLES OF THYROID DISEASES
Congenital Hypothyroidism
Juvenile Hypothyroidism
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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●● RepresentativeRepresentative drugsdrugs
levothyroxine (L-T4, levoxyl, synthroid)
liothyronine (T3, cytomel, triostat)
liotrix (T4 plus T3) (euthyroid, thyrolar)
Thyroid drugs
●● PharmacokineticsPharmacokinetics
easily absorbed; the bioavailablity of T4 is 80%, and T3 is
95%.
Drugs that induce hepatic microsomal enzymes (e.g.,
rifampin, phenbarbital, phenytoin, and etc) improve their
metabolism.

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5.Therapeutic uses of thyroidal drugs
The most important uses are as replacement therapy in
deficiency states:
1 . Cretinism:
It is due to failure of thyroid development or a defect in hormone
synthesis (sporadic cretinism) or due to extreme iodine
deficiency (endemic cretinism).
It is usually detected during infancy or childhood.
Treatment with thyroxine (8-12 pg/kg) daily should be started as
early as possible, because mental retardation that has already
ensued is only partially reversible.
Response is dramatic:physical growth and development are
restored and further mental retardation is prevented.

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2. Adult hypothyroidism
• Develops as a consequence of thyroiditis,
thyroidectomy; or may be idiopathic.
• Important drugs that can cause
hypothyroidism are 131 I, iodides, lithium and
amiodarone.
• Treatment with T4 is most gratifying.
• Individualization of proper dose is critical,
aiming at normalization of serum TSH levels.
Increase in dose is mostly needed during
pregnancy.

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3. Myxoedema coma
• It is an emergency; characterized by progressive mental
deterioration due to acute hypothyroidism.
• Rapid thyroid replacement is crucial,Though liothyronine
(T3) acts faster, its use is attended by higher risk of
cardiac arrhyethemia,angina, etc.
• Drug of choice is thyroxine
• Corticosteroids to cover attendant adrenal insufficiency,
ventilatory and cardiovascula support.
4.Nontoxic goiter:
It may be endemic or sporadic. Endemic is due to iodine
deficiency may be accentuated by factors present in food
or milk.
A defect in hormone synthesis may be responsible for
sporadic cases.
In both the cases deficient production of thyroid
hormone leads to excess TSH secretion and thyroid
enlarges, more effective trapping of iodide occurs and
probably greater prproportion of T 3 is synthesized.
Thus, treatment with T4 is in fact replacement therapy in
this condition works.

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HYPERTHYROIDISM
• Elevated levels of T3 and T4 in the blood.
• Causes :
1. Carcinomas
2.Thyroiditis
3.Autoimmune
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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GRAVES' DISEASE
• Most common cause of
hyperthyroidism 60-80%.
• Autoimmune disorder associated
with circulating immunoglobulins
that bind to and stimulate the
thyrotropin ( TSH) receptor ,
resulting in sustained thyroid over
activity & it can be familial.
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

30. 30Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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Manifestations of Hyperthyroidism
• Nervousness , irritability.
• Tremors
• palpitation
• Weight loss
• sweating
• Heat intolerance
• Diarrhea
• short breath
• Itching
• Thyroid EnlargementCompiled by: Prof.Anwar
Baig (AIKTC.SOP)

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Anti-thyroid drugs
Drugs used for the treatment of hyperthyroidism :
1.Inhibition of hormone synthesis :
Thioamides (Propylthiouracil and Methimazole).
2. Blockade of hormone release :
Iodides, Iodinated contrast media.
3. Radioactive Iodine 131
4. Anion Inhibitors :
Perchlorates, Thiocynates.
5. Beta blocking drugs : Propranolol.
6. Surgery
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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Anti-thyroid drugs
peroxidase
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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Thiomides
1. Propylthiouracil: Protype of the group
It inhibits the synthesis of the thyroid hormones but
does not inactivate already formed and stored
thyroxine. Labelled as goitrogens.
2. Methyl thiouracil: is equal in potency to PTU.
But have allergic manifestations
3.Methimazole: chemically similar to PTU but 10
times more potent than PTU
4.Carbimazole: as effective as PTU
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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Mode of Action of Thioamides
It interfere with:
1. iodination of tyrosine
2. Coupling and condensation of
iodotyrosines
3. Block the oxidation of iodides
4. Inhibit the peroxidase enzyme
systems
5. Little effect on iodine trapping by
thyroid gland
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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Therapeucitc Uses
1.Hyperthyroidism: relief but little
effect on associated exophthalmos in
graves disease.
2.Prepration of thyrotoxic patient
for surgical treatment.
Sulphonamides and related compounds
possess antithyroidal activity.
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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Contraindications
• It crosses placenta can cause foetal
goiter.
• Use should be minimized in pregnancy.
• Should not be used in lactating mother.
Toxicity:
Goiterogenic action
Allergic action (Urticaria,purpuric rashes)
Sever lucopenia and aganulocytosis
Hepatitis and nephritis may occur rarely
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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Pharmacokinetic comparision between
Propylthiouracil and Methimazole
PropylthiouracilPropylthiouracil MethimazoleMethimazole
AbsorptionAbsorption AbsorbedAbsorbed fromfrom GITGIT AbsorbedAbsorbed fromfrom GITGIT
ProteinProtein
bindingbinding
80-80- toto 90%90% MostMost ofof drugdrug isis
freefree
accumulationaccumulation thyroidthyroid thyroidthyroid
ExcretionExcretion KidneysKidneys asas inactiveinactive
metabolitemetabolite withinwithin 2424
hrshrs
ExcretionExcretion slowslow,60-,60-
70%70% ofof drugdrug isis
recoveredrecovered inin urineurine
inin 4848 hrshrs
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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Pharmacokinetic comparision between
Propylthiouracil and Methimazole
PropylthiouracilPropylthiouracil MethimazoleMethimazole
HalfHalf lifelife 1.51.5 hrshrs (( shortshort
halfhalf-- lifelife))
66 hrshrs (( longlong halfhalf--
lifelife))
AdministrationAdministration EveryEvery 6- 86- 8 hrshrs AsAs aa singlesingle dosedose
PregnancyPregnancy
recommendedrecommended inin
pregnancypregnancy..
NotNot recommendedrecommended
inin pregnancypregnancy
BreastfeedingBreastfeeding LessLess secretedsecreted inin
breastbreast milkmilk
RecommendedRecommended
secretedsecreted
NotNot recommendedrecommended

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Drug that destroy thyroid tissue
2. Radioactive Iodine
• I131 mainly used.
• It emits beta and gamma radiations.
• It accumulates in thyroidal gland and
destructive action is becz of beta
rays.
• Gamma rays are only used to
calculate the amount of Iodine
present.
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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Therapeutic uses
• Selected cases of hyperthyroidism:
recurrence rate is low.
• Thyroid carcinoma:
• Daignostic use: localisation of
metastatic deposits of thyroid
cancer in the lungs and bones
• Angina pectoris: occasionally
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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Selection of the patients
1.uncomplicated hyperthyroidsm
2. recurrent or persistent hyperthyroidsm after
subtotal thyroidectomy
3.Failure or response to anti thyroidal drug
4.Presence of severe exophthalmos
•Advantage is low mortality, uncommon
recurrence
•Disadvantage is incidence of hypothyroidism
is high
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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Contraindications
• I131 is contraindicated during pregnancy
and lactation
Toxicity:
• May produce many temporary but
potentially dangerous reactions like
mild pain in thyroid area, swelling of
thyroid gland and bone marrow
depression.
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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3. Drug with uncertain mode of action
Iodide
• Oldest agent used in management of thyroid
disorders
• Used in the treatment of iodine deficiency
goiter, paradoxically when it is administered to
hyperthyroid patients there is reduction in
vascularity and swelling of the gland.
• Gland shrinks and symptoms improves
(mechanism is ill understood)
• High iodide content in blood inhibits thyroid
hormone release.
• Antagonized the ability of TSH and C-AMP to
stimulate the proteolysis and hormone release.
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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Clinical uses
1. Prior to thyroid surgery to decrease vascularity of the
gland .
2. Following radio active iodine therapy.
Examples
Organic iodides as :iopanoic acid or ipodate
Precautions /toxicity:
1. Should not be used as a single therapy
2. Should not be used in pregnancy
3. May produce iodism ( acniform rash, swelling of
salivary glands, mucous membrane ulceration, metallic
taste bleeding disorders and rarely anaphylaxis ).
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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4. IONIC INHIB ITORS
Certain monovalen thyroid probably because
of similar hydrated ionic size­
T4/T3 cannot be synthesized.
Thiocyanate also inhibits iodination at high
doses.
They are toxic and not used now.
Thiocyanates: can cause liver, kidney, bone
marrow and brain toxicity.
Perchlorates:
produce rashes,fever,aplastic anaemia,
agranulocytosis.
Nitrates: are weak drugs, can induce
methemoglobinaemia and vascular effects .

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5.ADRENOCEPTOR BLOCKING AGENTS:
• Adjunctive therapy to relief
the adrenergic symptoms of
hyperthyroidism such as
tremor, palpitation, heat
intolerance and nervousness.
• E.g. Propranolol, Atenolol ,
Metoprolol.
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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5. Antiadrenergic drug contd...
• Tachycardia,palpitation,hypertension are
adrenergic mediated symptoms of
thyrotoxocosis.
• To control these antiadrenergic drugs like
propranolol and guanethidine are used as
adjuvant therapy.
• Propranolol appears to be superior over
guanethidine : releves anxiety and tension
• Propranolol reduces the peripheral
conversion of T4 to T3
• Propranolol is contraindicated in asthmatic
patients
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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6. THYROIDECTOMY
• Sub-total thyriodectomy is the treatment of choice in
very large gland or multinodular goiter
Compiled by: Prof.Anwar
Baig (AIKTC.SOP)

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