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DEBRE TABOR UNIVERSITY

Pharmacology of thyroid hormones and


anti thyroid drugs for second year
medicine students
By Tezera Jemere
(MSC in pharmacology)
College Of Health Sciences
March, 2017
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Presentation outline
Definition of thyroid hormones
Chemistry of thyroid hormones
Synthesis of thyroid hormones
Mechanisms of action of thyroid hormones
Actions of thyroid hormones
Pharmacokinetics
Treatment of hypothyroidism
Treatment of hyperthyroidism

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THYROID HORMONE
The thyroid gland secretes 3 hormones-thyroxine
(T4), triiodothyronine (T3) and calcitonin.
The former two are produced by thyroid follicles,
have similar biological activity and the term 'thyroid
hormone' is restricted to these only.
Calcitonin produced by interfollicular 'C' cells is
chemically and biologically entirely different.
It is considered along with parathormone with which
it regulates calcium metabolism.

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CHEMISTRY

R= h t3

Both T4 and T3 are iodine containing derivatives of


thyronine which is a condensation product of two
molecules of the amino acid tyrosine.
Thyroxine; is 3, 5,3', 5' -tetraiodothyronine while T3
is 3,5, 3' triiodothyronine.
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Synthesis of Thyroid Hormones
Regulation:
The hypothalamus in the brain secretes thyroid
releasing hormone, TRH, that target the pituitary
gland which, in turn, secretes thyroid stimulating
hormone, TSH.
The pituitary glands sensitivity toward TRH varies
with the bodys need for thyroid hormones.
TSH is absorbed into the thyroid, stimulating the
thyroid to absorb iodine and synthesize hormones.
Thyroid hormones provide negative feedback for
TSH production via a homeostatic feedback loop.
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Regulation of thyroid function

TRH: thyrotropin-releasing hormone


TSH: thyroid-stimulating hormone

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Intra-thyroidal synthesis and processing
of thyroidal hormones
1. Iodide is taken up at the basolateral cell membrane
and transported to the apical membrane
2. Polypeptide chains of Tg (thyroglobulin) are
synthesized in the rough endoplasmic reticulum, and
posttranslational modifications take place in the
Golgi apparatus.
3. Newly formed Tg is transported to the cell surface in
small apical vesicles (AV)
4. Within the follicular lumen, iodide is activated and
iodinates tyrosyl residues on Tg, producing fully
iodinated Tg containing MIT, DIT, T4 and a small
amount of T3 (organification and coupling), which is
stored as colloid in the follicular lumen
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Intra-thyroidal synthesis & processing
of thyroidal hormones
5. Upon TSH stimulation, villi at the apical membrane
engulf the colloid and endocytose the iodinated Tg
as either colloid droplets (CD) or small vesicles
(MPV)
6. Lysosomal proteolysis of the droplets or vesicles
hydrolyzes Tg to release its iodinated amino acids
and carbohydrates
7. T4 and T3 are released into the circulation
8. DIT and MIT are deiodinated, and the iodide and
tyrosine are recycled
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HOI-Hypoiodous acid; EOI-Enzyme linked hypoiodate.TSH
activates steps 1, 2, 3, 4, and 5; Ionic inhibitors block step 1;
Excess iodide interferes with steps 1, 2, 3 and 5 with primary
action on step 3 and 5; PTU inhibits steps 2 and 6; Carbimazole
inhibits step 2 only.
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Mechanism of TH Activation in Body
Hydrophobic molecule transported in the
bloodstream with a requisite carrier protein, TBG.
Albumin also serves as a TH carrier protein.
Transported across the cell membrane using a
transporter complex. TH enters nucleus.
The iodine at position 5 on the outer ring serves to
sterically hinder the thyroid hormone binding
enzyme. T4 is converted to T3, the active form.
Deiodinase, specifically IDI or IDII, cleaves the
iodine at position 5 to yield T3.

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Thyroid hormones
Relation between T4 & T3
Thyroid secretes more T 4 than T3.
T4 is the major circulating hormone because it is 15 times
more tightly bound to plasma proteins.
T3 is 5 times more potent than T4 and acts faster.
Peak effect of T3 comes in 1-2 days while that of T4
takes 6-8 days.
T3 is more avidly bound to the nuclear receptor than
T4and the T4-receptor complex is unable to
activate/derepress gene transcription.
~ 30 % of T4 is converted to T3 in the thyroid cells, liver
and kidney by a type of 5' deiodinase(5'DI).
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Thyroid hormones
Mechanism of action
Both T3 and T4 penetrate cells by active transport
and produce majority of their actions by combining
with a nuclear thyroid hormone receptor (TR) which
belongs to the steroid and retinoid superfamily of
intracellular receptors.
ACTIONS
1. Growth and development T4 and T3 are essential
for normal growth and development.
Congenital deficiency of T4 and T3 resulting in
cretinism emphasizes their importance.
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Thyroid hormones Contd
2. Intermediary metabolism
A. Lipid
T4 & T3 indirectly enhance lipolysis by potentiating the
action of catecholamines and other lipolytic hormones,
probably by suppressing a phosphodiesterase lead to
increased cAMP
Lipogenesis is also stimulated.
All phases of cholesterol metabolism are accelerated,
but its conversion to bile acids dominates.
Hyperthyroidism is characterized by hypocholesterolemia.
LDL levels in blood are reduced.
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Thyroid hormones Contd
B. Carbohydrate
Carbohydrate metabolism is stimulated.
Glycogenolysis and gluconeogenesis in liver as well
as faster absorption of glucose from intestines more
than compensate it lead to hyperglycaemia and
diabetic-like state with insulin resistance occur in
hyperthyroidism.
C. Protein Synthesis
Overall effect ofT3 is catabolic-increased amounts of
protein being used as energy source.
T3, T4 in low concentrations inhibit mucoprotein
synthesis which so characteristically accumulates in
myxoedema.
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Thyroid hormones Contd
Pharmacokinetics
Both T4 and T3 are absorbed after oral
administration.
Food, calcium preparations, and aluminum-
containing antacids can decrease the absorption of
T4 but not of T3.
T4 is converted to T3 by one of two distinct
deiodinases, depending on the tissue.
The hormones are metabolized through the
microsomal P450 system.
Drugs that induce the P450 enzymes, such as
phenytoin, rifampin, and phenobarbital, accelerate
metabolism of the thyroid hormones.
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Hypothyroidism
Insufficient amount of thyroid hormone synthesized
causing lethargy and weight gain, among other
symptoms.
Primary hypothyroidism is typically caused by
Hashimotos Disease, an auto-immune disorder in
which the thyroid is destroyed by antibodies.
Impaired hypothalamus and pituitary function,
typically due to a tumor, can inhibit the secretion of
TSH, causing secondary hypothyroidism.
A diet insufficient in iodine causes hypothyroidism as
well.
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Goiter
Enlarged thyroid, symptom of hypothyroidism.
Goiters form for different reasons depending on the
cause of hypothyroidism
Hashimotos disease, also known as chronic
lymphocytic thyroiditis, causes goiters due to the
accumulation of lymphocytes.
Hashimotos or other thyroid disorders including
infection, signals the increased production of TSH
which accumulates in the thyroid causing a
characteristic goiter.
Goiters form due to an insufficient amount of
ingested iodine and serve to increase the surface
area of the thyroid and aid in its absorption of iodine.
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Pharmacological treatment:

Synthetic hormones:

Levothyroxine, liothyronine, liotrix (combination of


L-thyroxine and liothyronine)

Neonatal, infantile and juvenile hypothyroidism:-

Early full replacement therapy vital to improve


likelihood of normal intellectual development,
normal growth

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If pituitary & hypothalamic hypothyroidism:-

Treatment with hydrocortisone should


precede thyroid replacement therapy:

Rationale: acute adrenocortical insufficiency


may be caused by the increase in metabolic
rate with increase glucocorticoid clearance
following thyroid hormonal treatment

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Adults:
Rapid treatment desirable especially in patients with:
myxedema coma
hypothyroid patients needing to undergo emergency
surgery
IV levothyroxine with hydrocortisone may be appropriate
Patients with myxedema coma and systemic illness may
have reduced ability to convert T4 to T3
In these cases supplemental liothyronine may be added to
levothyroxine.

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Treatment for Hypothyroidism
Hormone replacement therapy
Administered orally with a bioavailability ranging
from 48%-80%.
LevothyroxineSynthetic T4
LiothyronineSynthetic T3
LiotrixCombination of synthetic T4 and T3
Natural Thyroid HormonesThyroid hormones
derived from pigs, contains T4 and T3.
Dosage specific to individual and is determined by
their TSH serum levels. Typically 1.5g T4 per kg
body weight.
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Treatment for Hypothyroidism
Because thyroid hormones serve to increase heart
rate, T4, the inactive form, is typically administered to
older patients who have an increased risk for heart
attack on account of their age. Synthetic T3 is
reserved for younger patients, who do not have a
history of heart problems and individuals non-
responsive to T4 treatment.
Some men are inefficient in the conversion of T4 to T3,
making combination drugs like Liotrix and Armour
Thyroid ideal treatment options.
Dosage for individuals suffering from secondary
hypothyroidism determined by the amount of free T4 and T3
circulating in their system.
Administering too high of a dosage leads to hyperthyroid
symptoms.
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Potential Drug Interactions
Drugs that reduce thyroid hormone production
Lithium, Iodine-containing medications & Amiodarone
Drugs that reduce thyroid hormone absorption
Sucralfate , Ferrous sulfate, Cholestyramine, Colestipol
Aluminum-containing antacids, Calcium products
Drugs that increase metabolism of thyroxine
Rifampin, Phenobarbital, Carbamazepine, Warfarin
Oral hypoglycemic agents
Drugs that displace thyroid hormone from protein
binding
- Furosemide, Mefenamic acid & Salicylates
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TSH Replacement Drugs
Thyrotropin alphaA synthetic form of TSH. Administered
intravenously.
Used in thyroid cancer treatment.
Tumors of the hypothalamus or pituitary gland can cause the
uncontrolled release of TSH, which accumulates in the thyroid
and can cause subsequent follicular or papillary cancer of the
thyroid. Partial or total thyroidectomy typical.
Following thyroidectomy, the individual is dependent on
exogenous thyroid hormones to regulate metabolism, but
thyrotropin alpha is also used to suppress the release of
endogenous TSH, which could trigger cancerous growth again.
Used as a diagnostic tool to determine the reoccurrence of
cancer.

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Hyperthyroidism
The over production of thyroid hormones.
Symptoms include fatigue, weight lose, rapid heart beat,
anxiety, swollen eyes, and sensitivity to hot
temperatures.
Causes:
Graves disease, and autoimmune disorder in which
antibodies serve as agonists to the TSH receptors on
the thyroids surface, causing thyroid growth and
activation of hormone synthesis and secretion.
Extra-pituitary unregulated thyroid stimulation
Thyroid tumors which cause the uncontrolled synthesis
and secretion of thyroid hormones.
Thyroiditis, inflammation of the thyroid typically caused
by infection.
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Treatment of Hyperthyroidism
Manage dehydration: IV glucose/Saline, vitamin B
complex
Glucocorticoids (possible reduction in adrenal reserve;
increase glucocorticoid requirement and thyrotoxicosis)
Digitalis may be required to control elevated ventricular
rates in the presence of atrial fibrillation
Block hormone synthesis by large dose propylthiouracil;
followed by large doses of iodine, oral or parenteral;
sodium ipodate may be used instead of iodine
Propranolol (adrenergic antagonist) in the absence of
CHF
Combination treatment with propylthiouracil, iodine,
dexamethasone is likely to result in serum T3 levels
returning
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TJA
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Treatment Contd
Anti-thyroid drugsInhibits thyroid hormone
synthesis by irreversibly binding to thyroid
peroxidase inhibiting its ability to break down iodine
(I2I-) and covalently attach it to the tyrosine
residue of thyroglobulin.
Thiourea
Propylthiouracil
Methimazole
Carbamizole Degraded to methimazole in the body.
Radioactive Iodine Iodine and iodide
Thyroidectomy -Blockers

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Thioureas

PTU Methimazole Carbimazole

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Propylthiouracil (PTU)
MOA
Thyroid
PTU inhibits thyroperoxidase & prevent oxidizing
anion iodide (I) to iodine (I0).
The essential steps in the formation of thyroxine
(T4).
It inhibits tetraiodothyronine 5'deiodinase or 5'-
deiodinase which converts T4 to the active form
T3 peripherally.
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PTU Contd
Medical use:
used to treat hyperthyroidism due to Graves'
disease and toxic multinodular goiter.
In thyrotoxic crisis, more effective than
methimazole.
Pharmacokinetics
Administration is oral, with peak serum
concentrations occurring in one hour, and actively
concentrated to the thyroid gland.
Euthyroid status may not be achieved until 24
months after treatment initiation.
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PTU Contd
It is approximately 70% protein-bound and significantly
ionized at normal physiologic pH,
while methimazole is substantially less protein bound.
However both are equally transferred across the
placenta.
Plasma half-life is one hour and is not altered
appreciably by the thyroid status of the patient.
Due to the concentration in the thyroid, however, dosing
intervals may last 8 hours or longer.
Less than 10% of the drug is excreted unchanged.
The remaining fraction undergoing extensive hepatic
metabolism via glucuronidation.
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PTU Contd
Adverse effects
Propylthiouracil is generally well tolerated, with side
effects occurring in one of every 100 patients.
Most common skin rash, itching, hives, abnormal
hair loss, and skin pigmentation.
common swelling, nausea, vomiting, heartburn, loss
of taste, joint or muscle aches, numbness and
headache, allergic reactions, and hair whitening.
Agranulocytosis and aplastic anemia, risk of serious
liver injury, including liver failure and death,

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PTU Contd
As a result PTU is no longer recommended in
non-pregnant adults and in children as the
front line antithyroid medication.
Agranulocytosis lead to infectious lesions of the
throat, GIT and skin with an overall feeling of illness
and fever.
Thrombocytopenia may lead to problems with
excessive bleeding.
Life-threatening side effect is sudden, severe,
fulminant liver failure resulting in death or liver
transplantation in 0.01% of people taking PTU.
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Precaution
PTU is classified as Drug Class D in pregnancy.
Class D signifies there is positive evidence of
human fetal risk.
Maternal benefit may outweigh fetal risk in life-
threatening situations.
PTU is preferred over methimazole (which is also
a class D) only in the first trimester of pregnancy
and in woman who may become pregnant
because of the increased risk of teratogenicity of
methimazole during critical organogenesis.
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In the second and third trimester, this risk is
diminished and methimazole is preferred to avoid
the risk of liver complications from PTU in the
mother.
The primary effect on the fetus from transplacental
passage of PTU is the production of a mild
hypothyroidism when the drug is used close to term.
This usually resolves within a few days without
treatment.
The hypothyroid state may be observed as a goiter in
the newborn, and is the result of increased levels of
fetal pituitary thyrotropin.
The incidence of fetal goiter after PTU treatment in
reported cases is approximately 12%.

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Methimazole

Mechanism of action
It inhibits thyroperoxidase & prevent oxidizing
anion iodide (I) to iodine (I2), hypoiodous acid
(HOI), enzyme linked hypoiodate (EOI) facilitating
iodine's addition to tyrosine residues on the
hormone precursor thyroglobulin, a necessary step
in the synthesis of triiodothyronine (T3) and
thyroxine (T4).

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Methimazole Contd
Medical uses
It is used to treat hyperthyroidism ( Graves' disease).
It may be taken before thyroid surgery to lower thyroid
hormone levels and minimize the effects of thyroid
manipulation.
Pharmacokinetics
Bioavailability 93%
Protein binding None
Metabolism Liver
Biological half-life 5-6 hours
Excretion Kidney
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Methimazole Contd
Adverse effects
Skin rash, itching, abnormal hair loss, upset
Upset stomach, vomiting, loss of taste,
Abnormal sensations (tingling, prickling, burning,
tightness, and pulling), drowsiness, dizziness.
Swelling, joint and muscle pain,
Agranulocytosis, thrombocytopenia, aplasia cutis
congenita (prenatal exposure)

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Methimazole Contd
Drug interactions
Thiamazole has been demonstrated to potently inhibit all
CYP450 enzymes, meaning that the plasma concentration
of all hepatically metabolized drugs will be significantly
increased when taken with, or after, methimazole.
This must be considered when starting a patient on
methimazole, increasing their dose, or starting a
thiamazole patient on another drug.
Many drugs will need their doses lowered and dosing-time
intervals increased when co-administered with thiamazole.
For some hepatically metabolized drugs with very low
therapeutic indexes, co-administration with thiamazole may
not be possible at all.
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Iodine and iodide
Actions and applications
Low dose of iodine (physiological dose) could prevent and
cure simple (endemicity) goiter. Add 1/10000~1/100000
potassium iodide or sodium iodide to salt could prevent the
disease.
Large dose of iodine could inhibit the release of T3 and T4
(due to the inhibition of TG hydratase).
Used as adjunctive therapy for hyperthyroidism:
1. preparation before operation: administration of aqueous
iodine solution two weeks before operation degenerates the
glandular tissue, decreases vessels and bleeding;
2. adjunctive therapy for thyroid crisis: could be used combined
with thiourea homologues.

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Iodine and iodide
Adverse effects and application notes
Acute effects: acute circumscribed edema,laryngeal
edema and apnoea.
Chronic toxicity: mouth and throat burning sensation,
increase secretion of salivary, eye irritation and so on.
Induce dysthyroid and hyperthyroidism after long
medication.
Iodine could pass into the milk and through placenta,
leading to neonatal goiter. Pregnant and lactating women
should take the drug with cautious.
Allergic and active tuberculosis patients are forbidden to
take.

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Radioactive iodine131I
Actions
T1/2 is 8.04 days
131I could be uptaken by throid , participate in the
synthesis of T3, T4 and is stored in follecular colloid.
131I mainly generates ray99with average and
maximum path of 0.5mm and 2mm respectively.
The irradiation function is limited in the thyroid.
It can destroy the glandular organ but can seldom destroy
the surrounding tissues.
ray generated by 131I accounts for 1 and can be
detected in vitro.
It is usually used in the examination of thyroid iodine up
taking function.
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Radioactive iodine131I
Clinical application
Thyroid iodine uptake function examination:
iodine uptake rate high when hyperthyroid,
time of iodine uptake peak antelocation
iodine uptake rate low when hypothyroid, time
of iodine uptake peak retroposition
Hyperthyroidism
Trace amount could be used in diagnosis of
thyroid functional status and thyroid adenoma.

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Radioactive iodine Contd
Adverse effects and application notes
Hypothyroidism is the predominant complication.
The adverse effects can be reduced by strict dose
control and resisted by thyrine.
Contraindication
Patients with Total white blood cells less than
3000/mm3 are not suitable to take it.
pregnant and lactating women,
patients younger than 20 years old.
patients with severe liver or kidney diseases.

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receptor blockers
Valuable adjunctive therapy drugs for
hyperthyroidism and thyroid crisis.
They could improve symptoms caused by
augmented sympathetic activity such as speed up
heart rate and increase heart contraction force .
They can also reduce the thyroid hormone secretion
and T3 synthesis by inhibiting 5`-deiodinase .
Control hyperthyroidism symptoms and can be used
in preparation before operation .

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receptor blockers
Clinical application
Adjunctive therapy for hyperthyroidism and
hyperthyroidism crisis.
Mechanism of pharmacological actions
Excited sympathetic-adrenergic system 1
receptor blockage heart rate drop.
Central receptor blockage to reduce
anxiety 2 receptor on noradrenerginic
peripheral nerve ending presynaptic
membrane blockage reduces the release of
NA.
Appropriately reduce T3, T4 secretion.

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