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THYROID AND ANTI
THYROID DRUGS
By : Dr. Abdul Latif Mahesar
Department of medical pharmacology
KKUH , King Saud University
1
7
Normal thyroid gland secretes
T3 (triiodothyronine) and
T4 (tetraiodothyronine).
To maintain
Normal growth and development of
Nervous
Skeletal
Reproductive systems
8
It also controls metabolism of
Fats
Carbohydrates
Proteins and
Vitamins
9
and hence controls
Normal energy levels
also
Normal body temperature
Thyroid status also affects
Secretion and degradation of
Catecholamine
Cortisol
Insulin
Estrogen /Progesterone
Testosterone
10
The thyroidal hormone are responsible for
optimal growth, development ,function and
maintenance of all body tissues
Its effects depends upon protein synthesis and
potentiation of the secretion and action of
growth hormone
11
Deficiency of thyroidal hormones lead to
Hypothyroidism
Increased thyroidal hormone secretions lead to
Hyperthyroidism
12
Irreversible Mental retardation (Critinism) with
low IQ and Dwarfism results due to deficiency of
thyroxine in early life/pregnacy
Hyperactivity of thyroid resembles sympathetic
over activity, this may be due to oversensitivity of
β-adrenergic receptors or increase in their
number and enhanced amplification of the beta
receptors signals
Also there is increase in the activity of
catechloamine
13
Increased catechol and epinephreine
activity may cause
Palpitation
Anxiety
Sweating
Tremors
Nervousness
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15
Manifestations of Hyperthyroidism
Restlessness , nervousness , irritability.
Tremors
Palpitation
Sweating
Heat intolerance
Weight loss
muscle wasting
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|Manifestations cont’d
Diarrhea
Short breath
Itching
Tiredness
Exophthalmos
Menstrual disturbances
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Manifestations of Hypothyroidism
Fatigue and lack of energy
weight gain
Dry and cold skin
Intolerance to cold
Slowed thinking
Depression
Bradycardia
Dry hairs
Constipation
Infertility
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Causes of hypothyroidism
Drugs
Auto immune destruction
Blocked hormone formation
Impaired synthesis of T4
Destruction or removal of gland
Iodine deficiency
Receptor blocking antibodies
Pituitary or hypothalamic disease.
26
SYNTHESIS OF THYROID HORMONES
Iodide , an ions is actively taken up by the
thyroid gland (Iodine trapping)/iodine
uptake
Iodine is stored in the thyroid gland and is
concentrated 25 times more
Iodide an ion is then oxidized to iodine by
thyroidal peroxidase enzyme
27
It iodinates tyrosine (with in thyroglobulin,
a glycoprotein molecule) to form mono-
iodotyrosine (MIT) and Di-iodotyrosine
(DIT), called organification or iodination.
28
Biosynthesis of thyroid hormones ,also showing various sites of anithyroid drug actions
29
Two molecules of DIT unite to form T4
(tetra- iodothyroine) and one molecule of
MIT and DIT combine to form T3 (tri-
iodothyronine).
These hormones are released by exocytosis
and proteolysis of thyroglobulin.
Ratio of T4 to T3 in thyroglobulin is 5:1
Most of T3 in circulation is derived from
metabolism of T4. 30
HORMONE TRANSPORT .
T4 and T3 are reversibly bound to thyroxine binding
globulin (TBG).
0.04% of total T4 and 0.4% of T3 exist in free form
Starvation , pregnancy , steroid hormones affects their
binding , but their free concentration is maintained in
euthyroid gland
31
Metabolism of thyroxine in to active T3 and inactive T3 (rT3)
32
Thyroid Hormone Production and Metabolism per day 33
PERIPHERAL METABOLISM
Small amount is biologically inactivated by deamination,
decarboxylation conjugation and excreted as Glucuronide
or sulphate, but
The primary pathway of peripheral thyroxine metabolism
is DEIODINATION.
Deiodination of T4 at outer ring to active and 3-4 times
more potent T3. and
34
Metabolism cont’d
De-Iodination of inner ring produces reverse
T3(rT3), metabolically inactive.
Drugs like ipodate, β-blockers and
corticosteroids and starvation inhibits 5-
deiodinase.
This results low T3(active form) and high
rT3.(inactive form)
35
Hypothalamic –pitutary – thyroid axix
Thyroid regulation 36
37
THYROID REGULATION
Thyrotropin releasing hormone (TRH) is secreted
by hypothalamic cells in pituitary portal venous
system.
It acts on pituitary and causes synthesis and
release of thyroid stimulating hormone (TSH).
This in turn acts on thyroid cells to increase
release and synthesis of T3 and T4.
38
These thyroid hormones in a negative feed
back fashion act on pituitary to block action of
TSH and on hypothalamus to inhibit TRH.
Level of iodine in blood also regulates
thyroidal secretion independent of TSH. (large
doses of iodide inhibits iodine organification)
THYROXINE ISOMERS: Naturally
occurring molecules are L- isomers; where as
synthetic molecules are D-isomers. D -isomers
have only 4% activity of L-isomers.
39
MECHANISM OF ACTION
Free form of T3 and T4 enter cell by
diffusion /active transport .
T4 is converted to T3 and enters
nucleus and binds to T3 receptors, this
leads to increased formation of mRNA
and subsequent protein synthesis.
40
T3
T4
T3
T3
T3 PP
T4
PB T3 T3
Pre-m RNA
cytoplasm Nucleus
Response
Protein mRNA
Mechanims of action of thyroid cellular level
Mechanism of action of thyroxine at hormones
41
Pharmacokinetics of administered thyroid
hormones
T4, best absorbed in duodenum and ileum, this
can be altered by food and drugs, such as
calcium preparations and antacids containing
aluminum, intestinal flora .
Absorption of T4 is 80% and of T3 is 95%.
Absorption is not affected by mild
hypothyroidism but impaired in myxedema with
illeus, in this condition parental route is
preferred.
42
In hyperthyroidism metabolic clearance of T3
and T4 is increased and their half life is decreased
and opposite is true in hypothyrodism.
Enzyme inducers increase metabolism of T3 and
T4 but concentration is maintained in euthyroid.
Same compensatory mechanism occurs if binding
sites are altered as in pregnancy, estrogen
therapy and use of oral contraceptives.
43
Thyroid preparations
LEVOTHYROXINE:(T4)
This is the preparation of choice for thyroid replacement
and suppression therapy, because it is stable and has a
long (7 days) half life, to be administered once daily.
Oral preparations available are from 0.025 to 0.3 mg
tablets
For parentral use 200-500µg (100µg/ml when
reconstituted) for injection.
44
LIOTHYRONINE(T3):
This is more potent (3-4 times) and rapid
acting than levothyroxine but has a short half
life (24 hours) compared to levo, is not
recommended for routine replacement
therapy, it requires multiple dosing in a day.
It should be avoided in cardiac patients.
Oral preparation available are 5-50µg tablets
For parentral use 10µg/ml 45
Comparison of T4 to T3
T4 production is more than T3
T4 is converted to T3 in periphery
T3 is more potent than T4
T3 acts faster thanT4
T3 enters cell easily than T4
T3 binds to receptors in nucleus.
46
ANTITHYROID AGENTS:
Mechanism
Agents which interfere production of thyroid
hormone
.
Agents which modify tissue response to thyroid
hormones
Glandular destruction with radiation or surgery.
47
Agents :
Thioamides
Iodides
Radio active iodine
Iodinated contrast media
Adrenoceptor- blocking Agents
Anion inhibitors 48
Anti –thyroid agents ( Mechanissm)
49
THIOAMIDES:
Methimazole
Carbimazole
Propylthiouracil
Methimazole is 10 times more active than
propylthiouracil.
50
Mechanism of Action
They act by:
Inhibiting thyroidperoxidase –catalysed
reaction to block iodine organification.
They block coupling of iodotyrosine
They inhibit peripheral Deiodination of T4 to
T3.
Onset of drug is slow requiring 3-4 weeks
before stores of T4 are depleted. 51
Pharmacokinetic comparision between Propylthiouracil and
Methimazole
Propylthiouracil Methimazole
Absorption Rapid but incomplete At variable rates but
complete
Vol.of Dist. Approximates body Similar
waters
Protein binding more less
accumulation In thyroid Similar
Excretion Kidneys as inactive Excretion slow,60-
Glucuronide in 24 hrs 70% of drug is
recovered in urine in
48 hrs 52
Pharmacokinetic comparision between Propylthiouracil and
Methimazole
Propylthiouracil Methimazole
Half life 1.5 hrs 6 hrs
Administration Every 6-8 hrs As a single dose in 24 hrs
Duration of activity 100 mg inhibits iodine 30 mg exerts Antithyroid
organification for 7 hrs effect for longer than 24 hrs
Pregnancy Preferred, though cross Cross placenta and
placenta and is conc .in fetal concentrated by fetal thyroid
thyroid but is highly protein
bound ,cross placenta less
readily
Nursing mothers Less secreted in breast milk secreted
53
Adverse Effects ( thioamides)
It occurs in 3-12 % of treated patients
Maculopapular rash and fever are earlier effects.
Urticarial rash, vasculitis, arthralgia ,cholestetic
jaundice ,lymphadenopathy, and
hypoprothrombenemia.
Most dangerous complication is agranulocytosis
this is infrequent but may be fatal. 54
IODIDES:
They inhibit organification and hormone release.
With a dose of > 6 mg /day.
They should be initiated after onset of thioamides
therapy.
It also decreases the vascularity of hyperplastic
gland (making it valuable for preparation for
surgery)
Improvement is rapid within 2-7 days (valuable
in thyroid storm) 55
Iodides cont’d
Well and rapidly absorbed from intestines
Rapidly taken by thyroid gland and concentrated there
Moderate increase leads to hormone secretion
but substantial excess inhibits hormone release and
promotes its storage, making the organ less vascular
and firmer.
iodides stores in thyroid delays response to thioamides
56
Precautions /toxicity:
Should not be used as a single therapy
Should not be used in pregnancy
May produce iodism causing acniform rash,
swelling of salivary glands, mucous
membrane ulceration, metallic taste
bleeding disorders and rarely anaphylaxis.
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RADIOACTIVE IODINE
131 I isotope , administered orally
It is rapidly absorbed, concentrated in thyroid gland
and stored in follicles.
It has a half life of 5 days
It is easy to administer ,effective , painless and less
expensive
It causes destruction of parenchyma ,necrosis and
follicular disruption. 58
Radio active iodine cont’d
Therapeutic effect is due to emission of β-rays.
Patients with age above 40 years only can be
treated with this
It crosses placenta and excreted in breast milk
It may cause genetic damage and leukemia and
neoplasia ,it may be carcinogenic
59
IODINATED CONTRAST MEDIA
Ipodate , iopanoic acid administered orally
Diattrizoate administered intravenously
These drugs rapidly inhibit the conversion of T4 to T3.
They are relatively non toxic
Useful adjunctive therapy in thyroid storm
Valuable alternative when thioamides or iodides
contraindicated. 60
ADRENOCEPTOR BLOCKING AGENTS:
Many symptoms of thyrotoxicosis mimic ,
especially those which are associated with
sympathetic stimulation.
Beta blocking drugs without intrinsic
sympathomimic activity are the agents of choice
in these conditions
e.g. Propranolol.
In conditions where Beta blockers cannot be used
then Diltiazem is used.
61
HYPOTHYRODISM:
It is a syndrome resulting from deficiency of thyroid hormones and
manifested by reversible slowing down of all body function.
Infants and children suffer severely ,results in dwarfism and irreversible
mental retardation
Diagnosed by low free thyroxine and elevated serum TSH
For treatment : replacement therapy is appropriate
Levothroxine is most satisfactory: Infants and children require more T4
/kg body weight than adults.
Average dose in children 10-15 µg/kg/day and in adults: 1.7
µg/kg/day.
It takes 6-8 weeks to reach steady state level.
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In long standing condition, in older patients and in
patients with cardiac ailments, treatment is started with
reduced dosage.
Thyroxine is given once daily due to long half life.
In older patients and in patients with underlying cardiac
diseases treatment is started with reduced dose
levothyroxine is given in a dose of 12.5 – 25 µg/day for
two weeks and then increasing it after every two weeks.
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ADVERSE EFFECTS OF OVER DOSE
CHILDEREN : Restlessness, insomnia
,accelerated bone maturation.
ADULTS : Nervousness, heat intolerance ,
palpitation, weight loss
Atrial fibrillation and osteoporosis in chronic
over treatment with T4.
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MYXEDEMA COMA:
It is an end state of untreated hypothyroidism.
It develops quite and progress slowly to stupor , coma and
death.
The treatment of choice is loading dose of levothyroxine
intravenously 300-400µg initially followed by 50µg daily.
I/V T3 can be used but it may prove cardiotoxic
I/V hydrocortisone it may be used in case of adrenal and
pituitary insufficiency.
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HYPOTHROIDSM AND PREGNANCY.
These woman suffer form anovulatory
cycles and infertility
In pregnant hypothyroid patient 20-30 %
increase in thyroxine is required because of
elevated maternal TBG and because of early
development of fetal brain which depends
on maternal thyroxine
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HYPERTHYROIDISM
This is the syndrome that results when tissue is
exposed to high levels of thyroid hormone.
GRAVES' DISEASE
Most common form of hyperthyroidism.
It is autoimmune disorder
There is genetic defect in suppressor T lymphocyte ,
B lymphocytes synthesize antibodies against thyroid
antigens.
67
T3 and T4 are elevated and TSH is
suppressed.
Radio iodine uptake is elevated.
68
Management of Grave’s disease
Drug therapy
surgical thyroidectomy
Destruction of the gland with radioactive iodine
69
When patient is young with small gland and mild
disease
Drug therapy:
Methimazole / propylthiouracil until disease
undergoes spontaneous remission.
this may take 1-2 years with 60-70 % relapse.
70
therapy is started with large divided doses ,then
shifted to maintenance therapy with single daily
dose.
Propylthiouracil is better than methimazole.
this may lead to increase in TSH and stimulation
of thyroid, this can be prevented by addition of
levothyroxine.
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THYROIDECTOMY
A near-total thyriodectomy is the treatment of
choice in very large gland or multinodular
goiter
In case of large or multinodular goiter and
to simplify surgery (to diminish vascularity)
saturated solution of potassium iodide 5 drops
twice daily for two weeks prior to surgery
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RADIOACTIVE IODINE 131I
Preferred in most patients over 21 years of age
in a dose of 80-120µCi/gm of thyroid weight.( in
patients without underlying cardiac disease)
in patients with underlying heart disease ,severe
disease , elderly patient use methimazole until
patient become euthyroid , then stop the medicine
for 5-7 days.
Major complication of this therapy is
hypothyroidism which occurs in 80% of patients.
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Adjuncts Therapy
During acute phase β-blockers without
intrinsic sympathomimetic activity are
extremely helpful
eg : Propranolol
74
THYROID STORM:
It is sudden acute exacerbation of all of the
symptoms of thyrotoxicosis, presenting as a life
threatening syndrome.
There is hyper metabolism, and excessive
adrenergic activity, death may occur due to heart
failure and shock.
Vigorous management is mandatory. Propranolol
1-2mg slows I/v or 40-80 mg orally every 6 hours
75
Potassium iodide 10 drops orally daily or
Iodinated contrast media(Na ipodate 1 g
orally daily)
Propylthiouracil 250 mg orally every six
hours or 400 mg every six hours rectally.
Hydrocortisone 50 mg I/V every 6 hours to
prevent shock.
If above methods fail plasmapheresis or
peritoneal dialysis. 76
Thyrotoxicosis during pregnancy
Definitive therapy with 131I or subtotal
thyroidectomy prior to pregnancy to avoid acute
exacerbation during pregnancy or after delivery
During pregnancy radioiodine is contraindicated.
Propylthiouracil is better choice during pregnancy.
Dose must be kept minimum i.e., <300 mg daily.
77
ANION INHIBITORS
Perchlorate (Clo4) ; pertechnetate(TcO4)
and thiocynate (SCN) can block uptake of
iodide by the gland by competitive inhibition
For this purpose large doses of the drug are
required
They are rarely used clinically now days ,as
it has been shown to cause aplastic anemia.
78
