Transcript thyroid and anti thyroid drugs

THYROID AND ANTI
THYROID DRUGS
By : Dr. Abdul Latif Mahesar
Department of medical pharmacology
KKUH , King Saud University
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Normal thyroid gland secretes
T3 (triiodothyronine) and
T4 (tetraiodothyronine).
To maintain
Normal growth and development of
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Nervous
Skeletal
Reproductive systems
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It also controls metabolism of
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Fats
Carbohydrates
Proteins and
Vitamins
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and hence controls
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Normal body temperature
Normal energy levels
Thyroid status also affects
Secretion and degradation of
 Catecholamine
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Cortisones
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Estrogens
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progesterone and
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insulin
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Mental retardation (Cretinism) and dwarfism
results due to deficiency of thyroxine in early life.
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Hyperactivity of thyroid resembles sympathetic
over activity, this may be due to oversensitivity of
β-adrenergic receptors or increase in their
number.
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There may also be increase in the production of
catecholamines
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increased epinephrine activity causes
Tremors
Sweating
Anxiety
Nervousness
lid lag retraction
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Manifestations of Hyperthyroidism
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Restlessness , nervousness , irritability.
Tremors
palpitation
Weight loss
sweating
Heat intolerance
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|Manifestations cont’d
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Diarrhoea
Short breath
Itching
Tiredness
Light periods
Exophthalmos
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Manifestations of Hypothyroidism
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Fatigue and lack of energy
weight gain
Dry and cold skin
Dry hairs
Constipation
Slowed thinking
Bradycardia
Heavy menses
Intolerance to cold
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Causes of hypothyroidism
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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.
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SYNTHESIS OF THYROID HORMONES
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Iodide , an ions is actively taken up by the
thyroid gland (Iodine trapping)/iodine
uptake
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Iodine is stored in the thyroid and is
concentrated 25 times more
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Iodide an ion is then oxidized to iodine by
thyroidal peroxidase.
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It iodinates tyrosine (with in thyroglobulin,
a glycoprotein molecule) to form monoiodotyrosine (MIT) and Di-iodotyrosine
(DIT), called organification or iodination.
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Biosynthesis of thyroid hormones ,also showing various sites of anithyroid drug actions
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Two molecules of DIT unite to form T4
(tetra- iodothyroine) and one molecule of
MIT and DIT combine to form T3 (triiodothyronine).
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These hormones are released by exocytosis
and proteolysis of thyroglobulin.
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Ratio of T4 to T3 in thyroglobulin is 5:1
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Most of T3 in circulation is derived from
metabolism ofT4.
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HORMONE TRANSPORT .
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T4 and T3 are reversibly bound to thyroxine binding
globulin (TBG).
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0.04% of total T4 and 0.4% of T3 exist in free form
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Starvation , pregnancy , steroid hormones affects their
binding
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Metabolism of thyroxine in to active T3 and inactive T3 (rT3)
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Thyroid Hormone Production and Metabolism per day 25
PERIPHERAL METABOLISM
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Small amount is biologically inactivated by deamination,
decarboxylation conjugation and excreted as Glucuronide
or sulphate, but
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The primary pathway of peripheral thyroxine metabolism
is DEIODINATION.
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Deiodination of T4 at outer ring to active and 3-4 times
more potent T3. and
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Metabolism cont’d
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De-Iodination of inner ring produces reverse
T3(rT3), metabolically inactive.
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Drugs like ipodate, β-blockers and
corticosteroids; starvation inhibits 5deiodinase.
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This results low T3 and high rT3.
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Hypothalamic –pitutary – thyroid axix
Thyroid regulation
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THYROID REGULATION
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Thyrotropin releasing hormone (TRH) is secreted
by hypothalamic cells in pituitary portal venous
system.
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It acts on pituitary and causes synthesis and
release of thyroid stimulating hormone (TSH).
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This in turn acts on thyroid cell to increase
release and synthesis of T3 and T4.
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These thyroid hormones in a negative feed
back fashion act on pituitary to block action of
TSH and on hypothalamus to inhibit TRH.
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Level of iodine in blood also regulates
thyroidal secretion independent of TSH. (large
doses of iodide inhibits iodine organification)
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THYROXINE ISOMERS: Naturally
occurring molecules are L- isomers; where as
synthetic molecules are D-isomers. D -isomers
have only 4% activity of L-isomers.
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T3
T4
T3
T3
T3
T4
PB
T3
cytoplasm
Response
T3
Nucleus
Protein
PP
Pre-m RNA
mRNA
Mechanims
of action
of thyroid
Mechanism
of action
of thyroxine
at hormones
cellular level
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MECHANISM OF ACTION
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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.
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Pharmacokinetics of administered
thyroid hormones
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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%.
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Absorption is not affected by mild
hypothyroidism but impaired in myxedema with
ileus, for this parental route is preferred.
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In hyperthyroidism metabolic clearance of T3
and T4 is increased and their half life is decreased
and opposite is true in hypothyrodism.
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Enzyme inducers increase metabolism of T3 and
T4 but concentration is maintained in euthyroid.
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Same compensatory mechanism occurs if binding
sites are altered as in pregnancy, estrogen therapy
and use of oral contraceptives.
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Thyroid preparations
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LEVOTHYROXINE:(T4)
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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.
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Oral preparations available are from 0.025 to 0.3 mg
tablets
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For parentral use 200-500µg (100µg/ml when
reconstituted) for injection.
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LIOTHYRONINE(T3):
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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.
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It should be avoided in cardiac patients.
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Oral preparation available are 5-50µg tablets
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For parentral use 10µg/ml
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Comparison of T4 to T3
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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.
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ANTITHYROID AGENTS:
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Mechanism
Agents which interfere production of thyroid
hormone
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Agents which modify tissue response to thyroid
hormones
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Glandular destruction with radiation or surgery.
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Drugs :
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Thioamides
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Iodides
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Radio active iodine
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Iodinated contrast media
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Adrenoceptor- blocking Agents
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Anion inhibitors
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Anti –thyroid agents ( Mechanissm)
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THIOAMIDES:
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Methimazole
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Carbimazole
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Propylthiouracil
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Methimazole is 10 times more active than
propylthiouracil.
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Mechanism of Action
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They act by:
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Inhibiting thyroidperoxidase –catalysed
reaction to block iodine organification.
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They block coupling of iodotyrosine
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They inhibit peripheral Deiodination of T4 to
T3.
Onset of drug is slow requiring 3-4 weeks
before stores of T4 are depleted.
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Pharmacokinetic comparision between Propylthiouracil and
Methimazole
Absorption
Propylthiouracil
Methimazole
Rapid but incomplete
At variable rates but
complete
Similar
Vol.of Dist.
Approximates body
waters
Protein binding more
less
accumulation
In thyroid
Similar
Excretion
Kidneys as inactive
Glucuronide in 24 hrs
Excretion slow,6070% of drug is
recovered in urine in
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48 hrs
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
organification for 7 hrs
30 mg exerts Antithyroid
effect for longer than 24 hrs
Pregnancy
Preferred, though cross
placenta and is conc .in fetal
thyroid but is highly protein
bound ,cross placenta less
readily
Cross placenta and
concentrated by fetal thyroid
Nursing mothers
Less secreted in breast milk
secreted
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Adverse Effects ( thioamides)
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It occurs in 3-12 % of treated patients
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Maculopapular rash and fever are earlier effects.
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Urticarial rash, vasculitis, arthralgia ,cholestetic
jaundice ,lymphadenopathy, and
hypoprothrombenemia.
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Most dangerous complication is agranulocytosis
this is infrequent but may be fatal.
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IODIDES:
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They inhibit organification and hormone release.
With a dose of > 6 mg /day.
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They should be initiated after onset of thioamides
therapy.
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It also decreases the vascularity of hyperplastic
gland (making it valuable for preparation for
surgery)
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Improvement is rapid within 2-7 days (valuable
in thyroid storm)
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Iodides cont’d
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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
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Precautions /toxicity:
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Should not be used as a single therapy
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Should not be used in pregnancy
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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
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It is rapidly absorbed, concentrated in thyroid gland
and stored in follicles.
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It has a half life of 5 days
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It is easy to administer ,effective , painless and less
expensive
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It causes destruction of parenchyma ,necrosis and
follicular disruption.
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Radio active iodine cont’d
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Therapeutic effect is due to emission of β-rays.
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Patients with age above 40 years only can be
treated with this
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It crosses placenta and excreted in breast milk
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It may cause genetic damage and leukemia and
neoplasia ,it may be carcinogenic
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IODINATED CONTRAST MEDIA
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Ipodate , iopanoic acid administered orally
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Diattrizoate administered intravenously
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These drugs rapidly inhibit the conversion of T4 to T3.
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They are relatively non toxic
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Useful adjunctive therapy in thyroid storm
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Valuable alternative when thioamides or iodides
contraindicated.
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ADRENOCEPTOR BLOCKING AGENTS:
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Many symptoms of thyrotoxicosis mimic ,
especially those which are associated with
sympathetic stimulation.
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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.
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HYPOTHYRODISM:
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It is a syndrome resulting from deficiency of thyroid hormones and
manifested by reversible slowing down of all body function.
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Infants and children suffer severely ,results in dwarfism and irreversible
mental retardation
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Diagnosed by low free thyroxine and elevated serum TSH
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For treatment : replacement therapy is appropriate
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Levothroxine is most satisfactory: Infants and children require more T4
/kg body weight than adults.
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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.
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Thyroxine is given once daily due to long half life.
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In older patients and in patients with underlying cardiac
diseases treatment is started with reduced dose
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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:
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It is an end state of untreated hypothyroidism.
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It develops quite and progress slowly to stupor , coma and
death.
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The treatment of choice is loading dose of levothyroxine
intravenously 300-400µg initially followed by 50µg daily.
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I/V T3 can be used but it may prove cardiotoxic
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I/V hydrocortisone it may be used in case of adrenal and
pituitary insufficiency.
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HYPOTHROIDSM AND PREGNANCY.
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These woman suffer form anovulatory
cycles and infertility
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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
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This is the syndrome that results when tissue is
exposed to high levels of thyroid hormone.
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GRAVES' DISEASE
Most common form of hyperthyroidism.
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It is autoimmune disorder
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There is genetic defect in suppressor T lymphocyte ,
B lymphocytes synthesize antibodies against thyroid
antigens.
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T3 and T4 are elevated and TSH is
suppressed.
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Radio iodine uptake is elevated.
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Management of Grave’s disease
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Drug therapy
surgical thyroidectomy
Destruction of the gland with radioactive iodine
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When patient is young with small gland and mild
disease
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Drug therapy:
Methimazole / propylthiouracil until disease
undergoes spontaneous remission.
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this may take 1-2 years with 60-70 % relapse.
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therapy is started with large divided doses ,then
shifted to maintenance therapy with single daily
dose.
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Propylthiouracil is better than methimazole.
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this may lead to increase in TSH and stimulation
of thyroid, this can be prevented by addition of
levothyroxine.
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THYROIDECTOMY
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A near-total thyriodectomy is the treatment of
choice in very large gland or multinodular
goiter
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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
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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)
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in patients with underlying heart disease ,severe
disease , elderly patient use methimazole until
patient become euthyroid , then stop the medicine
for 5-7 days.
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Major complication of this therapy is
hypothyroidism which occurs in 80% of patients.
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Adjuncts Therapy
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During acute phase β-blockers without
intrinsic sympathomimetic activity are
extremely helpful
eg : Propranolol
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THYROID STORM:
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It is sudden acute exacerbation of all of the
symptoms of thyrotoxicosis, presenting as a life
threatening syndrome.
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There is hyper metabolism, and excessive
adrenergic activity, death may occur due to heart
failure and shock.
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Vigorous management is mandatory. Propranolol
1-2mg slows I/v or 40-80 mg orally every 6 hours
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Potassium iodide 10 drops orally daily or
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Iodinated contrast media(Na ipodate 1 g
orally daily)
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Propylthiouracil 250 mg orally every six
hours or 400 mg every six hours rectally.
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Hydrocortisone 50 mg I/V every 6 hours to
prevent shock.
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If above methods fail plasmapheresis or
peritoneal dialysis.
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Thyrotoxicosis during pregnancy

Definitive therapy with 131I or subtotal
thyroidectomy prior to pregnancy to avoid acute
exacerbation during pregnancy or after delivery
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During pregnancy radioiodine is contraindicated.
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Propylthiouracil is better choice during pregnancy.
Dose must be kept minimum i.e., <300 mg daily.
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ANION INHIBITORS
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Perchlorate (Clo4) ; pertechnetate(TcO4)
and thiocynate (SCN) can block uptake of
iodide by the gland by competitive inhibition
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For this purpose large doses of the drug are
required
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They are rarely used clinically now days ,as
it has been shown to cause aplastic anemia.
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