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THYROID AND ANTI-THYROID DRUGS
Mr. D.Raju, M.pharm,
Lecturer
ANATOMY AND PHYSIOLOGY OF THE THYROID
GLAND
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Member of the Endocrine System
« Secretes thyroid hormones, thyroxine and
calcitonin, which regulate metabolism and growth.
« Located in neck adjacent to the 5th cervical
vertebra (C5).
« Composed of epithelial cells which specialize in the
absorption of iodine and, of course, secretion of
thyroid hormones.
« Follicles surround a protein core, the colloid, where
thyroglobulin, a substrate in thyroid hormone
synthesis, and thyroid hormones are stored.
SYNTHESIS OF THYROID HORMONES
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Regulation:
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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 gland’s sensitivity toward TRH varies with
the body’s 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.”
●Regulation
of thyroid function
TRH: thyrotropin-releasing hormone
TSH: thyroid-stimulating hormone
●Synthesis
of thyroid hormones
MIT: monoiodotyrosine
Thyroid hormones
triiodothyronine (T3)
DIT: diiodotyrosine
tetraiodothyronine (T4, thyroxine)
Materials
iodine & tyrosine
Steps
1. Iodide is trapped by sodium-iodide symporter
2. Iodide is oxidized by thyroidal peroxidase to iodine
3. Tyrosine in thyroglobulin is iodinated and forms MIT & DIT
4. Iodotyrosines condensation
MIT+DIT→T3;
DIT+DIT→T4
TH SYNTHESIS
« Thyroid
peroxidase (TPO) catalyzes the conversion
of iodide (I2) to iodine (I-) using H2O2 as a cofactor.
« TPO then catalyzes the addition of iodine to the C-3
and C-5 position of a tyrosine residue of
thyroglobulin.
« Two iodinated thyrosine rings condense to form
thyroxine, or T4, with four iodine substituents.
« Triiodothyronine, or T3, with three iodine
substituents, accounts for about 10% of thyroid
hormone production.
●MECHANISM
OF ACTIONS
OF THYROID HORMONES
•
Some of T4 are converted to
T3 in kidney and liver
•
The actions of T3 on several
organ systems are shown
•
BMR: basal metabolic rate;
CNS: central nervous system
T3, via its nuclear
receptor, induces
new proteins
generation which
produce effects
CONDITIONS THAT IMPAIR THYROID FUNCTION:
HYPOTHYROIDISM
« Insufficient
amount of thyroid hormone synthesized
causing lethargy and weight gain, among other
symptoms.
« Primary hypothyroidism is typically caused by
Hashimoto’s 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
THS, causing secondary hypothyroidism.
« A diet insufficient in iodine causes hypothyroidism
as well.
SYMPTOMS OF THYROID DYSFUNCTION: GOITER
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Enlarged thyroid, symptom of hypothyroidism.
Goiters form for different reasons depending on the cause
of hypothyroidism
« Hashimoto’s disease, also known as chronic
lymphocytic thyroiditis, causes goiters due to the
accumulation of lymphocytes.
« The decreased amount of thyroid hormones in the body,
due to Hashimoto’s 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.
TREATMENT FOR HYPOTHYROIDISM
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Hormone replacement therapy
Administered orally with a bioavailability ranging from 48%-80%.
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Dosage specific to individual and is determined by their TSH serum levels.
Typically 1.5μg T4 per kg body weight.
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Levothyroxine—Synthetic T4
Liothyronine—Synthetic T3
Liotrix—Combination of synthetic T4 and T3
Natural Thyroid Hormones—Thyroid hormones derived from pigs, contains T4 and T3
² Armour Thyroid
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 Litrix 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.
CONDITIONS THAT IMPAIR THYROID FUNCTION:
HYPERTHYROIDISM
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The over production of thyroid hormones.
Symptoms include fatigue, weight lose, rapid heart
beat, anxiety, swollen eyes, and sensitivity to hot
temperatures.
Causes:
« Grave’s disease, and autoimmune disorder in which
antibodies serve as agonists to the THS receptors
on the thyroid’s surface, causing thyroid growth and
activation of hormone synthesis and secretion.
« Thyroid tumors which cause the uncontrolled
synthesis and secretion of thyroid hormones.
« Thyroiditis, inflammation of the thyroid typically
caused by infection.
TREATMENT FOR HYPERTHYROIDISM
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Anti-thyroid drugs—Inhibits thyroid hormone synthesis by
irreversibly binding to TPO inhibiting its ability to break
down iodine (I2→I-) and covalently attach it to the tyrosine
residue of thyroglobulin.
« Propylthiouracil
« Methimazole
« Carbamizole─Degraded to methimazole in the body.
Radioactive Iodine
Thyroidectomy
β-Blockers used in the treatment of thyroiditis to treat
symptoms.
●Pharmacological
effect
see physiological effect
● Clinical
use
1. Hypothyroidism: cretinism & myxedema;
2. simple goiter: for pathogeny remaining unclear
(endemic goiter directly supply iodine)
3. Others:
● Adverse
reactions
Overmuch leads to thyrotoxicosis;
Angina or myocardial infarction usually appears in
ageds
Antithyroid drugs
● Drugs
Class
Representative
propylthiouracil
Thioamides
methylthiouracil
methimazole
carbimazole
Iodides
Radioactive iodine
β-adrenoceptor blockers
KI, NaI
131I
propranolol
І. Thioamides
◆Structure
The thiocarbamide
group is essential for
antithyroid activity
Pharmacological action
Inhibition of the synthesis of T3 & T4
Mechanism
All thioamides inhibit peroxidase-catalyzing reactions
Iodine organification
First choice for
thyroid crisis
Iodotyrosines condensation
Propylthiouracil also inhibit T4 converting to T3
Characteristics
① Result appears slowly: in 3-4 w hyperthyroid ameliorated,
and in 2-3 months BMR normalized;
② Long-term use leads to thyroid hyperplasia
③ Methimazole is 10 times as potent as propylthiouracil
Clinical use
treatment of hyperthyroid
1. Mild hyperthyroid and those surgery & 131I
not permitted;
2. Operation preparation;
3. Thyroid crisis (comprehensive therapy).
Adverse reactions
1. Long-term use leads to thyroid hyperplasia;
2. Pruritic maculopapular rash is the most common
adverse raaction
3. The severe adverse reaction is agranulocytosis
Iodides (NaI, KI)
Pharmacological action
Inhibition of T3 & T4 release and synthesis
Decrease of size & vascularity of the hyperplastic gland
Clinical use
Ministrant treatment of hyperthyroid
1. Operation preparation;
2. Thyroid crisis.
Adverse reactions
1. Acneiform rash (similar to that of bromism);
2. Swollen salivary glands, mucous membrane ulcerations, and etc.
RADIOACTIVE IODINE (131I)
131I
is the only isotope for treatment of thyrotoxicosis.
Its therapeutic effect depends on emission of β rays with an
effective half-life of 5 days & a penetration range of 0.4-2 mm.
Woman in pregnancy or lactation is forbidden!
β-adrenoceptor blockers
βblockers are effective in treatment of thyrotoxicosis.
Propranolol is the most widely studied and used.
THYROID TREATMENT: POTENTIAL DRUG
INTERACTIONS
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Drugs that reduce thyroid hormone production
« Lithium
« Iodine-containing medications
« Amiodarone (Cordarone)
Drugs that reduce thyroid hormone absorption
« Sucralfate (Carafate)
« Ferrous sulfate (Slow Fe)
« Cholestyramine (Questran)
« Colestipol (Colestid)
« Aluminum-containing antacids
« Calcium products
Drugs that increase metabolism of thyroxine
« Rifampin (Rifadin)
« Phenobarbital
« Carbamazepine (Tegretol)
« Warfarin (Coumadin)
« Oral hypoglycemic agents
Drugs that displace thyroid hormone from protein binding
« Furosemide (Lasix)
« Mefenamic acid (Ponstel)
« Salicylates
TSH REPLACEMENT DRUGS
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Thyrotropin alpha—A synthetic form of TSH. Administered
intravenously.
Used in thyroid cancer treatment.
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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.