Download – Thyroxine T4 (90%) – Triiodothyronine T3

Thyroid Drugs
Learning Objectives:
By the end of the lecture the students should be able to :
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Describes Physiology, synthesis and feed back control of thyroid hormone synthesis
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Define Hypothyroidism and differentiate between Cretinism and Myxedema coma.
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Explain the Drugs for the treatment of hypothyroidism .
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Understand the machanism, pharmacokinetic, indications and contraindications of
LEVOTHYROXINE (synthetic analog of thyroid hormone).
Thyroid Hormones
Thyroid hormones:
– Thyroxine T4 (90%)
– Triiodothyronine T3
Thyroid gland also secretes Calcitonin – serum calcium lowering hormone
Thyroid Hormones - Facts
Thyroid hormones are required for the growth and development of all tissues.
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Thyroid hormone is critical for nervous, reproductive and skeletal growth.
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Thyroid deprivation in early life results in irreversible mental retardation.
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Thyroid hormones also augment sympathetic system function primarily by increasing the
number of adrenergic receptors.
Hypothalamus-pituitary-thyroid axis
TSH secretion by anterior pituitary is stimulated by hypothalamic TRH
Feedback inhibition of TSH and TRH occurs with high levels of circulating thyroid
hormones (T3 & T4)
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Dopamine, Glucocorticoids and somatostatin can suppress TSH secretion
Thyroid hormone synthesis
Uptake of iodide by thyroid gland
Oxidation of iodide
Organification
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Iodination of tyrosine residues on thyroglobulin – MITs and DITs
Coupling – formation of T4 and T3
Proteolysis of thyroglubulin and secretion of thyroid hormones
Conversion of T4 to T3 in peripheral tissues
Thyroid hormone synthesis
Thyroid hormones
Mechanism of action
T4 and T3 must dissociate from thyroxine binding globulin (TBG) in plasma before
entering into the cells.
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In the cells, T4 is deiodinated to T3 that enters nucleus and attaches to specific receptors
which promotes mRNA and protein synthesis.
Hypothyroidism
Clinical manifestations: Lethargy, wt. gain, bradycardia, constipation, cold intolerance,
menstrual irregularities
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Cretinism (congenital hypothyroidism)
Myxedema coma: most extreme manifestations of untreated hypothyroidism
Synthetic Thyroid Hormone
synthetic levothyroxine (synthetic T4) .
synthetic liothyronine (synthetic T3) is 3-4x more potent
not used alone for long term treatment secondary to short half life and large peaks in
serum T3 levels
Synthetic Thyroid Hormone(Levothyroxine T4)
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reasons for its use:
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stability
content uniformity
low cost
lack of allergenic foreign protein
easy laboratory measurements of serum levels
long half-life (7days)
once a day dosing
Thyroid hormones
Mechanism of action
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T4 and T3 must dissociate from thyroxine binding globulin (TBG) in plasma before
entering into the cells.
In the cells, T4 is deiodinated to T3 that enters nucleus and attaches to specific receptors
which promotes mRNA and protein synthesis.
PHARMACOKINETICS
Absorption –
Absorption of orally administered T4 from the gastrointestinal (GI) tract ranges from
40% to 80%.
The majority of the Levothyroxine dose is absorbed from the jejunum and upper ileum.
T4 absorption is increased by fasting, and decreased in malabsorption syndromes and by
certain foods such as soybean infant formula.
Dietary fiber decreases bioavailability of T4. Absorption may also decrease with age.
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Distribution –
Circulating thyroid hormones are greater than 99% bound to plasma proteins, including
thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin
(TBA).
The higher affinity of both TBG and TBPA for T4 partially explains the higher serum levels,
slower metabolic clearance, and longer half-life of T4 compared to T3.
Many drugs and physiologic conditions affect the binding of thyroid hormones to serum
proteins
Metabolism –
The major pathway of thyroid hormone metabolism is through sequential deiodination.
Approximately eighty-percent of circulating T3 is derived from peripheral T4 by
monodeiodination.
The liver is the major site of degradation for both T4 and T3, with T4 deiodination also occurring at
a number of additional sites, including the kidney and other tissues.
Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates and
excreted directly into the bile and gut where they undergo enterohepatic recirculation.
Elimination –
Thyroid hormones are primarily eliminated by the kidneys.
A portion of the conjugated hormone reaches the colon unchanged and is eliminated in
the feces.
Approximately 20% of T4 is eliminated in the stool.
Urinary excretion of T4 decreases with age.
INDICATIONS AND USAGE
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Hypothyroidism – As replacement or supplemental therapy in congenital or acquired
hypothyroidism of any etiology.
Pituitary TSH Suppression – In the treatment or prevention of various types of
euthyroid goiters , including thyroid nodules, subacute or chronic lymphocytic thyroiditis
(Hashimoto’s thyroiditis), multinodular goiter and, as an adjunct to surgery and
radioiodine therapy in the management of thyrotropin-dependent well-differentiated
thyroid cancer.
CONTRAINDICATIONS
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Levothyroxine is contraindicated in:
patients with untreated subclinical (suppressed serum TSH level with normal T3 and T4
levels) or overt thyrotoxicosis of any etiology and in patients with acute myocardial
infarction.
Levothyroxine is contraindicated in patients with uncorrected adrenal insufficiency since
thyroid hormones may precipitate an acute adrenal crisis by increasing the metabolic
clearance of glucocorticoids
Levothyroxine sodium is contraindicated in patients with hypersensitivity to any of the
inactive ingredients in Levothyroxine sodium tablets.
side effects
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Hyperthyroidism due to therapeutic overdosage
Seizures
Hypothyroidism
Children/infants
Hypersensitivity to inactive ingredients
drug interactions
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Levothyroxine increases the response to oral anticoagulant therapy.
The therapeutic effects of digitalis glycosides may be reduced by Levothyroxine.
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Consumption of certain foods may affect Levothyroxine absorption thereby necessitating
adjustments in dosing.
Soybean flour (infant formula), cotton seed meal, walnuts, and dietary fiber may bind and
decrease the absorption of Levothyroxine sodium from the GI tract.
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