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Pharmacology – III
PHL-418
Thyroid and Anti-thyroid Drugs
Dr. Hassan Madkhali
Assistant Professor
Department of Pharmacology
E mail: [email protected]
Topics
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Endocrine system Introduction
Pituitary and hypothalamic hormones
Thyroid and anti-thyroid Drugs
Adrenal Drugs
Pancreatic Drugs
Gonadal hormones and inhibitors
Major endocrine glands
(Male left, female on the right.)
1. Pineal gland 2. Pituitary gland 3. Thyroid gland
4. Thymus 5. Adrenal gland 6. Pancreas
7. Ovary 8. Testis
https://en.wikipedia.org/wiki/Endocrine_gland
Thyroid Gland
www.urmc.rochester.edu
Thyroid gland Function
• Thyroid gland is responsible for the
secretion of three hormones essential for
proper regulation of metabolism (increase
metabolic rate).
– Thyroxine (T4)
– Triiodothyronine (T3)
– Calcitonin
T3 and T4
• Both produced in the thyroid gland
through the iodination and coupling of the
amino acid tyrosine.
• Body needs about 1 mg of iodine per
week from the diet.
Biosynthesis of thyroid hormones
-Human Physiology, p331. Stuart Fox. 10th ed.
-Endocrinology: Basic and Clinical Principles, p 291. Totowa, NJ, Humana Press.
Biosynthesis of thyroid 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
3.
Newly formed Tg is transported to the cell surface in small
apical vesicles.
4.
Within the follicular lumen, iodide (I−) is oxidized to iodine (I2)
by thyroperoxidase.
5.
Iodine binds to 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.
6.
Upon TSH stimulation, villi at the apical membrane engulf the
colloid and endocytose the iodinated Tg.
7.
T4 and T3 are released into the circulation
8.
DIT and MIT are deiodinated, and the iodide and tyrosine are
recycled
Regulation of thyroid function
• Thyrotropin-releasing hormone
(TRH) from hypothalamus releases
thyroid-stimulating hormone from
anterior pituitary.
• TSH is stimulated when the blood
levels of T3 and T4 are low.
• TSH acts by stimulation of the
thyroid follicular cells by binding to
TSH receptor on the basal surface
of the thyroid follicle cells.
• This leads to iodide uptake.
• T3 and T4 exert negative feedback
on both the pituitary production of
TSH and the hypothalamic
production of TRH.
Thyroid hormones effects on
metabolism
• The effect of thyroid hormones on metabolic processes appear to
be mediated by activation of nuclear receptors that lead to
increase formation of RNA and subsequent protein synthesis
(regulating gene expression in targeted cells to increase
metabolism).
• Stimulate carbohydrate metabolism and lipolysis, or the break
down of fats.
• Increase protein synthesis.
• CNS development.
• Growth.
• Cardiac effects: increase cardiac output and heart rate.
Thyroid Disorders
A- Hypothyroidism
• A condition characterized by diminished
production of the thyroid hormone.
– Primary hypothyroidism stems from an
abnormality in the gland itself.
– Secondary hypothyroidism begins at the level
of the pituitary gland and results from reduced
levels of TSH (thyroid stimulating hormone).
– Third type is caused by reduction in the
amount of TRH of thyrotropin releasing
hormone by the hypothalamus.
Hypothyroidism - Adults
• Presenting clinical manifestations
– Weight gain
– Constipation
– Fatigue
– Irregular menstrual cycle in women
– Edema
– More common in females than males
– Cold intolerance.
Hypothyroidism
• Laboratory value to look at:
• TSH – thyroid stimulating hormone will be
increased - it is working hard to stimulate
the production of T3 and T4
• T3 and T4 levels would be low
Hypothyroidism
• All newborns are tested at birth for thyroid
function
• If untreated can lead to retardation due to
effects on brain development.
• Hashimoto’s hypothyroidism is an
autoimmune disease and considered as the
most common cause of hypothyroidism in
USA.
Treatment of Hypothyroidism
• Thyroid drugs such as levothyroxine (brand names:
Synthroid or Levothroid), is a synthetic form of T4.
• It acts by binding to thyroid receptor in the cell
nucleus and cause metabolic effects through the
gene expression and protein synthesis.
• Take on empty stomach in the morning
• Do not take with antacids or iron preparations
• If on Coumadin may need to use smaller dose of
Coumadin
• Do not stop when feeling better
• Dosage of other drugs may need to be reduced due
to slow metabolism in liver and excretion in urine
Synthroid Dosing
• Adult: 25 to 300 mcg / day
• Pediatrics: 3-5 mcg / kg / day
• How provided in 5 mcg, 25 mcg, 75 mcg
and 100 mcg tablets
• IV: 200 mcg per vial in 6 and 10 mL vials.
B- Hyperthyroidism
• Excessive secretion of thyroid hormones.
• Causes:
– Graves’ disease (is an autoimmune disease that
affects the thyroid. It frequently results in
hyperthyroidism and an enlarged thyroid.
– Plummer’s disease or toxic nodular disease
(is a multinodular goiter associated with a
hyperthyroidism).
– Thyroid storm: caused by stress or infection
Clinical Manifestations
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Diarrhea
Flushing
Increased appetite
Muscle weakness
Fatigue
Heart palpitations
Irritability
Nervousness
Sleep disturbances
Heat intolerance
Altered menses
Laboratory Values
• TSH would be low
• T3 and T4 would be high
Treatment of Hyperthyroidism
Anti-thyroid Drugs
• Methimazole and propylthiouracil (PTU)
act by inhibiting the enzyme
thyroperoxidase.
• Inhibiting the incorporation of iodine
molecules into the amino acid tyrosine.
• Propylthiouracil has an additional ability to
inhibit the conversion of T4 to T3 in the
peripheral circulation.
Treatment of Hyperthyroidism
Anti-thyroid Drugs
• Methimazole is usually preferred over propylthiouracil
because it reverses hyperthyroidism more quickly and
has fewer side effects.
• Propylthiouracil used to be the drug of choice during
pregnancy because it causes less severe birth defects
than methimazole.
• But experts now recommend that propylthiouracil be
given during the first trimester only to avoid liver damage
• After the first trimester, women should switch to
methimazole for the rest of the pregnancy.
Propylthiouracil or PTU
• Most common drug used by
hyperthyroidism.
• Will take about two weeks before the client
will see change.
• Dosing: adults 300 to 900 mg / day
• Pediatrics: 50 to 150 mg / day
• Never discontinue the drugs abruptly
• Drug therapy is life-long
• Follow-up is important to monitor dosing
and therapeutic effects of the drug therapy.
Special problem:
Thyroid storm or thyroid crisis
• Signs and symptoms:
– Tachycardia and cardiac arrhythmias
– Fever
– Heart failure
– Flushed skin
– Confusion / apathetic attitude / behavioral
changes
– Hypotension
A. Thyroid hormone receptor agonists
1. Synthesis of natural thyroid hormone
2. Thyroid hormone preperations
1. Levothyroxine (T4)
2. Liothyronine (T3)
3. Liotrix
4. Thyroid USP
B. Anti-thyroid drugs
1.
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Thioamides
Anion inhibitors of thyroid function
Iodide
Radioactive iodine
Anion inhibitors of thyroid function
-Anion inhibitors of thyroid function act by inhibiting
the action of the sodium-dependent iodide
transporter located on follicular cell’s basolateral
membranes.
- Used in iodide-induced hyperthyroidism.
- Since their effects can be overcome by large
doses of iodides, their effectiveness some what
unpredictable.
-Examples: perchlorate (-CIO4) and thiocyanate(SCN).
Methimazole
Thank you
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