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Thyroid & Antithyroid Drugs

Dr. Meera Ababneh, Pharm.D, PhD.

Thyroid Gland

Thyroid Gland
Thyroid cells are the only cells in the body which can absorb iodine. These cells combine iodine and the amino acid tyrosine to make triiodothyronine (T3) and tetraiodothyronine (T4, thyroxine) Every cell in the body depends upon thyroid hormones for regulation of their metabolism.

Function of the Thyroid Gland


secretion of the following hormones:
triiodothyronine (T3) ; 59% iodine tetraiodothyronine (T4; also known as thyroxine); 65% iodine calcitonin

Synthesis of Thyroid Hormones

Regulation of Thyroid Hormones

Thyroid Hormones: Effects on Metabolism


TH serves as a nuclear transcription factor, regulating gene expression in targeted cells to increase metabolism. Increase the bodys basal metabolic rate, BMR, to maintain electrochemical gradient in cell. Stimulate carbohydrate metabolism and lipolysis, or the break down of fats. Affects protein synthesis

Synthetic Thyroid Hormones


For hormone replacement therapy in hypothyroidism Synthetic levothyroxine is characterized by its:
stability content uniformity low cost lack of allergenic foreign protein easy laboratory measurement of serum levels long half-life (7 days) The administration of T4 produces both hormones

Levothyroxine
Dosage
Infants : 16 months of age is 1015 mcg/kg/d Adult is about 1.7 mcg/kg/d. Adults

Pharmacokinetics
Should be taken 30min before or 1 hour after meals (delayed absorption for soy, other foods and drugs) Takes 6-8 weeks to reach steady state levels Labs should be repeated after 2 months

Synthetic Thyroid Hormones


liothyronine (T3) is three to four times more potent than levothyroxine
it is not recommended for routine replacement therapy
shorter half-life (24 hours) its higher cost greater difficulty of monitoring its adequacy of replacement by conventional laboratory tests T3 should be avoided in patients with cardiac disease

Antithyroid Agents
Reduction of thyroid activity and hormone effects can be accomplished by
agents that interfere with the production of thyroid hormones agents that modify the tissue response to thyroid hormones glandular destruction with radiation or surgery.

Thioamides
The major action is to prevent hormone synthesis by inhibiting the thyroid peroxidasecatalyzed reactions and blocking iodine organification. blocking coupling of the iodotyrosines.

Thioamides
The thioamides methimazole and propylthiouracil are major drugs for treatment of thyrotoxicosis Pharmacokinetics:
almost completely absorbed in the GIT serum half life: 90mins propylthiouracil (PTU) ; 6 hours (methimazole) excretion: kidney 24 hours (PTU) ; 48 hours (Methimazole) can cross placental barrier (lesser with PTU) Methimazole 10x more potent than PTU PTU more protein-bound

Thioamides
Adverse Effects:
maculopapular rash benign transient leukopenia agranulocytosis hepatitis (PTU) ; cholestatic jaundice (Methimazole) vasculitis lupus-like syndrome

Anion Inhibitors
Monovalent anions such as (ClO4), pertechnetate (TcO4), and thiocyanate (SCN) can block uptake of iodide by the gland by competitive inhibition of the iodide transport mechanism can be overcome by large doses of iodides ? useful for iodide-induced hyperthyroidism (amiodarone-induced hyperthyroidism) rarely used due to its association with aplastic anemia

Iodine131
preparations: sodium iodide 131 MOA: trapped within the gland and enter intracellularly and delivers strong beta radiations destroying follicular cells Penetration range-400-2000m Clinical uses: Graves, primary inoperable thyroid CA Contraindication: pregnancy

Iodine131
Advantages
Easy administration Effectiveness Low expense Absence of pain

Iodine131
Thioamides should be given initially and stop 5-7 days before radioactive iodine administration in elderly or patients with heart disease 131I dosage generally ranges between 185 MBq to 555 MBq repeated after 6 months Adverse effects permanent hypothyroidism potential for genetic damage may precipitate thyroid crisis

Inorganic Iodines
major anti-thyroids before the introduction of thioamides (1950s) preparations:
strong iodine solution (Lugols) potassium iodide iodone

Inorganic Iodines
MOA:
acutely blocks release of thyroid hormone from the gland by inhibiting thyroglobulin proteolysis

inhibit iodide organification


Uses:
useful in thyroid storms: 2-7 days Preoperatively - iodides decrease vascularity, size and fragility of hyperplastic gland

Caution:
it may delay onset of thioamide effects; should be given after initiation of thioamides

Beta Blockers
Drugs: Propranolol, Metoprolol, Atenolol MOA:
Membrane-stabilizing action: inhibits T4 to T3 (propranolol at high dose) Ameliorate many disturbing s/sxs of hyperthyroidism secondary to increased circulating catecholamines by blocking beta receptors

Indications: Graves, Thyroid storm

Corticosteroids
Prednisone is given for patients with Graves ophthalmopathy 1mg/kg/day (60mg/day 3 divided doses); if it should be given for more than 4 weeks, taper to decrease risk of adrenal crisis

Hypothyroidism
Hypothyroidism is a syndrome resulting from deficiency of thyroid hormones and is manifested largely by a reversible slowing down of all body functions . In infants and children, there is striking retardation of growth and development that results in dwarfism and irreversible mental retardation.

Hypothyroidism
Primary infant born without a thyroid gland Secondary throiditis, tumor, destruction of thyroid tissue from radiation .
Hashimoto's thyroiditis, an immunologic disorder in genetically predisposed individuals

Hypothyroidism
All newborns are tested at birth for thyroid function. If untreated can lead to retardation due to effects on brain development. Treatment is life-long replacment of the hormone.

Hypothyroidism - Adults
Presenting clinical manifestations
Weight gain Constipation Fatigue Irregular menstrual cycle in women Edema More common in females than males

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.

Special cases in Hypothyroidism


Myxedema and Coronary Artery Disease
In this situation, the low levels of circulating thyroid hormone actually protect the heart against increasing demands that could result in angina pectoris or myocardial infarction. Correction of myxedema must be done cautiously to avoid provoking arrhythmia, angina, or acute myocardial infarction.

Special cases in Hypothyroidism


Myxedema coma
Medical emergency End state of untreated hypothyroidism It is associated with progressive weakness, stupor, hypothermia, hypoventilation, hypoglycemia, hyponatremia, water intoxication, shock, and death. Loading dose of T4 300-400micrograms IV initially f/by `50micrograms daily IV T3 more cardiotoxic and difficult to moniter

Special cases in Hypothyroidism


Hypothyroidism and Pregnancy
The daily dose of thyroxine should be adequate In many hypothyroid patients, an increase in the thyroxine dose (about 3050%) is required to normalize the serum TSH level during pregnancy. It is reasonable to counsel women to take an extra 25 mcg thyroxine tablet as soon as they are pregnant

Hyperthyroidism
Excessive secretion of thyroid hormone and usually involves an enlarged thyroid gland. TSH levels would be low and the T3 and T4 high.

Clinical Presentation
Skin: sweating; heat intolerance Eyes: diplopia (Graves' disease) Cardio: increased heart rate, stroke volume, cardiac output, pulse pressure; high-output heart failure GI: increased appetite; increased frequency of bowel movements CNS:Nervousness; hyperkinesia; emotional lability Menstrual irregularities; decreased fertility; increased gonadal steroid metabolism

Graves Disease
The most common form of hyperthyroidism is Graves' disease, or diffuse toxic goiter. Graves' disease is an autoimmune disorder Management of Graves' Disease
antithyroid drug therapy surgical thyroidectomy destruction of the gland with radioactive iodine.

Antithyroid Drug Therapy


Drug therapy is most useful in young patients with small glands and mild disease.
Methimazole or propylthiouracil is administered until the disease undergoes spontaneous remission. This is the only therapy that leaves an intact thyroid gland, but it does require a long period of treatment and observation (1218 months), and there is a 5070% incidence of relapse

Thyroid Storm(thyrotoxic crisis)


sudden acute exacerbation of all of the symptoms of thyrotoxicosis presenting as a life-threatening syndrome Vigorous management is mandatory.:
Propranolol, 12 mg slowly intravenously or 4080 mg orally every 6 hours Saturated solution of potassium iodide, 10 drops orally daily. Propylthiouracil, 250 mg orally every 6 hours Hydrocortisone, 50 mg intravenously every 6 hours

Hyperthyroidism and Pregnancy


Ideal situation- treat before pregnancy radioiodine is contraindicated ? Propylthiouracil can be given in the first trimester and then methimazole can be given for the remainder of the pregnancy Alternatively, a subtotal thyroidectomy can be safely performed during the mid trimester. It is essential to give the patient a thyroid supplement during the balance of the pregnancy.