Antithyroid drugs ANJALI SAJI

Role of the Thyroid gland participates in normalizing growth and development and

energy levels and the proper functioning and maintenance of tissues / organs

critical for the nervous, skeletal and reproductive tissues it affects secretion and degradation rates of all hormones

Function of the Thyroid Gland secretion of the following hormones:

triiodothyronine (T3) ; 59% iodine tetraiodothyronine (T4; also known as

thyroxine); 65% iodine calcitonin

THYROID PHYSIOLOGY

Iodide Metabolism The recommended daily adult iodide (I-) intake is

150 mcg Biosynthesis of Thyroid Hormones Transport of Thyroid Hormones

thyroxine-binding globulin (TBG) about 0.04% of total T4 and 0.4% of T3 exist in

the free form.

Biosynthesis of thyroid hormones

Steps in Biosynthesis

Iodide trapping

Oxidation of iodide to iodine

Iodide Organification

Formation of T4 and T3

Release of T4 and T3

Peripheral metabolism of thyroid hormones The primary pathway for the peripheral metabolism of thyroxine (T4) is

deiodination deiodination of T4 may occur by monodeiodination of the outer ring, producing 3,5,3'-triiodothyronine (T3), which is three to four times more potent than T4

Anti-thyroid Drugs Thioamides

Iodides

radioactive iodine

Beta adrenoceptor blocking agents

Biosynthesis of thyroid hormones

Thioamides Methimazole Propylthiouracil (PTU) Carbimazole MOA:

inhibit synthesis by acting against iodide organification (both)

coupling of iodotyrosines (both) Blocks peripheral conversion of T4 to T3 (PTU)

Thioamides Pharmacokinetics:

almost completely absorbed in the GIT serum half life: 90mins(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

Thioamide uses

Definitive therapy Graves disease Toxic nodular goitre

Preoperatively In thyrotoxic patients

Along with RAI PTU in hyperthyroidism in pregnancy

Thioamides Adverse Effects:

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

Iodine131

preparations: sodium iodide 131

MOA: trapped within the gland and enter intracellularly and delivers strong beta radiations destroying follicular cells

Penetration range-400-2000µm Clinical uses: Grave’s,

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

131I dosage generally ranges between 80-120uCi/g of estimated thyroid wt. corrected for uptake. May be repeated after 6 months

Adverse effects permanent hypothyroidism potential for genetic damage may precipitate thyroid crisis

Anion Inhibitors Monovalent anions such as

perchlorates, pertechnetate and thiocyanate can block uptake of iodide by the gland by competitive inhibition

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

Inorganic Iodines major anti-thyroids before the

introduction of thioamides (1950s) preparations:

strong iodine solution (Lugol’s) 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

Iodinated Contrast Media Iodinated contrast media Ipodate (oral) Iopanoic acid (oral) Diatrizoate (intravenous) valuable in hyperthyroidism (but is not

labeled for this indication) MOA: inhibits conversion of T4 to T3 in the liver,

kidney, brain and pituitary Another MOA is due to inhibition of

hormone release secondary to iodide levels in blood

Useful in thyroid storms (adjunctive therapy)

Beta Blockers Drugs: Propranolol,esmolol, Atenolol MOA:

Membrane-stabilizing action: inhibits T4 to T3

Ameliorate symptoms – tremor,palpitation,anxiety secondary to increased circulating catecholamines by blocking beta receptors

Indications: Grave’s, Thyroid storm

Corticosteroids gain rapid control of hypermetabolic effects of peripheral

T4 and T3 Methyl Prednisolone iv is given for patients with Grave’s

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

Thyroid storm

Sudden exacerbation of thyrotoxic symptoms Life threatening condition Vigorous management

Propanalol 1-2mg i/v or 40-80mg PO Q6h Diltiazem 90-120mg Po Q8-6 hrs or 5-10mgs

intravenous infusion/hour

Thyroid storm

Potassium iodide Propylthiouracil Hydrocortisone

Supportive therapy Plasmapheresis/peritoneal dialysis

Hyperthyroidism and Pregnancy

Ideal situation- treat before pregnancy Pregnancy-Radioactive iodine CI Propylthiouracil

Dose limitation≤ 300mgs/day Methimazole alternative- fetal scalp defects

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