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ANTI -THYROID DRUGS
RENJU.S.RAVI
OVERVIEW
INTRODUCTION HISTORY SYNTHESIS OF THYROID HORMONES CLASSIFICATION OF ANTI THYROID DRUGS STRUCTURE -ACTIVITY RELATIONSHIP INDIVIDUAL GROUPS HYPERTHYROIDSM IN PREGNANACY THYROID STORM
HISTORY
Thyroid gland – Wharton in 1656 Gull – Thyroid hypofunction in man Physiological significance was recognized by Graves and
Basedow. Isolation and Crystallisation of Thyroxine(T4) – Kendall in 1915. Antithyroid drugs were developed as derivatives of Thiourea
which was disovered to cause goiter in rats. Thiourea was the 1st drug used in man,followed by Thiouracil –
Introduced by Astwood in 1951. T3 --- detected ,isolated,and synthesized by Gross and Pitt-Rivers
in 1952.
Synthesis of thyroid hormones Steps
1. Uptake of Iodide ion by thyroid gland(NaI-symporter).
2. Oxidation of iodide and the iodination of tyrosyl groups.
3. Coupling of iodotyrosine residues.
4. Resorption of the thyroglobulin colloid from the lumen into the cell.
5. Proteolysis of thyroglobulin and the release of T4 and T3 into the blood.
6. Recycling of the iodine within the thyroid cell via de-iodination of mono/diiodotyrosines and reuse of the I‾
7. Peripheral conversion of T4 to T3
CLASSIFICATION
Hormone synthesis inhibitors (Antithyroid drugs) :
Propylthiouracil,Carbimazole, Methimazole.
Hormone release inhibitors: Iodine,Iodides of Na/K+, Organic iodide.
Destroy Thyroid tissue: Radioactive iodine (131,125,123)
Inhibit Ionic trapping (Ionic Inhibitors): Perchlorates, Pertechnetate, Thiocyanates.
SITE OF ACTION OF ANTI-THYROID DRUGS
STRUCTURE ACTIVITY RELATIONSHIP
Three general categories into which most of the agents can be assigned:
Thioureylenes include all the compounds currently used clinically
Aniline derivatives, of which the sulfonamides make up the largest number, embrace a few substances that have been found to inhibit thyroid hormone synthesis;
Polyhydric phenols, such as resorcinol, which have caused goiter in humans when applied to abraded skin.
THIOAMIDES :
Inhibit hormone synthesis by inhibiting peroxidase.
Propylthiouracil also inhibits peripheral de-iodination of T4 and T3.
Methimazole is more potent and longer acting than propylthiouracil.
Slow in onset ~ 4 weeks. Thiocarbamide group – essential for anti thyroid
activity
PHARMACOKINETICS
Well absorbed orally, widely distributed PTU – highly plasma protein bound t1/2 1 – 10hrs Partly metabolized in the liver and the thyroid
gland ; Carbimazole is converted to its active metabolite, Methimazole.
Cross placental barrier and are secreted in breast milk (PTU – less readily)
excreted in the urine unchanged
ADVERSE EFFECTS
Common adverse effects includes maculopapular rash, GI side effects, arthralgia.
Hypothyroidism Rare – exfoliative dermatitis, vasculitis ,lupus-like
reaction… Severe hepatitis – seen with propylthiouracil Agranulocytosis ( reversible) – dangerous
complication
USES
1) Non-operative therapy of hyperthyroidism.
2) Preoperative therapy of hyperthyroidism: combined with iodide
3) Thyrotoxic crisis: combined with propanalol,larger dose of iodide…
IODINE & IODIDES Iodine – oldest and fastest acing agent. - paradoxical effect on thyroid gland. Iodides blocks the organification and release,
through inhibition of proteolysis. It decrease the size and vascularity – used before
surgery. Jod-Basedow phenomenon in susceptible individuals It is an ideal agent for the treatment of severe
thyrotoxicosis and preoperatively.
Anti-thyroid effect is not for long term as gland ‘escapes’ from its effect and thyrotoxicosis may return.
Excess iodide
- interferes with the expression of NIS on the cell membrane;
- attenuates TSH and cAMP induced thyroid stimulation ;
- interferes with the iodination of tyrosil and thyronil residues of thyroglobulin.
USES
1) Preoperative therapy of hyperthyroidism: combined with thiourea derivatives
2) Thyrotoxic crisis: combined with thiourea derivatives(PTU) 3) Prophylaxis of endemic goiter 4) KI - limiting the potential damage to thyroid gland by
radiation emergencies
Lugol’s solution: 5% iodine and 10% potassium iodide.
Saturated solution of KI: yields a dose of 38 mg of iodine/dose.
ADVERSE REACTIONS1) Acute effects: hypersensitivity to iodine. Manifestations are swelling of
lips,eyelids, angioedema of larynx,fever,joint pain,petechial hemorrhages..
(2) Chronic intoxication (iodism)
Others – salivary gland inflammation and acne. Long term use of high doses – Hypothyroidsm and
goiter Chronic use in pregnancy avoided – fetal/infantile goiter
Radioactive Iodine :
I-131 is the only isotope used in treatment of thyrotoxicosis while others are used in diagnosis.
Administered as sodium salts of I–131 orally.
t1/2 – 8 days Therapeutic effect depends on emission of beta rays – destroys
the thyroid gland. Penetrate 0.5-2mm of tissue. Follicular cells undergo pyknosis and
necrosis followed by fibrosis without damage to surrounding tissues.
Patients eventually becomes hypothyroid – managed with thyroxine.
INDICATIONS
Most common indication – hyperthyroidism due to Grave’s disease and Toxic Nodular Goiter.
Indicated in elderly patients, allergy to thioamides, recurrent hyperthyroidism and in patients with systemic diseases contraindicating surgery. Average therapeutic dose- 3-6m curie
Advantages : Simple,inexpensive No surgical risk ,scar or injury to parathyroids and
nerves Contol of hyperthyroidism is permanent
Disadvantages Permanent hypothyroidism may result Long latent period of response Cannot be used during pregnancy Not suitable for young patients
Adverse effects Focal soreness in the neck Hypothyroidism Damage to fetal thyroid Thyroid carcinoma,Leukemia.. Radiation induced genetic damage
IONIC INHIBITORS :
Monovalent ions like perchlorate, pertechnetate, thiocyanate ,nitrates inhibit the iodide trapping by the thyroid gland.
Anion inhibitors are uncommon in use because of serious toxicity.
These are effective in iodine induced hyperthyroidism
Iodinated contrast media : Diatrizoate / Iohexol / Ipodate
They are valuable in hyperthyroidism and as adjunctive in thyroid storm.
They inhibit the peripheral conversion of T4 into T3. Inhibition of hormone release is an additional mechanism High rate of relapse. Recurrent hyperthyroidism after the use of ipodate is
resistant to treatment with thioamides. A/E – anaphylaxis, precipitation of hyperthyroidism,acute
renal failure…
Drugs that can cause hypothyroidsm: Lithium is known to inhibit synthesis and release of
thyroid hormones. Amiodarone – inhibits peripheral conversion of T4
toT3.
Antiepileptic drugs /Rifampicin – enhance hormone metabolism.
Sulphonamides, PAS – inhibits iodination and coupling reaction.
Expectorants ,topical antiseptics such as tincture iodine – inhibit hormone release.
HYPERTHYROIDSM IN PREGNANCY
Occurs in about 0.2 – 0.4% of all pregnancies Due to Grave’s Disease (common), Toxic nodules,
Thyroiditis… RISK – Pre-Eclampsia, LBW, Fetal and Neonatal
Hyperthyroidism Medical therapy –TREATMENT OF CHOICE SURGERY – 2nd trimester of pregnancy Current guidelines suggest that a pregnant patient
should be on PTU during the 1st trimester due to less teratogenicity ,then switched over to Methimazole due to its lower hepatotoxic potential.
THYROID STORM
Thyrotoxic crisis, is an acute, life-threatening state induced by excessive release of thyroid hormones.
TREATMENT Treat the precipitating cause and together with
the following: Supportive measures Antithyroid drug :High-dose propylthiouracil is
preferred because of its ability to inhibit peripheral conversion of T4 to T3.
Iodides and Iopanoic acid
To control tachycardia and cardiac arrhythmia: β-blockers like Propranolol is used; Diltiazem can be used if propranalol is contraindicated.
Corticosteroids: hydrocortisone followed by oral prednisolone.
