ANTITYROID DRUGS

Introduction
• An antithyroid agent is a hormone antagonist acting upon thyroid hormones.
• The main antithyroid drugs are carbimazole (in the UK), methimazole (in the US), and propylthiouracil/PTU. A
less common antithyroid agent is potassium perchlorate.

Graves' disease
• In Graves' disease, treatment with antithyroid medications must be given for six months to two years, in order
to be effective. Even then, upon cessation of the drugs, the hyperthyroid state may recur. Side effects of the
antithyroid medications include a potentially fatal reduction in the level of white blood cells.
• A randomized control trial testing single dose treatment for Graves' found methimazole achieved euthyroid
state more effectively after 12 weeks than did propylthiouracil (77.1% on methimazole 15 mg vs 19.4% in the
propylthiouracil 150 mg groups). But generally both drugs are considered equivalent.
• A study has shown no difference in outcome for adding thyroxine to antithyroid medication and continuing
thyroxine versus placebo after antithyroid medication withdrawal. However, two markers were found that can
help predict the risk of recurrence. These two markers are an elevated level of thyroid stimulating hormone
receptor antibodies (TSHR-Ab) and smoking. A positive TSHR-Ab at the end of antithyroid drug treatment
increases the risk of recurrence to 90% (sensitivity 39%, specificity 98%), a negative TSHR Ab at the end of
antithyroid drug treatment is associated with a 78% chance of remaining in remission. Smoking was shown to
have an impact independent to a positive TSHR-Ab.
• Competitive antagonists of thyroid stimulating hormone receptors are currently being investigated as a possible
treatment for Grave's disease.

Adverse effects
• The most dangerous side-effect is agranulocytosis (1/250, more in PTU); this is an idiosyncratic reaction which
generally resolves on cessation of drug. It occurs in about 2 to 0.3% of cases treated with antithyroid drugs.
Others include granulocytopenia (dose dependent, which improves on cessation of the drug) and aplastic
anemia and-for propylthiouracil-severe, fulminant liver failure. Patients on these medications should see a
doctor if they develop sore throat or fever.
• The most common side effects are rash and peripheral neuritis. These drugs also cross the placenta and are
secreted in breast milk. Lugol's iodine is used to block hormone synthesis before surgery.

Mechanism of Action
• The mechanisms of action are not completely understood. Some scientists believe that anti-thyroids inhibit
iodination of tyrosyl residues in thyroglobulin. It is thought that they inhibit the thyroperoxidase catalyzed
oxidation reactions by acting as substrates for the postulated peroxidase iodine complex, thus competitively
inhibiting the interaction with the amino acid tyrosine.
• Propylthiouracil additionally may reduce the de-iodination of T4 into T3 in peripheral tissues.

Classification of Antithyroid Drugs

Inhibitor of Hormone Synthesis
• Carbimazole
• Methimazole
• Propylthiouracil

Radioactive Iodine
• ¹³¹ (Radioactive iodine)

Inhibitor of Hormone Release

• Iodine
• lodides of Na, k
• Organic iodides
lonic Inhibitors
• Thiocynate (-SCN)
• Perchlorates(-Cl04)
• Nitrates(NO3)

ANTITHYROID DRUGS
PROPYLTHIOURACIL & CARBIMAZOLE/ METHIMAZOLE

PROPYLTHIOURACIL CARBIMAZOLE
POTENCY LESS POTENT MORE POTENT
PLASMA PROTEIN BINDING HIGHER LESSER
HALF-LIFE 1-2 hours ~ 6 hours
DURATION OF ACTION 4- 8 hours 12- 24 hours
DOSING FREQUENCY 2-4 TIMES DAILY SINGLE (SOMETIMES 2 TIMES DAILY)
PERIPHERAL T4 --> T3 CONVERSION INHIBIT CONVERSION DO NOT INHIBIT CONVERSION

Drugs Used in Thyroid Disease

Hypothyroidism
• Levothyroxine (T4)
• Liothyronine (T3)
Hyperthyroidism
• Thioamides (propythiouracil)
• Iodided (Lugol solution)
• Beta Blockers (propranolol)
• ¹³¹I

CLASSIFICATION
1. Inhibit hormone synthesis (Antithyroid drugs)
• Propylthiouracil
• Thizmazole (Mercazolil)
• Carbimazole (ANTITHYROX)
2. Inhibit iodide trapping (lonic inhibitors)
• Perchlorates (-ClO4)
3. Inhibit hormone release
• Iodine
• lodides of Na and K
4. Destroy Thyroid Tissue
• Radioactive iodine (I¹³¹).

Compounds in groups and may be collectively called goitrogens because if given in excess they cause enlargement of
thyroid by feedback release of TSH.
Mechanism of Action of Antithyroid Drugs

Propylthiouracil Carbimazole (prodrug)—> Methimazole

• Less potent • 3 times more potent
• More Plasma protein binding • Less Plasma protein binding
• Penetration across Placenta and Milk barrier, but • Placenta, Milk (Cross placental and milk barrier)
more protein bound, so SAFER IN PREGNANCY Can cause teratogenic effects, especially when
• Rapidly acting, short acting given during first trimester, so LESS SAFE IN
• t 1/2: 1- 2 hours PREGNANCY
• Slow acting, long lasting
• t 1/2: 6-10 hours
Common action: Inhibiting/decreasing tyrosine iodination, coupling and T3, T4 levels

• (Also, T4 -------> T3) (inhibits peripheral • No such effect of inhibiting peripheral conversion
conversion of T4 to T3) of T4 to T3
• Useful in emergency: Thyrotoxic crisis/ thyroid Useful in Hyperthyroidism-Long term
storm management
• Tablet 25, 50 mg (Start 50-100 mg TID, then 25- Tablet 2.5, 5, 10 mg (Start 5-10 mg TID, then 5-15
50 BID OR TID) mg OD or BID)

THYROID INHIBITORS
Inhibit hormone synthesis
(Antithyroid drugs)
• Propylthiouracil
• Methimazole
• Carbimazole

Inhibit lodide trapping

(lonic inhibitors)
• Thiocyanates (-SCN)
• Perchlorates (-ClO4)
• Nitrabes (-NO3)

Inhibit hormone release

lodine
• lodides of Na, K
• Organic iodide
Destroy thyroid tissue
Radioactive iodine
• ¹³¹I

Thyroid hormones: Introduction

Hormone Source Remarks

Triiodothyroxine T3
Tetraiodothyroxine, T4, Thyroid follicles Referred as thyroid hormone
Also known as thyroxine

Considered along with Parathormone

Calcitonin Parafollicular C cells Regulates Calcium metabolism

Thyroid Hormones: Introduction

Thyroid Hormone: Synthesis

Thyroid Hormone: Synthesis

• lodide Uptake
• Oxidation and lodination
• Coupling
• Storage and release
• Peripheral conversion of T4 to T3
Thyroid Hormone: Transport
 • Avidly bound to plasma proteins; 0.03 %-0.08 % T4 & 0.2- 0.5 % T3 in free form
• Bound to 3 plasma proteins:
o Thyroxine Binding Globulin (TBG)
o Thyroxine Binding prealbumin (trans-thyretin)
o Albumin
• Plasma bound lodine: mostly is thyroid hormone (90-95 % T4)
o Normal Concentration of PBI = 4- 10 mcg/dl (0.1- 0.2 T3)

Thyroid Hormone: Metabolism and Excretion

• Metabolic inactivation occurs by deiodination and glucuronide/sulphate conjugation
• Primary site: Liver, others: salivary glands, kidney
• Excreted in bile ---> undergoes deconjugation ---> significant enterohepatic circulation ---> finally excreted in
urine.

Thyroid Hormone: Regulation of Secretion

Thyroid Hormones: Actions

Normal Hyperthyroidism Hypothyroidism/

Deficiency States
Intermediary Metabolism Lipid: indirectly enhances Hypercholesterolemia
lipolysis; elevated plasma
free fatty acid; Lipogenesis
also stimulated

Carbohydrate: metabolism
stimulated; tissue utilization
of sugar increased; Hyperglycemia, diabetic
glycogenolysis and like state, insulin
gluconeogenesis increased, resistance
faster absorption of glucose
from intestine

Protein: overall catabolic,

prolong action: negative
 nitrogen balance and tissue
wasting

Weight loss

Calorigeneis Increase basal metabolic rate

(BMR); Metabolic rates in
brain, gonads, uterus, spleen,
lymph nodes, not
significantly affected.
Cardiovascular System Hyperdynamic state of Atrial fibrillation, Reduces Myocardial O2
circulation due: increased Arrhythmias demand
peripheral demand, direct Congestive Heart Failure
cardiac actions. Angina
Fast bounding pulse
Nervous System Profound functional effects Anxious, nervous, Mental retardation
excitable, tremors, (Cretinism)
hyperreflexia Sluggishness, behavioral
symptoms (Myxedema)
Skeletal Muscle Increased muscle tone, Flabby and weak
tremor, weakness due to (Myxedema)
myopathy
Gastrointestinal Increase propulsive activity Diarrhea Constipation
Reproduction Indirect effect on Impaired female fertility
reproduction Oligomenorrhea
Maintenance of pregnancy
and lactation
Kidney No diuresis in euthyroid Diuresis in myxedematous
patients points on treatment with
T 3 & T4
Hematopoiesis Facilitates erythropoiesis Anemia
Growth and Development Maturation of nervous • Congenital
system deficiency leading
to cretinism
• Delayed
developmental
milestones
• Retardation and
nervous deficit
• Adult: Impaired
intelligence and
slow movements

Thyroid Hormones
Mechanism of Action:
• Penetrates cells by active transport → binds to nuclear thyroid hormone receptor bound to the thyroid hormone
response element (TRE) conformation changes occur (heterodimerization of receptor with retinoid X receptor
(RXR)) → releases coreporessor and binding of coactivator occurs → gene transcription induced → production of
specific mRNA and protein synthesis → metabolic and anatomic effects.
• Sensitization of adrenergic receptors to catecholamines → tachycardia, arrhythmia, raised BP, tremor,
hypoglycemia
Thyroid Hormones: Uses
• Cretinism
• Adult Hypothyroidism
• Myxoedema coma
• Nontoxic Goiter
• Thyroid Nodule
• Papillary carcinoma of thyroid
• Empirical use

Anti-thyroid drugs

Antithyroid Drugs
Mechanism of Action:
• Binds to the Thyroid Peroxidase and prevent oxidation of iodide/iodotyrosil residues thereby:
o Inhibit iodination of tyrosine e residues in thyroglobulin
o Inhibit coupling of iodothyronine residues to for T3 and T4
• Thyroid colloid is depleted over time and blood levels of thyroid hormones are progressively lowered.
• Additionally for Propylthiouracil: inhibits peripheral conversion of T4 to T3 by Deiodinase (D1)

Classification
Inhibits Hormone synthesis
• Propylthiouracil, Methimazole, Carbimazole
Inhibits iodine trapping (ionic inhibitors)
• Thiocynate, Perchlorates, Nitrates
Inhibits hormone release
• lodine, lodides of Na and K, Organic lodide
Destroy Thyroid Tissue
• Radioactive iodine (¹³¹I, ¹²⁵I, ¹²³I)

Thioamides: Pharmacokinetics
• Well absorbed orally
• Widely distributed (enters milk and placenta)
• Higher concentration in thyroid, longer intrathyroid half life
• Metabolised in liver
• Excreted in urine

Thioamides: Adverse Effects

Due to Overtreatment:
• Hypothyroidism, goiter
Important side effects:
• Gastrointestinal intolerance, skin rashes, joint pain
Infrequent side effects:
• Loss or graying of hair, loss of taste, fever, liver damage
Rare but serious:
• Agranulocytosis

Thioamides: Uses
Control Thyrotoxicosis in:
• Grave's Disease
• Toxic Nodular Goiter
Can be used as:
• Definitive therapy
 • Preoperatively
• Along with ¹³¹I

lonic Inhibitors
Mechanism of Action
• Inhibits iodide trapping by NIS into the thyroid → T3 and T4 not synthesized
• Toxic and not clinically used these days

lodine and lodides

• Fastest acting thyroid inhibitor
• Peak effects seen after 10-15 days followed by “thyroid escape"
o Seen more in multinodular goiter
• Mechanism of Action (not clear):
o Inhibition of hormone release - termed as 'thyroid constipation'
o Endocytosis of colloid and proteolysis of thyroglobulin comes to halt.
o Excess of iodine inhibits its own transport by interfering with expression of NIS (Na+/I− symporter)
o Attenuates TSH (thyroid-stimulating hormone) and CAM (complementary and alternative medicine)
induced thyroid stimulation
o Rapid and brief interference with iodination of tyrosyl and thyronil residues of Thyroglobulin

lodine and lodides: Uses

• Preoperative preparation
• Thyroid storm
• Prophylaxis of endemic goiter
• As antiseptic

lodine and lodide: Adverse Effects

• Acute Reaction
• Chronic overdose (iodism)
• Long term use of high doses:
o Hypothyroidism and goiter
• Flaring of acne in adolescents
• Pregnancy/Lactating mothers:
o Fetal/infantile goiter and hypothyroidism
• Aggravation of thyrotoxicosis in multinodular goiter

Radioactive lodine
• ¹³¹I emits X-rays and B-particles
o X-rays: tracer studies
o B-particles: destructive effect on thyroid tissues
• Mechanism of Action:
o Concentrated by thyroid, incorporated into colloid → emits radiation from within the follicle → undergo
pyknosis and necrosis followed by fibrosis
o Partial ablation can be achieved

Radioactive lodine
• Administered as sodium salt of ¹³¹I dissolved in water and taken orally.
• Use:
o Diagnostic: 25-100 mCurie is given: no damage to thyroid cells occur at this dose
o Therapeutic:
▪ Hyperthyroidism due to Grave's disease or Toxic nodular goiter
▪ Average Dose: 3-6 mCurie; higher dose for toxic multinodular goiter