Antithyroid drugs

Antithyroid Drugs

Thyroid gland secrets following three hormones

·                                                     

                                                              Thyroxin (T₄)

·                                                           Tri-iodothyronine (T₃)

·                                                           Calcitonin

Thyroxin and Triiodothyronine regulate body metabolic rate to Maintain normal body growth and maturation. Triiodothyronine (T₃) is more potent than Thyroxin (T₄).  T₃ has a faster onset of action and 10 times more affinity to bind to nuclear receptor sites. Hormone nuclear receptor affinity increases protein synthesis through mRNA. Hormone mitochondrial affinity increases metabolic rate to produce energy. Calcitonin regulates calcium and phosphate level in blood.

Inadequate secretion of thyroid hormones produces hypothyroidism. In children, it is called cretinism or juvenile myxedema. In adult it is called myxedema. Excess secretion of thyroid hormones into blood circulation produces hyperthyroidism. It is also called thyrotoxicosis. It increases:

·         Basal metabolic rate: Heart, muscles, liver, kidney, liver etc are stimulated by high energy level due to increase in basal metabolic rate.

·         Cardiovascular function: There will be increase in heart rate (Tachycardia, positive inotropic effect) increase in cardiac force of contraction (positive chronotropic effect) and increase in cardiac output.

·         Protein Synthesis: This effect severely affect fetus and infants

·         Metabolic effect: Increase in carbohydrate metabolism Increases

o    carbohydrate absorption from GIT,

o   Glucose cellular uptake  and

o   Glucose utilisation.

           It increase apatite but glucose level remain normal.

o   Fat metabolism increases fatty acid level in blood.

·         Hyperthermia and sweating

·         Weight loss

·         Insomnia, anxiety, nervousness and tremor

·         Hair thinning

·         Increase in sympathetic nervous system activity (Catecholamine activity).

            

  Hyperthyroidism is associated with following diseases 

•       Goitre

o   Diffusive toxic goitre (Grave’s Goitre)

o   Nodular Goitre (Plummer’s  Disease)

•  Thyroiditis

Grave’s disease is an auto immune disorder. IgG antibody target TSH receptors that stimulate production of thyroid hormones. It usually occurs in middle aged and young women. It produces Grave’s  ophthamopathy i.e. eye bulgging (exophthalmia).

Nodular goitre occurs in older patients. It is due to nontoxic goitre for longer period. Exophthalmia is absent and other symptoms remain same as Grave’s goitre.

Thyroiditis means inflammation of thyroidgland

Hyperthyroidism is treated by

• ·         Removing part or all thyroid gland
• ·         Inhibiting hormone synthesis
• ·         Blocking hormone release

Antithyroid Drugs Classification:

1.       Thioamides (Goitrogens): Methyl thiouracil, Propylthiouracil, Methimazole, Carbimazole

2.       Radioactive iodine: Iodine (I¹³¹), Iodine (I¹²³)

3.       Iodine: Lugol’s iodine solution, Potassium iodide

4.       Adjuvants: β-adrenoceptor blockers

5.       Ionic inhibitors: Potassium thiocyanate, Potassium perchlorate

1. Thioamides (Hormone synthesis inhibitors or Goitrogens): Thioamides interfere in thyroid synthesis. They produce action by interfering in

• ·         Thyroglobulin tyrosil residues oxidative deamination
• ·         Iodotyrosil residues coupling to form iodothyronins (T₃ and T₄)
• ·         Oxidation of iodine by peroxidise enzyme.

Propylthiouracil is most commonly used thioamides as antithyroid drug. It also inhibits conversion of T₄ to T₃ by peripheral deiodination. This decreases concentration of circulating thyroid hormones. Methimazole does not stop peripheral conversion of T₄ to T_3. But methimazole is 10 times more potent than propylthyouracil.

ADME: They are well absorbed from GIT. Propylthiouracil plasma half life is 75 minutes. Thus its several doses is required per day. Methimazole has plasma half life 4-6 hrs.  Carbimazole is metabolised to methimazole. All these has tendency to accumulate in thyroid gland. Thus, in spite of short half life they are administered once in a day. Both unmetabolised and metabolised drugs are excreted by kidney and milk. They can cross placental barrier.

Propylthiouracil is preferred in pregnancy. It strongly bonds with plasma proteins. Thus, it does not easily cross placental barrier. Dose must be managed carefully during pregnancy and lactation to avoid hypothyroidism in fetus and neonates respectively.

They are used to treat mild to moderate hyperthyroidism. They are not effective to treat thyroid storm (life threatening condition associated with untreated or under treated hyperthyroidism).

Side effects: Agranulocytosis (low WBC), edema and rashes.

Radioactive iodine: Thyroid gland absorbs I¹³¹ . It is deposited in thyroid follicles colloid. Rays emitted from I¹³¹ affect parenchymal cells. That brings changes in colloid and produces fibrosis. Some follicles retain their function and some lost their function. This decreases secretion of thyroid hormones. I¹²¹  is used to diagnose function of thyroid gland.

Iodine: It is oldest agent to treat thyroid disorder. It controls synthesis and release of thyroid hormones. It blocks release of TSH and cAMP that inhibit release of thyroid hormones. But this effect last for short period and thyroid gland starts to synthesise and release of thyroid hormones.

Adjuvants: β-adrenergic blockers: Both nonselective and selective (Cardioselective) β-adrenergic blockers are used as antithyroid drug. They control various symptoms of hyperthyroidism like heart ratem anxiety, tremor etc.

Uses:

• ·         They are life saving drug in thyroid storm,
• ·         They are used begore thyroidectomy
• ·         They are used in thyroid postpartum
• ·         They are used with thioamide
• ·          They are used with radioactive iodine

 Ionic inhibitors: Thyocyssium perchlorate and potassium perchlorate inhibit iodine absorption by thyroid gland. They are not used due to their serious adverse effects like aplastic anaemia, agranulocytosis.