Antithyroid Drugs

Recap:

Thyroid gland produces 2 iodinated hormones

• T3 (triiodothyronine)
• T4 (tetraiodothyronine)

They promote metabolism, growth & development. Both hormone need iodine, the iodine binds to thyrosine in the thyroglobulin (colloid) to produce T3/T4. This process is called organification.

Hyperthyroidsim:

• Graves disease
  • Increase TSH receptor stimulation
    • Increase production of T3 & T4 by thyroid gland
• Types of treatment for hyperthyroidism:
  • Drugs that decrease hormone synthesis
  • Selective radiation with Iodine-131.
  • Surgical removal of part/all of the thyroid gland (thyroidectomy)
  • Use Propanolol (B-blocker) for treating increaed sympathetic effect of thyroid hormones.
    • Useful for preoperation & thyroid storm

Hypothyroidism:

• Usually caused by Autoimmune thyroiditis (Hashimoto)
• Primary thyroid failure
• Symptoms:
• Reversible slowing of body functions
• Lethargy
• Tiredness
• Decreased BMR
• Decreased appetite
• Decreased Cardiac output
• Dry skin
• Cold intolerance
• Increased weight
• Constipation
• Myxoedema
• Diagnosis
• Low free thyroxin (T3,T4)
• but High TSH (Primary hypothyroidism)
• In infants, may lead to cretinism (dwarfism) & mental retardation
• Requires thyroid replacement therapy (thyroxine)

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Drugs used to treat hyperthyroidism

a. Drugs that decrease hormone synthesis

1. Thionamides (methimazole, propylthiouracil)

Mechanism:

• Inhibit organification by blocking enzyme thyroxine peroxidase which promotes coupling of iodide with tyrosine (to produce MIT/DIT)
• Onset of effect up to 3-4 weeks
  • Long duration due to time for depletion of horrmone that were already produced, requires 3-4 weeks to be used up)
• All given par-oral
• Drug accumulates in thyroid
• Goal is to administer thionamides until patient is euthyroid and then decrease maintanence dose to prevent lapse into hypothyroidism
• May stop treatment after 1-2 years
• Cross sensitivity between propylthiouracil & methimazole ~50%
• Both sensitive by 50%

Adverse effects:

• Immunosuppressive
• Agranulocytosis
  • manifests commonly in sore throat
• Other
  • Nausea
  • Taste disturbance
  • Pruritic rash
  • Fever
  • Vasculitis
  • Arthralgia (joint ache)
  • Cholestatic jaundice
  • hepatitis
  • lymphadenopathy
  • hypoprothrombinaemia

2. Propylthiouracil

• Inhibits peripheral deiodination of T4 to T3
• Reserved for patients who are intolerant to Carbimazole
• 1/10 activity of Methimazole

Adverse effect: High Agranulocytosis

• Fever/Sore throat should be reported (precedes agranulocytosis)

3. Carbimazole (prodrug)

• Drug of choice in Grave’s disease*
• Converted in vivo to methimazole
  • 1st pass effect

4. Anion Inhibitors (Potassium Perchlorate)

• Inhibits the uptake of iodine (competitively, so organification cannot happen without iodine)

Adverse effect: Aplastic anaemia

• Therefore, rarely used.

5. Iodide (Supersaturated potassium iodide solution SSKI, Lugol’s solution)

• Inhibits organification & hormone release
• *Decreases size & vascularity of gland
• Useful for pre-thyroidectomy
• Goiters are highly vascular (prevent excessive blood loss)
• Reduces conversion of T4 to T3
• Inhibits thyrotropin action

Course of action:

• Quick effect (2-7 days)
• Useful in thyroid storm
• Faster than thionamides (3-4 weeks)
• Short term treatment
• antithyroid effect decreases

Adverse effects:

• Iodism (rare)
• Can be easily reversed by withdrawal of iodide
• Seen in iodism:
• Rash
• Swollen salivary glands
• Conjunctivitis
• Rhinorhoea
• drug fever
• metalic taste

b. Selective radiation with Iodine-131

• Emits beta rays which destroys thyroid tissue within few weeks
• Given par-oral
• Drug concentrated on thyroid (only act on thyroid)

Procedure:

• Stabilize patient with Carbimazole 1st
• Stop Carbimazole 3-4 days before administer Iodine-131
• Takes 3-4 days to become euthyroid

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Drugs used to treat hypothyroidism

a. Thyroxine – T4 (Levothyroxine sodium)

• Treatment of choice**
• Na+ salt of L-thyroxine
• levothyroxine sodium
• Synthetic (most widely used thyroid hormone)
• Given par-oral

Course of action:

• Effects delayed until plasma protein & tissue binding sites are occupied
• More protein bound
• When binding sites are saturated, then the free T4 effect will be seen
• Levels of TSH will drop when adequate levels of T4 are reached

b. Thyroxine – T3 (Liothyronine sodium)

• Na+ salt of T3
• Used together with hydrocortisone (steroid) in hypothyroid coma

Course of action:

• Faster action than T4
• Less protein bound
• More free drug, more effect
• Clinical response about 4 times as rapid as T4, so more adverse effects
• Therefore less used than T4

c. Combination of T3 & T4 (Liotrix)

• Constituent of many commercial thyroid hormone in fixed ratio of T4:T3 –> 4:1
• Ratio normally released in the body
• More T4 as compared to T3 in the body
• Mimics ratio of normal thyroid secretion
• Expensive
• No special advantage
• The cheaper Levothyroxine T4 will be automatically converted to T3 in the body
• Given T4 only should do the trick, no need for a combination

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Clinical scenario:

A 25 y.o male presented with clinical features of bulging of both eyes, excessive sweating (hyperhydrosis), fine tremor of outstretched hands and loss of weight.

What is the likely diagnosis?

• Hyperthyroidism
• After ruling out cancer, anorexia, or salbutamol overdose (causes fine tremor)

What would the BP be like?

• Increased.
• Increased sympathetic activity due to increased metabolism

What is the condition of the bulging eyes called?

• Exophthalmus
• Proptosis: 1 eye bulging

The patient goes into thyroid storm. Name 2 drugs that you will use.

• Iodide
• Propanolol

What are their mechanisms of action?

• Iodide inhibits organification & hormone release, also reduces conversion of T4 to T3
• Propanolol is a beta blocker. It decreases the sympathetic activy & the blood pressure.

Iodide is used in cough syrup – TRUE?

Iodide increases T4-T3 – FALSE

Iodide causes rapid & acute thyrotoxicosis -FALSE