Thyroid Drugs

Question 1

Levothyroxine

Answer 1

Mechanism of action:

Thyrotropin releasing hormone (TRH) from the hypothalamus stimulates the pituitary to release thyroid stimulating hormone (TSH), which stimulates the thyroid gland to synthesize and release thyroid hormone.

T4 is the most common type of thyroid replacement.
Exogenously administered T4 is converted (deiodinated) to the more active form of T3.

Pharmacokinetics:

Levothyroxine (T4) is dosed daily and has good oral availability. Food reduces its absorption so ideally it should be taken on an empty stomach. There are also a number of other agents that can reduce levothyroxine absorption, including di/trivalent cations like Ca2+, Mg2+and Al3+. Levothyroxine should not be administered within 4 hours of these agents.

It has a long half-life of 7 days meaning that steady state requires (5 half-lives) about 35 days; dose adjustments based on TSH (thyroid stimulating hormone) levels should not be made before steady state is reached

Contraindications:

• caution must be taken in conditions in which tachycardia is dangerous (coronary artery disease, aortic stenosis, mitral stenosis) because of the risk of tachycardia if the dose of thyroid replacement is too high

Side effects:

• hyperthyroidism related signs and symptoms:

o cardiac toxicity is one of the most important adverse effects:

 tachycardia

atrial fibrillation: one must consider thyroid function as a cause of atrial fibrillation, including endogenous (not drug related) hyperthyroidism
o anxiety
o tremor
o diarrhea
o reduction in bone mineral density

Thyroid hormone contains iodine. Therefore, other iodinated agents such as amiodarone or iodinated contrast media can impact thyroid hormone levels. Beta blockers, and corticosteroids, and severe illness or starvation can also produce the same effect.

Question 2

Liothyronine

Answer 2

Mechanism of action:

Thyrotropin releasing hormone (TRH) from the hypothalamus stimulates the pituitary to release thyroid stimulating hormone (TSH), which stimulates the thyroid gland to synthesize and release thyroid hormone

Shorter half‐life, so more fluctuation in levels

– Increased risk of cardiovascular adverse effects

Possible alternative to levothyroxine if
patients cannot tolerate that drug
– Otherwise levothyroxine is preferred

Question 3

Dessicated thyroid

Answer 3

• What about combining T3 and T4?
• Dessicated thyroid is an older product with T3
and T4 (porcine source)
• Problems:
– Quality unreliable (variation between batches)

Question 4

‘Natural’ Thyroid supplementation

Answer 4

• Natural Health Products (NHP) for thyroid are
available without a Rx
• Many have not been thoroughly studied by
Health Canada

Question 5

methimazole

Answer 5

thionamides: act primarily by blocking the synthesis of thyroid hormone. They:

inhibit the thyroid peroxidase catalyzed reactions
 block iodine oxidation
 block coupling of the iodinated tyrosine

Contraindications:

Pregnancy: Thionamides penetrate the placental barrier and should be avoided in pregnancy. If antithyroid medication must be used, PTU is favoured over methimazole in the first trimester as it appears to be the safer option at that stage.

Side effects

• Most common side effect is skin rash. Symptoms of hypothyroid can result from an excessive dose.
Serious/rare:
- Agranulocytosis:
- Hepatotoxicity

Question 6

Anti‐thyroid drugs: I131

Answer 6

I131 (radioactive iodine): destroys the thyroid gland via radiation

o I131 has a half life of 8 days and emits primarily beta radiation which penetrates up to a depth of 1 to 2 mm. The full effects of therapy may not be seen for several months.

o I131preferentially destroys the thyroid gland because of the avid uptake of I by the thyroid

Indications

• hyperthyroidism
• thyroid cancer

Side effects

Hypothyroidism: almost all patients require life-long thyroid replacement following radioactive ablation.
• Sialadenitis: inflammation of the salivary glands due to uptake of 131I. Salivary damage can result in xerostomia (dry mouth), altered taste, increased dental caries, and pain.

Question 7

Notes

Answer 7

Important notes
• Beta blocker therapy is an important part of hyperthyroidism treatment. However, it mainly treats the “downstream effects” (signs and symptoms) of hyperthyroidism. Beta blockers also appear to inhibit peripheral conversion of T4 to T3. Beta blocker therapy begins to relieve symptoms within hours of starting treatment and so is an important component of therapy because anti-thyroid medication can require 3-4 weeks before patients experience clear improvement in their symptoms.
• Hyperthyroid remission can occur and so treatment with thionamides can be used without thyroid ablation or thyroidectomy, although in many patients relapse will occur upon discontinuation of therapy. I131 represents a more permanent/reliable solution, but results in hypothyroidism.
• Patients treated with I131 may experience an acute increase in thyroid hormone levels (a ‘flare’) due to leakage of stored T3/T4 from the damaged gland. Therefore in some high risk patients it may be preferable to stabilize them using anti-thyroid medications first before moving to I131. If this is done, the thionamide should be discontinued several days before I131 administration so that it doesn’t prevent I131 uptake.
• Due to its higher risk of hepatotoxicity, PTU is typically reserved for patients

Question 8

propylthiouracil (PTU)

Answer 8

PTU also inhibits the peripheral deiodination of T4 to T3

Contraindications:

• Pregnancy: Thionamides penetrate the placental barrier and should be avoided in pregnancy. If antithyroid medication must be used, PTU is favoured over methimazole in the first trimester as it appears to be the safer option at that stage.