1. Drugs used in the management of thyroid disorders Flashcards
Biosynthesis of T4 and T3
- Uptake of iodide from the blood into the thyroid follicular cell via the Na/I symporter.
- The iodide is transported into the follicle colloid via Pendrin
- Oxidation of iodide by thyroid peroxidase
- Iodination of tyrosyl residues on thyroglobulin to form mono or di-iodotyrosyl residues by thyroid peroxidase (organification)
- Coupling of 2 diiodotyrosyl residues or 1 monoiodotyrosyl residue with a diiodotyrosyl residue to form T4 and T3 respectively.
- Endocytosis of colloid from the follicular lumen containing thyroglobulin
- Fusion with lysosomes
- TSH increases the activity of thiol endopeptidases, which selectively cleave thyroglobulins yielding hormone containing intermediates
- Processed by exopeptidases to release T4 and T3.
What is the Wolff-Chaikoff effect?
- The Wolff–Chaikoff effect is an autoregulatory phenomenon.
- During initial iodine exposure, excess iodine is transported into the thyroid gland by the sodium–iodide symporter.
- This transport results in transient inhibition of thyroid peroxidase and a decrease in the synthesis of thyroid hormone.
Causes of hypothyroidism
- Primary hypothyroidism → due to failure of thyroid gland itself
• Chronic autoimmune thyroiditis (Hashimoto thyroiditis); Antibodies directed against thyroid gland, specifically thyroid peroxidase
• Iodine deficiency
• Drugs such as amiodarone - Central hypothyroidism (secondary hypothyroidism)
• Due to pituitary failure → Diminished TSH secretion, resulting in lower thyroid hormones
• Hypothalamic failure → Diminished thyrotropin-releasing hormone, resulting in lower thyroid hormones - Congenital Hypothyroidism
Symptoms of hypothyroidism
- Fatigue and lethargy
- Mental slowness
- Dry skin
- Weight gain
- Irregular menses
- Hair loss
Drugs used in the management of hypothyroidism
- Levothyroxine (L-T4)
2. Liothyronine (L-T3)
Onset of action of levothyroxine (L-T4)
Oral: 3 to 5 days
IV: 6 to 8 hours
Onset of action of liothyronine (T3)
3 hours
Half-life of levothyroxine (L-T4)
6 to 8 days
Half-life of liothyronine (L-T3)
0.75 days
How long should thyroid function be monitored during levothyroxine therapy?
6 to 8 weeks
Reasons for persistently elevated TSH levels after levothyroxine therapy
Inadequate dosing, poor compliance, malabsorption, drug or food interaction
What precipitates myxedema coma and how would a patient with myxedema coma present?
Myxedema coma occurs as a result of long-standing, undiagnosed or undertreated hypothyroidism and is usually precipitated by a systemic illness (infection, heart attack, etc)
Primary signs and symptoms of myxedema coma is altered mental status and low body temperature, hypoglycemia, low blood pressure
Adverse reactions of levothyroxine (T4) or liothyronine (T3)
- In adults, overdosing can cause cardiac arrest, hypertension, palpitations, tachycardia, anxiety, heat intolerance, hyperactivity, insomnia, irritability and weight loss. In children overdosing can cause insomnia, restlessness, accelerated growth and bone maturation,
- Long term use of high dose L-T4 has been associated with increased bone resorption and reduced bone mineral density, especially in post-menopausal women.
Levothyroxine dosage modifications with estrogen hormone replacement therapy
Increase in levothyroxine dose maybe required due to increased thyroxine-binding globulin levels, which then binds levothyroxine and reduces the amount available for action
What is observed in subclinical hypothyroidism
Raised TSH with normal serum thyroid hormone levels → progress to overt hypothyroidism
How should levothyroxine be dosed in elderly patients
Levothyroxine dose requirement gradually decreases with age due to age-related decreases in thyroxine degradation and in lean body mass.
How should levothyroxine be dosed in pregnant patients
30 to 50% increase in dose of levothyroxine during pregnancy, as early as the first 4-6 weeks of gestation
How should levothyroxine be dosed in patients with ischemic heart diseases
- Due to the positive inotropic and chronotropic effects of thyroid hormone on the heart, starting a full dose of levothyroxine could precipitate acute coronary syndrome in hypothyroid patients with silent ischaemic heart diseases.
- Therefore, newly diagnosed hypothyroid patients with ischemic heart disease should be started on a small dose of levothyroxine and slowly up titrated every 4–6 weeks until euthyroidism is achieved.
Causes of hyperthyroidism
- Graves’ disease
- Hyperactive thyroid nodules
- Increased iodine consumption
- Increased thyroid hormone consumption
- Inflammation and release of stored thyroid hormones
Drugs used in the management of hyperthyroidism
- Thioamides (anti-thyroid drugs)
- High concentration of iodine
- Radioactive iodine
Examples of thioamides
- Carbimazole
2. Propylthiouracil (PTU)
MOA of thioamides
- Thought to inhibit thyroid peroxidase enzyme (TPO) and interfere with the incorporation of iodine into tyrosyl residues of thyroglobulin (iodination)
- Inhibit coupling of iodotyrosyl residues to form iodothyronines
- Propylthiouracil (not carbimazole) also inhibits deiodination of T4 to T3.
Plasma half-life of PTU
75 mins
Plasma half-life of carbimazole
4-6 hours
Therapeutic uses for thioamides
- Graves disease
- Thyroid storm
- Overactive thyroid gland
- To attain an euthyroid state rapidly in preparation for radioiodine therapy or thyroidectomy
Adverse effects of thioamides
- Agranulocytosis → if patient develops a sore throat, fever, or other signs or symptoms of infection, they should stop and have a complete blood count
- Mild, occasionally purpuric, urticarial papular rash
- Cholestatic jaundice with carbimazole
- Severe liver injury and acute liver failure with PTU
Usage of thioamides in pregnancy
Propylthiouracil may be the preferred agent during organogenesis, in the first trimester of pregnancy.
Switch from propylthiouracil to thiamazole for the second and third trimesters
Examples of high concentrations of iodine/iodide
- Lugol’s solution
2. Potassium iodide
MOA of iodide
High concentrations of iodide can:
- Suppress iodination of tyrosine and also coupling of monoiodotyrosyl and diiodotyrosyl residues thus inhibiting thyroid hormone synthesis
- Can decrease thyroid gland size and vascularity when given over 1 to 2 weeks
- Can be used to temporarily inhibit T4 and T3 synthesis and release into the circulation (useful in thyroid storm)
Therapeutic uses of iodide
- Preparation for thyroidectomy, as it reduces thyroid hormone synthesis and release, and reduces thyroid size and vascularity
- Thyrotoxic crisis
- Endemic goitre
Contraindication in iodide
Pregnancy → may cause fetal goiter
Adverse effects of iodide
- Allergic reactions → angioedema, laryngeal edema → suffocation and rashes
- Chronic intoxication with iodide (iodism) → metallic taste, GI intolerance, soreness of the teeth and gums, increased salivation, irritation of the eyes, along with lacrimation and rhinorrhoea, may also complain of a severe headache
Examples of radioactive iodine
131 I → treatment
123 I → diagnostic purposes
MOA if radioactive iodine
- Radioactive iodine, like iodine is rapidly and efficiently trapped by the thyroid sodium-iodide transporter, into the follicular cells, from which it is slowly liberated.
- Destructive β particles originate within the follicle and act almost exclusively on the follicular cells, with little or no damage to surrounding tissue.
Therapeutic uses for radioactive iodine
- Graves’ disease
2. Toxic nodular goiter
Can radioactive iodine therapy be co-administered with thioamides
No, must stop thioamides at least 3 days before RAI as it may affect efficacy
Advantages of radioactive iodine as compared to surgery
Less discomfort, low cost, hospitalisation not required, and patients can participate in their day-to-day duties
Adverse effects of radioactive iodine
- High incidence of delayed hypothyroidism
- Small but significant increase in certain types of cancer, including stomach, kidney and breast. These tissues express the sodium iodine transporter (NIS)
- Radioactive iodine therapy has been associated with worsening Graves’ ophthalmopathy
- Adverse effects may set in 1 to 2 months after treatment
- Main contraindication is for pregnant women
- Concentration of isotope in the fetal thyroid
- Exposure of fetal tissues to radiation
How can beta blockers help the treatment of thyrotoxic storm
Control the peripheral effects of excess thyroid hormones, in addition to slightly decreasing T4 to T3 conversion
How can glucocorticoids help in the treatment of thyrotoxic storm
- Reduce T4 to T3 conversion and treat the potential risk of adrenal insufficiency due to severe thyrotoxicosis
- Used in Graves’ ophthalmopathy to reduce the inflammation and swelling
