Hypothyroidism - Pharmacology Notes

1. Definition & Overview

• In infants/children: striking retardation of growth and development - dwarfism and irreversible mental retardation (cretinism)
• In adults: fatigue, lethargy, cold intolerance, mental slowness, depression, dry skin, constipation, mild weight gain, fluid retention, muscle aches, irregular menses, infertility

2. Etiology & Pathogenesis

3. Diagnosis

• Primary hypothyroidism: Low free T4 + elevated serum TSH (TSH is the single best test)
• Central hypothyroidism (secondary/tertiary): Low free T4 with low/normal TSH
• TSH changes precede changes in free T4 and free T3 - Goodman & Gilman's, p. 2401

4. Thyroid Hormone Preparations

5. Levothyroxine - The Drug of Choice

Why T4 over T3?

• Better tolerated than T3 preparations
• Longer half-life (~7 days) - once-daily dosing
• Steady state achieved in 6-8 weeks
• Relies on endogenous Dio1/Dio2 deiodinases to convert T4 → T3, maintaining physiological T3 levels
• More closely mimics normal thyroid gland physiology

Pharmacokinetics (Katzung's, p. 1087; Goodman & Gilman's, p. 2415-2417)

• Absorption: Best in duodenum and ileum; oral bioavailability ~70-80% (tablet); improved with liquid-filled capsules (Tirosint)
• Serum T4 peaks: 2-4 hours after oral ingestion
• Plasma half-life: ~7 days (once-daily dosing is sufficient; missing one dose has minimal effect - take double dose the next day)
• Routes: Oral (preferred); IV for myxedema coma or when oral not possible
• IV dose: ~80% of the patient's oral requirement

Absorption impaired by:

• Food (bran, soy, coffee)
• Calcium carbonate, iron supplements, antacids - separate by at least 4 hours
• Severe myxedema with ileus
• Malabsorptive states: atrophic gastritis, H. pylori gastritis, celiac disease, lactose intolerance, bariatric surgery

Metabolism increased by (CYP inducers):

• Rifampin, phenobarbital, carbamazepine, phenytoin, tyrosine kinase inhibitors, HIV protease inhibitors
• These require higher levothyroxine doses in patients dependent on replacement

Figure: CYP450 enzyme inducers accelerate thyroid hormone metabolism (Lippincott Illustrated Reviews: Pharmacology)

6. Dosing Guidelines

Adults

• Average dose: 1.7 mcg/kg/day (~125 mcg/day) - based on lean body mass
• Older adults (>65 years): 1.6 mcg/kg/day (lower because body mass declines)
• Post-thyroidectomy (thyroid cancer suppression): 2.2 mcg/kg/day (supratherapeutic to suppress TSH)

Children (require more T4/kg than adults)

• 1-6 months: 10-15 mcg/kg/day
• Requirements decrease with age toward adult dosing

Starting doses - titrated by clinical context:

• Follow-up blood tests: ~6 weeks after any dose change (due to 7-day T4 half-life and 6-8 week steady-state)
• Goal of therapy: Normalize TSH (primary hypothyroidism) or normalize free T4 (central hypothyroidism) + symptom relief
• Therapeutic TSH range: 0.5-2.5 mIU/L

7. Toxicity / Overtreatment Signs

• Children: Restlessness, insomnia, accelerated bone maturation/growth
• Adults: Nervousness, heat intolerance, palpitations, tachycardia, unexplained weight loss
• Chronic overtreatment (elderly): Atrial fibrillation and accelerated osteoporosis

8. Combination Therapy (T4 + T3)

• Multiple trials show combination levothyroxine + liothyronine is NOT superior to levothyroxine alone
• Some patients remain symptomatic on T4 alone - possibly due to genetic variations in deiodinases (Dio2 Thr92Ala polymorphism) or hormone transporters
• No long-acting liothyronine preparation exists; no T4/T3 combination matching the natural 11:1 T4:T3 secretion ratio
• Desiccated thyroid extract (DTE): A double-blind crossover study found patients who preferred DTE tended to lose weight on it
• Bottom line: Levothyroxine monotherapy recommended; combination therapy may be considered in select patients who feel unwell despite euthyroid TSH/free T4

9. Special Management Scenarios

A. Myxedema + Coronary Artery Disease

• Low thyroid hormone paradoxically protects the heart against increased demands
• Correcting myxedema too quickly risks angina, atrial fibrillation, or MI
• If coronary artery surgery is indicated, perform it BEFORE correcting myxedema
• In cardiac patients: start 12.5-25 mcg/day; if angina or arrhythmia develops - stop or reduce dose immediately

B. Myxedema Coma (Emergency)

• End state of untreated hypothyroidism: weakness, stupor, hypothermia, hypoventilation, hypoglycemia, hyponatremia, shock, death
• ICU management; mechanical ventilation may be needed
• All drugs must be given IV (poor GI absorption in myxedema)
• Treatment:
  • Levothyroxine IV: loading dose 300-400 mcg, then 50-100 mcg daily
  • Liothyronine (T3) IV: 5-20 mcg initial, then 2.5-10 mcg every 8 hours (adds T3 but more cardiotoxic and harder to monitor)
  • Lower doses for elderly, small, or cardiac patients
  • IV hydrocortisone if associated adrenal/pituitary insufficiency
  • Caution with opioids and sedatives (extreme caution)
  • Cautious IV fluids (avoid water overload - large pools of empty T3/T4 binding sites)

C. Hypothyroidism in Pregnancy

• Hypothyroid women often have anovulatory cycles - reduced fertility until euthyroid
• Dose must be adequate - fetal brain development depends on maternal T4 in early pregnancy
• Dose typically needs to increase ~25-30% during pregnancy (due to elevated TBG from estrogen, placental Dio3 expression, transplacental T4 transfer)
• Practical advice: Take one extra dose twice a week as soon as pregnancy is confirmed
• Separate levothyroxine from prenatal vitamins/calcium by at least 4 hours
• Target TSH:
  • First trimester: 0.1-2.5 mIU/L
  • Second trimester: 0.2-3.0 mIU/L
  • Third trimester: 0.3-3.0 mIU/L
• Maintain total T4 at or above upper range of normal

D. Subclinical Hypothyroidism

• Defined as elevated TSH + normal free T4 levels
• Treatment decision is individualized; generally treat if TSH >10 mIU/L, symptomatic, or with goiter

E. Drug-Induced Hypothyroidism

• First step: Remove the offending agent if possible
• If the drug cannot be stopped (e.g., amiodarone for arrhythmias, lithium for bipolar): treat with levothyroxine replacement
• Amiodarone-induced hypothyroidism: levothyroxine therapy is safe and effective

10. Drug Interactions Summary (Katzung Table 38-3)

11. Liothyronine (T3) - When Used

• Oral bioavailability ~95% (nearly complete)
• Half-life shorter than T4
• Absorbed unaffected by mild hypothyroidism
• Used in myxedema coma as adjunct IV therapy
• For parenteral use, IV route preferred for both T4 and T3

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