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🦋 THYROID HORMONES, ANTITHYROID DRUGS & STEROIDS — Pharmacology Notes

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PART 1: THYROID PHYSIOLOGY (Foundation)

Thyroid Hormone Synthesis — Step by Step

Pendred Syndrome: Mutation of pendrin (SLC26A4) → goiter + sensorineural deafness.

Regulation (HPT Axis)

• TRH (hypothalamus) → stimulates TSH (pituitary) → stimulates T3/T4 synthesis and release
• T3/T4 exert negative feedback on both TRH and TSH
• T4 is the main circulating prohormone; peripheral conversion to T3 by 5'-deiodinase is the primary source of circulating T3

Transport

• 99% of T4 and T3 are protein-bound in plasma to: Thyroxine-Binding Globulin (TBG, primary), Transthyretin (TTR), Albumin

• Only free hormone is biologically active
• TBG is increased by: estrogens, pregnancy, oral contraceptives, hepatitis → raises total T4 but NOT free T4

Mechanism of Action

• T3 (and T4) enter cells via MCT8 and OATP1C1 transporters
• Bind nuclear thyroid hormone receptors (TR-α, TR-β) → TR/RXR heterodimer binds thyroid response elements (TREs) on DNA → regulates gene transcription
• Nongenomic effects: rapid effects on ion channels, mitochondria, cell membrane

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PART 2: THYROID HORMONE PREPARATIONS (Replacement Therapy)

1. Levothyroxine (T4) — Drug of Choice

• Average replacement dose: 1.6 mcg/kg/day (~100–125 mcg/day in adults)
• Elderly without cardiac disease: start 50 mcg/day
• Elderly/cardiac patients: start 12.5–25 mcg/day, increase by 12.5–25 mcg every 2 weeks
• Myxedema coma (IV): Loading dose 300–400 mcg IV, then 50–100 mcg/day IV

• Calcium carbonate, iron salts, antacids, sucralfate, cholestyramine — separate by 4 hours
• Omeprazole/PPIs — reduce absorption
• Phenytoin, rifampicin, carbamazepine — increase hepatic metabolism of T4

• Palpitations, tachycardia, heat intolerance, tremor, weight loss, insomnia
• In elderly: atrial fibrillation, accelerated osteoporosis (especially in postmenopausal women)
• In children: restlessness, insomnia, accelerated bone maturation

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2. Liothyronine (T3)

• More cardiotoxic than T4; harder to monitor
• Not preferred for long-term replacement due to fluctuating levels and risk of thyrotoxicosis

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3. Desiccated Thyroid (Natural/Armour Thyroid)

• Contains both T3 and T4 from porcine/bovine thyroid
• Standardized by iodine content, not hormone assay
• Higher T3 content can cause supraphysiological T3 peaks
• Not preferred over levothyroxine per current guidelines

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Clinical Uses of Thyroid Hormones

1. Hypothyroidism (primary, secondary) — levothyroxine
2. Myxedema coma — IV levothyroxine ± T3
3. TSH suppression in thyroid cancer (after thyroidectomy)
4. Goiter due to Hashimoto's thyroiditis
5. Euthyroid sick syndrome — replacement generally NOT indicated

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Special Situations

• Fetal brain development depends on maternal T4 in first trimester (fetal thyroid begins functioning at ~10–12 weeks)
• TSH targets: 1st trimester < 2.5 mIU/L; 2nd/3rd < 3.0 mIU/L
• Dose requirement increases ~30–50% during pregnancy

• Low T4 is protective for the heart in ischemic disease
• Restore euthyroidism cautiously — consider revascularization first

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PART 3: ANTITHYROID DRUGS AND THYROID INHIBITORS

Classification

1. Thioamides (thioureas) — PTU & Methimazole
2. Iodide (Lugol's iodine, SSKI) — Wolff-Chaikoff effect
3. Radioactive Iodine (RAI, ¹³¹I)
4. Ionic inhibitors — Perchlorate, Thiocyanate
5. Iodinated radiocontrast agents — Iopanoic acid, Sodium ipodate
6. Anion inhibitors: NaClO₄ (perchlorate)

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A. THIOAMIDES

Propylthiouracil (PTU)

• Minor: Rash (most common ~5%), pruritus, urticaria, GI disturbance, arthralgia
• Major:
  • Agranulocytosis (0.2–0.5%) — most serious; WBC monitoring essential; presents as sore throat/fever → STOP drug immediately
  • Hepatotoxicity (PTU-specific, potentially fatal) — black box warning; can cause fulminant hepatic necrosis
  • Hypothyroidism (overtreatment)
  • Lupus-like syndrome, vasculitis (ANCA-positive)
  • Hypoprothrombinemia

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Methimazole (MMI) / Carbimazole

• Agranulocytosis (0.2–0.5%) — less hepatotoxic than PTU
• Rash, urticaria
• Cholestatic jaundice (rare)
• Aplasia cutis — congenital scalp defect in neonate (if used in 1st trimester) → use PTU instead in 1st trimester
• Hypothyroidism

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B. IODIDE (Lugol's Solution, SSKI)

• Iodism: metallic taste, sore teeth/gums, burning mouth, sore throat, rhinorrhea, conjunctivitis
• Parotitis, salivary gland enlargement
• Acneiform rash
• Allergic reactions
• In susceptible patients: hypothyroidism or paradoxically, iodide-induced hyperthyroidism (Jod-Basedow effect)

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C. RADIOACTIVE IODINE (¹³¹I)

• Hypothyroidism is common/expected (up to 80% at 10 years in Graves')
• Cannot use in pregnancy or breastfeeding (crosses placenta, excreted in milk)
• Avoid in children and adolescents if possible
• Not for thyroid cancer of the medullary/anaplastic type
• Worsening of Graves' ophthalmopathy — treat with steroids if moderate/severe eye disease

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D. IONIC INHIBITORS

• Competitively inhibit NIS → block iodide uptake into the thyroid
• Rarely used clinically due to toxicity (perchlorate → aplastic anemia)
• Perchlorate still used in amiodarone-induced hyperthyroidism (Type I) or to prevent iodide overload

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E. IODINATED CONTRAST AGENTS (Iopanoic acid, Ipodate)

• Inhibit peripheral deiodinase → reduce T4→T3 conversion
• Also have Wolff-Chaikoff effect
• Used in thyroid storm as adjunctive therapy
• Largely replaced by other agents; availability limited

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THYROID STORM MANAGEMENT Summary

1. PTU 600 mg loading dose → then 200–300 mg q6h (blocks synthesis AND T4→T3 conversion)
2. 1 hour later: Lugol's iodine (blocks release)
3. Propranolol 60–80 mg q4–6h (controls adrenergic symptoms, also blocks T4→T3)
4. Hydrocortisone/dexamethasone (blocks T4→T3 conversion, treats potential adrenal insufficiency)
5. Supportive: cooling, IV fluids, antipyretics (avoid aspirin — displaces T4 from TBG)

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PART 4: CORTICOSTEROIDS (Adrenal Steroids)

Adrenal Cortex Zones and Products

Biosynthesis

• 17α-hydroxylase (CYP17): needed for cortisol and androgen synthesis
• 21-hydroxylase (CYP21A2): converts 17-OH-progesterone → 11-deoxycortisol (most common CAH deficiency)
• 11β-hydroxylase (CYP11B1): final step to cortisol
• 11β-HSD2: inactivates cortisol → cortisone in kidney (protects MR from cortisol)
• 11β-HSD1: reactivates cortisone → cortisol (mainly liver)

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Mechanism of Action of Glucocorticoids

1. Diffuse into cells → bind intracellular glucocorticoid receptor (GR-α)
2. GR-ligand complex translocates to nucleus → binds Glucocorticoid Response Elements (GREs) → activates or represses gene transcription
3. Key anti-inflammatory mechanisms:
   • ↑ Lipocortin (Annexin A1) → inhibits phospholipase A2 → ↓ arachidonic acid → ↓ prostaglandins + leukotrienes
   • ↓ NF-κB activity → ↓ cytokine production (IL-1, IL-2, IL-6, TNF-α)
   • ↓ COX-2 expression
   • ↓ T-cell proliferation; ↓ macrophage activation
4. Nongenomic effects: rapid effects at membrane level

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Pharmacological Properties of Key Glucocorticoids

Prednisone and cortisone are prodrugs → converted to prednisolone and cortisol (active) by 11β-HSD1 in liver. Avoid in severe liver disease — use prednisolone or hydrocortisone instead.

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Pharmacological Effects of Glucocorticoids

Metabolic Effects

• Carbohydrate: ↑ gluconeogenesis, ↑ hepatic glycogen, ↓ peripheral glucose uptake → hyperglycemia ("steroid diabetes")
• Protein: ↑ catabolism → muscle wasting, thin skin, striae, poor wound healing
• Fat: Lipolysis + redistribution → central obesity, moon face, buffalo hump (Cushing's phenotype)
• Calcium: ↓ GI absorption, ↑ renal excretion → osteoporosis

Anti-inflammatory/Immunosuppressive

• ↓ Neutrophil migration to sites of inflammation (though total WBC ↑ — "demargination")
• ↓ T-cell and B-cell function; ↓ cytokine release
• ↓ Capillary permeability, edema, fever
• Stabilize lysosomal membranes

Cardiovascular/Renal

• Mineralocorticoid effects (especially hydrocortisone, cortisone): Na⁺ retention, K⁺ loss, hypertension, edema
• Maintain vascular responsiveness to catecholamines

Other Effects

• Bone: Inhibits osteoblast activity → osteoporosis with long-term use
• CNS: Mood changes (euphoria, psychosis), altered sleep
• GI: ↑ acid secretion, risk of peptic ulcer (especially with NSAIDs)
• Eyes: Posterior subcapsular cataracts (chronic use), raised intraocular pressure → glaucoma
• Growth: Suppresses linear growth in children (chronic use)
• HPA Axis: Negative feedback → adrenal suppression with chronic use

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Clinical Uses of Corticosteroids

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Adverse Effects of Glucocorticoids (CHRONIC USE)

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Mineralocorticoids

Fludrocortisone (9α-fluorocortisol)

• Most potent oral mineralocorticoid in clinical use
• Mechanism: Binds mineralocorticoid receptor (MR) → ↑ Na⁺/K⁺-ATPase in distal nephron → Na⁺ retention, K⁺/H⁺ excretion
• Uses:
  • Primary adrenal insufficiency (Addison's disease) with hydrocortisone
  • Congenital adrenal hyperplasia (salt-wasting type)
  • Orthostatic hypotension (sympathetic neuropathy)
• Adverse Effects: Hypertension, edema, hypokalemia, cardiac hypertrophy

Aldosterone

• Endogenous mineralocorticoid; NOT used therapeutically (short-acting, extensive first-pass)

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HPA Axis Suppression and Steroid Withdrawal

• Systemic glucocorticoids > 3 weeks
• Dose equivalent to > 7.5 mg/day prednisone
• Any patient who appears Cushingoid

• Fatigue, weakness, arthralgia, nausea, orthostatic hypotension
• Adrenal crisis (life-threatening) if steroids stopped abruptly after long-term use

• Taper slowly; the longer the duration of use, the slower the taper
• Use stress-dose steroids during illness, surgery, or trauma in patients on or recently stopped chronic steroids
• Stress dose = Hydrocortisone 50–100 mg IV before surgery

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Inhibitors of Steroidogenesis (Used in Cushing's Syndrome)

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Mineralocorticoid Antagonists

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QUICK SUMMARY TABLE

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