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Antithyroid Drugs - Comprehensive Pharmacology Notes

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Overview / Classification

1. Thioamides (Thioureylenes) - primary drugs
2. Iodides - adjunct/preoperative
3. Radioactive Iodine (¹³¹I) - definitive therapy
4. Anion Inhibitors - limited use (perchlorate)
5. Adjuvant Agents - beta-blockers, calcium channel blockers

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1. THIOAMIDES

Members

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Mechanism of Action

1. Inhibit thyroid peroxidase (TPO) - block oxidation of iodide and incorporation into tyrosyl residues of thyroglobulin (iodine organification)
2. Block coupling of iodotyrosines (MIT + DIT) to form T3 and T4
3. Do NOT block iodide uptake (iodide trapping is unaffected)
4. PTU only - additionally inhibits peripheral deiodination of T4 to T3 (blocks Type 1 deiodinase) - methimazole does NOT do this

Because they block synthesis (not release), onset of action is slow - 3-4 weeks until stored T4 is depleted.

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Pharmacokinetics

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Therapeutic Uses

1. Graves' disease - as definitive treatment awaiting spontaneous remission (~40% remission rate over 12-18 months)
2. Before radioactive iodine - to hasten recovery while awaiting radiation effect
3. Preoperative preparation for thyroidectomy - to achieve euthyroid state
4. Thyroid storm - PTU preferred (also blocks T4→T3 peripheral conversion)

• Effective as a single daily dose → better adherence
• Less toxic than PTU
• Lower risk of hepatotoxicity

• First trimester of pregnancy (less placental transfer; MMI associated with rare embryopathy/aplasia cutis)
• Thyroid storm (blocks peripheral T4→T3 conversion)
• Patients with adverse reactions to MMI (not agranulocytosis or hepatitis)

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Dosing

• Response usually seen in 3-6 weeks
• Euthyroid state achieved in ~12 weeks
• After euthyroidism: dose reduced, then continued for 12-18 months total
• Monitor TFTs every 2-4 months initially, then every 4-6 months

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Adverse Effects / Toxicity

Minor (more common, ~5%)

• Maculopapular pruritic rash (most common)
• Urticaria
• Arthralgia
• Fever, headache
• Nausea, vomiting

Major (serious)

Cross-sensitivity between PTU and MMI is ~50% - switching is not safe in severe reactions.

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Use in Pregnancy

• First trimester: PTU preferred - less protein-bound (crosses placenta less), MMI linked to embryopathy (aplasia cutis, choanal atresia, esophageal atresia - "MMI embryopathy")
• Second + Third trimester: Switch to MMI (avoid PTU-associated liver failure in pregnancy)
• Current guidelines: Minimize antithyroid drugs as much as possible in first trimester
• Keep serum free T4 in the upper half of normal (to avoid fetal hypothyroidism)
• Both drugs are classified as FDA Pregnancy Category D
• Both cross the placenta and can cause fetal goiter/hypothyroidism

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2. IODIDES

Forms Used

• Potassium iodide (KI) - saturated solution (SSKI), Lugol's solution (5% I₂ + 10% KI)

Mechanism of Action

• Inhibit hormone release - block thyroglobulin proteolysis (main action at high doses)
• Inhibit organification - Wolff-Chaikoff effect
• Decrease vascularity, size, and fragility of the hyperplastic gland (important pre-surgically)
• Rapid improvement in thyrotoxic symptoms within 2-7 days

Clinical Uses

1. Preoperative preparation for thyroidectomy (reduce vascularity + friability) - give 10-14 days before surgery
2. Thyroid storm - rapid control
3. Radiation emergency - KI blocks thyroid from absorbing radioactive iodine isotopes

Disadvantages

• Increase intraglandular iodine stores → may delay thioamide therapy or prevent radioactive iodine use for weeks
• Escape phenomenon - gland escapes iodide block after 2-8 weeks → severe exacerbation in iodine-rich gland
• Jod-Basedow phenomenon - iodide-induced hyperthyroidism in susceptible patients
• Avoid in pregnancy (fetal goiter)
• Rule: Always start thioamide FIRST, then add iodide (never give iodide alone)

Toxicity (Iodism)

• Acneiform rash
• Swollen salivary glands
• Mucous membrane ulcerations
• Metallic taste
• Conjunctivitis, rhinitis

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3. RADIOACTIVE IODINE (¹³¹I)

• Emits beta particles (main cytotoxic effect) and gamma rays
• Concentrated by thyroid, destroying hyperplastic gland tissue
• Effect takes 6-18 weeks to become apparent
• Contraindicated in pregnancy (absolute contraindication - can destroy fetal thyroid)
• Main complication: hypothyroidism (occurs in majority of patients eventually)
• Antithyroid drugs may be given before RAI to hasten euthyroidism, but should be stopped a few days before RAI dosing

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4. ANION INHIBITORS

• Perchlorate (ClO₄⁻), pertechnetate (TcO₄⁻), thiocyanate (SCN⁻)
• Block iodide uptake (trapping) by competitive inhibition of iodide transport
• Overcome by large doses of iodide (unpredictable)
• Potassium perchlorate - used for amiodarone-induced hyperthyroidism
• Rarely used due to risk of aplastic anemia

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5. ADJUVANT AGENTS (No intrinsic antithyroid activity)

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6. THYROID STORM - Management

1. PTU 500-1000 mg loading, then 250 mg every 4 h (blocks synthesis AND peripheral conversion)
2. Iodide (give 1 hour AFTER PTU) - SSKI or Lugol's solution
3. Beta-blocker - propranolol IV or oral
4. Corticosteroids - dexamethasone (blocks T4→T3 conversion, treats relative adrenal insufficiency)
5. Supportive care - IV fluids, cooling, treat precipitating cause

Mnemonic for thyroid storm treatment: BIPC - Beta-blocker, Iodide, PTU, Corticosteroids

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Summary Comparison: PTU vs Methimazole

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Quick Memory Aids

• "PTU = First trimester + Thyroid storm" (two P-situations)
• Thioamides block SYNTHESIS, not RELEASE → slow onset (3-4 weeks)
• Iodides block RELEASE → fast onset (2-7 days) but only short-term
• Agranulocytosis - rare but dangerous; warn every patient about sore throat/fever
• PTU Black Box = fulminant hepatic necrosis
• Carbimazole = prodrug → converted to methimazole in vivo
• Perchlorate blocks UPTAKE; Thioamides block ORGANIFICATION + COUPLING; Iodides block RELEASE

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Antithyroid Drugs

As per K.D. Tripathi - Essentials of Medical Pharmacology

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DRUGS USED IN HYPERTHYROIDISM

• Propylthiouracil (PTU) - 100 mg tabs
• Methimazole (Thiamazole) - 5, 10, 20 mg tabs
• Carbimazole - 5, 10 mg tabs (prodrug of methimazole; used in India & UK)

• Lugol's iodine (5% I₂ + 10% KI)
• Saturated solution of potassium iodide (SSKI)
• Radioiodine (¹³¹I)

• Propranolol (adjuvant)
• Atenolol (adjuvant)

• Potassium perchlorate
• Potassium thiocyanate

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A. THIOAMIDES

Mechanism of Action

1. Inhibition of thyroid peroxidase (TPO) - they compete with iodide for the peroxidase enzyme, thereby preventing oxidation of iodide and its incorporation into tyrosine residues of thyroglobulin (iodine organification blocked)
2. Inhibition of coupling - block the coupling of iodotyrosines (MIT and DIT) to form T3 and T4
3. PTU additionally inhibits peripheral conversion of T4 to T3 (inhibits 5'-deiodinase) - methimazole does NOT have this action
4. They do NOT block iodide uptake (trapping) by the thyroid gland
5. They do NOT block release of preformed hormones

Important: Since synthesis (not release) is blocked, onset of action is slow - clinical effect takes 3-4 weeks (until preformed hormone stores are depleted).

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Pharmacokinetics

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Dose & Regimen

• Euthyroid state usually achieved in 6-8 weeks
• Total treatment duration: 12-18 months (block-and-replace or titration regimen)
• Monitor T3, T4, TSH periodically

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Therapeutic Uses

• Goal: achieve remission; ~40-50% remit after 12-18 months treatment
• Titration regimen: dose reduced as euthyroid state is achieved
• Block-replace regimen: full blocking dose + levothyroxine added

• Render patient euthyroid before surgery (reduces risk of thyroid storm)
• Combined with iodides 10 days before surgery

• Given before RAI to control symptoms; stopped few days before RAI dose

• PTU preferred (also blocks peripheral T4→T3 conversion)
• Loading dose PTU 600-1000 mg, then 200-400 mg every 6 h

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Choice of Drug in Special Situations

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Adverse Effects

A. Minor (more common)

• Skin rash (most common - maculopapular, pruritic) ~5%
• Urticaria
• Fever, arthralgia
• Nausea, GI upset
• Headache, paresthesias

B. Major (serious - require drug stoppage)

• Incidence: 0.1-0.5% with both drugs
• Usually in first 2-3 months of therapy
• Presents as: fever, sore throat, oral ulcers → patient must be warned
• Mechanism: immune-mediated destruction of granulocytes
• Management: Stop drug immediately, hospitalize, broad-spectrum antibiotics, G-CSF
• Cross-sensitivity between PTU and carbimazole/methimazole: ~50% - switching is NOT safe
• WBC should be monitored; patient counselled to report sore throat/fever

• PTU: Fulminant hepatic necrosis (Black Box Warning in USA) - rare (1 in 10,000 adults; 1 in 2000 children) but can be fatal or require liver transplant
• Methimazole/Carbimazole: Cholestatic jaundice (milder, reversible)

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Contraindications

• Severe agranulocytosis or hepatic necrosis on prior thioamide use
• Severe liver disease (PTU)

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B. IODIDES

Preparations

• Lugol's solution: 5% I₂ + 10% KI; dose: 0.1-0.3 mL (3-5 drops) TDS
• SSKI (Saturated KI): 1 drop = 35 mg KI; dose: 1-5 drops TDS

Mechanism of Action

1. Inhibits hormone release - main action; inhibits thyroglobulin proteolysis (= Plummer effect); this gives rapid relief within 2-7 days
2. Inhibits organification - Wolff-Chaikoff effect (transient; gland escapes after 10-14 days)
3. Decreases vascularity, size, and fragility of hyperplastic thyroid gland - important before surgery
4. Reduce synthesis of T3 more than T4

Clinical Uses

1. Preoperative preparation for thyroidectomy (given for 10-14 days before surgery along with thioamide - reduces vascularity and operative bleeding)
2. Thyroid storm - for rapid control (acts in 2-7 days)
3. Radiation emergency - KI given prophylactically to block uptake of radioactive iodine isotopes (nuclear accidents)
4. Adjunct to RAI therapy in severe cases

Disadvantages / Precautions

• Escape phenomenon: Gland escapes iodide block after 2-8 weeks → may cause severe rebound hyperthyroidism. Hence, never give iodides alone; always use with thioamide
• Increase iodine stores → delays or prevents RAI therapy; so avoid iodides if RAI is planned
• Jod-Basedow phenomenon - can induce hyperthyroidism in susceptible patients (e.g., iodine deficient patients)
• Avoid in pregnancy - may cause fetal goiter
• Rule: Start thioamide first → then add iodide (after 1-2 weeks)

Toxicity (Iodism)

• Acneiform skin rash
• Swollen salivary glands (sialadenitis)
• Coryza, lacrimation, conjunctivitis
• Metallic taste
• Mucous membrane ulcerations
• Rarely: iododerma (serious skin reaction)

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C. RADIOIODINE (¹³¹I)

• Emits β-particles (main cytotoxic effect; range 0.5-2 mm) and γ-rays
• Concentrated by thyroid follicular cells → causes local irradiation → thyroid cell death
• Onset: 6-18 weeks for full effect
• Definitive therapy in adults (especially Graves' disease, toxic nodular goiter)
• Main complication: Hypothyroidism (most patients eventually become hypothyroid)
• Absolute contraindication: Pregnancy, lactation (destroys fetal thyroid)
• Also contraindicated in children < 5 years (relative)
• Pre-treatment with antithyroid drugs should be stopped 5-7 days before RAI (to allow iodine uptake)

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D. IONIC / ANION INHIBITORS

• Rarely used clinically
• Potassium perchlorate: risk of aplastic anemia limits use

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MANAGEMENT OF THYROID STORM (KDT Style)

Mnemonic: "BIDS" - Beta-blocker, Iodide (after PTU), Dexamethasone, Supportive care (with PTU as backbone)

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KEY POINTS FOR EXAM (KDT Favourites)

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Hormones Regulating Calcium

Pharmacology & Physiology Notes - KDT Style

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CALCIUM HOMEOSTASIS - OVERVIEW

Normal Serum Calcium

• Total serum calcium: 8.5-10.4 mg/dL (2.1-2.6 mM)
• Three chemical forms:
  • Ionized (free) Ca²⁺ → 50% (physiologically active form)
  • Protein-bound (mainly albumin) → 40%
  • Complexed (with citrate, phosphate, bicarbonate) → 10%

Clinical pearl: Ionized Ca²⁺ is the physiologically relevant fraction. For every 1 g/dL fall in albumin from normal (4 g/dL), add 0.8 mg/dL to measured total calcium (corrected calcium).

Body Distribution

• >99% of total body calcium is in bone and teeth (as hydroxyapatite crystals)
• Remaining <1% is in extracellular fluid and cells

Three Target Organs

1. Bone (storage and mobilization)
2. Kidney (reabsorption and excretion)
3. Intestine (absorption)

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HORMONES REGULATING CALCIUM

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1. PARATHYROID HORMONE (PTH)

Source

• Secreted by chief cells of the 4 parathyroid glands (located on the posterior surface of the thyroid)

Chemistry

• Single polypeptide chain of 84 amino acids (MW ~9,500 Da)
• Synthesized as pre-pro-PTH (115 aa) → Pro-PTH (90 aa) → PTH (84 aa)
• Biological activity resides in the N-terminal portion (residues 1-27 required for full activity)
• The fragment lacking first 6 amino acids inhibits PTH action

Regulation of Secretion

• Low Ca²⁺ → CaSR less occupied → PTH secretion ↑ (Green arrow in diagram)
• High Ca²⁺ → CaSR activated → PTH secretion ↓ (Red arrow)
• CaSR is a GPCR - activation stimulates Gq/Gi → inhibits PTH

Mnemonic: "Low Ca²⁺ → Call the Parathyroid" - PTH is the emergency hormone for hypocalcemia

Mechanism of Action / Effects

A. Effects on Bone (Raises Ca²⁺)

• Chronic/continuous PTH → stimulates osteoclast activity → bone resorption → releases Ca²⁺ and PO₄³⁻ into blood (catabolic effect)
• Intermittent/pulsatile PTH → stimulates osteoblasts → bone formation (anabolic effect - basis for teriparatide use)
• Primary target cell is the osteoblast, which then signals to osteoclasts via RANKL/OPG system

B. Effects on Kidney (Raises Ca²⁺, Lowers PO₄³⁻)

• ↑ Ca²⁺ reabsorption in distal convoluted tubule (DCT) → serum Ca²⁺ rises
• ↓ Phosphate reabsorption in proximal tubule (phosphaturic effect) → serum PO₄³⁻ falls
• ↑ 1α-hydroxylase activity → converts 25-OH Vitamin D to active calcitriol (1,25-dihydroxyvitamin D) → indirectly ↑ intestinal Ca²⁺ absorption

C. Effects on Intestine (Indirect)

• PTH has NO direct effect on intestine
• Acts indirectly by stimulating renal calcitriol production → calcitriol then increases intestinal Ca²⁺ and PO₄³⁻ absorption

Summary of PTH Actions

↓ Ca²⁺ → ↑ PTH
         ├─→ Bone: ↑ resorption → Ca²⁺ + PO₄ released
         ├─→ Kidney: ↑ Ca²⁺ reabsorption + ↓ PO₄ reabsorption + ↑ calcitriol synthesis
         └─→ Intestine (via calcitriol): ↑ Ca²⁺ absorption
         
Net result: ↑ Serum Ca²⁺ + ↓ Serum PO₄³⁻

PTH Receptor

• PTH receptor 1 (PTH1R/PTHR) - coupled to Gs (↑ cAMP) and Gq (↑ IP₃/DAG)
• Both PTH and PTHrP (PTH-related peptide) bind this receptor

Hypoparathyroidism vs Hyperparathyroidism

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2. VITAMIN D (Calciferol)

Forms

• Vitamin D₂ (Ergocalciferol) - from plants/fungi; formed by UV irradiation of ergosterol
• Vitamin D₃ (Cholecalciferol) - from animal sources; formed in skin by UV irradiation of 7-dehydrocholesterol

Synthesis / Activation Pathway

Skin (UV radiation)
7-dehydrocholesterol → Cholecalciferol (Vitamin D₃)
                              ↓
                         Liver (CYP2R1/CYP27A1)
                    25-Hydroxylation → 25-OH-Cholecalciferol
                    (Calcidiol / 25-OHD) ← STORAGE FORM; t½ = 3 weeks
                              ↓
                    Kidney proximal tubule (CYP27B1 / 1α-hydroxylase)
              1α-Hydroxylation → 1,25-(OH)₂-Cholecalciferol
                    (CALCITRIOL) ← ACTIVE FORM; t½ = 4-6 hours

Best measure of Vitamin D status = 25-OHD (serum) (longer half-life, stable, reflects stores) Deficiency: <15 ng/mL; Insufficiency: 15-30 ng/mL; Normal: >30 ng/mL

Regulation of 1α-Hydroxylase (Key Enzyme - CYP27B1)

Mechanism of Action

• Calcitriol binds to Vitamin D Receptor (VDR) - a nuclear receptor
• Primarily acts by transcriptional regulation (gene expression)
• VDR forms heterodimer with Retinoid X Receptor (RXR) → binds Vitamin D Response Elements (VDREs) on DNA

Actions / Effects

A. Intestine (Primary action)

• ↑ Calcium absorption (both active transport in duodenum and passive in jejunum/ileum)
• ↑ Phosphate absorption
• Mechanism: induces synthesis of calcium-transport proteins (TRPV6, calbindin-D)

B. Kidney

• ↑ Calcium reabsorption (DCT)
• ↑ Phosphate reabsorption

C. Bone

• Promotes bone mineralization - provides adequate Ca²⁺ and PO₄³⁻ for hydroxyapatite
• Stimulates osteoblast and osteoclast activity (bone remodeling)
• At high doses: bone resorption (similar to PTH)

D. Other (Extra-skeletal) Effects

• Immune modulation (macrophage activation, T-cell regulation)
• Muscle function (weakness in deficiency)
• Cell differentiation and anti-proliferative effects
• Suppresses renin gene expression (cardioprotective)
• Directly suppresses PTH gene transcription in parathyroid glands

Vitamin D Deficiency

Preparations (Pharmacological Use)

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3. CALCITONIN

Source

• Secreted by parafollicular cells (C cells) of the thyroid gland
• Also produced by: lung, intestine, pituitary (minor sources)

Stimulus for Secretion

• ↑ Serum Ca²⁺ → ↑ calcitonin secretion (direct calcium sensing via CaSR)
• Gastrin, glucagon, CCK (after meals - anticipatory response)

Mechanism of Action

• Acts via calcitonin receptor (CTR) - a GPCR coupled to Gs → ↑ cAMP
• Primary target: osteoclasts (directly inhibits them)

Actions / Effects

A. Bone (↓ Ca²⁺, ↓ PO₄³⁻)

• Direct inhibition of osteoclast activity → ↓ bone resorption → ↓ serum Ca²⁺ and PO₄³⁻
• Rapid action (within minutes)
• Tachyphylaxis (escape) develops with prolonged use - osteoclasts downregulate CTR

B. Kidney

• ↑ Renal excretion of Ca²⁺ and PO₄³⁻ (phosphaturic + calciuric)
• Inhibits tubular reabsorption of Ca²⁺ and phosphate

C. Intestine

• Minor inhibitory effect on Ca²⁺ absorption

Physiological Role

• Physiological significance is debated - calcitonin does not play a major role in day-to-day Ca²⁺ regulation in humans
• More important role in protecting the skeleton during pregnancy and lactation (high bone turnover states)
• Acts as a counter-regulatory hormone to PTH

Pharmacological Uses

• Paget's disease of bone (↓ bone resorption/turnover)
• Hypercalcemia (acute management - onset in hours, but tachyphylaxis develops)
• Osteoporosis (salmon calcitonin nasal spray - pain relief + modest anti-fracture)
• Bone pain in metastatic bone disease

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4. FGF-23 (Fibroblast Growth Factor-23)

Source

• Secreted by osteocytes and osteoblasts (bone)

Stimulus for Secretion

• High serum phosphate
• High 1,25-(OH)₂D (calcitriol)

Receptor

• Acts via FGFR1/Klotho complex in the kidney (Klotho is an obligate co-receptor)

Actions

• Potent phosphaturic agent - inhibits NaPi-IIa and NaPi-IIc sodium-phosphate cotransporters in proximal tubule → ↓ phosphate reabsorption → ↓ serum PO₄³⁻
• Inhibits 1α-hydroxylase (CYP27B1) → ↓ calcitriol synthesis
• Stimulates 24-hydroxylase (CYP24A1) → ↑ calcitriol catabolism
• Net result: ↓ serum PO₄³⁻ + ↓ calcitriol
• Also suppresses PTH secretion

Clinical Relevance

• Elevated in Chronic Kidney Disease (CKD) → contributes to calcitriol deficiency and secondary hyperparathyroidism
• X-linked hypophosphatemia (XLH) - FGF-23 excess → phosphate wasting rickets
• Tumor-induced osteomalacia - FGF-23 secreted by tumors → hypophosphatemia + osteomalacia

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5. PTHrP (Parathyroid Hormone-related Peptide)

Source

• Produced by many tissues (fetal parathyroid, breast, placenta, smooth muscle)
• NOT normally found in adult serum (except pregnancy/lactation)

Receptor

• Binds same receptor as PTH (PTH1R/PTHR)

Actions

• Similar to PTH: ↑ Ca²⁺, ↓ PO₄³⁻
• Physiological roles: fetal bone development, placental calcium transport, smooth muscle relaxation

Clinical Significance

• Humoral hypercalcemia of malignancy (HHM) - most common cause of hypercalcemia in cancer patients (squamous cell carcinoma, renal cell carcinoma)
• Tumors secrete PTHrP → mimics PTH → severe hypercalcemia

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INTEGRATED REGULATION - QUICK SUMMARY

HYPOCALCEMIA:
↓ Ca²⁺ → ↑ PTH → Bone resorption ↑ + Renal Ca²⁺ reabsorption ↑ + ↑ Calcitriol
        Calcitriol → ↑ Intestinal Ca²⁺ absorption + ↑ Renal Ca²⁺ reabsorption
Result: ↑ Serum Ca²⁺ → Negative feedback → ↓ PTH

HYPERCALCEMIA:
↑ Ca²⁺ → ↓ PTH + ↑ Calcitonin → ↓ Bone resorption + ↑ Renal Ca²⁺ excretion
Result: ↓ Serum Ca²⁺

HYPERPHOSPHATEMIA:
↑ PO₄³⁻ → ↑ FGF-23 + ↑ PTH → ↑ Renal phosphate excretion + ↓ Calcitriol
Result: ↓ Serum PO₄³⁻

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EXAM-IMPORTANT COMPARISON TABLE

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KEY FACTS FOR EXAMS (KDT Favourites)

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