---

Antithyroid Drugs - Complete 2nd Year MBBS Pharmacology

---

PART 1: ANTITHYROID DRUGS - Classification, Pharmacokinetics, Adverse Effects, Uses

---

Classification of Antithyroid Drugs

ANTITHYROID DRUGS
│
├── 1. THIOAMIDES (Thioureylenes)
│       ├── Propylthiouracil (PTU)
│       ├── Methimazole (MMI)
│       └── Carbimazole* → converted to Methimazole
│                         (* used in India, UK, Europe)
│
├── 2. IONIC INHIBITORS (Anion Inhibitors)
│       ├── Potassium Perchlorate
│       ├── Thiocyanate
│       └── Pertechnetate
│
├── 3. IODINE / IODIDES
│       ├── Lugol's iodine (5% I₂ + 10% KI)
│       └── Potassium iodide (SSKI)
│
├── 4. RADIOACTIVE IODINE
│       └── ¹³¹Iodine (¹³¹I)
│
└── 5. ADJUVANT DRUGS
        ├── Beta-blockers (Propranolol)
        ├── Calcium channel blockers
        └── Glucocorticoids (in thyroid storm)

---

Mechanism of Action of Thioamides

Normal thyroid hormone synthesis:
    Iodide (I⁻)  →  [TPO + H₂O₂]  →  Active Iodine (I⁰)
                                              ↓
    Tyrosyl residues on Thyroglobulin + I⁰  →  MIT, DIT
                                              ↓
    MIT + DIT  →  [TPO coupling]  →  T₃, T₄
    
WHERE THIOAMIDES ACT:
    ✦ Block TPO (thyroid peroxidase) → inhibit oxidation of I⁻
    ✦ Block organification (iodination of tyrosines)
    ✦ Block coupling of MIT + DIT → no T₃/T₄ formed
    ✦ PTU ONLY: also blocks peripheral conversion of T₄→T₃
                (via inhibition of deiodinase type 1)
    ✦ No effect on already-stored thyroglobulin
      → onset of action delayed 3-4 weeks
      (until preformed hormone stores are depleted)

---

Pharmacokinetics of Thioamides

---

Therapeutic Uses of Thioamides

1. Graves' disease - primary antithyroid drug therapy (12-18 months); only treatment that preserves thyroid gland
2. Preparation for thyroid surgery - render patient euthyroid preoperatively
3. Adjunct before/after radioiodine - hasten control while awaiting RAI effect
4. Thyroid storm - PTU preferred (also blocks T₄→T₃)
5. Toxic nodular goiter
6. Neonatal Graves' disease - PTU/MMI in short course

• Lower risk of serious liver injury
• Once-daily dosing
• Faster onset to euthyroid state

• First trimester of pregnancy (methimazole is teratogenic - "aplasia cutis" + choanal atresia)
• Thyroid storm (dual action - also inhibits T₄→T₃)

• Methimazole: 15-40 mg/day (mild-moderate), up to 60-80 mg/day (severe)
• PTU: 100 mg every 6-8 hours (up to 1200 mg/day in thyroid storm)

---

Adverse Effects of Thioamides

ADVERSE EFFECTS (occur in 3-12% of patients)

COMMON (mild):
├── Maculopapular pruritic rash (4-6%) - most common
├── Urticaria
├── Nausea, GI distress
├── Arthralgia / joint pain
├── Altered taste/smell (methimazole)
└── Mild fever

UNCOMMON (moderate):
├── Vasculitis
├── Lupus-like syndrome
├── Lymphadenopathy
└── Hypoprothrombinemia

RARE BUT SERIOUS (dangerous):
├── AGRANULOCYTOSIS ⚠️ (0.1-0.5%)
│     - Granulocyte count <500 cells/mm³
│     - Usually within first 90 days
│     - Risk ↑ with MMI >40 mg/day and in elderly
│     - Rapidly reversible on stopping drug
│     - Treat with broad-spectrum antibiotics + G-CSF
│     - 50% cross-sensitivity between PTU and MMI
│
├── HEPATOTOXICITY ⚠️
│     - PTU: Severe hepatitis, potentially fatal acute 
│            liver failure (BLACK BOX WARNING)
│     - MMI: Cholestatic jaundice (less severe)
│     - Asymptomatic transaminase elevation possible
│
└── Polyserositis, exfoliative dermatitis

---

Onset of Action - Important for Exams

WHY IS ONSET DELAYED?

Thioamides block NEW hormone synthesis
BUT do NOT affect stored hormone in thyroglobulin

Timeline:
Day 1 → Drug blocks TPO → no new hormone made
Week 1-3 → Stored thyroglobulin still releasing T₃/T₄
Week 3-4 → Stores depleted → clinical effect appears

PTU onset: slightly slower (no intrathyroidal accumulation)
Methimazole onset: faster (accumulates in gland)

---

PART 2: CARBIMAZOLE - MOA, Therapeutic Uses, Adverse Effects

---

What is Carbimazole?

Carbimazole
    │
    │  (Carbethoxy derivative of methimazole)
    │  Available in India, UK, Europe
    │
    ▼
Absorbed orally
    │
    ▼
Converted in liver to METHIMAZOLE (active form)
    │
    ▼
All antithyroid activity is due to METHIMAZOLE

---

Mechanism of Action (Carbimazole → Methimazole)

MECHANISM OF CARBIMAZOLE (via Methimazole):

Step 1: Absorption
    Carbimazole  →[gut/liver]→  METHIMAZOLE

Step 2: Methimazole acts on thyroid peroxidase (TPO)

    Iodide (I⁻)
         ↓ [TPO + H₂O₂]
    ×  ← BLOCKED by Methimazole
         ↓
    Active iodine (I⁰) -- NOT FORMED
    
    Result:
    • No organification (iodination of tyrosines)
    • No coupling of MIT + DIT
    • T₃ and T₄ synthesis halted
    
Step 3: Does NOT block T₄→T₃ conversion
    (Unlike PTU, methimazole/carbimazole does not 
     inhibit peripheral deiodinase)

Step 4: IMMUNOSUPPRESSIVE effect (unique to thioamides)
    • Reduces TSH-receptor antibody titers in Graves' disease
    • May contribute to long-term remission

---

Therapeutic Uses of Carbimazole

1. Graves' disease (diffuse toxic goiter) - first-line in UK, India
2. Toxic multinodular goiter
3. Toxic adenoma
4. Preoperative preparation for thyroidectomy (render euthyroid + reduce gland vascularity when combined with iodine)
5. Adjunct to radioiodine - used before/after RAI to hasten control
6. Thyrotoxicosis in pregnancy - switched to PTU in first trimester

---

Adverse Effects of Carbimazole

CARBIMAZOLE ADVERSE EFFECTS

COMMON:
├── Rash (maculopapular, urticarial)
├── Nausea, GI upset
├── Headache
├── Altered taste/smell
└── Joint pains (arthralgia)

SERIOUS:
├── Agranulocytosis (0.1-0.5%)
│   ⚠️ Warn patient: report sore throat/fever immediately
│   → Stop drug → Do WBC count
│
├── Cholestatic jaundice
│   (less severe than PTU-related hepatotoxicity)
│
└── Aplasia cutis (scalp skin defect in neonate)
    ← If used in first trimester → switch to PTU

TERATOGENICITY:
    Choanal atresia + aplasia cutis syndrome
    Risk: First trimester exposure
    → PTU preferred in first trimester
    → Switch back to carbimazole/MMI in 2nd/3rd trimester

---

PART 3: PROPRANOLOL IN THYROTOXICOSIS - Pharmacological Basis and Treatment

---

Why Use Propranolol in Thyrotoxicosis?

PATHOPHYSIOLOGY OF THYROTOXICOSIS SYMPTOMS:

Excess T₃/T₄
    │
    ├── Upregulation of β-adrenergic receptors
    │         ↓
    │    SYMPATHOMIMETIC EFFECTS:
    │    • Tachycardia / palpitations
    │    • Tremor
    │    • Anxiety / nervousness
    │    • Sweating
    │    • Heat intolerance
    │    • Lid lag / lid retraction (stare)
    │    • Atrial fibrillation
    │
    └── Increased sensitivity to catecholamines
              ↓
         All symptoms exacerbated

PROPRANOLOL → Blocks β₁ and β₂ receptors → Rapid symptomatic relief

---

Pharmacological Basis of Propranolol in Thyrotoxicosis

PROPRANOLOL: NON-SELECTIVE β-BLOCKER (β₁ + β₂)

1. β₁ BLOCKADE (cardiac):
   ├── ↓ Heart rate → controls tachycardia
   ├── ↓ Cardiac output
   └── Controls palpitations, arrhythmias (AF)

2. β₂ BLOCKADE (peripheral):
   ├── ↓ Tremor
   ├── ↓ Anxiety
   └── ↓ Sweating

3. UNIQUE EFFECT (beyond beta-blockade):
   Propranolol INHIBITS peripheral conversion of T₄ → T₃
   (deiodinase type 1 inhibition)
   ├── This reduces levels of active T₃
   ├── Also seen with PTU (additive effect)
   └── High doses required (>160 mg/day)

4. Does NOT affect:
   ├── Thyroid hormone synthesis
   ├── Thyroid hormone release
   └── Underlying disease process

---

Role in Treatment

WHEN TO USE PROPRANOLOL:

A. ADJUVANT THERAPY (most common use):
   Given ALONGSIDE thioamides while waiting for
   antithyroid drugs to work (3-4 week delay)
   ↓
   Rapid symptomatic relief in first 2-4 weeks

B. THYROID STORM:
   Essential component of treatment
   High doses: 40-80 mg every 4-6 hours
   Controls dangerous tachycardia/arrhythmias

C. PREOPERATIVE PREPARATION:
   When surgery needed urgently
   Used with iodine to reduce gland vascularity

D. RAI PREPARATION/POST-RAI:
   Controls symptoms before and after radioiodine
   (RAI takes 6-12 weeks to work)

E. THYROTOXIC CRISIS / STORM:
   IV propranolol: 0.5-1 mg slowly IV (monitored)
   Oral: 40-80 mg every 4-6 hours

DOSES:
   Mild thyrotoxicosis: 40-120 mg/day in divided doses
   Thyroid storm: up to 240-480 mg/day

---

Contraindications of Propranolol in Thyrotoxicosis

CONTRAINDICATIONS:
├── Asthma / COPD (β₂ blockade causes bronchospasm)
├── Heart failure / cardiac decompensation
├── Heart block (2nd/3rd degree)
├── Severe bradycardia
└── Raynaud's phenomenon (peripheral vascular disease)

ALTERNATIVES when propranolol contraindicated:
├── Atenolol (β₁ selective) - safer in mild respiratory disease
├── Metoprolol (β₁ selective)
├── Diltiazem (Ca²⁺ channel blocker) - for rate control
└── Verapamil - when beta-blockers absolutely contraindicated

---

Mechanism Summary - Propranolol vs. Thioamides

COMPARISON OF ACTION:

                    Propranolol     PTU/MMI
                    -----------     -------
Blocks TPO              No            YES
Stops T₃/T₄ synthesis  No            YES
Blocks T₄→T₃            YES           PTU only
Symptomatic relief      RAPID         Delayed 3-4 wks
Controls tachycardia    YES           Indirect only
Treats underlying cause No            No
Reduces TSH-RAb         No            YES (partial)

→ Used TOGETHER for optimal early management

---

PART 4: RADIOACTIVE IODINE (¹³¹I) - Advantages and Disadvantages

---

Mechanism of Action of ¹³¹I

RADIOACTIVE IODINE (¹³¹I):

Physical Properties:
├── Half-life: 8 days
├── Emits: β-particles (90%) + γ-rays (10%)
├── β-particles: tissue penetration 0.5-2 mm
│   → THERAPEUTIC EFFECT (local destruction)
└── γ-rays: for scanning/imaging

HOW IT WORKS:
    Oral ¹³¹I
         ↓
    Absorbed → enters blood
         ↓
    Taken up by thyroid via NIS 
    (sodium/iodide symporter)
         ↓
    ¹³¹I concentrated in follicular cells
         ↓
    β-radiation → DNA damage → follicular cell death
         ↓
    Gland shrinks → hormone production ↓
         ↓
    Euthyroid/hypothyroid state achieved

Duration: Effect takes 6-12 weeks to manifest
Cure rate: 80% after single dose; ~20% need 2nd dose

---

Dosing / Administration

• Standard dose for Graves': 5-15 mCi (185-555 MBq) orally as a single dose
• Larger doses for toxic multinodular goiter
• Thyroid cancer: 30-150 mCi ablative doses (higher)
• Patient is euthyroid within 6-12 weeks in most cases

---

Advantages of Radioactive Iodine

ADVANTAGES OF ¹³¹I:

1. SIMPLICITY
   └── Single oral dose (tablet/liquid)

2. NO SURGERY
   └── Avoids operative risks (recurrent laryngeal
       nerve injury, hypoparathyroidism, bleeding)

3. COST-EFFECTIVE
   └── Cheaper than surgery overall

4. OUTPATIENT PROCEDURE
   └── No hospitalization required in most countries

5. HIGH EFFICACY
   └── 80% cured with one dose
   └── ~99% cured with repeat doses

6. PREFERRED FOR:
   ├── Elderly patients (poor surgical candidates)
   ├── Recurrent hyperthyroidism after surgery
   ├── Cardiac disease complicating thyrotoxicosis
   ├── Failure of antithyroid drug therapy
   └── Allergic to thioamides

7. PERMANENT CURE
   └── Eliminates the relapse rate seen with drug therapy

8. NO GENERAL ANESTHESIA REQUIRED

9. DOES NOT WORSEN exophthalmos significantly
   (though mild worsening possible)

---

Disadvantages of Radioactive Iodine

DISADVANTAGES OF ¹³¹I:

1. DELAYED EFFECT (MAJOR)
   └── Takes 6-12 weeks to achieve euthyroid state
   └── Bridging therapy with propranolol ± thioamides needed

2. HYPOTHYROIDISM (MOST COMMON CONSEQUENCE)
   ├── High incidence of permanent hypothyroidism
   ├── ~80% at 10 years, ~100% eventually
   └── Lifelong levothyroxine replacement required

3. RADIATION THYROIDITIS
   ├── Release of stored T₃/T₄ into circulation
   ├── Worsening of hyperthyroid symptoms
   ├── Rarely → thyroid storm
   └── Prevented by pretreatment with thioamides

4. RISK OF MALIGNANCY (controversial)
   ├── Some studies: small ↑ risk of stomach, kidney, 
   │   breast cancer (all express NIS transporter)
   └── Overall cancer death rate NOT increased

5. CONTRAINDICATED IN PREGNANCY ⚠️ (ABSOLUTE)
   ├── After 1st trimester: fetal thyroid concentrates ¹³¹I
   ├── → Fetal hypothyroidism + cretinism
   └── Even in 1st trimester: radiation to fetal tissues

6. CONTRAINDICATED IN BREASTFEEDING
   └── ¹³¹I excreted in breast milk

7. CONTROVERSIAL IN CHILDREN
   ├── Theoretical neoplastic risk in developing thyroid
   └── Most centers avoid in patients <25-30 years

8. WORSENING OF GRAVES' OPHTHALMOPATHY
   └── Radioiodine may worsen pre-existing eye disease
   └── Prophylactic glucocorticoids recommended in
       those with significant ophthalmopathy

9. RADIATION PRECAUTIONS NEEDED
   ├── Limit close contact with young children, pregnant women
   └── For 7-14 days post-treatment

10. NOT SUITABLE FOR LARGE GOITERS
    └── Very large/retrosternal goiters: surgery preferred
    (poor ¹³¹I access + risk of airway compromise)

---

Summary Table: Three Treatment Modalities for Thyrotoxicosis

┌─────────────────┬────────────────┬──────────────┬──────────────┐
│ Feature         │ Antithyroid    │ Radioiodine  │ Surgery      │
│                 │ Drugs          │ (¹³¹I)       │ (Thyroidecto-│
│                 │                │              │ my)          │
├─────────────────┼────────────────┼──────────────┼──────────────┤
│ Mechanism       │ Block TPO      │ Radiation    │ Physical     │
│                 │ ± T₄→T₃        │ cell death   │ removal      │
├─────────────────┼────────────────┼──────────────┼──────────────┤
│ Onset           │ 3-4 weeks      │ 6-12 weeks   │ Immediate    │
├─────────────────┼────────────────┼──────────────┼──────────────┤
│ Relapse rate    │ 50-60%         │ Very low     │ Low (5-10%)  │
├─────────────────┼────────────────┼──────────────┼──────────────┤
│ Hypothyroidism  │ If overdosed   │ ~80-100%     │ Common       │
│ risk            │                │ long term    │              │
├─────────────────┼────────────────┼──────────────┼──────────────┤
│ Pregnancy       │ PTU (1st tri)  │ Contraindic- │ 2nd trimester│
│                 │ MMI (2nd/3rd)  │ ated         │ only         │
├─────────────────┼────────────────┼──────────────┼──────────────┤
│ Preferred in    │ Young pts,     │ Elderly,     │ Large goiter,│
│                 │ pregnancy,     │ failed drugs,│ malignancy   │
│                 │ mild disease   │ post-surgery │ suspected    │
└─────────────────┴────────────────┴──────────────┴──────────────┘

---

Quick Flowchart: Management of Thyrotoxicosis (Graves')

GRAVES' DISEASE DIAGNOSED
         │
         ▼
Start Propranolol → IMMEDIATE symptom control
+ Start Methimazole/Carbimazole
         │
         ▼ (3-4 weeks)
    Euthyroid?
    /           \
  YES           NO
   │         ↑ dose or switch
   │
   ▼
Continue 12-18 months
(check for remission)
         │
     Remission?
    /           \
  YES            NO → Choose Definitive Rx
  Stop Rx              │
                  ┌────┴─────┐
                  ▼          ▼
          Radioiodine    Thyroidectomy
          (if >25 yr,    (if large goiter,
          no pregn.)     malignancy
                         suspected)

---

Key Points for 2nd Year MBBS Exam

---

• Goodman & Gilman's Pharmacological Basis of Therapeutics, 13th Ed., Chapter 47 (Thyroid & Antithyroid Drugs), Tables 47-5
• Katzung's Basic & Clinical Pharmacology, 16th Ed., Chapter 38 (Thyroid & Antithyroid Drugs)
• Lippincott Illustrated Reviews: Pharmacology, Chapter 23