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Drugs - Thyroid Diseases

Thyroid Hormones Function of Thyroid Hormones

Triiodothyronine (T3) General Metabolic Effects T3, T4 are similar
Tetraiodothyronine (T4) Growth, Development, Body Temperature, Energy Optimal Growth, Development, Function of all body tissues
Calcitonin Calcium Metabolism Critical for Nervous, Skeletal, Reproductive tissues
T3 , T4 – contain 60% Iodine as essential part of the molecule Potentiation of Secretion, Action of Growth Hormone
Calorigenesis
Synthesis of Thyroid Hormones ↑ Metabolic Rate – can influence metabolism of drugs
Thyroid Hyperactivity resembles Sympathetic Nervous System stimulation
CVS Effects – Lid Lag, Excessive Sweating, Anxiety, Nervousness, Tremor
(but Catecholamine release is not affected)
Are partially alleviated by β-Adrenoceptor Antagonists

Drugs used in Thyroid Disor ders

Hypothyroidism Hyperthyroidism
Thyroid Hormones (Replace ment) Antithyroid Drugs
Thyroid Hormones Iodine (for Iodine De ficiency) β-Blockers
T3, T4 released by Exocytosis, Proteolysis of Thyroglobulin
DIT, MIT are also release along with T3, T4 Thyroid Hormones
T4 : T3 = 5 : 1 Replacement in Deficiency States
Proteolysis blocked by ↑ Levels of Iodine (not in drug induced hypothyroidism)
T4 converted to T3 in peripheral circulation Kinetics
T3, T4 reversibly bound to Plasma to Thyroxine Binding Globulin Absorbed best
Very small amounts present in Free state • Duodenum
T3 is 3-4X ↑ Potent than T4 • Ileum
Oral Bioavailability
Metabolism of Thyroid Hormones • Levothyroxine 80%
• T3 almost 100%
Absorption diminished in severe hypothyroidism
• Consider switching to Parenteral (IV)
Metabolism is affected by Microsomal Enzyme Inducers
T3 should be Avoided in Patients with Cardiac Disease
(↑ Risk of Cardiotoxicity)

Preparations
Dessicated Thyroid (N ot Recommended )
Cheap
Allergic reaction (Animal Product)
Synthetic Levothyroxine (T4)
Liothyronine (T3)
Combination of T4, T3 (Liotrix)
Liotrix (4:1 combination of T4:T3) Not much advantage

T4, T3
Regulation T4 (Levothyroxine) T3 (Liothyronine)
Pituitary-Thyroid Axis Autoregulation Converted to T3 Intracellularly
Synthetic T4 Synthetic T3
Uniform content Uniform content
Non-Allergenic Non-Allergenic
Easy measurability of levels Difficult to monitor adequacy
Half-Life - ↑ (7 Days) Half-Life - ↓ (24 Hours)
Once Daily Dosing Multiple Dosing
↓ Cost ↑ Cost
Recommended for Routine Recommended for Short Term
Replacement Therapy Suppression of TSH
3-4X ↑ AcƟve than T4
(↑ Risk of Cardiotoxicity)

Thyroxine
Naturally occurring T3, T4 are levo-isomers
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Antithyroid Agents
β-Adrenoceptor
Thioamides Iodides Radioactive Iodine Anion Inhibit ors
Blocking Agents
Carbimazole Potassium Iodide (Most commonly used) 131 I Perchlorate (Potassium) Propranolol
Methimazole Oral Solution – Syrup, Tablets Pertechnetate (most commonly used)
Propylthiouracil Lugol’s Iodine Thiocyanate
(100mg/mL KI + 50 mg/mL Iodine )
MOA Have multiple effects on Thyroid Glands MOA MOA MOA
Major anti-thyroid agents prior to Thiomides Destruction of Thyroid Parenchyma Block Iodide uptake by Thyroid Block Cardiac β Receptors
Not used as sole therapy now due to β-rays Clinical Use (Direct Action)
MOA Advantages Disadvantages Not much use except in Iodide Inhibit Peripheral Conversion
Inhibition of Hormone Release Easy administration Possible genetic Induced Hyperthyroidism (T4 → T3)
Clinical Use Effective damage Control Cardiac Symptoms of
Improvement in Thyrotoxic symptoms occurs ↓ Cost Neoplasia Thyrotoxicosis
within 2-7 days (useful in Thyroid Storm) Painless Leukaemia
Useful for Pre-Operative Preparation for Should not be administered
Thyroid Surgery (↓ Size, Vascularity, Fragility) Pregnant
Disadvantages Nursing Women
• ↑ Glandular Stores of Iodine
• Delay onset of Thioamide actions
• Prevent action of Radioactive Iodine
(for several weeks)
Should be used after initiation of Thioamides
Inhibit Peroxidase enzyme in Thyroid
Avoided if Radio-Iodine therapy is planned
↓ T3, T4 Synthesis
Should not be used alone
Block Iodotyrosines from Colloid
• Escape from Iodine block can occur
Block Iodine release from peripheral hormone
• Withdrawal cause severe Thyrotoxicosis
Pharmacokinetics Pharmacokinetics Pharmacokinetics
Propylthiouracil Methimazole Inhibit Organification of Iodine Rapidly absorbed
Rapidly absorbed Variable Rate of Absorption Inhibit release of hormones Concentrated in Thyroid
Peak serum level – 1 h Completely Absorbed ↓ Size, Vascularity of Hyperplastic Thyroid
Bioavailability – 50-80% Can cross Placenta
(First Pass Effect) (avoid Chronic use in Pregnancy)
Half-Life – 1.5 h Half-Life – 6 h (Foetal Goitre)
Almost Completely Excreted by Excreted slowly (65-70%) by Kidney
Kidney (as Glucuronide) within 24 h
Dosing – 6-8 hourly Dosing once daily
Accumulated by Thyroid Gland Accumulated by Thyroid Gland
Cross Placental Barrier Cross Placental Barrier
(↓ Readily) (Preferable – Pregnancy)
Not Excreted in Milk
Adverse Effects Adverse Effects Adverse Effects
Maculopapular Pruritic Rash Toxicity – Iodism Aplastic Anaemia
Fever Uncommon, Reversible on Cessation (Potassium Perchlorate)
Rare Adverse Effects • Acneiform Rash
• Vasculitis • Swollen Salivary Glands
• Arthralgia • Mucous Membrane Ulceration
• SLE-Like Reaction • Conjunctivitis, Rhinorrhoea
• Hepatitis • Drug Fever
• Lymphadenopathy • Metallic Taste
Agranulocytosis (Rare, Potentially Fatal)(Reversibly on cessation) • Bleeding Disorders
Cross-Sensitivity (Present in about 50%)(Switching not recommended) • Anaphylactoid Reaction
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Thyroid Storm
Sudden, Acute Exacerbation of Thyrotoxicosis
Requires vigorous management
Drugs
Cardiac Symptoms
• Propranolol (Slow IV) – Except in presence of Severe Heart Failure
• Diltiazem (if Propranolol is contraindicated)
↓ Release of Thyroid Hormones
• Saturated solution of Potassium Iodide solution
(10 drops, Orally, Daily)
↓ Synthesis of Thyroid Hormones (Orally, Rectally)
• Propylthiouracil
• Methimazole
Hydrocortisone (50mg IV 6 hourly)
• Prevents Shock
• Blocks T4 → T3 conversion
General supportive measures

Drug Interactions
↓ Thyroid Hormone Production
Lithium
Iodine-containing medications
Amiodarone (Cordarone)
↓ Thyroid Hormone Absorption
Sucralfate (Carafate)
Ferrous Sulfate (Slow Fe)
Cholestyramine (Questran)
Colestipol (Colestid)
Aluminium-containing Antacids
Calcium produ cts
↑ Metabolism of Thyroxine
Rifampicin (Rifadin )
Phenobarbital
Carbamazepine (Tegretol)
Warfarin (Coumadin )
Oral Hypoglycaemic Agents
Displace Thyroid Hormone
from Protein Binding
Furosemide (Lasix)
Mefenamic Acid (Ponstan)
Salicylates