Thyroid & Antithyroid Drugs

• Medical treatment involves the use of thyroid and antithyroid hormones.

Objectives

• Identify thyroid and antithyroid hormones used in treatment.
• Know thyroid hormone analogs/preparations.
• Know thyrotropin preparations.
• Know thioamide drugs.
• Know antithyroid agents like potassium iodide solution and RAI.
• Comprehend the mechanisms, pharmacokinetics, and pharmacodynamics of thyroid and antithyroid hormones.
• Understand possible drug interactions and adverse effects.
• Know the main indications and contraindications.

Thyroid Physiology

• The thyroid gland secretes triiodothyronine (T3) and tetraiodothyronine (T4, thyroxine).
• These hormones normalize body temperature, growth and development, and energy levels.
• Iodide is ingested daily for hormone synthesis.
• The hypothalamic-pituitary-thyroid axis regulates thyroid hormone production.
• Peripheral metabolism of thyroxine (T4) involves deiodination by 5'-deiodinase enzymes (D1, D2, D3).
• D1 accounts for 24% of circulating T3.
• D2 generates 64% of peripheral T3 & controls T3 in brain and pituitary.
• D3 deiodination produces inactive 3,3',5'-triiodothyronine (reverse T3 [rT3]).

Evaluation of Thyroid Function

• Total thyroxine (T4) normal value is 4.8 - 10.4 mcg/dL (62–134 nmol/L).
• Total triiodothyronine (T3) normal is 59–156 ng/dL (0.9-2.4 nmol/L).
• Free T4 (FT4) normal is 0.8 - 1.44 ng/dL (10–18 pmol/L).
• Free T3 (FT3) normal is 169–371 ng/dL (2.6–5.7 pmol/L).
• Thyrotropic hormone (TSH) normal is 0.45–4.12 µIU/mL (0.45–4.12 mIU/L).
• The 123I uptake at 24 hours normal is 5-35%.
• Antithyroglobulin antibodies (Tg-Ab) normal is <200 IU/mL.
• Thyroperoxidase antibodies (ATPO) normal is ≤100 WHO units.
• Isotope scan uses 123I or 99mTcO4 with a normal pattern.
• Serum thyroglobulin normal for women is 1.5-38.5 mcg/L, and for men is 1.4-29.2 mcg/L.
• TSH receptor-stimulating antibody or thyroid-stimulating immunoglobulin (TSI) is Negative <140% of baseline.

Thyroid Agents

• Thyroid hormones are best absorbed in the duodenum and ileum.
• Absorption is modified by intraluminal factors such as food, drugs, gastric acidity, and intestinal flora.
• Oral bioavailability of L-thyroxine averages 70–80%.
• T3 is almost completely absorbed (95%).
• T4 and T3 absorption seems unaffected by mild hypothyroidism but can be affected with severe myxedema with ileus.
• Metabolic clearances of T4 and T₃are ↑, and half-lives are ↓ in hyperthyroidism patients.
• The opposite is seen in hypothyroidism patients
• Drugs that induce hepatic microsomal enzymes increase T4 and T3 metabolism.
• The mechanism of action of T3 and T4 are responsible for optimal growth, development, function, and maintenance of all body tissues.
• These are critical for the development and functioning of nervous, skeletal, and reproductive tissues.
• They are accompanied by a pervasive influence on metabolism of drugs as well as carbohydrates, fats, proteins, and vitamins.
• Secretion and degradation rates of virtually all other hormones, including catecholamines, cortisol, estrogens, testosterone, and insulin, are affected by thyroid status.
• Thyroid preparations are synthetic, like levothyroxine (T4), liothyronine, and liotrix, or of animal origin called desiccated thyroid.

Levothyroxine T4

• It is often the preparation used for thyroid replacement and suppression therapy:
  • It is stable
  • Shows content uniformity
  • Is low cost
  • Has no allergenic foreign protein
  • Easy laboratory measurement of serum levels -Long half-life, 7 days, allows for once-daily to weekly administration -It is long-term safe
  • Generic ones give comparable efficacy
• Mechanism of action
  • Synthetic form of thyroxine is converted to active metabolite, L-triiodothyronine (T3).
  • T3 and T4 then bind to thyroid receptor proteins within the cell nucleus exerting metabolic effects.
  • Affecting control of DNA transcription and protein synthesis.
• Pharmacokinetics
  • Oral onset is 3-5 days.
  • IV onset its 6-8 hours
  • Erratic oral absorption
  • Fasting bioavailability approximately 79% to 81%
  • Protein binding greater than 99% to plasma proteins
  • Hepatic metabolism
  • Euthyroid half life is 6-7 days
  • Hypothyroid half life is 9-10 days
  • Hyperthyroid half life is 3-4 days
  • It is excreted in urine and feces
• Indications
• Hypothyroidism
• Congenital hypothyroidism or those of any origin
• Can be primary, secondary, tertiary.
• Contraindications
  • Uncorrected adrenal insufficiency
  • Hypersensitivity.

Adverse Reactions

• Cardiovascular: Angina pectoris, arrhythmia, flushing, increased blood pressure and pulse, myocardial infarction, palpitations, tachycardia.
• CNS: Anxiety, lability, fatigue, headache, heat intolerance, hyperactivity, insomnia, irritability, myasthenia, nervousness.
• Dermatologic: Alopecia, diaphoresis, skin rash
• Endocrine/metabolic: Goiter, menstrual disease, weight loss
• GI: Abdominal cramps, diarrhea, increased appetite, vomiting
• Genitourinary: Reduced fertility
• Hepatic: Decreased liver enzymes
• Neuromuscular/Skeletal: Decreased bone mineral density, muscle spasm, tremor
• Respiratory: Dyspnea
• Miscellaneous: Fever
• Drugs that decrease serum concentration: aluminum hydroxide, bile acid sequestrants, calcium sulfonate, carbamazepine, ciprofloxacin, fosphenytoin, iron, lanthanum, magnesium, multivitamins, orlistat, patiromer, phenytoin, polaprezinc, rifampin, sevelamer, sodium sulfonate, sucralfate, sucroferric oxyhydroxide
• Drugs that diminish the therapeutic effect: amiodarone, apalutamide, calcium, estrogen, ritonavir, SSRIs, somatropin
• Drugs that diminish absorption: raloxifene
• Drugs that increase serum concentration: semaglutide
• Food Interactions: enteral nutrition, soybean flour/soy/grapefruit juice/espresso coffee/cottonseed meal/walnuts/calcium/iron/fiber

Liothyronine (T3)

• More potent than levothyroxine, but shorter half-life, 24 hours
• Is converted intracellularly to T3 by deiodinase enzymes.
• Production of both hormones makes T3 administration unnecessary.
• Use with caution in persons with cardiac disease due to risk of cardiotoxicity from significant increases in peak T3 levels.
• Best reserved for temporary TSH suppression.
• Can combine with levothyroxine.
• MoA: Exact mechanism is unknown but believed to be mediated by controlling DNA transcription and protein synthesis.
• Pharmacokinetics:
  • Oral onset is within a few hours
  • Oral absorption is good
  • Elimination half-life spans 0-75 days -Excreted in urine and feces.
• Indications:
  • Primary
  • Secondary (pituitary)
  • Tertiary (hypothalamic)
  • Congenital thyroid issues and hypothyroidism
  • Can be combined with surgery and radiotherapy
  • Myxedema coma/precoma: Given IV
• Contraindications:
  • Hypersensitivity -Adrenal insufficiency
  • Thyrotoxicosis
• Adverse Reactions:
  • Arrhythmia (6%)
  • Tachycardia (3%)
  • Hypotension (≤2%)
  • Myocardial infarction (≤2%)
• Drug interactions:
  • Amiodarone
  • Bile acid sequestrants
  • Calcium sulfonate
  • Calcium salts
  • Carbamazepine
  • Cardiac glycosides
  • Ciprofloxacin
  • Estrogen derivatives
  • Phenytoin
  • Piracetam
  • Rifampin
  • Ritonavir
  • SSRIs
  • Sodium iodide
  • Sodium sulfonate
  • Theophylline derivatives
  • Tricyclic antidepressants
  • Vitamin K antagonists
  • Fosphenytoin

Anti-thyroid Agents

Thioamides: Methimazole and Propylthiouracil (PTU)

• Methimazole treats thyrotoxicosis including Graves disease and toxic multinodular goiter
  • Is the usual drug of choice for adults and children
  • It is 10 times more potent than PTU
  • It inhibits synthesis of thyroid hormones -Blocking iodine oxidation in the thyroid gland -Blocking thyroxine and triiodothyronine
  • It does not inactivate circulating T₄ or T3.
  • Treatment should last 12 to 18 months.
  • A reduction in goiter size is the best clinical guide to remission
  • Remission lasts roughly 50% to 60% of the time
• Has 12 to 18 hours oral onset
• Can last for 36 to 72 hours
• It is fully absorbed: distributed into the thyroid gland
• It is hepatically metabolized -Elimination lasts 4-6 hours
• Excreted in urine
• Indications: hyperthyroidism
• Graves' disease
• Surgery for toxic Multi nodular golter is not appropriate
• Amelioration of symptoms while waiting on thyroid radiation and / or thyrotoxic interventions.
• Contraindications:
  • Hyesensitivity
  • Breast feeding
  • Acute pancreatitis
• Adverse effects:
  • Cardiovascular: Edema, periarteritis.
  • CNS: Drowsiness, headache, drug fever, neuritis, parestesia, vertigo.
  • Dermatologic: Alopecia, pruritus, skin pigmentation, skin rash, urticaria.
  • Endocrine/metabolic: Hypoglycemic coma, hypothyroidism, autoimmune syndrome
  • GI: Ageusia, enlargement of salivary glands, epigastric distress, nausea, vomiting
  • Hematologic/oncologic: Agranulocytosis/aplastic anemia/granulocytopenia/hypoprothrombinemia/leukopenia/lymphadenopathy/thrombocytopenia
  • Hepatic: Hepatitis, jaundice.
  • Neuromuscular/skeletal: Arthralgia, lupus-like syndrome, myalgia.
  • Renal: Nephritis.
• Drug interactions: -BCG vaccine -Cardiac glycosides -Chloramphenicol -ophthalmic -Cladribine -Clozapine -Deferiprone

Propylthiouracil

• Is reserved for use in the 1st trimester of pregnancy or thyroid storm
• Alternative treatment for patients with adverse reactions to methimazole
• It inhibits the synthesis of thyroid hormones
  • Interfering with thyroid peroxidase (TPO)
  • Blocking T₄ to T3 conversion in peripheral tissues.
• Effects appear 24-36 hours after oral dose
• Can last for 12 - 24 hrs
• Concentrated in thyroid gland
• Metabolized in the liver
• Elimination is about an hour.
• Excreted through urine
• Contraindications: -Hypersensitivity -Breastfeeding
• Practically has the same adverse effects as methimazole but practically has no endocrine or metabolic reactions
• Has the same drug interaction as Methimazole

Radioactive Iodine

• Only isotope used for treating thyrotoxicosis
• Given orally in sodium solution
• Concentrated by thyrotoxic tissues and rapidly absorbed
• Emits beta particles to destroy thyroid tissue
• Results evident weeks post tx, via: -Epithelial swelling -Necrosis -Follicular disruption -Edema -Leukocyte infiltrate
• Advantages: -Easy administration -Effectiveness -Low expense -No pain
• Do not give this to pregnant women or nursing mothers

Beta-Adrenoceptor Antagonists

• The sympathomimetic agents are very effective in thyrotoxicosis management.
• Propanolol is most used.
• Improve hyperthyroid symptoms but do not alter thyroid hormone levels.

Management of Thyrotoxicosis

• Defined as suppressed TSH levels and normal thyroid hormone levels.
• Treatment is appropriate with TSH less than .01mIU/L.
• Type I(iodine induced)- treated with Thioamides
• Type I(inflammatory thyroiditis)- responds to glucocorticoids
• If hard to differentiate, give both.

Management of Hypothyroidism

• Signs and symptoms include stupor, hypothermia, altered mental status.
• Start levothyroxine
• Check urinary iodine, pituitary issues or Hashimoto's
• Thyroidectomy etc will require higher doses
• Replace hormones for life
• Replacement therapy uses levothyroxine.
• Levo + liothyronine not superior to levo, steady state not achieved w levo until week 6 or 8
• Dose per age and weight
• Infants and children need more T4 than adults
• Adults may need less due to lower body mass
• Give thyroxine on empty stomach for best results
• Give less thyroxine to older patients due to potential toxicity

Special Problems of Hyporthyroidism

• Do not treat mix edema due to coronary issues as one as a treatment may exacerbate the other
• Consider bypass treatment first prior to treating mix edema
• High T4 dose requirements for pregnant women's. Give an additional treatment separately
• Do not treat amiodarone induced