1. Thyroid and Antithyroid Drugs
Dr Safaeian
Isfahan University of Medical Sciences

2. Thyroid Physiology Thyroid gland secretes: Triiodothyronine (T3)
Tetraiodothyronine (T4, Thyroxine)
Calcitonin: important in regulation of calcium metabolism
T3 and T4 → contain 59% and 65% (respectively) of iodine as an essential part of the molecule.
They normalize growth and development, body temperature, and energy levels.

3. Iodide Metabolism
Recommended daily adult iodide (I–) intake is 150 mcg (200 mcg during pregnancy).
Iodide, ingested from food, water, or medication, is rapidly absorbed and enters an extracellular fluid pool.
Thyroid gland removes about 75 mcg a day from this pool for hormone synthesis, and balance is excreted in urine.
If iodide intake is increased, fractional iodine uptake by thyroid is diminished.

4. Biosynthesis of Thyroid Hormones
Transport of iodide into thyroid gland by Na+/I-
symporter ► can be inhibited by anions as thiocyanate (SCN–), pertechnetate (TcO4–), and perchlorate (ClO4–).
At the apical cell
membrane a second
I– transport enzyme
called pendrin controls
flow of iodide
across membrane.
Biosynthesis of Thyroid Hormones
Iodine: all forms of the element
Pendrin is also found in the cochlea of the inner ear and if deficient or absent, a syndrome of deafness and goiter, called Pendred's syndrome, ensues.

5. Biosynthesis of Thyroid Hormones
Oxidization of iodide by thyroidal peroxidase to iodineis ► transiently blocked by high levels of intrathyroidal iodide and blocked more persistently by thioamide drugs.
3. Iodide organification:
iodinatation of tyrosine
residues within thyroglobulin
molecule → formation of
monoiodotyrosine (MIT) and
diiodotyrosine (DIT).
Biosynthesis of Thyroid Hormones
Iodine: all forms of the element

6. Biosynthesis of Thyroid Hormones
4. DIT + DIT → L-thyroxine (T4)
MIT + DIT →T3
5. Exocytosis: T4 and T3 are released from thyroglobulin by proteolysis and exocytosis occurs ► blocked by high levels of intrathyroidal iodide.
Ratio of T4 to T3 = 5:1
Most of T3 is derived from
peripheral metabolism of T4.
T3 is 4 times more
potent than T4.
Biosynthesis of Thyroid Hormones

7. Transport and Peripheral Metabolism of Thyroid Hormones
T4 and T3 are bound to thyroxine-binding globulin (TBG) in plasma . Only ~ 0.04% of total T4 and 0.4% of T3 exist in free form.
T4 is deiodinized by 5´-deiodinase in outer ring to active T3 and in inner ring to reverse T3 (rT3), which is metabolically inactive.
5´-deiodinase is inhibited by:
- Amiodarone Iodinated contrast media
- β blockers Corticosteroids
- Severe illness or Starvation

8. Thyroid-Pituitary Relationships
Hypothalamus gland secretes
thyrotropin-releasing hormone (TRH).
TRH stimulates synthesis and release
of thyroid-stimulating hormone (TSH)
from pituitary gland.
TSH stimulates thyroid cells →
↑adenylyl cyclase activity →
↑synthesis and release of T4 and T3 .
Thyroid hormones block action
of TRH and TSH (negative feedback).

9. Autoregulation of Thyroid Gland
Thyroid gland also regulates its uptake of I- and hormone synthesis by intrathyroidal mechanisms that are independent of TSH and are primarily related to level of I- in blood.
Large doses of iodine inhibit I- organification (Wolff-Chaikoff block).
Large doses of iodine inhibit iodide organification (Wolff-Chaikoff block, see Figure 38–1).

10. Hypothyroidism Deficiency of thyroid hormones
Slowing down of all body functions
Can occur with or without thyroid enlargement (goiter).
Most common cause: Hashimoto’s thyroiditis: an autoimmune disorder → thyroid is destroyed by antibodies.
Secondary hypothyroidism: Impaired hypothalamus and pituitary function.
A diet insufficient in iodine causes
hypothyroidism.

11. Hypothyroidism
Myxedema coma: end state of untreated hypothyroidism → progressive weakness, stupor, hypothermia, hypoventilation, hypoglycemia, hyponatremia, water intoxication, shock, and death.
Cretinism: thyroid deprivation in early
life → mental retardation and dwarfism.

12. Signs and Symptoms of Hypothyroidism
Skin and appendages: Pale, cool Skin, dry and brittle hair, brittle nails, sensitivity to cold
Eyes, face: Drooping of eyelids; periorbital edema; loss of temporal aspects of eyebrows; puffy facies; large tongue
Cardiovascular system: ↑PVR; ↓HR, ↓stroke volume, ↓cardiac output, ↓pulse pressure; bradycardia, prolonged PR interval, flat T wave; pericardial effusion
Respiratory system: Pleural effusions; hypoventilation
GI system:↓Appetite; ↓bowel movements; ascites
CNS: Lethargy; slowing of mental processes; neuropathies
Peripheral vascular resistance

13. Signs and Symptoms of Hypothyroidism
Musculoskeletal system: Stiffness, Muscle fatigue, ↓deep tendon reflexes; ↑alkaline phosphatase, ↑LDH
Renal system: Impaired water excretion; ↓renal blood flow; ↓GFR
Hematopoietic system: ↓Erythropoiesis, Anemia
Reproductive system: Hypermenorrhea; infertility; ↓libido; impotence; oligospermia; ↓steroid metabolism
Metabolic system: ↓Basal metabolic rate, ↑Cholesterol, ↑TG, ↓hormone and drug metabolism
The anemia of hypothyroidism may be normochromic, hyperchromic, or hypochromic and may be due to decreased production rate, decreased iron absorption, decreased folic acid absorption, or to autoimmune pernicious anemia.

14. Treatment for Hypothyroidism
Hormone replacement therapy:
Synthetic:
Levothyroxine Sodium (T4) (Tab, Cap 50, 75, 100 mcg)
Liothyronine Sodium (T3) (Tab 25 mcg)
Liotrix (4:1 ratio of T4: T3)
Animal origin: desiccated thyroid

15. Thyroid Hormones: Pharmacokinetics
T4 absorption is modified by intraluminal factors such as food, drugs, and intestinal flora.
Oral bioavailability: T4 = 80% , T3 = 95%
Levothyroxine doses should be administered on an empty stomach in the morning 30–60 minutes before breakfast or at bedtime 4 hours after the last meal.

16. Thyroid Hormones: Pharmacokinetics
Interference with T4 absorption:  
Cholestyramine, colestipol, ciprofloxacin, proton pump inhibitors, sucralfate, aluminum hydroxide, ferrous sulfate, calcium carbonate, bran, soy, coffee

17. Thyroid Hormones: Mechanism of Action
Free T4 and T3 enter the cell by active transport.
Within the cell, T4 is converted to T3 .
T3 enters the nucleus → binds to a specific T3 receptor protein →↑formation of RNA and protein synthesis.
Large numbers of TR are found in the most hormone-responsive tissues (pituitary, liver, kidney, heart, skeletal muscle, lung, and intestine)
Few receptor sites occur in hormone-unresponsive tissues (spleen, testes).
Brain lacks an anabolic response to T3 , contains an intermediate number of receptors.
Affinity of receptor site for T4 is about 10 times lower than T3
Thyroid Hormones: Mechanism of Action

18. Effects of Thyroid Hormones
Responsible for optimal growth, development, function, and maintenance of all body tissues
Critical for nervous, skeletal, and reproductive tissues
Its effects depend on protein synthesis as well as potentiation of secretion and action of GH
Widespread influence on metabolism of drugs as well as carbohydrates, fats, proteins, and vitamins.
Effects of Thyroid Hormones

19. Effects of Thyroid Hormones
Affect secretion and degradation rates of other hormones (catecholamines, cortisol, estrogens, testosterone, insulin)
Thyroid hyperactivity resemble sympathetic nervous system overactivity→ ↑numbers and signal of β receptors (especially in cardiovascular system)
Other clinical symptoms indicative excessive epinephrine activity (tremor, excessive sweating, anxiety, nervousness)

20. Thyroid Preparations Choice: Synthetic levothyroxine, because of:
Its stability, content uniformity, low cost, lack of allergenic foreign protein, easy laboratory measurement of serum levels, and long half-life (7 days) → once-daily administration
Liothyronine: greater hormone activity and consequent greater risk of cardiotoxicity, best used for short-term suppression of TSH.
Thyroid hormones are not effective and can be harmful in management of obesity, abnormal vaginal bleeding, or depression if thyroid hormone levels are normal.
Thyroid Preparations
T3:its shorter half-life (24 hours), which
requires multiple daily doses; its higher cost; and the greater difficulty
of monitoring its adequacy of replacement by conventional
laboratory tests. Furthermore,

21. Hyperthyroidism (Thyrotoxicosis)
Over production of thyroid hormones.
Most common form: Graves' disease, or diffuse toxic goiter: autoimmune disorder with antibodies against TSH receptor in thyroid cell membrane with capacity to stimulate growth and biosynthetic activity of thyroid cell (with much longer duration of effect)
Thyroid storm (Thyrotoxic crisis): sudden acute exacerbation of thyrotoxicosis
and a life-threatening syndrome.

22. Signs and Symptoms of Hyperthyroidism
Skin and appendages: Warm, moist skin, sweating, heat intolerance; fine, thin hair, Plummer nail
Eyes, face: periorbital edema; exophthalmos
Cardiovascular system: ↓PVR; ↑HR, ↑stroke volume, ↑cardiac output, ↑pulse pressure; arrhythmias; angina
Respiratory system: Dyspnea; ↓vital capacity
GI system: ↑Appetite; ↑bowel movements
CNS: Nervousness; hyperkinesia; emotional lability
Peripheral vascular resistance

23. Signs and Symptoms of Hyperthyroidism
Musculoskeletal system: Weakness, Muscle fatigue, ↑deep tendon reflexes; hypercalcemia; osteoporosis
Renal system: Mild polyuria; ↑renal blood flow; ↑GFR
Hematopoietic system: ↑Erythropoiesis, Anemia
Reproductive system: Menstrual irregularities; ↓fertility; ↑gonadal steroid metabolism
Metabolic system: ↑Basal metabolic rate, hyperglycemia; ↓Cholesterol, ↓TG, ↑hormone and drug metabolism
1The anemia of hyperthyroidism is usually normochromic and caused by increased red blood cell turnover

24. Treatment for Hyperthyroidism
Anti-thyroid Therapy
Radioactive Iodine
Thyroidectomy
Three main therapies, each was equally effective in normalizing serum thyroid hormone concentrations within 6 weeks.

25. ANTITHYROID AGENTS Thioamides Anion Inhibitors Iodides
Iodinated Contrast Media
Radioactive Iodine

26. Thioamides Propylthiouracil (PTU) Methimazole
Carbimazole (converted to
methimazole)
Methimazole: 10 times more
potent than PTU.

27. Thioamides: Pharmacokinetics
PTU: bioavailability of 50–80% due to incomplete absorption or a large first-pass effect, half-life=1.5 hrs
Methimazole: completely absorbed , half-life=6 hrs
Excreted by kidney
Accumulated by thyroid gland.
Methimazole is preferred because of its longer duration of action, allowing for once daily dosing, more rapid efficacy, and lower incidence of side effects.
clinical experience suggests that methimazole is 20 to 30 times as potent on a milligram to milligram basis.
For patients with significant symptoms of hyperthyroidism, we suggest starting a thionamide (methimazole) to achieve euthyroidism quickly. The starting dose of methimazole varies according to the severity of the hyperthyroidism.
5.8 weeks ver 16.8 weeks PTU

28. Thioamides in pregnancy
PTU is preferred during the first trimester of because of more strongly protein-bound and crosses the placenta less readily.
In the second trimester ► switching from PTU to an equivalent dose of Methimazole because of risk of hepatitis with PTU.
Both are secreted in low concentrations in breast milk but are considered safe for nursing infant.
MMI rarely,associated with congenital malformations.
clinical experience suggests that methimazole is 20 to 30 times as potent on a milligram to milligram basis.

29. Thioamides: Pharmacodynamics
Prevent hormone synthesis by:
Inhibiting thyroid peroxidase
Blocking iodine organification
Block coupling of the iodotyrosines
Inhibiting peripheral deiodination of T4 to T3
Since synthesis rather than release of hormones is affected, onset of action is slow → requiring 3–4 weeks before stores of T4 are depleted.

30. Thioamides: Toxicity Nausea, GI distress
Altered sense of taste or smell with methimazole
Maculopapular pruritic rash
accompanied by systemic signs
such as fever
Rare: Hepatitis and cholestatic jaundice
Most dangerous: Agranulocytosis
A maculopapular rash is a type of rash characterized by a flat, red area on the skin that is covered with small confluent bumps. The term "maculopapular" is a compound: macules are small, flat discolored spots on the surface of the skin; and papules are small, raised bumps. It is also described as erythematous, or red.
dangerous leukopenia (lowered white blood cell count)

31. Thioamides: Recommendations
Monitoring ► periodic clinical assessment and measurements of serum T4
Since hyperthyroidism results in negative Ca balance, ↓bone density, and ↑fracture risk ► advise to ingest 1200 to 1500 mg elemental Ca daily.
Assessment of thyroid function at 4 to 6 week intervals until stabilized on maintenance thionamide therapy.
Persistently low serum TSH concentrations after more than 6 months of therapy with thionamide ► unlikely to have a remission when the drug is stopped.
thionamide should not be discontinued unless a decision has been made to proceed to destructive therapy.

32. Anion Inhibitors Perchlorate (ClO4–) Pertechnetate (TcO4–)
Thiocyanate (SCN–)
Block uptake of iodide by gland through competitive inhibition of iodide transport.
Rarely used clinically because of association with aplastic anemia.

33. Iodides: Saturated Solution of Potassium Iodide (SSKI; Lugol's solution)
Mechanism of Action:
Inhibit organification
Inhibit hormone release (inhibition of thyroglobulin proteolysis)
↓Size and vascularity of hyperplastic gland
Preoperative preparation for surgery
Rarely used as sole therapy.
Iodine elixirs, up to 10 drops of SSKI, 50 mg iodide per drop [0.05 mL]) daily, can be used to ameliorate very mild hyperthyroidism.
For mild hyperthyroidism that persists after a dose of radioiodine, smaller doses (1 to 2 drops per day) are usually sufficient.

34. Iodides: Disadvantages
Increase in intraglandular stores of iodine→ delay onset of thioamide therapy or prevent use of radioactive iodine therapy.
Should not be used alone → gland will escape from iodide block in 2–8 weeks, and its withdrawal→ severe exacerbation of thyrotoxicosis
Chronic use in pregnancy should be avoided→ cross placenta and can cause fetal goiter.
iodides should be initiated after onset of thioamide therapy and avoided if treatment with radioactive iodine seems likely.

35. Iodides Adverse Effects:
Acne, swollen salivary glands, mucous membrane ulcerations, conjunctivitis, rhinorrhea, drug fever, metallic taste, bleeding disorders and, rarely anaphylactoid reactions.
iodides should be initiated after onset of thioamide therapy and avoided if treatment with radioactive iodine seems likely.

36. Iodinated Contrast Media
Diatrizoate (orally)
Iohexol (orally or IV)
Rapidly inhibit conversion of T4 to T3
Adjunctive therapy in the treatment of thyroid storm
Toxicity is similar to that of iodides.
Patients who have severe hyperthyroidism or are allergic to thionamides may benefit from Iodinated contrast agents and iodine therapies.

37. Administered orally in solution as sodium 131I
Concentrated by thyroid.
Therapeutic effect: emission of β rays → destruction of thyroid parenchyma.
Advantages: easy administration, effectiveness, low expense, and absence of pain.
Should not be administered to pregnant women or nursing mothers or women desiring to become pregnant in the near future.
Avoid close contact with young children for several days after radioiodine administration.
Radioactive Iodine: 131I
to consider radioiodine or surgery six months in advance of a planned pregnancy
Avoid close contact with others by maintaining a distance of 1 meter (approximately 3 feet) for up to three days following treatment.
Sleep alone for 7 days unless otherwise instructed by your doctor

38. Adjuncts to antithyroid therapy:
β-Blockers
Diltiazem (control of tachycardia in patients in whom β blockers are contraindicated, eg, those with asthma)
Vitamin supplements
Barbiturates (accelerate T4 breakdown by hepatic enzyme induction and may be helpful as sedatives)
Bile acid sequestrants (rapidly lower T4 levels by increasing the fecal excretion of T4)
Diltiazem, 90–120 mg three or four times daily, can be
used to control tachycardia in patients in whom β blockers are
contraindicated, eg, those with asthma. Other calcium channel
blockers may not be as effective as diltiazem. Adequate nutrition
and vitamin supplements are essential. Barbiturates accelerate T 4
breakdown (by hepatic enzyme induction) and may be helpful
both as sedatives and to lower T 4 levels. Bile acid sequestrants (eg,
cholestyramine) can also rapidly lower T 4 levels by increasing the
fecal excretion of T 4 .

39. Adrenoceptor-Blocking Agents
Beta blockers without intrinsic sympathomimetic activity (eg, metoprolol, propranolol, atenolol)
Effective therapeutic adjuncts in management of thyrotoxicosis
Ameliorate symptoms of hyperthyroidism due to ↑beta-adrenergic tone (palpitations, tachycardia, tremulousness, anxiety, heat intolerance).
Beta-blocker should be started in most patients as soon as diagnosis of hyperthyroidism.
Adrenoceptor-Blocking Agents
(assuming there are no contraindications to its use)

40. Effect of thyroid function on drug effects
Anticoagulation: Lower doses of warfarin required in hyperthyroidism, higher doses in hypothyroidism
Glucose control: ↑hepatic glucose production and glucose intolerance in hyperthyroidism; impaired insulin action and glucose disposal in hypothyroidism
Cardiac drugs: Higher doses of digoxin required in hyperthyroidism; lower doses in hypothyroidism
Sedatives; Analgesics: ↑sedative and respiratory depressant effects from sedatives and opioids in hypothyroidism; converse in hyperthyroidism