1. THYROID AND ANTI THYROID DRUGS
By : Dr. Abdul Latif Mahesar
Department of medical pharmacology
KKUH , King Saud University

3. Normal thyroid gland secretes T3 (triiodothyronine) and T4
Normal thyroid gland secretes T3 (triiodothyronine) and T4 (tetraiodothyronine).
To maintain
Normal growth and development of
Nervous
Skeletal
Reproductive systems

4. It also controls metabolism of
Fats
Carbohydrates
Proteins and
Vitamins

5. and hence controls Normal body temperature Normal energy levels
Thyroid status also affects
Secretion and degradation of
Catecholamine
Cortisones
Estrogens
progesterone and
insulin

6. Mental retardation (Cretinism) and dwarfism results due to deficiency of thyroxine in early life.
Hyperactivity of thyroid resembles sympathetic over activity, this may be due to oversensitivity of β-adrenergic receptors or increase in their number.
There may also be increase in the production of catecholamines

7. increased epinephrine activity causes
Tremors
Sweating
Anxiety
Nervousness
lid lag retraction

10. Manifestations of Hyperthyroidism
Restlessness , nervousness , irritability.
Tremors
palpitation
Weight loss
sweating
Heat intolerance

11. |Manifestations cont’d
Diarrhoea
Short breath
Itching
Tiredness
Light periods
Exophthalmos

14. Manifestations of Hypothyroidism
Fatigue and lack of energy
weight gain
Dry and cold skin
Dry hairs
Constipation
Slowed thinking
Bradycardia
Heavy menses
Intolerance to cold

15. Causes of hypothyroidism
Drugs
Auto immune destruction
Blocked hormone formation
Impaired synthesis of T4
Destruction or removal of gland
Iodine deficiency
Receptor blocking antibodies
pituitary or hypothalamic disease.

16. SYNTHESIS OF THYROID HORMONES
Iodide , an ions is actively taken up by the thyroid gland (Iodine trapping)/iodine uptake
Iodine is stored in the thyroid and is concentrated 25 times more
Iodide an ion is then oxidized to iodine by thyroidal peroxidase.

17. It iodinates tyrosine (with in thyroglobulin, a glycoprotein molecule) to form mono-iodotyrosine (MIT) and Di-iodotyrosine (DIT), called organification or iodination.

18. Biosynthesis of thyroid hormones ,also showing various sites of anithyroid drug actions

19. Two molecules of DIT unite to form T4 (tetra- iodothyroine) and one molecule of MIT and DIT combine to form T3 (tri-iodothyronine).
These hormones are released by exocytosis and proteolysis of thyroglobulin.
Ratio of T4 to T3 in thyroglobulin is 5:1
Most of T3 in circulation is derived from metabolism ofT4.

20. HORMONE TRANSPORT.
T4 and T3 are reversibly bound to thyroxine binding globulin (TBG).
0.04% of total T4 and 0.4% of T3 exist in free form
Starvation , pregnancy , steroid hormones affects their binding

21. Metabolism of thyroxine in to active T3 and inactive T3 (rT3)

22. Thyroid Hormone Production and Metabolism per day

23. PERIPHERAL METABOLISM
Small amount is biologically inactivated by deamination, decarboxylation conjugation and excreted as Glucuronide or sulphate, but
The primary pathway of peripheral thyroxine metabolism is DEIODINATION.
Deiodination of T4 at outer ring to active and 3-4 times more potent T3. and

24. Metabolism cont’d
De-Iodination of inner ring produces reverse T3(rT3), metabolically inactive.
Drugs like ipodate, β-blockers and corticosteroids; starvation inhibits 5-deiodinase.
This results low T3 and high rT3.

25. Hypothalamic –pitutary – thyroid axix
Thyroid regulation

27. THYROID REGULATION
Thyrotropin releasing hormone (TRH) is secreted by hypothalamic cells in pituitary portal venous system.
It acts on pituitary and causes synthesis and release of thyroid stimulating hormone (TSH).
This in turn acts on thyroid cell to increase release and synthesis of T3 and T4.

28. These thyroid hormones in a negative feed back fashion act on pituitary to block action of TSH and on hypothalamus to inhibit TRH.
Level of iodine in blood also regulates thyroidal secretion independent of TSH. (large doses of iodide inhibits iodine organification)
THYROXINE ISOMERS: Naturally occurring molecules are L- isomers; where as synthetic molecules are D-isomers. D -isomers have only 4% activity of L-isomers.

29. Mechanims of action of thyroid hormones PP T3 T3 T4 PB T3 T3
Pre-m RNA
cytoplasm
Nucleus
Response
mRNA
Protein
Mechanims of action of thyroid hormones
Mechanism of action of thyroxine at cellular level

30. Free form of T3 and T4 enter cell by diffusion /active transport .
MECHANISM OF ACTION
Free form of T3 and T4 enter cell by diffusion /active transport .
T4 is converted to T3 and enters nucleus and binds to T3 receptors, this leads to increased formation of mRNA and subsequent protein synthesis.

31. Pharmacokinetics of administered thyroid hormones
T4, best absorbed in duodenum and ileum, this can be altered by food and drugs, such as calcium preparations and antacids containing aluminum, intestinal flora Absorption of T4 is 80% and of T3 is 95%.
Absorption is not affected by mild hypothyroidism but impaired in myxedema with ileus, for this parental route is preferred.

32. In hyperthyroidism metabolic clearance of T3 and T4 is increased and their half life is decreased and opposite is true in hypothyrodism.
Enzyme inducers increase metabolism of T3 and T4 but concentration is maintained in euthyroid.
Same compensatory mechanism occurs if binding sites are altered as in pregnancy, estrogen therapy and use of oral contraceptives.

33. Thyroid preparations LEVOTHYROXINE:(T4)
This is the preparation of choice for thyroid replacement and suppression therapy, because it is stable and has a long (7 days) half life, to be administered once daily.
Oral preparations available are from to 0.3 mg tablets
For parentral use µg (100µg/ml when reconstituted) for injection.

34. LIOTHYRONINE(T3) :
This is more potent (3-4 times) and rapid acting than levothyroxine but has a short half life (24 hours) compared to levo, is not recommended for routine replacement therapy, it requires multiple dosing in a day.
It should be avoided in cardiac patients.
Oral preparation available are 5-50µg tablets
For parentral use 10µg/ml

35. Comparison of T4 to T3 T4 production is more than T3
T4 is converted to T3 in periphery
T3 is more potent than T4
T3 acts faster thanT4
T3 enters cell easily than T4
T3 binds to receptors in nucleus.

36. Mechanism ANTITHYROID AGENTS:
Agents which interfere production of thyroid hormone .
Agents which modify tissue response to thyroid hormones
Glandular destruction with radiation or surgery.

37. Drugs :
Thioamides
Iodides
Radio active iodine
Iodinated contrast media
Adrenoceptor- blocking Agents
Anion inhibitors

38. Anti –thyroid agents ( Mechanissm)

39. THIOAMIDES: Methimazole Carbimazole Propylthiouracil
Methimazole is 10 times more active than
propylthiouracil.

40. Mechanism of Action They act by:
Inhibiting thyroidperoxidase –catalysed reaction to block iodine organification.
They block coupling of iodotyrosine
They inhibit peripheral Deiodination of T4 to
T3.
Onset of drug is slow requiring 3-4 weeks
before stores of T4 are depleted.

41. Pharmacokinetic comparision between Propylthiouracil and Methimazole
Absorption
Rapid but incomplete
At variable rates but complete
Vol.of Dist.
Approximates body waters
Similar
Protein binding
more
less
accumulation
In thyroid
Excretion
Kidneys as inactive Glucuronide in 24 hrs
Excretion slow,60-70% of drug is recovered in urine in 48 hrs

42. Pharmacokinetic comparision between Propylthiouracil and Methimazole
Half life
1.5 hrs
6 hrs
Administration
Every 6-8 hrs
As a single dose in 24 hrs
Duration of activity
100 mg inhibits iodine organification for 7 hrs
30 mg exerts Antithyroid effect for longer than 24 hrs
Pregnancy
Preferred, though cross placenta and is conc .in fetal thyroid but is highly protein bound ,cross placenta less readily
Cross placenta and concentrated by fetal thyroid
Nursing mothers
Less secreted in breast milk
secreted

43. Adverse Effects ( thioamides)
It occurs in 3-12 % of treated patients
Maculopapular rash and fever are earlier effects.
Urticarial rash, vasculitis, arthralgia ,cholestetic jaundice ,lymphadenopathy, and hypoprothrombenemia.
Most dangerous complication is agranulocytosis this is infrequent but may be fatal.

44. IODIDES:
They inhibit organification and hormone release. With a dose of > 6 mg /day.
They should be initiated after onset of thioamides therapy.
It also decreases the vascularity of hyperplastic gland (making it valuable for preparation for surgery)
Improvement is rapid within 2-7 days (valuable in thyroid storm)
Should not be used alone ! ?

45. Iodides cont’d Well and rapidly absorbed from intestines
Rapidly taken by thyroid gland and concentrated there
Moderate increase leads to hormone secretion
but substantial excess inhibits hormone release and promotes its storage, making the organ less vascular and firmer.
iodides stores in thyroid delays response to thioamides

46. Precautions /toxicity:
Should not be used as a single therapy
Should not be used in pregnancy
May produce iodism causing acniform rash, swelling of salivary glands, mucous membrane ulceration, metallic taste bleeding disorders and rarely anaphylaxis.

47. RADIOACTIVE IODINE 131 I isotope , administered orally
It is rapidly absorbed, concentrated in thyroid gland and stored in follicles.
It has a half life of 5 days
It is easy to administer ,effective , painless and less expensive
It causes destruction of parenchyma ,necrosis and follicular disruption.

48. Radio active iodine cont’d
Therapeutic effect is due to emission of β-rays.
Patients with age above 40 years only can be treated with this
It crosses placenta and excreted in breast milk
It may cause genetic damage and leukemia and neoplasia ,it may be carcinogenic

49. IODINATED CONTRAST MEDIA
Ipodate , iopanoic acid administered orally
Diattrizoate administered intravenously
These drugs rapidly inhibit the conversion of T4 to T3.
They are relatively non toxic
Useful adjunctive therapy in thyroid storm
Valuable alternative when thioamides or iodides contraindicated.

50. ADRENOCEPTOR BLOCKING AGENTS:
Many symptoms of thyrotoxicosis mimic , especially those which are associated with sympathetic stimulation.
Beta blocking drugs without intrinsic sympathomimic activity are the agents of choice in these conditions
e.g. Propranolol.
In conditions where Beta blockers cannot be used then Diltiazem is used.

51. HYPOTHYRODISM:
It is a syndrome resulting from deficiency of thyroid hormones and manifested by reversible slowing down of all body function.
Infants and children suffer severely ,results in dwarfism and irreversible mental retardation
Diagnosed by low free thyroxine and elevated serum TSH
For treatment : replacement therapy is appropriate
Levothroxine is most satisfactory: Infants and children require more T4 /kg body weight than adults.
Average dose in children µg/kg/day and in adults: 1.7 µg/kg/day.
It takes 6-8 weeks to reach steady state level.

52. In long standing condition, in older patients and in patients with cardiac ailments, treatment is started with reduced dosage.
Thyroxine is given once daily due to long half life.
In older patients and in patients with underlying cardiac diseases treatment is started with reduced dose
levothyroxine is given in a dose of 12.5 – 25 µg/day for two weeks and then increasing it after every two weeks.

53. ADVERSE EFFECTS OF OVER DOSE
CHILDEREN : Restlessness, insomnia ,accelerated bone maturation.
ADULTS : Nervousness, heat intolerance , palpitation, weight loss
Atrial fibrillation and osteoporosis in chronic over treatment with T4.

54. MYXEDEMA COMA: It is an end state of untreated hypothyroidism.
It develops quite and progress slowly to stupor , coma and death.
The treatment of choice is loading dose of levothyroxine intravenously µg initially followed by 50µg daily.
I/V T3 can be used but it may prove cardiotoxic
I/V hydrocortisone it may be used in case of adrenal and pituitary insufficiency.

55. HYPOTHROIDSM AND PREGNANCY.
These woman suffer form anovulatory cycles and infertility
In pregnant hypothyroid patient % increase in thyroxine is required because of elevated maternal TBG and because of early development of fetal brain which depends on maternal thyroxine

56. HYPERTHYROIDISM
This is the syndrome that results when tissue is exposed to high levels of thyroid hormone.
GRAVES' DISEASE
Most common form of hyperthyroidism.
It is autoimmune disorder
There is genetic defect in suppressor T lymphocyte , B lymphocytes synthesize antibodies against thyroid antigens.

57. T3 and T4 are elevated and TSH is suppressed.
Radio iodine uptake is elevated.

58. Management of Grave’s disease
Drug therapy
surgical thyroidectomy
Destruction of the gland with radioactive iodine

59. When patient is young with small gland and mild disease
Drug therapy:
Methimazole / propylthiouracil until disease undergoes spontaneous remission.
this may take 1-2 years with % relapse.

60. therapy is started with large divided doses ,then shifted to maintenance therapy with single daily dose.
Propylthiouracil is better than methimazole.
this may lead to increase in TSH and stimulation of thyroid, this can be prevented by addition of levothyroxine.

61. THYROIDECTOMY
A near-total thyriodectomy is the treatment of choice in very large gland or multinodular goiter
In case of large or multinodular goiter and to simplify surgery (to diminish vascularity) saturated solution of potassium iodide 5 drops twice daily for two weeks prior to surgery

62. RADIOACTIVE IODINE 131I
Preferred in most patients over 21 years of age in a dose of µCi/gm of thyroid weight.( in patients without underlying cardiac disease)
in patients with underlying heart disease ,severe disease , elderly patient use methimazole until patient become euthyroid , then stop the medicine for 5-7 days.
Major complication of this therapy is hypothyroidism which occurs in 80% of patients.

63. Adjuncts Therapy
During acute phase β-blockers without intrinsic sympathomimetic activity are extremely helpful
eg : Propranolol

64. THYROID STORM:
It is sudden acute exacerbation of all of the symptoms of thyrotoxicosis, presenting as a life threatening syndrome.
There is hyper metabolism, and excessive adrenergic activity, death may occur due to heart failure and shock.
Vigorous management is mandatory. Propranolol 1-2mg slows I/v or mg orally every 6 hours

65. Potassium iodide 10 drops orally daily or
Iodinated contrast media(Na ipodate 1 g orally daily)
Propylthiouracil 250 mg orally every six hours or 400 mg every six hours rectally.
Hydrocortisone 50 mg I/V every 6 hours to prevent shock.
If above methods fail plasmapheresis or peritoneal dialysis.

66. Thyrotoxicosis during pregnancy
Definitive therapy with 131I or subtotal thyroidectomy prior to pregnancy to avoid acute exacerbation during pregnancy or after delivery
During pregnancy radioiodine is contraindicated.
Propylthiouracil is better choice during pregnancy. Dose must be kept minimum i.e., <300 mg daily.

67. ANION INHIBITORS
Perchlorate (Clo4) ; pertechnetate(TcO4) and thiocynate (SCN) can block uptake of iodide by the gland by competitive inhibition
For this purpose large doses of the drug are required
They are rarely used clinically now days ,as it has been shown to cause aplastic anemia.