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THYROID AND ANTI THYROID DRUGS

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Title: THYROID AND ANTI THYROID DRUGS


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

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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 energy levels
  • also
  • Normal body temperature
  • Thyroid status also affects
  • Secretion and degradation of
  • Catecholamine
  • Cortisol
  • Insulin
  • Estrogen /Progesterone
  • Testosterone

6
  • The thyroidal hormone are responsible for
    optimal growth, development ,function and
    maintenance of all body tissues
  • Its effects depends upon protein synthesis and
    potentiation of the secretion and action of
    growth hormone

7
  • Deficiency of thyroidal hormones lead to
  • Hypothyroidism
  • Increased thyroidal hormone secretions lead to
  • Hyperthyroidism

8
  • Irreversible Mental retardation (Critinism) with
    low IQ and Dwarfism results due to deficiency of
    thyroxine in early life/pregnacy
  • Hyperactivity of thyroid resembles sympathetic
    over activity, this may be due to oversensitivity
    of ß-adrenergic receptors or increase in their
    number and enhanced amplification of the beta
    receptors signals
  • Also there is increase in the activity of
    catechloamine

9
  • Increased catechol and epinephreine activity may
    cause
  • Palpitation
  • Anxiety
  • Sweating
  • Tremors
  • Nervousness

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Manifestations of Hyperthyroidism
  • Restlessness , nervousness , irritability.
  • Tremors
  • Palpitation
  • Sweating
  • Heat intolerance
  • Weight loss
  • muscle wasting

12
Manifestations contd
  • Diarrhea
  • Short breath
  • Itching
  • Tiredness
  • Exophthalmos
  • Menstrual disturbances

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Manifestations of Hypothyroidism
  • Fatigue and lack of energy
  • weight gain
  • Dry and cold skin
  • Intolerance to cold
  • Slowed thinking
  • Depression
  • Bradycardia
  • Dry hairs
  • Constipation
  • Infertility

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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.

22
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 gland and is
    concentrated 25 times more
  • Iodide an ion is then oxidized to iodine by
    thyroidal peroxidase enzyme

23
  • It iodinates tyrosine (with in thyroglobulin, a
    glycoprotein molecule) to form mono-iodotyrosine
    (MIT) and Di-iodotyrosine (DIT), called
    organification or iodination.

24
Biosynthesis of thyroid hormones ,also showing
various sites of anithyroid drug actions
25
  • 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 51
  • Most of T3 in circulation is derived from
    metabolism of T4.

26
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 , but their free
    concentration is maintained in euthyroid gland

27
Metabolism of thyroxine in to active T3 and
inactive T3 (rT3)
28
Thyroid Hormone Production and Metabolism per day
29
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

30
Metabolism contd
  • De-Iodination of inner ring produces reverse
    T3(rT3), metabolically inactive.
  • Drugs like ipodate, ß-blockers and
    corticosteroids and starvation inhibits
    5-deiodinase.
  • This results low T3(active form) and high
    rT3.(inactive form)

31
Hypothalamic pitutary thyroid axix Thyroid
regulation
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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 cells to increase
    release and synthesis of T3 and T4.

34
  • 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.

35
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.

36
T3
T4
T3
PP
T3
T3
T4
T3
T3
PB
Pre-m RNA
cytoplasm
Nucleus
Response
mRNA
Protein
Mechanims of action of thyroid hormones
Mechanism of action of thyroxine at cellular level
37
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 illeus, in this
    condition parental route is preferred.

38
  • 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.

39
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 0.025 to
    0.3 mg tablets
  • For parentral use 200-500µg (100µg/ml when
    reconstituted) for injection.

40
  • 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

41
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.

42
ANTITHYROID AGENTS
  • Mechanism
  • Agents which interfere production of thyroid
    hormone
  • .
  • Agents which modify tissue response to thyroid
    hormones
  • Glandular destruction with radiation or surgery.

43
  • Agents
  • Thioamides
  • Iodides
  • Radio active iodine
  • Iodinated contrast media
  • Adrenoceptor- blocking Agents
  • Anion inhibitors

44
Anti thyroid agents ( Mechanissm)
45
THIOAMIDES
  • Methimazole
  • Carbimazole
  • Propylthiouracil
  • Methimazole is 10 times more active than
  • propylthiouracil.

46
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.

47
Pharmacokinetic comparision between
Propylthiouracil and Methimazole
Propylthiouracil Methimazole
Absorption Rapid but incomplete At variable rates but complete
Vol.of Dist. Approximates body waters Similar
Protein binding more less
accumulation In thyroid Similar
Excretion Kidneys as inactive Glucuronide in 24 hrs Excretion slow,60-70 of drug is recovered in urine in 48 hrs
48
Pharmacokinetic comparision between
Propylthiouracil and Methimazole
Propylthiouracil 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
49
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.

50
IODIDES
  • They inhibit organification and hormone release.
    With a dose of gt 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 ! ?

51
Iodides contd
  • 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

52
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.

53
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.

54
Radio active iodine contd
  • Therapeutic effect is due to emission of ß-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

55
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.

56
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.

57
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 10-15 µg/kg/day and in
    adults 1.7 µg/kg/day.
  • It takes 6-8 weeks to reach steady state level.

58
  • 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.

59
  • 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.

60
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 300-400µg 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.

61
HYPOTHROIDSM AND PREGNANCY.
  • These woman suffer form anovulatory cycles and
    infertility
  • In pregnant hypothyroid patient 20-30 increase
    in thyroxine is required because of elevated
    maternal TBG and because of early development of
    fetal brain which depends on maternal thyroxine

62
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.

63
  • T3 and T4 are elevated and TSH is suppressed.
  • Radio iodine uptake is elevated.

64
Management of Graves disease
  • Drug therapy
  • surgical thyroidectomy
  • Destruction of the gland with radioactive iodine

65
  • 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 60-70 relapse.

66
  • 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.

67
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

68
RADIOACTIVE IODINE 131I
  • Preferred in most patients over 21 years of age
    in a dose of 80-120µCi/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.

69
Adjuncts Therapy
  • During acute phase ß-blockers without intrinsic
    sympathomimetic activity are extremely helpful
  • eg Propranolol

70
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 40-80 mg orally every 6 hours

71
  • 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.

72
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., lt300
    mg daily.

73
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.
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