THYROID AND ANTI THYROID DRUGS

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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

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It also controls metabolism of

• Fats
• Carbohydrates
• Proteins and
• Vitamins

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and hence controls

• Normal body temperature
• Normal energy levels
• Thyroid status also affects
• Secretion and degradation of
• Catecholamine
• Cortisones
• Estrogens
• progesterone and
• insulin

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• 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 ß-adrenergic receptors or increase in their
  number.
• There may also be increase in the production of
  catecholamines

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• increased epinephrine activity causes
• Tremors
• Sweating
• Anxiety
• Nervousness
• lid lag retraction

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Manifestations of Hyperthyroidism

• Restlessness , nervousness , irritability.
• Tremors
• palpitation
• Weight loss
• sweating
• Heat intolerance

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Manifestations contd

• Diarrhoea
• Short breath
• Itching
• Tiredness
• Light periods
• Exophthalmos

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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

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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.

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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.

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

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Biosynthesis of thyroid hormones ,also showing
various sites of anithyroid drug actions
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• 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 ofT4.

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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

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

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Metabolism contd

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

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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 cell to increase
  release and synthesis of T3 and T4.

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• 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.

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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
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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.

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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.
  

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• 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.

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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.

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• 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
  

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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.

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ANTITHYROID AGENTS

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

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

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Anti thyroid agents ( Mechanissm)
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THIOAMIDES

• Methimazole
• Carbimazole
• Propylthiouracil
• Methimazole is 10 times more active than
  
• propylthiouracil.

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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.

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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
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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
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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.

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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 ! ?

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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

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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.

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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.

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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

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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.

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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.

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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.

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• 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.

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• 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.

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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.

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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

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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.

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

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Management of Graves disease

• Drug therapy
• surgical thyroidectomy
• Destruction of the gland with radioactive iodine

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• 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.

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• 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.

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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

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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.

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Adjuncts Therapy

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

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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

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• 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.

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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.

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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.