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THYROID AND ANTI THYROID DRUGS

VIEWS: 122 PAGES: 73

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


                                       1
7
    Normal thyroid gland secretes
       T3 (triiodothyronine) and
       T4 (tetraiodothyronine).
To maintain

      Normal growth and development of

   Nervous
   Skeletal
   Reproductive systems

                                         8
      It also controls metabolism of

   Fats
   Carbohydrates
   Proteins and
   Vitamins




                                       9
              and hence controls
   Normal energy levels
    also
    Normal body temperature

    Thyroid status also affects
    Secretion and degradation of

   Catecholamine
   Cortisol
   Insulin
   Estrogen /Progesterone
   Testosterone
                                   10
    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



                                                      11
   Deficiency of thyroidal hormones lead to
               Hypothyroidism

   Increased thyroidal hormone secretions lead to
               Hyperthyroidism




                                                     12
   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
    β-adrenergic receptors or increase in their
    number and enhanced amplification of the beta
    receptors signals

   Also there is increase in the activity of
    catechloamine

                                                       13
   Increased catechol and epinephreine
    activity may cause
   Palpitation
   Anxiety
   Sweating
   Tremors
   Nervousness

                                          14
15
    Manifestations of Hyperthyroidism
   Restlessness , nervousness , irritability.
   Tremors
   Palpitation
   Sweating
   Heat intolerance
   Weight loss
   muscle wasting


                                                 16
        |Manifestations cont’d
   Diarrhea
   Short breath
   Itching
   Tiredness
   Exophthalmos
   Menstrual disturbances


                                 17
18
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22
23
    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
                                       24
25
       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.
                                         26
    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
                                                    27
    It iodinates tyrosine (with in thyroglobulin,
    a glycoprotein molecule) to form mono-
    iodotyrosine (MIT) and Di-iodotyrosine
    (DIT), called organification or iodination.




                                                     28
Biosynthesis of thyroid hormones ,also showing various sites of anithyroid drug actions

                                                                                 29
   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 of T4.                           30
            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



                                                           31
Metabolism of thyroxine in to active T3 and inactive T3 (rT3)


                                                                32
Thyroid Hormone Production and Metabolism per day 33
          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




                                                           34
             Metabolism cont’d
   De-Iodination of inner ring produces reverse
    T3(rT3), metabolically inactive.

   Drugs like ipodate, β-blockers and
    corticosteroids and starvation inhibits 5-
    deiodinase.

   This results low T3(active form) and high
    rT3.(inactive form)
                                                   35
Hypothalamic –pitutary – thyroid axix
        Thyroid regulation              36
37
            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.
                                                     38
   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.
                                                39
          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.


                                              40
                                T3
T4
                                          T3
     T3
     T3                                                 PP
               T4

 PB                   T3                T3
                                                 Pre-m RNA
          cytoplasm        Nucleus

          Response
                                     Protein            mRNA



             Mechanims of action of thyroid cellular level
          Mechanism of action of thyroxine at hormones



                                                               41
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.
                                                    42
   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.
                                                    43
                 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.


                                                           44
   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                   45
        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.


                                         46
            ANTITHYROID AGENTS:
   Mechanism

   Agents which interfere production of thyroid
    hormone
.
   Agents which modify tissue response to thyroid
    hormones

   Glandular destruction with radiation or surgery.
                                                   47
                  Agents :
   Thioamides

   Iodides

   Radio active iodine

   Iodinated contrast media

   Adrenoceptor- blocking Agents

   Anion inhibitors                48
Anti –thyroid agents ( Mechanissm)
                                     49
              THIOAMIDES:

   Methimazole

   Carbimazole

   Propylthiouracil

   Methimazole is 10 times more active than
    propylthiouracil.
                                               50
            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.               51
    Pharmacokinetic comparision between Propylthiouracil and
                        Methimazole
                Propylthiouracil           Methimazole
Absorption      Rapid but incomplete       At variable rates but
                                           complete
Vol.of Dist.    Approximates body          Similar
                waters
Protein binding more                       less
accumulation    In thyroid                 Similar
Excretion       Kidneys as inactive        Excretion slow,60-
                Glucuronide in 24 hrs      70% of drug is
                                           recovered in urine in
                                           48 hrs          52
       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           30 mg exerts Antithyroid
                        organification for 7 hrs         effect for longer than 24 hrs

Pregnancy               Preferred, though cross          Cross placenta and
                        placenta and is conc .in fetal   concentrated by fetal thyroid
                        thyroid but is highly protein
                        bound ,cross placenta less
                        readily
Nursing mothers         Less secreted in breast milk     secreted


                                                                                53
             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.              54
                      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)                               55
                  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
                                                           56
            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.
                                             57
               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.                             58
        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


                                                       59
        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.                                      60
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.

                                                    61
                     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.
                                                                         62
    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.
                                                           63
    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.


                                                        64
                 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.

                                                          65
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

                                               66
             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.
                                                       67
    T3 and T4 are elevated and TSH is
    suppressed.

   Radio iodine uptake is elevated.




                                         68
    Management of Grave’s disease
    Drug therapy
   surgical thyroidectomy
   Destruction of the gland with radioactive iodine




                                                   69
   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.


                                                    70
    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.

                                                         71
             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

                                                72
       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.
                                                          73
             Adjuncts Therapy
   During acute phase β-blockers without
    intrinsic sympathomimetic activity are
    extremely helpful

    eg : Propranolol




                                             74
               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
                                                   75
   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.                        76
     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.


                                                       77
            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.
                                                78

								
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