Thyroid Hormone & Antithyroid Drugs by 0Ccf04c

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									Thyroid Hormone &
Antithyroid Drugs
Objectives:
 Kinetics & dynamics of thyroid H.
Indications of thyroid H.
Toxicity of thyroid H.
Antithyroid drugs.
Mechanism of actions
 Uses & toxicity
Thyroid storm.
Pharmacokinetics of thyroid hormones



   Well absorbed orally except in
    myxedema coma used by i.v.
   It is distributed allover the body.
   99.9 % is bound to thyroxine binding
    globulin (TBG).
Elimination of thyroid hormones

   Tissue deiodination:
     – 30-35 % of T4  T3 (5 times more potent than
       T4.
     – 45-50% of T4  reverse T3 (rT3) which is
       biologically inactive.
     – Further peripheral tissues deiodination, largely in
       the liver,  loss of activity.
   Small amount of thyroxine is eliminated by
    deamination, decarboxylation, or conjugation and
    excretion as glucuronide or sulfate.
Dynamics of thyroid H.

Mechanism of action:
   Thyroid hormones enter passively to
    the cytoplasm, bind cytoplasmic
    receptors, enter the nucleus, and bind
    to DNA response element, increasing
    RNA transcription and protein
    synthesis.
Effects of thyroid hormones

    Protein synthesis during growth.
    Increased metabolic rate and oxygen
     consumption.
    Increased sensitivity to catecholamine
     with proliferation of beta receptors
     (particularly important in the
     cardiovascular system).
Uses of thyroid hormones:

   Replacement therapy: in hypothyroidism (critinism
    and myxedema).

    * levothyroxine (T4) is used better than liothyronine
    (T3) because it has a delayed onset & long duration
    of action, T4 is converted to T3 in the body plus it
    has a low cost, stability and easily monitoring of
    blood level.
   Myxedema coma: use liothyronine (T3) 25 μg i.v/6h

    * liothyronine is strong (5 times more active than
    T4), rapidly acting & has a short duration of action.
   Simple non toxic goiter: use T4 to suppress TSH.
   TSH dependent cancer thyroid: use T4 to suppress
    TSH.
   Gynecological disorders: amenorrhea & habitual
    abortion.
   Hypercholesterolemia: (thyroxine increases the
    metabolism of cholesterol to bile acid).
    *use d-thyroxine in euthyroid or cardiac patients.
Toxicity of thyroxine
It is similar to hyperthyroidism


   Increased basal metabolic rate BMR,
    heat production, hyperpyrexia,
    warmness, flushes, and intolerance to
    heat.
   increase of HR, cardiac work & output,
    angina, arrhythmia, hypertension and
    CHF.
    Antithyroid Agents

Thionamides (Thiourea derivatives)
carbimazole, methimazole & propylthiouracil
Pharmacokinetics:

   Well absorbed orally, distributed allover the body,
    concentrated in the thyroid gland, pass BBB & placental
    barrier.

   Carbimazole is a pro-drug converted in the liver to its active
    metabolite methimazole.

   Excreted in urine and milk causing critinism of the suckling
    baby
Pharmacodynamics:
Mechanism of action:

  Inhibit oxidation of iodide ions to iodine.
Iodide peroxidase             iodine
 Inhibit organification of iodine

 Ioddine + tyrosine               iodotyrosines
 Inhibit coupling of iodotyrosines.

MIT + DIT                    T3
 Propylthiouracil also inhibits the peripheral
   conversion of T4 to T3.
Effects:
   Inhibit thyroid function after 2-4 weeks
    (until depletion of the stored thyroxine in
    the colloid).
   Increase TSH, so increasing the size and
    vascularity of the thyroid gland (goiter).
   Increase release of exophthalmos producing
    agent which aggravates exophthalmos.
Uses:
   Mild hyperthyroidism (total therapy 12-18 months
    before withdrawal).
   Temporary control of moderate & severe
    hyperthyroidism until preparing the patient for
    subtotal thyroidectomy.
   Temporary use of thionamides until the effect of
    the radioactive iodine (131I) takes place (3months).
   Propylthiouracil is preferred in thyroid storm and for
    ladies during breast feeding of the baby as little
    passes into milk.
Preparing the patient for
subtotal thyroidectomy.


   Thionamide (6 weeks to be euthyroid).
    Potassium iodide (2 weeks) to
    decrease the size & vascularity of the
    gland prior to surgery.
Treatment of thyroid
storm
Thyroid storm is a life-threatening emergency due to liberation of
huge amounts of the hormone
 Propranolol slowly i.v 1-2 mg or 40-80 mg orally/6h. If
  propranolol is contraindicated use diltiazem 90-120 mg orally
  tid.
 Propylthiouracil 300-400 mg/4h then give sodium iodide 1.0 g
  i.v/24h or potassium iodide orally 10 drops/day to retard the
  release of thyroid hormones.
 Dexamethasone 2 mg/h or hydrocortisone i.v 50 mg /6h. to
  prevent shock, inhibits conversion of T4 to T3 and decrease
  the release of thyroid hormones.
 Chlorpromazine for mental disturbance,
 Aspirin and cooling for hyperthermia,
 Treatment of CHF as usual.
During pregnancy:
 Use the smallest possible dose of carbimazole or methimazole
  because they pass the placenta causing fetal goiter.
 In the 2nd trimester, surgery is preferred to the continued
  drug therapy
During breast feeding:
 Use propylthiouracil because it is little passing into the breast
  milk.
Adverse effects:
   Rash, fever, agranulocytosis, increase size and vascularity of
    the gland, liver & kidney damage, SLE, loss of hair
    pigmentation & critinism in baby.
Iodide therapy
   Lugol's solution (5 % iodine + 10 % potassium iodide) orally
    0.3 ml tid.
   Potassium iodide orally 60 mg tid.
Mechanism of action:
   Attenuate the effect of TSH on the thyroid gland, so decrease
    the size & vascularity.
   Decrease exocytosis and proteolysis of thyroglobulin.
   Decrease release of T4 & T3.
   The antithyroid effect is of rapid onset 1-2 days and
    maintained for 10-15 days
   Cannot be used for long time therapy because of relapse of
    hyperthyroidism due to increased TSH (paradoxical effect of
    iodide therapy).
Uses:
   Preoperative to decrease size and vascularity of the
    gland.
   Thyroid storm.
Toxicity:
   overdoses of iodine may cause iodism (metallic
    taste, excessive salivation, with painful salivary
    gland, diarrhea, productive cough, running eyes &
    nose, sore throat and rashes mimic chicken-pox).
   It is treated by fluids (saline) and diuretics.
NB:
 iodine therapy maximizes iodine stores in the
  thyroid. This effect delays the response to
  thionamides.
Iodinated Radiocontrast media (ipodate):
 It is rapidly reducing T3 concentration in
  thyrotoxicosis.
 It inhibits conversion of T4 to T3.
 It also decreases the release of T4 from the gland
Radioactive iodide
       The beta radiations of 131I destroy thyroid
        parenchyma, so decreasing hormonal release.
Advantages:
     Easy administration (orally).
     Effective.

     It is not expensive.

     Suitable for old ages and cardiac patients
      with moderate to severe hyperthyroidism and
      unfit to surgery.
Adverse effects:
        As with iodine therapy, overdoses may cause iodism.
        overdose is treated by large dose of sodium or
         potassium iodide to compete with the radioiodine
         uptake by the gland, and then hasten excretion by
         fluids and diuretics.
        Local pain & congestion at the site of the gland.
        Hypothyroidism.
        Malignant changes in the thyroid after many years
Contraindications: pregnancy, children and
  nursing mother.
Beta blockers
   B-blockers decrease the supersensitivity of the
    tissues to catecholamines in hyperthyroidism.
   B-blockers don’t block all the metabolic effects of
    the hormone, so not used alone except in mild
    thyrotoxicosis in preparation for radioiodine
    therapy.
   The chosen B-blockers should be non-selective
    and without intrinsic sympathetic activity e.g.
    propranolol & timolol

								
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