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Thyroid and Anti thyroid drugs. Role of the Thyroid gland. participates in normalizing growth and development and energy levels and the proper functioning and maintenance of tissues / organs critical for the nervous, skeletal and reproductive tissues

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Role of the thyroid gland
Role of the Thyroid gland

participates in normalizing growth and development and energy levels and the proper functioning and maintenance of tissues / organs

critical for the nervous, skeletal and reproductive tissues

it affects secretion and degradation rates of all hormones


Function of the thyroid gland
Function of the Thyroid Gland

secretion of the following hormones:

triiodothyronine (T3) ; 59% iodine

tetraiodothyronine (T4; also known as thyroxine); 65% iodine

calcitonin


Thyroid physiology
THYROID PHYSIOLOGY

  • Iodide Metabolism

    • The recommended daily adult iodide (I-) intake is 150 mcg

  • Biosynthesis of Thyroid Hormones

  • Transport of Thyroid Hormones

    • thyroxine-binding globulin (TBG)

    • about 0.04% of total T4 and 0.4% of T3 exist in the free form.



Biosynthesis of thyroid hormones1
Biosynthesis of thyroid hormones


Steps in biosynthesis
Steps in Biosynthesis

  • Iodide trapping

  • Oxidation of iodide to iodine

  • Iodide Organification

  • Formation of T4 and T3

  • Release of T4 and T3


Peripheral metabolism of thyroid hormones

  • The primary pathway for the peripheral metabolism ofthyroxine (T4) is deiodination deiodination of T4 may occur by monodeiodination of the outer ring, producing 3,5,3'-triiodothyronine (T3), which is three to four timesmore potent than T4


Basic pharmacology of thyroid & antithyroid drugsThyroid hormones

  • A model of thyroid hormone action is depicted in Figure 38-4

Figure38-4. Regulation of transcription by thyroid hormones

  • T3 and T4 are triiodothyronine and thyroxine, respectively.

  • PB, plasma binding protein;

  • F, transcription factor; R, receptor; PP, proteins that bind at the proximal promoter.


Hypothyroidism
Hypothyroidism

A syndrome resulting from a deficiency of thyroid hormones and is manifested largely by a reversible slowing down of all body functions.

There is a striking retardation of growth and development.

In children, manifested as dwarfism and severe MR.


Synthetic thyroid hormone
Synthetic Thyroid Hormone

synthetic levothyroxine (syntheticT4)

Brand names: Eltroxin , Euthyrox,Levoxyl, Levothroid, Synthroid

for hormone replacement therapy in hypothyroidism

DOSE

Infants and Children require more T4/Kg body weight than adults

Average dose for an infant -10-15 micrograms/kg/d

Average dose for an adult – 1.7micrograms/kg/d

Once daily

Pharmacokinetics

should be taken 30min before or 1 hour after meals (delayed absorption for soy, other foods and drugs)

takes 6-8 weeks to reach steady state levels

Labs should be repeated after 2 months


Synthetic thyroid hormone1
Synthetic Thyroid Hormone

reasons for its use:

stability

content uniformity

low cost

lack of allergenic foreign protein

easy laboratory measurements of serum levels

long half-life (7days)

once a day dosing


Synthetic thyroid hormone2
Synthetic Thyroid Hormone

Uses

Hormone replacement therapy

In young patients or those with mild disease- full replacement therapy started

In older patients and in patients with cardiac disease -start treatment with reduced dosage

Myxedema Coma – medical emergency

Loading dose –of T4 – 300-400micrograms I/V initially f/by `50micrograms daily

I/V T3 – more cardiotoxic and difficult to moniter

Hypothyroidism and Pregnancy – daily dose –adequate


Synthetic thyroid hormone3
Synthetic Thyroid Hormone

synthetic liothyronine (synthetic T3) is 3-4x more potent

(Cytomel,Triostat)

not used alone for long term treatment secondary to short half life and large peaks in serum T3 levels

increase risk for cardiac side effects secondary to hyperthyroid states during treatment


Hyperthyroidism
Hyperthyroidism

A thyroid disorder caused by an antibody-mediated auto-immune reaction, but the trigger for this reaction is still unknown

most common cause of hyperthyroidism


Anti thyroid drugs
Anti-thyroid Drugs

Thioamides

Iodides

radioactive iodine

Beta adrenoceptor blocking agents




Thioamides
Thioamides

Methimazole

Propylthiouracil (PTU) Carbimazole

MOA:

inhibit synthesis by acting against iodide organification (both)

coupling of iodotyrosines (both)

Blocks peripheral conversion of T4 to T3 (PTU)


Thioamides1
Thioamides

Pharmacokinetics:

almost completely absorbed in the GIT

serum half life: 90mins(PTU) ; 6 hours (methimazole)

excretion: kidney – 24 hours (PTU) ; 48 hours (Methimazole)

can cross placental barrier (lesser with PTU)

Methimazole 10x more potent than PTU

PTU more protein-bound


Thioamide uses
Thioamide uses

  • Definitive therapy

    • Graves disease

    • Toxic nodular goitre

  • Preoperatively

    • In thyrotoxic patients

  • Along with RAI


Thioamides2
Thioamides

Adverse Effects:

maculopapular rash

benign transient leukopenia

agranulocytosis

hepatitis (PTU) ; cholestatic jaundice (Methimazole)

vasculitis

lupus-like syndrome


Iodine 131
Iodine131

preparations: sodium iodide 131

MOA: trapped within the gland and enter intracellularly and delivers strong betaradiations destroying follicular cells

Penetration range-400-2000µm

Clinical uses: Grave’s, primary inoperable thyroid CA

Contraindication: pregnancy


Iodine 1311
Iodine131

Advantages

Easy administration

Effectiveness

Low expense

Absence of pain


Iodine 1312
Iodine131

Thioamides should be given initially and stop 5-7 days before radioactive iodine administration

131I dosage generally ranges between 80-120uCi/g of estimated thyroid wt. corrected for uptake. May be repeated after 6 months

Adverse effects

permanent hypothyroidism

potential for genetic damage

may precipitate thyroid crisis


Anion inhibitors
Anion Inhibitors

Monovalent anions such as perchlorates, pertechnetate and thiocyanate can block uptake of iodide by the gland by competitive inhibition

can be overcome by large doses of iodides

useful for iodide-induced hyperthyroidism (amiodarone-induced hyperthyroidism)

rarely used due to its association with aplastic anemia



Inorganic iodines
Inorganic Iodines

major anti-thyroids before the introduction of thioamides (1950s)

preparations:

strong iodine solution (Lugol’s)

potassium iodide

iodone


Inorganic iodines1
Inorganic Iodines

MOA:

acutely blocks release of thyroid hormone from the gland by inhibiting thyroglobulin proteolysis

inhibit iodide organification

Uses:

useful in thyroid storms: 2-7 days

Preoperatively - iodides decrease vascularity, size and fragility of hyperplastic gland

Caution:

it may delay onset of thioamide effects; should be given after initiation of thioamides

The gland will escape from inhibition after 2-8 weeks.


Iodinated contrast media
Iodinated Contrast Media

Iodinated contrast media

Ipodate (oral)

Iopanoic acid (oral)

Diatrizoate (intravenous)

valuable in hyperthyroidism (but is not labeled for this indication)

MOA: inhibits conversion of T4 to T3 in the liver, kidney, brain and pituitary

Another MOA is due to inhibition of hormone release secondary to iodide levels in blood

Useful in thyroid storms (adjunctive therapy)


Beta blockers
Beta Blockers

Drugs: Propranolol, Metoprolol, Atenolol

MOA:

Membrane-stabilizing action: inhibits T4 to T3

Ameliorate many disturbing s/sxs of hyperthyroidism secondary to increased circulating catecholamines by blocking beta receptors

Indications: Grave’s, Thyroid storm


Corticosteroids
Corticosteroids

Prednisone is given for patients with Grave’s ophthalmopathy

1mg/kg/day (60mg/day 3 divided doses); if it should be given for more than 4 weeks, taper to decrease risk of adrenal crisis


Thyroid storm
Thyroid storm

  • Sudden exacerbation of throtoxic symptoms

  • Life threatening condition

  • Vigorous management

    • Propanalol 1-2mg i/v or 40-80mg PO Q6h

    • Diltiazem 90-120mg Po Q8-6 hrs or 5-10mgs intravenous infusion/hour


Thyroid storm1
Thyroid storm

  • Potassium iodide

  • Propylthiouracil

  • Hydrocortisone

  • Supportive therapy

  • Plasmapheresis/peritoneal dialysis


  • Hyperthyroidism and pregnancy
    Hyperthyroidism and Pregnancy

    • Ideal situation- treat before pregnancy

    • Pregnancy-Radioactive iodine CI

    • Propylthiouracil

      • Dose limitation≤ 300mgs/day

    • Methimazole alternative- fetal scalp defects


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