Thyroid and Anti thyroid drugs

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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 - PowerPoint PPT Presentation

Transcript of Thyroid and Anti thyroid drugs

Page 1: Thyroid and Anti thyroid drugs
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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

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Function of the Thyroid Gland secretion of the following

hormones: triiodothyronine (T3) ; 59%

iodine tetraiodothyronine (T4; also

known as thyroxine); 65% iodine

calcitonin

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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.

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Biosynthesis of thyroid hormones

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Biosynthesis of thyroid hormones

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Steps in Biosynthesis

Iodide trapping

Oxidation of iodide to iodine

Iodide Organification

Formation of T4 and T3

Release of T4 and T3

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Peripheral metabolism of thyroid hormones

The primary pathway for the peripheral metabolism of thyroxine (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 times more potent than T4

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Basic pharmacology of thyroid & antithyroid drugs Thyroid hormones

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

Figure 38-4. 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.

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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.

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Synthetic Thyroid Hormone synthetic levothyroxine (synthetic T4) 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

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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

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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

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Synthetic Thyroid HormoneSynthetic 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

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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

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Anti-thyroid Drugs

Thioamides

Iodides

radioactive iodine

Beta adrenoceptor blocking agents

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Mechanism of action of anti thyroid drugs

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Biosynthesis of thyroid hormones

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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)

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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

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Thioamide uses

Definitive therapy Graves disease Toxic nodular goitre

Preoperatively In thyrotoxic patients

Along with RAI

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Thioamides

Adverse Effects: maculopapular rash benign transient leukopenia agranulocytosis hepatitis (PTU) ; cholestatic jaundice

(Methimazole) vasculitis lupus-like syndrome

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Iodine131

preparations: sodium iodide 131

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

Penetration range-400-2000µm

Clinical uses: Grave’s, primary inoperable thyroid CA

Contraindication: pregnancy

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Iodine131

Advantages Easy administration Effectiveness Low expense Absence of pain

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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

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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

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Biosynthesis of thyroid hormones

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Inorganic Iodines

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

preparations: strong iodine solution

(Lugol’s) potassium iodide iodone

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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.

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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)

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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

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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

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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

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Thyroid storm

Potassium iodide Propylthiouracil Hydrocortisone

Supportive therapy Plasmapheresis/peritoneal dialysis

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Hyperthyroidism and Pregnancy

Ideal situation- treat before pregnancy

Pregnancy-Radioactive iodine CI Propylthiouracil

Dose limitation≤ 300mgs/day Methimazole alternative- fetal scalp

defects