Post on 31-Dec-2015
description
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 secretion of the following
hormones: triiodothyronine (T3) ; 59%
iodine tetraiodothyronine (T4; also
known as thyroxine); 65% iodine
calcitonin
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 hormones
Biosynthesis of thyroid hormones
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 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
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.
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 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
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 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 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
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
Thioamides
Iodides
radioactive iodine
Beta adrenoceptor blocking agents
Mechanism of action of anti thyroid drugs
Biosynthesis of thyroid hormones
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)
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
Definitive therapy Graves disease Toxic nodular goitre
Preoperatively In thyrotoxic patients
Along with RAI
Thioamides
Adverse Effects: maculopapular rash benign transient leukopenia agranulocytosis hepatitis (PTU) ; cholestatic jaundice
(Methimazole) vasculitis lupus-like syndrome
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
Iodine131
Advantages Easy administration Effectiveness Low expense Absence of pain
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
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
Biosynthesis of thyroid hormones
Inorganic Iodines
major anti-thyroids before the introduction of thioamides (1950s)
preparations: strong iodine solution
(Lugol’s) potassium iodide iodone
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 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
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
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
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 storm
Potassium iodide Propylthiouracil Hydrocortisone
Supportive therapy Plasmapheresis/peritoneal dialysis
Hyperthyroidism and Pregnancy
Ideal situation- treat before pregnancy
Pregnancy-Radioactive iodine CI Propylthiouracil
Dose limitation≤ 300mgs/day Methimazole alternative- fetal scalp
defects