Normal cell:plasma of I-

Hyperthyroidism cell: plasma

20-40:1

>100:1

Thyroid peroxidase

activated form: I*

Steps of thyroid hormone synthesis

1. Uptake of I- into follicular cells (active transport pump)

2. Oxidation/activation of I- (H2O2 and TPO)

3. Coupling (iodination of Tg--> ability to place 2 DIT or 1 DIT +1 MIT in close proximity. In presence of TPO and H2O2 MIT and DIT undergo coupling--> T3 and T4).

4. Storage (mature Tg containing MIT, DIT, T3, T4 stored in colloid of the thyroid: reason that inhibition of synthesis does not produce change in plasma [] of T3 and T4. All of this has to be significantly reduced in order to have effect.

5. Proteolysis and release (endocytosis produces membrane-boumd colloid droplet w/ Tg lysosomes fuse with colloid droplets--> phagolysosome phagosomes toward the BM  (lyse Tg liberating T4, T3, MIT, DIT. MIT and DIT are deiodinated by microsomal deiodinase with liberated iodide reutilized. 5' deionization (t4-->t3 that can't be inhibited by propylthyrouracil IMPORTANT)

T4 comes from ______

T3 comes from _______

thyroid gland

thyroid gland and deiodination of T4 in organs

T3 vs. T4

Serum concentration

Fraction of total unboaund

Volume of distribution

Fraction IC

1/2 days

Production rate

Fraction directly from thyroid

Metabolic potency (relative)

Time to peak

low vs. high

high vs. low

everywhere vs. plasma

high vs. low

1-2 days vs. 6-7 days

low vs. high

20% vs 100%

1 vs. .3

2 vs. 9

Propylthiouracil

Iopanoic acid

Amiodarone

Propranolol

GCC

First few months after birth

Physiologic jaundice

Constipation

Somnolence

Feeding problems

Retardation of linear growth

Delayed puberty

Poor school performance

Protruding tongue

Broad flat nose, wide set eyes

Dry skin, coarse hair

Impaired mental development

Retardation of bone growth/dentition

Fatigue, lethargy, constipation

Slowing of central and mm activity

Decreased appetite, increased weight

Deeper, hoarse voice

Myxedema: doughy cool skin, enlarged heart, can lead to coma

low Iodine uptake

elevated serum cholesterol (primary hypothyroidism)

elevated CPK and ALT

Pernicious anemia (hashimotos)

Iodide given in conjunction with T4

T4 negatively inhibits TSH secretion so T4 given first. This way when iodide is given it does't cause hyperthyroidism. 

Due to decreased metabolic activity

Elderly

Theose with CHF

Amount of T4 secreted by thyroid gland every day

Amount of T4 given as replacement therapy

80/day

150-200/day because only 50-75% is absorbed orally

Thyroid USP: powder of animal thyroid glands (.17 to .23% organic iodide). Available in tablets containing 15-500 mg of powder.

Thyroglobulin USP: purified extract of pig thyroid. Contains USP standard iodide. Bioassayed. 15-300mg. 

Neither used often due to allergy, purity, variation

Safer because pro-hormone

Levothyroxine (L isomer of synthetic T4)

Liothyronine (given if can't convert T4-->T3. L isomer of synthetic T3 5-50 nanograms)

Liotrix (given if can't convert T4-->T3. Developed to mimic thyroid output)

Larger pool

Missing dose not as serious

T3 serum profiles more uniform than with T3.

Thyroid enlargement, heat intolerance, decrease in weight, increase in appetite, diarrhea, tiredness, irritability, tachycardia, ocular changes, hand tremors, tongue tremor

Even with tx automimmune disease persists (still have ocular manifestations)

Propylthiouracil and methimazole (thioamides)

Developed by

MOA: 

Absorption

Volume of distribution

1/2 lives

Dosing

Placental crossing

Understanding the fact that phenylthiourea caused goiter in rats.

MOA: inhibit TPO (organification and coupling), inhibit peripheral dediodination of T4-->T3

Absorption: rapid (PTU>methimazole)

PTU undergoes first pass

VD: High, elimination via excretion

1/2: PTU: 1.5 hours, Methimazole: 6 hours

Dosing: PTU q 6 hours, methimazole qd (both accumulate in thyroid so longer effect than 1/2 life)

Both cross placental barrier (PTU less so)

Long onset of therapeutic effect (4-6 weeks)

Difficulty in dosing (can lead to secondary hypothyroidsim)

Therapy is pallative but decreases excess synthesis, allows for recovery from stimulus, ablative therapy may be required, some patients may decrease in autoantibody production, but there is a high rate of relapse (50-70%)

Maculopapular pruritic rash

Lupus like sx

Agaranulocytosis

Cross reactivity

Monovalent anion inhibitors

Names:

MOA:

Problems:

Use of perchlorate

Perchlorate, Pertechnetate, Thiocyanate

MOA: block iodide uptake by follicle cells

Can be overcome by large doses of iodide, may cause aplastic anemia

Use of perchlorate also for iodide induced thyrotoxicosis (amiodarone induced hyperthyroidism)

Iodide preparations

Types:

Benefits:

Daily dose >6mg

KI,NaI, KI (oral)

Iodine is reduced to I- in GI (stronge iodine solution, USP, Lugols (5% iodine, 10% KI))

Benefits and issues: Decreased release of T3 and T4, transiently inhibit organification of iodide (wolff-chiakoff) so active T3 and T4 is reduced, reduces vascularity of hyperfunctioning thyroid (good for thyroid surgery), rapid recovery

Achieve rapid relief from thyrotoxicosis

Cute thyroid crisis, severe thyrocardiac disease, surgical emergencies

Iodine is almost alwoays used with thiourea

Uncommon and usually reversible

Acneform rash, drug fever, metallic taste, bleeding disorders

Used to diagnose thyroid diseases and as adjuvant in thyroid storm

Inhibit peripheral deiodination

Suppress T3 and T4 production (longer admin)

Not currently approved for suppression of production

Ablation for hyperthyroidism

Beta emitter with a half life of 8 days (utilized in hormone synthesis and stored in colloid). Beta particles released destroy some surrounding follicular tissue--> decreased hormone synthesis. Damage is selective for acinar cells and only penetrates a small distance in tissue.

Drawbacks: postradiation hypothyroidism, need replacement therapy, can cross placental barrier, excreted in breast milk

Prevent much of the sx of thyrotoxicosis

Propranolol is drug of choice (p.o q8h, 20-40mg)

Helps tx HTN, tachycardia, afib

Therapy is palliative: prevents negative effects of thyrotoxicosis, adjuvant with antithyroid therapies, withdrawn as levels return to normal

Sx and prevent release with combined: Propranolol, iodine, PTU

Tx sx: anipyretics, CHF, GCC, cause of storm (infection, stress)