Iodine is Forever Propylthiouracil, Methimazole, Levothyroxine

3.1 – “Iodine is Forever”: Propy Propylthiouracil, lthiouracil, meth methimazole, imazole, levothyr levothyroxine oxine Physiology • Thyroid hormones are T3 (triiodothyronine) & T4 (thyroxine). They are involved in most metabolic functions (like a secret criminal organization). Both contain iodine (anionic form: iodide). • Synthesis: o Iodide is transported into thyroid follicular cells (follicu-LAIR) via a sodium-iodide symporter (peanut box with iodide smuggled). This concentrates iodide; is an energy dependent process. o Iodide is oxidized to iodine by thyroid peroxidase (TPO) (transport with rusty truck). o TPO further catalyzes iodine biding to tyrosine to form iodotyrosine molecules; this process is organification (Organic Food truck with tyrosine tires) o iodotyrosine molecules are stored in the thyroid lumen bound to thyroglobulin (Thyro-Global). While bound, the mono- & di-iodotyrosine molecules couple; mono + di forms T3, di + di forms T4 (vegetables in logo are coupled). • Release & effects: o thyroglobulin is drawn into parafollicular cells, where T3 & T4 are cleaved off (bombs). T3 is the more potent form (activated bomb), T4 produced in greater quantities in the thyroid gland (more bombs with 4:00 timers in the lair) o In the peripheral tissues, T4 is de-iodinated to T3 by 5’-deiodinase (T4 detonator). o T3 enters the nucleus, acting as a transcription factor. Some effects: ▪ Increased sensitivity to SNS catecholamine-mediated stimulation by increasing β 1 receptors (catfish; dead man sensitive to catfish). Increased SNS sensitivity mediates many of the SSx of hyperthyroidism, including hypermetabolic & hyperadrenergic SSx (nervous henchmen with big bowtie) Hyperthyroi Hyperthyroidism dism • Presents with hypermetabolic & hyperadrenergic SSx (e.g. tachycardia, palpitations, insomnia, tremor, anxiety, heat intolerance, weight loss) (nervous henchmen with big bowtie) • Causes may include toxic adenoma, toxic multinodular goiter, thyroiditis • Most common cause is Graves’ disease. o Associated with Graves Ophthalmopathy (bulging infrared goggles). Activation of T-cells → lymphocytic infiltration of retroorbital space → cytokine production → fibroblast secretion of hydrophilic glycosaminoglycans → osmotic muscle swelling, muscle inflammation, and increased adipocyte count → exophthalmos. Note that chronic ophthalmopathy doesn’t necessarily correlate to treatment of thyroid levels; may decrease, may not. • Management: o In the US, patients with can be treated with ablative doses of radioactive iodine (I-131). This is done particularly with Graves’s disease. ▪ Can cause hypothyroidism in as many as 80% of patients (undone bowtie burned by radioactive vial) ▪ Can cause transient hyperthyroidism d/t dumping of excess thyroid hormone (anxious radioactive henchman). Particularly in those who are more susceptible (elderly, those with severe thyrotoxicosis), may treat with thioamide drug prior to radioablation to prevent. ▪ Can cause transient exacerbation of ophthalmopathy for unknown reasons; relatively contraindicated in patients with preexisting ophthalmopathy (bulging radioactive goggles) o thioamides ▪ Propylthiouracil (PTU) (secret agent with gunshot “PTU” sounds) • Inhibits TPO and 5’-deiodinase (shooting at bomb detonator). Acts centrally & peripherally. • Use generally limited to those with reactions to methimazole, in the first trimester of pregnancy, or treatment of acute thyrotoxicosis • Adverse effects: o Use limiting reaction: severe hepatotoxicity (mounted liver beaker). o Maculopapular pruritic rash o agranulocytosis (neutrophil <500). o drug-induced lupus (lupus wolf). May see ANCA-associated vasculitis. Usually asymptomatic, but may occasionally develop arthralgias & glomerulonephritis o bone marrow suppression & aplastic anemia (rare) (chew bones) ▪ Methimazole: • Inhibits TPO. Unlike PTU, does not have peripheral effects • Methimazole is 10x more potent that PTU and is the drug of choice for managing hyperthyroidism. • Adverse effects o agranulocytosis (neutrophil <500). o drug-induced lupus (lupus wolf). o bone marrow suppression & aplastic anemia (rare) (chew bones) o Methimazole is a first trimester teratogen. Use PTU instead. (pregnant lady drawing a spider on chalkboard) o β-blockers (blocked bugles being used to stick ‘em up) ▪ can be used to treat hyperadrenergic symptoms; also block 5-deiodinase. ▪ Should be started at the time of diagnosis o Glucocorticoids (moon face coasters) ▪ Treat hyperthyroidism by inhibiting 5’-deiodinase. ▪ Less effective than β-blockers, but have benefit of treating graves ophthalmopathy (knocking goggles off henchman’s face) Thyrotoxico Thyrotoxicosis, sis, aka thyrotoxic ccrisis, risis, aka thyro thyroid id storm • Life-threatening syndrome (Dr Storm) • May occur after acute precipitant or spontaneously in the situation of untreated thyroid disease • Management: o block sympathetic effects on organs using β blockers:. o Block thyroid TH synthesis. PTU preferred. o Block peripheral conversion of T3 to T4 (PTU, β blockers, & glucocorticoids) Hypothyroid • May present with dry & brittle hair (unkempt bartender), cold intolerance (ice cubes), weight gain (chubby), lethargy, fatigue, weakness, decreased basal metabolic rate, & myxedema • Untreated, can lead to myxedema coma (mixing cold drinks): progressive weakness, stupor, hypothermia, hypoventilation, hypoglycemia, hyponatremia, death. • Treat by giving levothyroxine (synthetic T4). • Side effects may mimic hyperthyroidism Radiation expo exposures sures • In the case of accidental radioactive iodine exposure, anions such as perchlorate, pertechnetate, & thiocyanate competitively inhibit the sodium-iodide transporter (obstructive box of anions with spy)