Term
| T/F: Thioamide drugs block the enzyme thyroidal peroxidase within the thyroid gland. |
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Definition
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Term
| T/F: Hypothyroidism can be diagnosed with high TSH levels with low T₄ levels. |
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Definition
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Term
| T/F: Levothyroxine is the drug of choice for hypothyroidism. |
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Definition
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Term
| T/F: Propylthiouracil has a black box warning of severe hepatitis. |
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Definition
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Term
| T/F: If Amiodarone-induced hypothyroidism—stop amiodarone therapy |
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Definition
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Term
| T/F: Graves’ disease will likely represent low TSH with high T₄ levels. |
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Definition
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Term
| Thyroid Physiology and Metabolism |
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Definition
- Normal thyroid gland function: secrete sufficient amount of thyroid hormones to normalize growth and development, body temperature, and energy levels
• Triiodothyronine (T3) and tetraiodothyronine (T4, thyroxine) • ~60%iodinefoundinbothmolecules
- Recommended adult daily intake of iodide:
• 150 mcg (200 mcg during pregnancy and lactation)
- Iodide ingestion is rapidly absorbed and enters extracellular fluid pool
• Gland removes 75 mcg/daily for hormone synthesis (remainder excreted in the urine) |
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Term
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Definition
So let's take a look at its biochemical pathway. Iodine first needs to be actively transported into the thyroid gland. And it's done so by the sodium iodide cotransporter. As you can see here, it actually can be inhibited by thiocyanate or perchlorate. Once the iodide is in, the peroxidase enzyme actually oxidizes the iodine into active iodine, where it's able to rapidly be converted to various thyroid molecules known as monoiodotyrisine, diiodotyrisine, tetraiodothyronine, and thyroxine.
It's important to keep in mind that this oxidation process can be inhibited by iodides and thioamides. So if you can imagine how is T4 formed, so it pretty basically two of the diiodotyrosine molecules. As you can see here, that T3 would be formed by one of the monoiodotyrosine molecule and two of the diiodotyrosine molecules, both of which are released by thyroglobulin by proteolysis.
Once these thyroid molecules are deiodinated, the iodine is then re-utilized, and it's able to be incorporated into the rest of our bodies. Please make a note here that the iodide can inhibit proteolysis to prevent that conversion. |
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Term
| Biosynthesis of Thyroid Hormones |
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Definition
- T4 formation
• 2 x diiodotyrosine (DIT) = l-thyroxine (T4)
- T3 formation
• [1 x monoiodotyrosine (MIT)] + [1 x DIT] = T3
- T4, T3, MIT, and DIT released from thyroglobulin by proteolysis
- MIT and DIT are deiodinated within the gland and the iodine is re-utilized
• Proteolysis blocked by high levels of intrathyroidal iodide |
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Term
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Definition
- T4:T3 = ~5:1
• Majority of hormone released is thyroxine
- Most of the T3 circulating in the blood is derived from peripheral metabolism of thyroxine
- T4 and T3 reversibly bind to protein thyroxine-binding globulin (TBG)
• ~0.04% total T4 exist in free form (FT4)
• ~0.4% total T3 exist in free form (FT3)
-Primary pathway for peripheral metabolism of T4- deiodination by 3–5’ deiodinase enzymes
• Monodeiodination = 3,5,3’- triiodothyronine (T3)
• 3–4x greater potency than T4
• D1: responsible for most of circulating T3
• D2: regulates T3 levels in the brain and pituitary
• D3: metabolically inactive 3,3’, 5’ T3 (reverse T3; rT3) |
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Term
| Medications decreasing T3 |
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Definition
| So the primary pathway for metabolism of T4 is by various deiodinase enzymes. So you can see here that various deiodinase enzymes have different functions in the thyroid, all of which play an important role in the modulation of thyroxine in the thyroid gland. So peripherally converting T4 to T3 can be inhibited by various medications. As you can see here, radiocontrast media, beta blockers, corticosteroids, and amiodarone all potentially can inhibit the peripheral conversion of T4 to T3. |
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Term
| Thyroid-Pituitary Relationships |
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Definition
- Hypothalamic cells secrete thyrotropin-releasing hormone (TRH)
• TRH->TSH (thyroid-stimulating hormone)
- TSH->increase synthesis and release of T4 and T3
- Thyroid hormones negative feedback fashion->block action of TRH -> inhibit the synthesis and secretion of TRH |
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Term
| Pharmacokinetics of Thyroid Hormones |
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Definition
- Location of thyroid hormone receptors
• Pituitary, liver, kidney, heart, skeletal muscle, lung, and intestine
- Inducers (rifampin, phenobarbital, carbamazepine, etc.) increase metabolism of T4 and T3
• May require dose increase
• Compensatory hyperfunction of thyroid
- Alteration of binding sites
- If TBG sites are increased (by pregnancy, estrogens, or oral contraceptives)
• Shift of hormone from free to bound stateàdecrease rate of elimination until normal free hormone level is restored
• Total and bound concentration will increase
• Free hormone concentration will remain normal |
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Term
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Definition
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Term
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Definition
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Term
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Definition
-for hypothyroidism
- Preparation of choice for thyroid replacement and suppression therapy
• Stability, content uniformity, low cost, lack of allergenic foreign protein, lab measurement of serum levels, and long half-life (seven days)
- T4->T3 intracellularly
• T4 produces both hormones (T3 administration is unnecessary) |
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Term
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Definition
-for hypothyroidism
- Although three to four times more potent vs. levothyroxine—not recommended for routine replacement
• Shorter half-life (24 hours), requires multiple daily doses, difficulty monitoring adequacy by conventional lab tests
- Avoid in cardiac disease due to greater risk of cardiotoxicity |
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Term
| Thyroid Preparations comparisons |
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Definition
- Liotrix (thyroxine plus liothyronine fixed-dose combination) and dessicated thyroid
• Have not been shown to be more effective than T4 alone
- Use of dessicated thyroid rather than synthetic preparations is never justified
• Disadvantage of protein antigenicity, product instability, variable hormone concentrations, and difficult in laboratory monitoring
• Outweigh the advantage of lower cost
- Equally effective doses: 60 mg dessicated thyroid = 88– 100 mcg levothyroxine ~37.5 mcg of liothyronine |
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Term
Has SE:
-Palpitations
-Excessive Sweating
-Diarrhea
-Insomnia
-Tachycardia |
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Definition
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Term
Has SE:
-Altered mental status
-Hyperthermia
-Severe hypertension
-Cardiac dysrhythmias (SVT)
-Diarrhea |
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Definition
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Term
Has SE:
-Arrhythmias
-Hypertension
-Palpitations
-Anxiety
-Insomnia |
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Definition
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Term
Has SE:
-Tachycardia
-Arrhythmias
-Tremors
-Diarrhea
-Myalgia |
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Definition
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Term
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Definition
-for hyperthyroidism (Thioamide)
• Drug of choice
• Potency: ~10 times more potent
than propylthiouracil
• MOA: prevent hormone synthesis by inhibiting thyroid peroxidase- catalyzed reactions and blocking iodine organification |
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Term
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Definition
-for hyperthyroidism (Thioamide)
• Black box warning: severe hepatitis
- Reserve for use during the first trimester of pregnancy, thyroid storm, and those intolerant to methimazole (other than agranulocytosis or hepatitis)
• MOA: prevent hormone synthesis by inhibiting thyroid peroxidase- catalyzed reactions and blocking iodine organification
• Inhibits peripheral deiodination of T4 and T3
-Synthesis of hormones (vs. release) is affected a-> slow onset of agents will require 3–4 weeks before T4 stores are depleted |
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Term
| preferred agent during first trimester pregnancy for hyperthyroidism |
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Definition
| Propylithiouracil (Thioamide) |
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Term
Has SE:
-Altered sense of taste or smell
-Cholestatic jaundice |
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Definition
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Term
Has SE:
-Severe hepatitis (BBW) |
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Definition
| Propylthiouracil (Thioamide) |
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Term
Has 3-12% toxicity:
Nausea and GI distress
Most common: maculopapular pruritic rash (4–6%) +/- fevers
Agranulocytosis: sore throat and fevers
Infrequent—fatal in ~0.1–0.5% of patients (risk maybe higher in elderly and in doses >40 mg/day of methimazole)—reversible
Cross sensitivity ~50%: switching drugs in severe reactions not recommended
Asymptomatic transaminases—high levels (two to three times ULN) require stoppage of therapy |
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Definition
| Methimazole and Propylthiouracil (Thioamides) |
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Term
| Pharmacology of Antithyroids: Iodides |
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Definition
• Inhibit organification and hormone release
• Decrease size and vascularity of gland
• Pharmacologic doses >6 mg
- Inhibit hormone release via inhibition of thyroglobulin proteolysis
• Rapid improvement in thyrotoxic symptoms: 2–7 days (e.g., thyroid storm)
• Preoperative utility
- Reduce size, vascularity, and fragility of hyperplastic gland |
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Term
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Definition
| So the other medication that I mentioned in the introduction is iodides. So iodides work by inhibiting organification of the hormone release, and so it's able to decrease the size and the vascularity of the gland at doses greater than 6 milligrams. And it does so by inhibiting the proteolysis step of the thyroid gland. And so it's able to have rapid improvement of thyrotoxic symptoms and has been shown to be beneficial for pre-operative surgeries where it's able to, again, reduce the size, vascularity, and the fragility of the hyperplastic gland. |
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Term
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Definition
- Increase in intraglandular stores of iodine
• Delay onset of thioamide therapy or prevent radioactive iodine therapy for several weeks
- Shouldinitiateiodidetherapyafteronsetofthioamidetherapy and avoided if radioactive iodine seems likely
• Should not be used as sole therapy
• Gland will escape iodide block in 2–8 weeks and may produce severe exacerbation of thyrotoxicosis in an iodine- enriched gland |
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Term
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Definition
• Avoid chronic use in pregnancy—cross the placenta—fetal goiter
• Acneiform rash, swollen salivary glands, mucous membrane ulcerations, conjunctivitis , rhinorrhea, drug fever, metallic taste, bleeding disorders, and rarely, anaphylaxis |
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Term
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Definition
• 131I is the only isotope used for treatment of thyrotoxicosis (others used for diagnosis)
• Oral solution
- Rapidly absorbed, concentrated by the thyroid and incorporated into storage follicles
• Destruction of the thyroid parenchyma
• Advantages: easy administration, effectiveness, low expense, and absence of pain
• Avoid in pregnant women or nursing mothers—crosses the placenta and excreted in breast milk |
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Term
| Adrenoceptor blocking agents |
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Definition
Beta-blockers without intrinsic sympathomimetic activity (ISA)
• Effective for the management of thyrotoxicosis
• Propranolol: most widely studied and used in thyrotoxicosis
• Clinical improvement of hyperthyroid symptoms without altering thyroid hormone levels
• Propranolol >160 mg/day may reduce T3 levels by ~20% by inhibiting peripheral conversion T4 a-> T3 |
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Term
| Overview of Hypothyroidism |
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Definition
- Syndrome resulting from deficiency of thyroid hormones manifested largely by a reversible slowing down of all body functions
• Decreased metabolic clearance of T4 and T3 with half-lives increased
• Pale, cool, dry brittle hair, decreased HR, hypoventilation, decreased appetite and bowel movements
• Infants and children à retardation of growth and development in dwarfism and irreversible mental retardation
• The laboratory diagnosis of hypothyroidism in the adult is easily made by the combination of low free thyroxine and elevated serum
TSH levels
- Most common cause is Hashimoto’s thyroiditis: immunologic disorder in genetically predisposed individuals
• Autoimmune destruction of thyroid |
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Term
Management of Hypothyroidism
Treatment of choice |
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Definition
- Levothyroxine
• Combination levothyroxine plus liothyronine not superior to levothyroxine alone
- Food and drugs can impair absorption
• Administer on empty stomach (60 minutes before meals, four hours after meals, or at bedtime)
- Long half-life: once daily dosing
• Steady state blood levels take 6–8 weeks—require slow dose changes |
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Term
Management of Hypothyroidism
Dosing |
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Definition
• Patients >50 years of age without cardiac disease; start at dosage of 50 mcg/day
• In patients with underlying cardiac disease, starting dose: 12.5–25 mcg/day for two weeks with titration of 12.5–25 mcg/d every two weeks until euthyroidism is observed
- Heart is sensitive to circulating thyroxine—if angina or cardiac arrhythmia develops, stop therapy or reduce dose immediately
• Average dose for adult: 1.7 mcg/kg/day or 125 mcg/day
• Infants 1–6 months: 10–15 mcg/kg/day
- Monitor for normal growth and development |
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Term
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Definition
Adults
• Increased nervousness
• Heat intolerance
• Episodes of palpitation
• Tachycardia
• Unexplained weight loss
• Elderly patients— increase risk of AFib and accelerated osteoporosis
Children:
• Restlessness
• Insomnia
• Accelerated bone maturation and growth
Monitor serum TSH and FT4 levels |
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Term
Management of Special Disease States
Myxedema coma |
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Definition
- End-state untreated hypothyroidism
• Progressive weakness, stupor, hypothermia, and death—medical emergency
• Poor oral absorption
- Treatment of choice
• Loading dose of IV levothyroxine: 300–400 mcg initially, followed by 50–100 mcg daily
• IV T3 can be used, but may be more cardiotoxic and difficult to monitor |
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Term
Management of Special Disease States
Drug-induced hypothyroidism |
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Definition
- Stop offending agent
• Levothyroxine therapy if not possible
- Amiodarone-induced hypothyroidism
• Levothyroxine may be necessary even after discontinuance due to amiodarone’s very long half-life (~60 days) |
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Term
| Overview of Hyperthyroidism |
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Definition
- Clinical syndrome when tissues are exposed to high levels of thyroid hormone
• Increased basal metabolic rate, drug metabolism, nervousness, weight loss with increased appetite
• Increased metabolic clearance of T4 and T3 with half-lives decreased
• Warm, increased heart rate, dyspnea, increased frequency of bowel movements
- Graves’ disease (or diffuse toxic goiter)
• Most common form
• Autoimmune disorder in which a defect in suppressor T lymphocytes stimulates B lymphocytes to synthesize antibodies to thyroidal antigens
• Diplopia, pretibial dermopathy
- Laboratory diagnosis:
• High T3, T4, FT4, and FT3 with low TSH |
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Term
| Management of Hyperthyroidism: Antithyroid Drug Therapy |
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Definition
Methimazole
- Preferred
• Lower risk of serious liver injury
• Once daily dosing -
- Dose:
• Initial: 20–40 mg/day for 4–8 weeks
• Maintenance: 5–15 mg once daily
Propylthiouracil
- Preferred in first trimester pregnancy and thyroid storm
- Dose: 100–150mg Q6H–Q8H until euthyroid followed by maintenance dose 50–150 mg once daily
• Inhibits T4 à T3 conversion
-Long period of treatment (12–18 months): 50–70% incidence of relapse
-Clinical guide to remission is reduction in the size of the goiter
-FT4 and TSH levels useful in monitoring the course of therapy |
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Term
| Management of Hyperthyroidism other options |
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Definition
Radioactive iodine (131I; RAI)
• Dosing
- Without heart disease: 80–120 uCi/g of estimated thyroid weight corrected for uptake
- With heart disease, severe thyrotoxicosis, or elderly:
• Treat with methimazole until euthyroid (3–5 days before RAI and restarted 3–7 days later with 4–6 weeks’ taper)
• Gland will shrink 6–12 weeks leading to euthyroid or hypothyroid (80% of patients)
Thyroidectomy (surgery)
• Treatment of choice for very large glands or multinodular goiters
• Treated with antithyroid drugs until euthyroid (~6 weeks)
• Potassium Iodide
- 10–14 days prior to surgery
- 5 drops BID to diminish vascularity of gland
• 80–90% patients will require thyroid supplementation |
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Term
Management of Hyperthyroidism
Adjunctive therapy: beta-blockers |
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Definition
• Acute phase of thyrotoxicosis
- Beta-blockers without ISA in symptomatic patients >60 years of age, HR >90 beats/min and in cardiovascular disease
• Propranolol or metoprolol to control tachycardia, hypertension, and atrial fibrillation
- Propranolol dose: 20–40 mg Q6H
- Metoprolol dose: 25–50 mg Q6H–Q8H
• Agents are gradually dose reduced as serum thyroxine levels normalize
• If beta-blockers are contraindicated (e.g., asthma) can use diltiazem to control tachycardia
- Diltiazem dose: 90–120 mg TID or QID |
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Term
Management of Special Disease State
Thyroid storm (thyrotoxic crisis) |
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Definition
• Sudden, life-threatening acute exacerbation of all symptoms of thyrotoxicosis
• Management to control severe cardiovascular manifestations:
- Propranolol 60–80 mg PO Q4H, or 1–2 mg IV slowly Q5: 10 minutes (total 10 mg)
- Esmolol 50–100 mg/kg/min
• If beta-blockers contraindicated (e.g., asthma)
- Diltiazem 90–120 mg PO TID or QID or 5–10 mg/h IV
• Propylthiouracil to block hormone synthesis
- Loading dose: 500–1,000mg, followed by 250 mg PO Q4H
- Retention enema (if cannot tolerate PO): 400 mg Q6H
• Potassium iodide to retard release of thyroid hormones
- 5 drops Q6H starting one hour post thioamides
• Hydrocortisone to protect against shock and block T4 à T3 conversion: 50 mg IV Q6H |
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Term
Levothyroxine (T4)
Liothyronine (T3)
MOA |
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Definition
| Activation of nuclear receptors resulting in gene expression with RNA formation and protein synthesis |
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Term
Has Toxicity:
decreased appetite, constipation, decreased erythropoiesis |
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Definition
Levothyroxine (T4)
Liothyronine (T3) |
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Term
| Methimazole Propylthiouracil [Thioamides] MOA |
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Definition
Inhibit thyroid peroxidase reactions Block iodine organification
Inhibit peripheral deiodination of T4 àT3 (primarily PTU) |
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Term
Has toxicity:
nausea, GI distress, agranulocytosis, hepatitis (PTU BBW) |
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Definition
| Methimazole Propylthiouracil [Thioamides] |
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Term
| Potassium Iodide [Iodides] MOA |
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Definition
Inhibit organification and hormone release
Reduce size and vascularity of gland |
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Term
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Definition
| Inhibition of Beta adrenoreceptors Inhibit T4 a-> T3 (propranolol only) |
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Term
Has Toxicity:
asthma, AV blockade, hypotension, bradycardia |
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Definition
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Term
| Radioactive Iodine (131I) MOA |
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Definition
| Radiation destruction of thyroid tissue |
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Term
| Overall summary for thyroid pharm |
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Definition
• Thyroidphysiologyensuressufficientquantityof thyroid hormones circulate in order to normalize growth and development.
- Low levels of thyroid hormones result in hypothyroidism; high levels lead to hyperthyroidism.
• Levothyroxineisthedrugofchoiceforthyroid replacement (hypothyroidism) due to stability and ability to measure serum levels.
• Methimazoleisthedrugofchoicefor hyperthyroidism due to enhanced potency but should be avoided in first trimester of pregnancy.
• End-stateuntreatedhypothyroidismcanleadto myxedema coma, which require intravenous therapy of levothyroxine.
• Thyrotoxiccrisisrequiresmultiplemedicationsto control the cardiovascular manifestations in addition to blockage of thyroid hormone synthesis.
- Beta-blockers for cardiovascular symptoms
- Propylthiouracil to block hormone synthesis |
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