Thyroid Disorders 101: AThyroid Disorders 101: A Review in Therapypy

Monique Grant, Pharm. D.Miami VA Healthcare Systemy

PGY1- Pharmacy Practice Resident

ObjectivesObjectives

To review homeostasis of theTo review homeostasis of the Hypothalamic-Pituitary-Thyroid axisTo review pathophysiology of Hypo- and p p y gy ypHyperthyroidismTo discuss current pharmacotherapy for p pyHypo- and HyperthyroidismTo discuss medications used in emergent Hypo- and Hyperthyroidism (Myxedema Coma and Thyroid Storm)

The BasicsThe Basics

Thyroid hormones are ymade in thyroglobulins located in thyroid cells

Th hThese hormones are thyroxine (T4) and triiodothyronine (T3)~80% of T3 is formed from the breakdown of T4 bybreakdown of T4 by 5’-monodeiodinase in periphery

HomeostasisHomeostasis

Iodide is actively ytransported via a Na+/I− symporter I i i did iInorganic iodide is oxidized by thyroid peroxidase and covalently bound (organified) to tyrosine

Catalyzes formationCatalyzes formation of iodothyronines

Normal Laboratory ValuesNormal Laboratory Values

Total T4: 4.5-12.5 mcg/dLTotal T4: 4.5 12.5 mcg/dLFree T4: 0.8-1.5 ng/dLTotal T3: 80-220 ng/dLTotal T3: 80-220 ng/dLT3 Resin Uptake: 22-34%Free Thyroxine Index: 1 0 4 3 unitsFree Thyroxine Index: 1.0-4.3 unitsTSH: 0.25-6.7 mIU/L*

*Single best screening test for hypo- and hyperthyroidism.

EpidemiologyEpidemiologyExperts believe more than 13 million Americans are affected by h id di dthyroid disorders

National Health and Nutrition Examination Survey (NHANES III) of 17,353 people:

N k th id di t f TSH T4No known thyroid disease, measurements of TSH, T4, thyroglobulin antibodies, and thyroid peroxidase antibodies Hypothyroidism found in 4.6 percent Hyperthyroidism found in 1 3 percentHyperthyroidism found in 1.3 percent Serum thyroid peroxidase antibody concentrations high in 11%Mean TSH significantly lower in blacks than in whites orMean TSH significantly lower in blacks than in whites or Mexican-Americans

Sex: Women > MenAge: risk increases with increased ageAge: risk increases with increased age

Pathophysiology of HypothyroidismPathophysiology of Hypothyroidism

Localized disease of the thyroid gland that results in y gdecreased thyroid hormone production Decreased secretion of thyroxine (T4) and t ii d th i (T3) l d t d ti i thtriiodothyronine (T3) leads to a reduction in the serum concentrations of the two hormones compensatory increase in TSH secretion. Characterized by:

Low serum T4Hi h TSHHigh serum TSH

Causes of Primary HypothyroidismCauses of Primary Hypothyroidism

Chronic autoimmune Infiltrative diseasesChronic autoimmune thyroiditisIatrogenic

Thyroidectomy

Infiltrative diseasesFibrous thyroiditis, hemochromatosis, sarcoidosisThyroidectomy

Radioiodine therapy or irradiation

Iodine deficiency or

Transient hypothyroidismPainless (silent, lymphocytic) thyroiditisS b t l tIodine deficiency or

excessDrugs

Subacute granulomatous thyroiditisPostpartum thyroiditisFollowing radioiodine tx for

Thionamides, lithium, amiodarone, interferon-alfa, interleukin-2, perchlorate

gGraves' hyperthyroidismWithdrawal of suppressive doses of thyroid hormone

Signs and SymptomsSigns and SymptomsSlowing of metabolic processes

F ti / kFatigue/ weaknessCold intoleranceDyspnea on exertionBradycardiayWeight gainConstipationGrowth failure

Accumulation of matrix substancesAccumulation of matrix substancesDry, Coarse skinPuffy facies and loss of eyebrowsPeriorbital edemaEnlargement of the tongue

OtherDiastolic hypertension; Pleural and pericardial effusionsa d pe ca d a e us o sMyalgia, Arthralgia, and paresthesiaDepression

Hypothyroidism TreatmentHypothyroidism Treatment

Usually lifelong; initial results seen in first 2 weeksy g;In Florida thyroid hormone is NO longer on “Negative Formulary”Treatment of choice is L-Thyroxine (Levothyroxine)Thyroxine (T4) characteristics:

T1/2 is approximately 7 days; >99% protein boundT1/2 is approximately 7 days; >99% protein boundDosing: 1.6 mcg/kg body weight per day (112 mcg/day in a 70-kg adult); smaller doses in elderly g y g ); yand post- menopausal womenMaintenance dose ranges from 50 to 200 mcg/day

T4 requirements correlate better with lean body mass than total body weight

Hypothyroidism TreatmentHypothyroidism TreatmentAlteration in absorption: Age, food, BAS, ferrous

lf tsulfateDrug Interactions: Warfarin, Theophylline, Digoxin, Carbamazepine, EstrogensContraindications: recent MI, uncorrected adrenal insufficiencyMonitoring: Reevaluate patient’s T4 and TSH every three to six weeks; adjust dose every 6 weeks

Should expect thyroid hormone concentrations to increase first, then TSH secretion to fall (negative feedback)feedback)

Patient Counseling: Take on empty stomach (at least 30 minutes before meal); drink with full glass of water; take at least 4 hours apart from calcium ironwater; take at least 4 hours apart from calcium, iron, and antacids

Available TherapyAvailable Therapy

GGenericname Composition Brand names Average adult

dose, µg/day

L th id L lLevothyroxine T4

Levothroid, Levoxyl, Synthroid, Tirosint, Unithroid

150 (men), 112 (women)

Liothyronine T3 Cytomel 50

Liotrix 4:1 mixture of Thyrolar T4 (75)/T3 (18 75)Liotrix T4 and T3 Thyrolar T4 (75)/T3 (18.75)

Thyroid USP Thyroid extract Armour thyroid 90 mg

Pork or beef Thyroid strong

Myxedema ComaMyxedema ComaEnd stage of lifelong uncorrected HypothyroidismMortality rates of 60% to 70% Clinical features include:

HypothermiaAdvanced stages of hypothyroid symptomsAltered mental status: delirium to comaHyponatremiaypHypoglycemia

Treatment:Levothyroxine (T4) 300 to 500 mcg IV bolusy ( ) gSecond day doses of T4 are typically 100 to 300 mcg given intravenously until the patient stabilizes and oral therapy is begun Hydrocortisone 100 mg IV every 8 hours should be given until coexisting adrenal suppression is ruled outTreat any other underlying conditions

Pathophysiology of HyperthyroidismPathophysiology of Hyperthyroidism

Serum T3 usually increases more than T4 does Usually because of increased secretion of T3 and conversion of T4 to T3 in peripheral tissuesconversion of T4 to T3 in peripheral tissues

In some patients, only T3 is elevated (T3 toxicosis)T3 toxicosis may occur in any of the usual disorders y ythat produce hyperthyroidismIf T3 toxicosis is untreated, the patient usually also develops laboratory abnormalities typical ofdevelops laboratory abnormalities typical of hyperthyroidism

Causes of HyperthyroidismCauses of HyperthyroidismHyperthyroidism with a Hyperthyroidism with a yp yhigh radioiodine uptake

Autoimmune thyroid disease

yp ylow radioiodine uptake

Subacute thyroiditisExogenous thyroid

Autonomous thyroid tissue (uptake may be low if recent iodine load l d t i di i d d

Exogenous thyroid hormone intakeEctopic hyperthyroidism

led to iodine-induced hyperthyroidism)TSH-mediated hyperthyroidismhyperthyroidismHuman chorionic gonadotropin-mediated hyperthyroidismhyperthyroidism

Signs and SymptomsSigns and SymptomsSigns:

Warm, smooth, moist skin; Fine/thin hairExophthalmos, “lid lag”Pretibial myxedemaPretibial myxedemaTachycardia, widened pulse pressure, systolic ejection murmurThyromegaly

Symptoms:Nervousness/ anxietyNervousness/ anxietyEmotional labilityFatigueHeat intoleranceHeat intoleranceWeight loss with increased appetite

Hyperthyroidism Treatment: Thioureylenes (Thionamides)

Mechanism of Action: Diversion of iodine away from potential iodination sites in thyroglobulin, preventing (“organification”)Inhibition of coupling of monoiodotyrosine and diiodotyrosine p g y yto form T4 and T3

Propylthiouracil (PTU): 300-600 mg daily divided in three to four doses Maximum dose: 1200 mg/dayfour doses. Maximum dose: 1200 mg/day

Also inhibits the peripheral conversion of T4 to T3; dose-related effect and occurs within hours of administrationT1/2 is approximately 1 to 2 5 hours; 60 80% protein boundT1/2 is approximately 1 to 2.5 hours; 60-80% protein bound

Methimazole (MMI) : 30 to 60 mg daily divided in three doses. Maximum dose: 120 mg/day

Approximately 10 times more potent than PTUT1/2 is approximately 6 to 9 hours; not protein bound

Thioureylenes cont’dThioureylenes cont d.Both cause symptoms to diminish in about 4 to 8 y pweeks. Monitoring: When patients generally start becoming euthyroid and can be tapered downeuthyroid and can be tapered down

Tapering should be done monthly (usual time interval for the endogenously produced T4 to reach a new steady-state)steady state)

ADRs: Common: Rash, arthralgias, fever, gastrointestinal intolerance (all up to 5%); leukopenia (up to 12%)intolerance, (all up to 5%); leukopenia (up to 12%)Severe: Agranulocytosis (0.5-6%), aplastic anemia (MMI)

Hyperthyroidism Treatment: IodidesHyperthyroidism Treatment: IodidesMechanism of Action:

Acutely blocks thyroid hormone releaseAcutely blocks thyroid hormone releaseInhibits thyroid hormone biosynthesis by interfering with intrathyroidal iodide utilization (the Wolff-Chaikoff effect)Decreases the size and vascularity of the thyroid gland

Potassium iodide:Potassium iodide: Saturated solution (SSKI), which contains 38 mg of iodide per dropLugol’s solution, which contains 6.3 mg of iodide per drop. Typical starting dose of SSKI is 3 to 10 drops daily (120 to 400 mg) in water or juiceor juice.

No documented advantage to using doses in excess of 6 to 8 mg/day. It should be administered 7 to 14 days preoperatively; or 3-7 days after RAI therapy.ADRADRs:

Common: skin rashes, drug fever, rhinitis, and conjunctivitis; salivary gland swelling; “iodism” (metallic taste, burning mouth and throat, sore teeth and gums, symptoms of a head cold, stomach upset and diarrhea; and gynecomastiagynecomastia

Radioactive Iodide (131I)

Hyperthyroidism Treatment: Adrenergic Blockers

Mechanism of Action: Ameliorates thyrotoxic symptoms

Propranolol:Inhibition of conversion of T4 to T3 is mediated by d-propranolol, while l-propranolol is responsible for anti-adrenergic effectsad e e g c e ec sDosing: Initial dose of 20 to 40 mg four times daily (to keep heart rate <90 beats/min)

Patients with increased clearance may need 240 to 480 mg/day

Contraindications: patients with asthma, heart blockpPrecautions: compensated congestive heart failure and bronchospastic chronic obstructive lung disease

Thyroid StormThyroid StormLife-threatening emergencyCharacterized by:

Severe thyrotoxicosisHyperthermia (fever usually >103oF)Hyperthermia (fever usually 103 F)TachycardiaTachypneaDehydrationDehydrationDeliriumN/V/DComa

Precipitating factors: Infection, trauma, surgery, RAI tx, withdrawal from anti-thyroid medicationsyMortality rate with aggressive treatment is ~20%

TreatmentTreatment

Preferred anti-thyroid agent: PTU 900-1200 mg/day y g g ypo in 4-6 divided dosesCan also use:

MMI 90-120 mg/day in 4-6 divided dosesSSKI or Lugol’s solution

Anti-adrenergic:Anti-adrenergic: Propranolol:

Initially: 1mg/min IV (max= 10mg; may repeat q 4-6H)Maintenance: 40-80 mg po q6H (max= 120mg q6H)

Corticosteroids:Hydrocortisone 100mg IV q8HHydrocortisone 100mg IV q8H

True or False QuestionsTrue or False Questions

Methimazole inhibits T4 to T3 conversion inMethimazole inhibits T4 to T3 conversion in the periphery

Liothyronine and Liotrix are not interchangeableg

Myxedema coma is the emergent result of y ede a co a s t e e e ge t esu t oHyperthyroidism

ReferencesReferencesAACE Thyroid Task Force. American Association of Clinical Endocrinologists medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hyperthyroidism and Hypothyroidism. Endocrine Practice. V l 8 N 6 N b /D b 2002 2006 d d i 457 469Vol.8 No.6. November/December 2002. 2006 amended version. p.457-469.Talbert, R. Thyroid Disorders. Pharmacotherapy: A Pathophysiologic Approach. Sixth Ed. p.1369-1390.Ross, D. Treatment of Hypothyroidism. UpToDate Online 16.3. <http://uptodateonline.com/online/content/topic.do?topicKey=thyroid/2117>. [Accessed December 12, 2008].Ross, D. Treatment of Graves’ hyperthyroidism. UpToDate Online 16.3.

htt // t d t li / li / t t/t i d ?t i K th id/4550& l t dTitl 6 150&<http://uptodateonline.com/online/content/topic.do?topicKey=thyroid/4550&selectedTitle=6~150&source=search_result>. [Accessed December 13, 2008].Ross, D. Beta blockers in the treatment of hyperthyroidism. UpToDate Online 16.3. <http://uptodateonline.com/online/content/topic.do?topicKey=thyroid/4878&selectedTitle=18~150&source=search_result>. [Accessed December 13, 2008].Micromedex. Levothyroxine. Drug monograph. Mi d Th id USP D hMicromedex. Thyroid USP. Drug monograph. Micromedex. Propylthiouracil. Drug monograph. Micromedex. Methimazole. Drug monograph.

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