Issues in the Treatment of Patients with Hypothyroidism

Behavioral Objectives

After completing this continuing education article, the pharmacist should be able to:

1. Understand thyroid hormone function and describe thecauses and pathophysiology of hypothyroidism.

2. Identify risk factors for mild and overt hypothyroidism.

3. Describe optimal approaches to the treatment ofhypothyroidism.

4. Understand side effects relevant to pharmacologic treatment.

5. Describe consequences of minor deficiency or excess ofthyroxine dosage in common clinical circumstances.

6. Understand the pharmacist's role in dispensing agents witha narrow therapeutic index and the possible consequences ofswitching thyroid hormone preparations.

Hypothyroidism is a commonendocrine disorder that resultsfrom suboptimal thyroid hormonelevels. Pharmacotherapy forhypothyroidism is accomplished throughhormone replacement with levothyroxine.Recently, the FDA granted AB-ratedstatus to a number of levothyroxine productsthat were already approved. Theseclassifications have raised issues regardingoptimum treatment of patients withthyroid disease. It is the purpose of thisarticle to review the pathophysiology, riskfactors, clinical manifestations, and managementof hypothyroidism. Currentissues related to treatment, includingadverse effects and issues surroundingswitching of levothyroxine products,which have a narrow therapeutic index(NTI), are also discussed.

Thyroid Hormone Physiologyand Function

Thyroid hormones are necessary fornormal metabolism, growth, anddevelopment, and virtually every tissueof the body is affected either directly orindirectly by them. The main functionsof thyroid hormones include regulationof basal metabolic rate and restingoxygen consumption; increasedheat production; increased glucose utilization,uptake, and synthesis; andpermissive sympathomimetic effectsincluding increased heart rate andforce of contraction.

The synthesis of the iodine-containingthyroid hormones thyroxine (T₄)and triiodothyronine (T₃) is controlledby the hypothalamic-pituitary-thyroidaxis. The hypothalamus synthesizesand releases the peptide thyrotropin-releasinghormone (TRH) that travelsthrough a portal blood system to theanterior pituitary, where it stimulatespituitary thyrotrophs to produce andrelease the peptide thyrotropin (thyroid-stimulating hormone; TSH). Thesecretion of TSH is pulsatile in the contextof a diurnal rhythm, with a peak atnight and lower levels during the daytime.¹

Thyrotropin enters the systemic circulation,where it travels to and stimulatesthe thyroid gland, in a trophicmanner, to produceT₄and T₃. The thyroidhormones then act through apowerful negative feedback mechanismat the levels of the hypothalamusand pituitary to inhibit further releaseof TRH and TSH, respectively. Thisendocrine axis allows for tight regulationof thyroid hormone production.

The major product of the thyroidgland is T₄, whichaccounts for approximately85% of thyroid hormone output.² Circulating T₄,with a half-life of7 days, is metabolized by monodeiodinationto T₃, with a half-life of 1 day, inthe liver, kidney, and target tissues, byspecific deiodinases.³ Thus, approximately87% of T₃is derived from T₄,and the remaining 13% is synthesizedby the thyroid gland.⁴ This conversionof T₄ to T₃ is critical because T₃ is recognizedas the more potent, biologicallyactive form of the hormone.^2,5BothT₄ and T₃ are subject to high levelsof plasma protein binding, includingto thyroxine-binding globulin, andonly the free fraction of hormone isavailable to bind to thyroid hormonereceptors. Three receptors have beenidentified that are thought to mediatethe primary actions of thyroid hormone.The TRa¹, TRb¹, and TRb² receptorsare members of the nuclear receptorsuperfamily.⁶ Interaction of T₃ withits receptor promotes the binding ofcofactors that can regulate the expressionof thyroid-hormone-responsivegenes, either through activation orrepression of transcription.^7,8 This typeof receptor interaction explains whythe beneficial effects of thyroid hormonereplacement may take weeks tooccur, because alteration of gene product(eg, enzymes, proteins) levels relieson new synthesis or breakdown ofproducts already present. Some effectsof thyroid hormone have been notedto occur more quickly than can beaccounted for by this mechanism, andrecent evidence suggests nongenomicactions related to the cyclic adenosinemonophosphate (cAMP), Ca2+, or proteinkinase cascades. This would implythe presence of a membrane-associatedreceptor for thyroid hormone.⁹

Hypothyroidism

Hypothyroidism is a common endocrinedisorder affecting between 10million and 14 million Americans^2,10,11that results from a deficiency in secretionof T₄ and T₃from the thyroidgland. It occurs more often in womenthan men and increases in incidencewith age.⁸ Hypothyroidism can bedefined based on different parametersof the pathophysiology. Primaryhypothyroidism describes the statewhere the defect is located at the thyroidgland itself, whereas secondary(central) hypothyroidism relates to anabnormality in the anterior pituitary orhypothalamus (sometimes the term tertiaryhypothyroidism is used to denote ahypothalamic irregularity). Dependingon the cause, hypothyroidism may beeither congenital, often due to geneticmutations related to dysfunction ofthyroid hormone biosynthesis or function,or acquired, as in autoimmunethyroiditis (Hashimoto's thyroiditis).Interestingly, the most common causeof congenital hypothyroidism worldwideis still iodine deficiency.¹² Lastly,hypothyroidism is termed clinical orovert when symptoms are present, andsubclinical or mild when no overt symptomsassociated with clinical hypothyroidismare present. To assist in thediagnosis and determination of thecause of hypothyroidism, TSH levelsare measured. In primary clinicalhypothyroidism, free T₄ and T₃ levelswill be low and TSH levels will be highdue to the lack of feedback from aninadequate amount of thyroid hormone.Subclinical hypothyroidism is biochemicallydefined as mildly elevatedTSH levels with normal T₄ and T₃ levels.¹³ Furthermore, assays for thyroidautoantibodies may be performed todetermine the cause of the condition.This may be important as the presenceof thyroid autoantibodies in the settingof subclinical hypothyroidism may signalincreased risk of future developmentof clinical hypothyroidism.^14,15

Clinical Manifestations

The clinical manifestations of hypothyroidismare well characterized andinclude deleterious effects on multipleorgan systems; the severity may varyconsiderably, however.^4,8,16 Myxedemarefers to the dry, waxy, nonpittingswelling of the skin with distinct facialchanges, including swollen lips andthickening of the nose. A goiter mayalso occur. Patients may complain ofcold intolerance, and hypothermia iscommon. Effects on brain function leadto slow mental processing, impairedmemory, and depression. Musclefatigue and cramping, gastrointestinal(GI) abnormalities such as constipation,weight gain even with decreasedfood intake, reproductive irregularitiessuch as infertility, menstrual disturbances,diminished libido, and cardiovascularproblems including bradycardia,diastolic hypertension, pericardial effusion,hypercholesterolemia, and coronaryatheroma may also be present.¹⁷

Risk Factors for Hypothyroidism

Hypothyroidism may be caused by oris associated with many risk factors(Table 1).^4,8 Patients with these risk factorsor other clinical manifestationsseen in hypothyroidism should be evaluatedfor the presence of this disorder.

Management of Hypothyroidism

The American Association of ClinicalEndocrinologists (AACE) and theAmerican Thyroid Association (ATA)have each published treatment guidelinesfor hypothyroidism.^18,19 Accordingto these guidelines, the pharmacologictreatment of choice for clinical hypothyroidismis synthetic levothyroxinesodium, which is biochemically andphysiologically identical to endogenousT₄.²⁰ Once absorbed, levothyroxineis converted to the more potent T₃.When given properly, levothyroxine isgenerally safe and effective²¹; it has anNTI, however, so dosing must be carefullycustomized to the individualpatient.

The mean dose of levothyroxine fororal replacement therapy in adultsshould be approximately 1.6 to 1.7 mg/kgof body weight per day.^18,19 The initialdose is usually at the lower end of theanticipated dose requirement in otherwisehealthy adults, but therapy maybe initiated at a low dose (12.5 mg perday) and titrated up based on subsequent TSH measurements every 6weeks in patients older than 50 yearsof age or those with a history of cardiacdisease. Children may requirehigher doses (up to 4.0 mg/kg per day),and older patients may requirereduced doses (<1.0 mg/kg per day).Once the patient's TSH levels arewithin the normal range, follow-upevaluations including biochemicalmeasurements should be performedevery 6 months or annually.

Levothyroxine is well absorbed fromthe GI tract; this can be diminished,however, in patients with malabsorptionprofiles^22,23 or with foods such assoy²⁴ and fiber.^25,26 This suggests theneed to take levothyroxine while fasting.In addition, many drugs mayinterfere with the absorption oflevothyroxine, including cholestyramine,ferrous sulfate, sucralfate, calciumcarbonate, and aluminumhydroxide.^18,19,27,28 This requires thatlevothyroxine administration be spacedat least 4 hours apart from theseagents.¹⁹ Moreover, levothyroxinemetabolism may be increased byrifampin²⁹ and sertraline,¹⁸ and plasmaprotein binding and metabolism maybe altered by the anticonvulsantsphenytoin, phenobarbital, and carbamazepine.⁸

According to the AACE,¹⁸ there isinsufficient evidence regarding whichpatients with hypothyroidism maybenefit from treatment with a combinationof T₄ and T₃ versus T₄ alone.The ATA¹⁹ does not recommend liothyroninetreatment for chronic hypothyroidismdue to the increased likelihoodof iatrogenic hyperthyroidism.Furthermore, a randomized controlledtrial by Clyde et al³⁰ found no benefitin patients with primary hypothyroidismthat were treated with combinationlevothyroxine and liothyronineversus levothyroxine alone.Combination therapy is also not recommendeddue to the increased possibilityof fluctuation or elevation of T₃concentrations.³¹ In addition, the useof desiccated thyroid hormone formulationsis not recommended.

Because levothyroxine has an NTI,the potential for insufficient treatmentor overtreatment, thus inducing iatrogenichyperthyroidism, must be recognized.It is estimated that 15% to 29%of patients receive inadequate doses oflevothyroxine, and 18% to 24%receive excessive doses based on serumTSH levels that are outside of the normalrange.^11,32,33 Adverse effects relatedto levothyroxine treatment occur dueto doses higher than optimal for theindividual patient and include symptomaticthyrotoxicosis (emotionallability, nervousness, irritability, poorconcentration, muscular weakness andfatigability, voracious appetite withweight loss, hyperdefecation, proximalmuscle tremor, moist skin, heat intolerance),⁴ subclinical thyrotoxicosiswith increased risks of bone loss,³⁴ andatrial fibrillation.³⁵ On the other hand,inadequate treatment with levothyroxinewill not sufficiently alleviatethe clinical manifestations of hypothyroidism.Such adverse effects andthe patient's perception that the drugis not working can result in poorpatient compliance. Although allergiesto levothyroxine preparations are rare,it is important for the clinician andpharmacist to ascertain whether apatient may have an allergy or adversereaction to any of the inactive ingredientsin the preparation given. Forexample, lactose intolerance may be acomplication that prevents the use ofa lactose-containing preparation oflevothyroxine such as Synthroid(Abbott Laboratories, Chicago, IL) insome patients.³⁶ If the patient is sufficientlysensitive to the small amountof lactose present in the tablet, abdominalbloating or other symptoms mayresult in poor patient compliance andinadequate treatment.

Management of HypothyroidismDuring Pregnancy

Levothyroxine is safe during pregnancy,and replacement therapy isadvisable in all pregnant patients withmild-to-severe hypothyroidism.^18,37-39The fetal thyroid gland does notbecome active until about 12 weeks'gestation. Therefore during this timethe mother is the sole source of thyroidhormones for the fetus. Haddow et al³⁹report that hypothyroidism in pregnantwomen can adversely affect theirchild's subsequent performance onneuropsychological tests and thatdecreases in performance can occureven when the mother's hypothyroidismis mild. Thus, treating thepregnant patient can benefit the childas well as reduce the morbidity of themother.³⁹ It is also recommended thatTSH levels be measured before pregnancy,if possible, and each trimester.^18,19 Measurement of TSH levels iscritical because pregnancy can increasethe dose requirement of levothyroxine inmany patients with hypothyroidism.³⁷Administration should return to theprepregnancy dose immediately afterdelivery, however, and serum TSH levelsshould be ascertained 6 to 8 weeks later.¹⁹

Untreated overt hypothyroidism duringpregnancy has been associatedwith increased risk of maternal hypertension,preeclampsia, anemia, postpartumhemorrhage, cardiac ventriculardysfunction, spontaneous abortion,fetal death, and low birth weight, andevidence suggests the potential forabnormal fetal brain development.^18,38Furthermore, slight increases in maternalTSH levels during pregnancy may beassociated with increased risk of spontaneousabortion. Whether levothyroxinetherapy can prevent this isunknown. However, it has been determinedthat, in most of these women,thyroid autoantibodies develop thatmay also contribute to fetal death.^18,38,40

The treatment of hypothyroidism inpregnant patients is thus advised,although tight control of dose is necessarythrough the repeated measurementof TSH levels. Because of thenarrow therapeutic window of levothyroxine,too little or too muchreplacement therapy can result inadverse effects occurring in both themother and child.

Hypothyroidism in the Elderly

Hypothyroidism in elderly patientsoften is associated with subtle symptoms,and many are frequentlyascribed simply to old age. Symptomsmay include deafness, dry skin, hairloss, hoarseness of voice, ataxia, andmental dysfunction (confusion,dementia, depression). Screening forhypothyroidism using TSH measurementsis recommended in womenmore than 60 years of age, anyone witha prior history of treatment for thyroiddisease, and those with a history ofautoimmune disease, symptoms ofcognitive dysfunction, or hypercholesterolemia.^19,41

Levothyroxine therapy should beadministered at a dose directed atreturning TSH levels into the normalrange. The elderly tolerate the effects ofexcess levothyroxine poorly. Thuspatient monitoring is critical toachieve optimal therapy.

Hypothyroidism in Patientswith Heart Disease

Hypothyroidism is associated withhyperlipidemia and coronary arterydisease. Approximately 3% of patientswith chronic hypothyroidism reportangina, and about the same percentagecomplain of angina during levothyroxinetreatment. In these patients, theangina does not change but mayworsen in up to 40% of patients afterlevothyroxine treatment, thus requiringless than full replacement therapy.¹⁷ Thyroid hormone has both positiveinotropic and chronotropic effectson the heart and thus may exacerbatemyocardial ischemia and precipitatemyocardial infarction or sudden deathin patients with underlying cardiacdisease. It is recommended that inpatients with symptomatic heart diseasethe initial dose of levothyroxinebe 25 mg daily, with upward titration in12.5-to 25-mg increments every 3 to 6weeks, with vigilant clinical andmyocardial monitoring.⁸ Again, TSHand freeT₄assessment is critical inthese patients to properly move thepatient toward a euthyroid state, withoutadversely affecting any underlyingcardiac issues.

Hypothyroidism in Other CommonClinical Circumstances

Hypothyroidism necessitates specialconsiderations in patients with type 1diabetes mellitus, infertility, depression,or euthyroid sick syndrome.

Diabetes

Because type 1 diabetes mellitus hasan autoimmune component, it increasesthe risk of acquiring otherautoimmune-related disorders includingchronic thyroiditis, and it is estimatedthat 10% of patients with type1 diabetes will develop this condition,which may initially present subclinically.Furthermore, approximately25% of women with type 1 diabeteswill develop postpartum thyroiditis.^42,43 Measurement of TSH and examinationfor goiter should be performedat regular intervals in patients withdiabetes.

Infertility

Some patients with infertility ormenstrual irregularities will in facthave chronic thyroiditis associatedwith subclinical or clinical hypothyroidism,and the thyroiditis is contributingto the reproductive abnormality.Once chronic thyroiditis isconfirmed, proper levothyroxine therapymay restore fertility and normalizemenstrual cycles, particularly inpatients with high TSH levels.^44-46

Depression

The AACE states that the diagnosis ofsubclinical or clinical hypothyroidismmust be considered in every patientwith depression because a small proportionof patients with depressionhave primary hypothyroidism.¹⁸ Ifhypothyroidism is found, appropriatelevothyroxine treatment should be initiated.Sometimes in psychiatric practice,depressed patients are treated withlevothyroxine as well as with antidepressants,but the evidence does notshow that levothyroxine alone alleviates depression in these patients.^45,47Patients receiving lithium must bescreened periodically because lithiummay induce goiter and hypothyroidism.¹⁸

Euthyroid Sick Syndrome

Lastly, the evaluation of hypothyroidismin chronically ill individuals isconfounded by several factors. Otheragents often administered to thesepatients, such as corticosteroids, mayinterfere with thyroid function tests.Also, the body tends to compensate bydecreasing metabolic rate in states ofstarvation or illness, which may lowerT₄ and TSH levels. Often levothyroxinetreatment will be deferred until thepatient recovers and has been assessedby a clinical endocrinologist.¹⁸

Management of SubclinicalHypothyroidism

Subclinical hypothyroidism is definedas mildly increased serum TSH levelswith normal T₄ and T₃. It may representearly thyroid failure, because itoften progresses to overt hypothyroidism.Prevalence is common andranges from 1% to 10% of the adultpopulation, with increasing incidencein women, with advancing age, and inthose with high dietary iodine intake.The treatment of subclinical hypothyroidismwith levothyroxine is controversial,however. The ATA recommendsscreening for thyroid dysfunctionbeginning at 35 years of age and every5 years thereafter.¹⁶ It is during routinescreening using TSH measurementsthat asymptomatic subclinical hypothyroidismis usually discovered. Themost common cause is autoimmunethyroiditis, and those patients withthyroid antibodies have a greater riskof progressing to clinical hypothyroidism.^14,15

In addition to progression of hypothyroidism,other health problemsassociated with subclinical hypothyroidisminclude hyperlipidemia andcognitive deficits.¹⁴ The AACE recommendsthat treatment begin in patientswith TSH levels >10 mIU/mL or inpatients with TSH levels between 5 and10 mIU/mL and goiter or positive antithyroidperoxidase antibodies. The targetTSH level with treatment should be0.3 to 3 mIU/mL.¹⁸ Initial dosage oflevothyroxine should be between 25and 50 mg per day with follow-up TSHmeasurement in 6 to 8 weeks. The ATAalso states that treatment of subclinicalhypothyroidism is advisable, especiallyif thyroid autoantibodies are positive.¹⁹

In contrast, some experts believethat the data do not support the associationof subclinical thyroid diseasewith symptoms or adverse clinical outcomesand do not recommend treatmentin patients with TSH levelsbetween 4.5 and 10 mIU/L.⁴⁸ Furthermore,Gussekloo et al⁴⁹ state that, inthe very elderly, individuals with highserum TSH do not experience adverseeffects and may have a prolonged lifespan, but they recognize that the determinationof whether to treat thesepatients will require a well-designed,randomized, placebo-controlled clinicaltrial. Whether subclinical hypothyroidismis treated with levothyroxineor not, patients require proper clinicaland biochemical monitoring, anddosage adjustments should be made asneeded to prevent iatrogenic hyperthyroidism.The importance of this is suggestedin a study by Parle et al,⁵⁰ wherea single measurement of low serumthyrotropin in individuals 60 years ofage or older was associated withincreased mortality, particularly due tocirculatory and cardiovascular diseases.

Coma Due to PrimaryHypothyroidism

Coma due to primary hypothyroidismis a rare life-threatening conditionin which severe hypothyroidismsuddenly worsens and is complicatedby multiple organ system failure. It predominantlyoccurs in the elderly and isoften precipitated by another illness.Clinical manifestations other thancoma include bradycardia, hypothermia,respiratory failure, and cardiovasculardysfunction. Therapy includes alarge replacement dose with or withouta 500-mg loading dose of intravenouslevothyroxine. Liothyroninein divided doses may also be indicatedbecause conversion of T₄ to T₃ is likelycompromised in these patients. Furthermore,glucocorticoids and treatmentof underlying or precipitatingdisorders should be aggressive. Managementis in the intensive care unitand with the consultation of a clinicalendocrinologist.^8,19

Current Issues in LevothyroxineTreatment

The FDA granted AB-rated status to anumber of levothyroxine products(Table 2).⁵¹ Levothyroxine productshave an NTI. Therefore treatment forhypothyroidism should be individualizedto the patient, and biochemicalmonitoring should be used to evaluatethe appropriateness of therapy. Thedetermination of bioequivalence oflevothyroxine products is challengingbecause levothyroxine is biochemicallyand physiologically identical to theT₄produced endogenously.

Blakesley et al20 performed mathematicalcorrections based on knownphysiologic principles that wereintended to account for the contributionsof endogenous T₄. They foundthat, with no baseline correction forendogenous T₄,administered levothyroxinedoses that differed by 25% to33% could not be distinguished. Differencesin these amounts could be distinguished,however, when T₄ levelswere mathematically corrected usingone of the following methods: (1) themean of the three T₄ values taken at-0.5, -0.25, and 0 hours before dosingsubtracted from each concentrationafter dosing; (2) each T₄ concentrationcorrected for the hypothetical decay ofendogenous T₄ with a 7-day half-life,beginning with the level obtainedimmediately before dosing; or (3) thesubtraction of T₄ concentration measuredat the analogous time point onthe day prior to administration of thelevothyroxine dose from each T₄ concentrationafter dosing. Acknowledgingthis, the FDA adopted methodnumber 1 as its basis for granting ABratings to levothyroxine products.Even using this method, however,products with dosages that differed by12.5% are still deemed bioequivalent.

In response to the FDA's actions, theAACE, the ATA, and the EndocrineSociety released a joint position statementon the use and interchangeabilityof thyroxine products.52 The statementexpresses concern about theFDA's method for determining bioequivalenceand asserts that the FDAhas failed to address questions relatedto the bioequivalence of thyroxinepreparations. Bioequivalence is genericallydefined as the relative bioavailabilitiesof the active ingredients of 2products and is related to the rate andextent of absorption of the activeingredient.20 FDA guidelines for determiningbioequivalence of levothyroxineproducts through pharmacokineticstudies require the administration of asingle dose, administered to healthypeople (with normal thyroid function)at a strength several times the normaltherapeutic dose.53 This should raisethe serum concentration significantlyabove the endogenous level of T₄ producedby the person so that pharmacokineticmonitoring is meaningful. It ispossible, however, that endogenous T₄contributes in a significant way to themeasurement of hormone levels. TheFDA's methods employ area under thecurve and maximum concentrationmeasurements to determine bioequivalence,and the joint position statementargues that "corrected" values fail toaccount for the subjects'own endogenouscontribution to T₄ levels, andthus can still be off by 12.5%. Theseorganizations express concern thatTSH levels are not part of the FDA'sdeterminations for equivalence.

When considering switching levothyroxinepreparations in a hypothyroidpatient, these issues must be considered.Furthermore, the pharmacistmust remember that the potentialeffects of drug substitution are borneby the patient and should counsel thepatient to be aware of any changes insymptoms or the appearance of newsymptoms. Because levothyroxine hasan NTI, iatrogenic hyperthyroidism orthe inadequate replacement of thyroidhormone is possible if a switch to a formulationthat in vivo has a significantlydifferent therapeutic profilethan the previous preparation in anindividual patient occurs. For this reason,AACE guidelines18 suggest the useof a high-quality preparation oflevothyroxine. Accordingly, the AACEhas a Best Physician Practice Statementthat reads, "Patients should be maintainedon the same brand namelevothyroxine product. If the brand oflevothyroxine medication is changed,either from one brand to anotherbrand, from a brand to a generic product,or from a generic product toanother generic product, patientsshould be retested by measuring serumTSH in six (6) weeks, and the drug retitratedas needed. Since small changesin levothyroxine administration cancause significant changes in TSH serumconcentrations, precise and accurateTSH control is necessary to avoidpotential adverse iatrogenic effects."

Because the prescribing physicianmay not be aware of possible switchesin levothyroxine preparations, thepharmacist should recommend topatients that they be evaluated biochemicallyfor TSH levels approximately6 weeks after a switch and thedrug retitrated if necessary. Open communicationbetween the pharmacistand physician is highly recommended.Furthermore, the pharmacist shouldeducate the patient that levothyroxinetherapy is often lifelong and thatswitching formulations, particularlymultiple times, may lead to excessmedical cost in terms of follow-upexaminations as well as the appearanceof unwanted adverse effects.

Until the FDA and the societies thathave a main focus on hypothyroidismtreatment agree on standardized evaluationprotocols for levothyroxine products,these issues regarding switchingwill remain. It is fair to investigate thepossibility of some sort of correctionfor endogenously produced T₄ to get abetter comparison of whether 2levothyroxine preparations are trulybioequivalent.

It is the role of the pharmacist tomaintain open lines of communicationbetween physician and pharmacy,and pharmacy and patient, and toencourage appropriate interactionbetween patient and physician. If apreparation of levothyroxine ischanged at the pharmacy, the pharmacistshould make the patient fullyaware of the switch and recommendthat the patient follow up with his orher physician for evaluation, especiallyif symptoms change. In addition, moststates have not designated a list ofdrugs that are not substitutable, eg, NTIdrugs,⁵⁴ and it is the responsibility ofpharmacists to understand the regulationswithin their jurisdiction regardingthis matter.

Summary

Hypothyroidism is a common endocrinedisorder that is managed pharmacologicallywith thyroid hormonereplacement therapy. Levothyroxinepreparations have an NTI. Thereforedosage should be individualized toeach patient. Levothyroxine negativelyfeeds back upon the hypothalamusand anterior pituitary to decrease levelsof TRH and TSH. Thus measurement ofTSH levels is a sensitive assessment ofwhether the patient is receiving theproper dosage of levothyroxine.Recently the FDA gave AB-rating statusto a number of generic formulations oflevothyroxine. The endocrine societiesdisagree with these ratings, because thedosages of these products can differ byas much as 12.5% and still be deemedbioequivalent. Thus, these productsshould not be treated as true generics.The pharmacist should understandthat small dosage changes or switchinglevothyroxine preparations can havean adverse impact on the patient andshould counsel the patient to be mindfulof any changes in symptom profile.Furthermore, the pharmacist shouldencourage patients to maintain goodcommunication with their physicianfor the proper evaluation and treatmentof their hypothyroidism. Lastly,pharmacists should be encouraged totake a more proactive role regardingissues related to NTI agents and possiblyinfluence the FDA and the clinicalsocieties to agree to mandate a universaldecision regarding NTI agents.

Mitchell R. Emerson, PhD: Assistant Professor of Pharmaceutical Sciences, Midwestern University, College of Pharmacy—Glendale

For a list of references, send a stamped,self-addressed envelope to: ReferencesDepartment, Attn. A. Stahl, Pharmacy Times,241 Forsgate Drive, Jamesburg, NJ 08831;or send an e-mail request to: astahl@mwc.com.

MWC Office of Continuing Professional Education is accredited by the Accreditation Council for PharmacyEducation as a provider of continuing pharmacy education. This program is approved for2 contact hours (0.2 CEU) under the ACPE universal program number of 290-000-05-001-H01. The program is available for CE credit through February 28, 2008.

CE ANSWER FORM INSTRUCTIONS

TESTING AND GRADING PROCEDURES

1. Each participant achieving a passing grade of 70% or higher onany examination will receive a statement of credit giving thenumber of CE credits earned. This form should be safeguardedand may be used as documentation of credits earned.

2. Participants receiving a failing grade on any exam will be notifiedand permitted to take 1 reexamination at no extra cost.

3. All answers should be recorded on the answer form attached.For each question, decide which choice is the best answer, andcircle the letter of the response representing your choice.

4. Mail your completed exam form to the following address: PharmacyTimes, 405 Glenn Drive, Suite 4, Sterling, VA 20164-4432.

NEW SCORING OPTIONS

1. Mail

2. Fax: 703-404-1801

3. This lesson is FREE on-line; receive instant grading, as wellas download your certificate—www.pharmacytimes.comPlease print clearly—certificate will be issued frominformation given.

Please mail completed forms to:Pharmacy Times CE Department, 405 Glenn Drive, Suite 4,Sterling, VA 20164-4432

This educational lesson will be available to pharmacists on-line at www.pharmacytimes.com.

(Based on the article starting on page 117.) Choose the 1 most correct answer.

1. TSH is produced by which of thefollowing structures?

• Hypothalamus
• Anterior pituitary
• Posterior pituitary
• Thyroid

2. The major thyroid hormone receptorsutilize what form of signal transduction?

• Modification of gene expression
• Increases in cAMP levels
• Increases in Ca²⁺ levels
• Increases in phosphorylation

3. What is the half-life of T₄?

• 1 day
• 3 days
• 7 days
• 14 days

4. Subclinical hypothyroidism is definedbiochemically by which of the following?

• Low T₄ andlow TSH
• Normal T₄ and low TSH
• Low T₄ and elevated TSH
• Normal T₄ and T₃and elevated TSH

5. Which of the following is not aclinical manifestation ofhypothyroidism?

• Myxedema
• Heat intolerance
• Constipation
• Fatigue

6. Which of the following is not a riskfactor for hypothyroidism?

• History of autoimmune disorders
• Subclinical hypothyroidism
• Male gender
• Postpartum status

7. The treatment of choice forhypothyroidism is which of thefollowing?

• Thyrotropin
• Levothyroxine
• Liothyronine
• Combination of levothyroxine and liothyronine

8. Compared with adults, in children thedose of levothyroxine based on bodyweight is which of the following?

• Lower
• Higher
• Equal
• Levothyroxine is not indicated forchildren

9. Which of the following agents canincrease the metabolism oflevothyroxine?

• Cholestyramine
• Ferrous sulfate
• Calcium carbonate
• Rifampin

10. Which of the following is not anadverse effect of too muchlevothyroxine?

• Nervousness
• Weight loss
• Decreased appetite
• Hyperdefecation

11. Which of the following is correctregarding levothyroxine dose duringpregnancy?

• It should be increased.
• It should be decreased.
• It should not be changed.
• It is not indicated during pregnancy.

12. What percentage of hypothyroidpatients will experience worsened anginawith levothyroxine treatment?

• 10%
• 20%
• 40%
• 70%

13. The American Thyroid Associationrecommends screening for thyroiddisease beginning at what age?

• 25
• 35
• 45
• 55

14. The most common cause ofsubclinical hypothyroidism is which ofthe following?

• Autoimmune thyroiditis
• Pituitary ischemia
• Pituitary tumor
• Thyroidectomy

15. Which of the following is incorrectregarding myxedema coma?

• It predominantly occurs in theelderly.
• Bradycardia is a clinicalmanifestation.
• Liothyronine is not indicated.
• Glucocorticoids may be part of thetreatment.

16. Which of the following has the FDAnot determined to be therapeuticallyequivalent to Levoxyl?

• Unithroid
• Synthroid
• Levo-t
• Levothyroxine sodium (Mylan)

17. Which of the following has the FDAnot determined to be therapeuticallyequivalent to levothyroxine sodium(Mylan)?

• Novothyrox
• Levoxyl
• Synthroid
• Unithroid

18. Which of the following is notassociated with subclinicalhypothyroidism?

• Hyperlipidemia
• Cognitive deficits
• Spontaneous abortion
• Low dietary iodine

19. Which of the following is incorrectregarding the guidelines the FDA uses fordetermining bioequivalence oflevothyroxine preparations?

• A large single dose of levothyroxineis used.
• Levothyroxine is administered tohealthy subjects.
• Area under the curve is measured.
• Area under the curve is correctedfor baseline T₄values.

20. Which of the following is incorrectregarding levothyroxine?

• It is biochemically identical toendogenous T₄.
• It is more potent than endogenousT₃.
• It has a narrow therapeutic index.
• It is well absorbed from the GI tract.