Pharmacotherapy of

Thyroid Disorders
THYROID HORMONE
PHYSIOLOGY
• Thyroxine (T4) and triiodothyronine (T3) are formed on
thyroglobulin, a large glycoprotein synthesized within the thyroid
cell.
• Inorganic iodide enters the thyroid follicular cell and is oxidized
by thyroid peroxidase and covalently bound (organified) to
tyrosine residues of thyroglobulin.
• Iodinated tyrosine residues monoiodotyrosine (MIT) and
diiodotyrosine (DIT) combine (couple) to form iodothyronines
in reactions catalyzed by thyroid peroxidase.
• Thus, two molecules of DIT combine to form T4, and MIT and DIT
join to form T3.
THYROID HORMONE
PHYSIOLOGY
• Proteolysis within thyroid cells releases thyroid hormone into
the bloodstream.
• T4 and T3 are transported by thyroid-binding globulin
(TBG), transthyretin, and albumin.
• Only the unbound (free) thyroid hormone can diffuse into cells,
elicit biologic effects, and regulate thyroid-stimulating hormone
(TSH) secretion from the pituitary.
THYROID HORMONE
PHYSIOLOGY
• T4 is secreted solely from the thyroid
• Most T3 is formed from breakdown of T4 catalyzed by the enzyme
5′- monodeiodinase in peripheral tissues.
• T3 is five times more active than T4.
• Thyroid hormone production is regulated by TSH secreted by the
anterior pituitary, which in turn is under negative feedback control
by the circulating level of free thyroid hormone and the positive
influence of hypothalamic thyrotropin-releasing hormone (TRH).
THYROID HORMONE
PHYSIOLOGY
• Thyroid hormone production is also regulated by
extrathyroidal deiodination of T4 to T3, which can be affected
by nutrition, nonthyroidal hormones, drugs, and illness.
THYROTOXICOSIS
(HYPERTHYROIDISM)
• Thyrotoxicosis results when tissues are exposed to excessive levels
of T4, T3, or both.
• TSH-secreting pituitary tumors release biologically active
hormone that is unresponsive to normal feedback control.
• The tumors may co-secrete prolactin or growth hormone;
therefore, patients may present with amenorrhea, galactorrhea, or
signs of acromegaly.
PATHOPHYSIOLOGY)
• In Graves disease, hyperthyroidism results from the action of
thyroid- stimulating antibodies (TSAb) directed against the
thyrotropin receptor on the surface of thyroid cell. These
immunoglobulins bind to the receptor and activate the enzyme
adenylate cyclase in the same manner as TSH.
• An autonomous thyroid nodule (toxic adenoma) is a thyroid mass
whose function is independent of pituitary control.
Hyperthyroidism usually occurs with larger nodules (>3 cm in
diameter).
PATHOPHYSIOL
• In multinodular goiter, follicles with autonomous function coexist
with normal or even nonfunctioning follicles. Thyrotoxicosis occurs
when autonomous follicles generate more thyroid hormone than
is required.
• Painful subacute (granulomatous or de Quervain) thyroiditis
often develops after a viral syndrome.
• Painless (silent, lymphocytic, or postpartum) thyroiditis is a
common cause of thyrotoxicosis; its etiology is not fully understood;
autoimmunity may underlie most cases
PATHOPHYSIOL
• Thyrotoxicosis factitia is produced by ingestion of exogenous
thyroid hormone.
• Amiodarone may induce thyrotoxicosis (2%–3% of patients) or
hypothyroidism. It interferes with type I 5′-deiodinase, leading to
reduced conversion of T4 to T3, and iodide release from the drug
may contribute to iodine excess. Amiodarone also acauses a
destructive thyroiditis with loss of thyroglobulin and thyroid
hormones.
CLINICAL
• Symptoms:
• Nervousness & anxiety, palpitations
• emotional lability & easy fatigability
• heat intolerance
• weight loss concurrent with increased appetite
• increased frequency of bowel movements
• proximal muscle weakness (noted on climbing stairs or arising from
a sitting position)
• and scanty or irregular menses in women.
CLINICAL
• Physical signs:
• warm, smooth, moist skin and unusually fine hair
• Separation of the ends of the fingernails from the nail beds (onycholysis)
• retraction of the eyelids and lagging of the upper lid behind the globe
upon downward gaze (lid lag);
• tachycardia at rest, widened pulse pressure, and systolic ejection murmur
• Occasional gynecomastia in men
• fine tremor of the protruded tongue and outstretched hands;
• hyperactive deep tendon reflexes.
CLINICAL
• Graves disease:
• Hyperthyroidism
• diffuse thyroid enlargement
• Exophthalmos
• pretibial myxedema
• thyroid acropachy
• In severe disease, a thrill may be felt and a systolic bruit may be
heard over the gland.
CLINICAL
• Subacute thyroiditis:
• severe pain in the thyroid region, which often extends to the ear.
• fever, malaise, myalgia, and signs and symptoms of thyrotoxicosis.
• The thyroid gland is firm and exquisitely tender on
physical examination.
CLINICAL
• Painless thyroiditis:
• Most patients present with mild thyrotoxic symptoms
• lid retraction and lid lag are present, but exophthalmos is absent.
• The thyroid gland may be diffusely enlarged without tenderness
CLINICAL
• Thyroid storm is a life-threatening medical emergency characterized
by decompensated thyrotoxicosis, high fever (often >39.4°C
[103°F]), tachycardia, tachypnea, dehydration, delirium, coma,
nausea, vomiting, and diarrhea.
• Precipitating factors include infection, trauma, surgery,
radioactive iodine (RAI) treatment, and withdrawal from
antithyroid drugs.
DIAGNO
• Elevated 24-hour radioactive iodine uptake (RAIU) indicates
true hyperthyroidism:
• the patient’s thyroid gland is overproducing T4, T3, or both (normal
RAIU 10%–30%).
• A low RAIU indicates that excess thyroid hormone is not a
consequence of thyroid gland hyperfunction but is likely caused
by thyroiditis or hormone ingestion.
DIAGNO
• This may be seen in painful subacute thyroiditis, painless thyroiditis,
struma ovarii, follicular cancer, and factitious ingestion of
exogenous thyroid hormone.
• TSH-induced hyperthyroidism is diagnosed by evidence of
peripheral hypermetabolism, diffuse thyroid gland enlargement,
elevated free thyroid hormone levels, and elevated serum
immunoreactive TSH concentrations.
DIAGNO
• Because the pituitary gland is extremely sensitive to even
minimal elevations of free T4, a “normal” or elevated TSH level in
any thyrotoxic patient indicates inappropriate production of TSH.
• TSH-secreting pituitary adenomas are diagnosed by
demonstrating lack of TSH response to TRH stimulation,
inappropriate TSH levels, elevated TSH α-subunit levels, and
radiologic imaging.
• In thyrotoxic Graves disease, there is an increase in the overall
hormone production rate with a disproportionate increase in
T3 relative to T4.
DIAGNO
• Measurement of serum free T4 (or total T4 and T3 resin uptake),
total T3, and TSH will confirm the diagnosis of thyrotoxicosis.
• For toxic adenomas, because there may be isolated elevation of
serum T3 with autonomously functioning nodules, a T3 level must
be measured to rule out T3 toxicosis if the T4 level is normal.
• If autonomous function is suspected, but the TSH is normal, the
diagnosis can be confirmed by failure of the autonomous nodule to
decrease iodine uptake during exogenous T3 administration
sufficient to suppress TSH.
DIAGNO
• In multinodular goiters, a thyroid scan shows patchy areas
of autonomously functioning thyroid tissue.
• In subacute thyroiditis, thyroid function tests typically run a triphasic
course in this self-limited disease. Initially, serum T4 levels are
elevated due to release of preformed thyroid hormone. The 24-hour
RAIU during this time is less than 2% because of thyroid
inflammation and TSH suppression by the elevated T4 level. As the
disease progresses, intrathyroidal hormone stores are depleted, and
the patient may become mildly hypothyroid with appropriately
elevated TSH level.
DIAGNO
• During the recovery phase, thyroid hormone stores are
replenished, and serum TSH elevation gradually returns to normal.
• During the thyrotoxic phase of painless thyroiditis, the 24-hour RAIU
is suppressed to less than 2%. Antithyroglobulin and antithyroid
peroxidase antibody levels are elevated in more than 50% of
patients.
DIAGNO
• Thyrotoxicosis factitia should be suspected in a thyrotoxic
patient without evidence of increased hormone production,
thyroidal inflammation, or ectopic thyroid tissue.
• The RAIU is low because thyroid gland function is suppressed by
exogenous thyroid hormone. Measurement of plasma
thyroglobulin reveals presence of very low levels.
TREATMENT
• Goals of Treatment:
• Eliminate excess thyroid hormone
• Minimize symptoms and long-term consequences
• Provide individualized therapy based on the type and severity of
disease, patient age and gender, existence of nonthyroidal
conditions, and response to previous therapy
Thyroidectom
• Surgical removal of the thyroid gland should be considered in
patients with a large gland (>80 g), severe ophthalmopathy, or lack of
remission on antithyroid drug treatment.
• If thyroidectomy is planned, propylthiouracil (PTU) or methimazole
is usually given until the patient is biochemically euthyroid (usually
6–8 weeks), followed by addition of iodides (500 mg/day) for 1–14
days before surgery to decrease vascularity of the gland.
Thyroidectom
• Levothyroxine may be added to maintain the euthyroid state
while thionamides are continued.
• Propranolol has been used for several weeks preoperatively and 7
to 10 days after surgery to maintain pulse rate less than 90
beats/min. Combined pretreatment with propranolol and 10 to 14
days of potassium iodide also has been advocated.
THIOUREAS
• PTU and methimazole block thyroid hormone synthesis by:
• inhibiting the peroxidase enzyme system of the thyroid,
preventing oxidation of trapped iodide and subsequent
incorporation into iodotyrosines and ultimately iodothyronine
(“organification”);
• inhibiting coupling of MIT and DIT to form T4 and T3.
• PTU also inhibits peripheral conversion of T4 to T3.
THIOUREAS
• Usual initial doses include PTU 300 to 600 mg daily (usually in three or
four divided doses) or methimazole 30 to 60 mg daily given in three
divided doses.
• Improvement in symptoms and laboratory abnormalities should
occur within 4 to 8 weeks, at which time a tapering regimen to
maintenance doses can be started.
• Make dosage change monthly because the endogenously produced T4
will reach a new steady-state concentration in this interval.
• Typical daily maintenance doses are PTU 50 to 300 mg and methimazole
5 to 30 mg. Continue therapy for 12 to 24 months to induce long-term
remission.
THIOUREAS
• Monitor patients every 6 to 12 months after remission.
• If a relapse occurs, alternate therapy with RAI is preferred to a
second course of antithyroid drugs, because subsequent courses are
less likely to induce remission.
• Minor adverse reactions include pruritic maculopapular rashes,
arthralgias, fever, and benign transient leukopenia (white blood
cell count <4000/mm3).
• The alternate thiourea may be tried in these situations, but
cross- sensitivity occurs in ~50% of patients.
THIOUREAS
• Major adverse effects include agranulocytosis (with fever,
malaise, gingivitis, oropharyngeal infection, and granulocyte
count
<250/mm3), aplastic anemia, lupus-like syndrome, polymyositis, GI
intolerance, hepatotoxicity, and hypoprothrombinemia.
• Because of the risk of serious hepatotoxicity, PTU should not be
considered first-line therapy except during the first trimester of
pregnancy (when the risk of methimazole-induced embryopathy
may exceed that of PTU-induced hepatotoxicity), intolerance to
methimazole, and thyroid storm.
IODID
• Iodide acutely blocks thyroid hormone release, inhibits thyroid
hormone biosynthesis by interfering with intrathyroidal iodide
use, and decreases size and vascularity of the gland.
• Symptom improvement occurs within 2 to 7 days of initiating
therapy, and serum T4 and T3 concentrations may be reduced for a
few weeks.
• Iodides are often used as adjunctive therapy to prepare a patient
with Graves disease for surgery, to acutely inhibit thyroid hormone
release and quickly attain the euthyroid state in severely thyrotoxic
patients with cardiac decompensation, or to inhibit thyroid hormone
release after RAI therapy.
IODID
• Potassium iodide is available as a saturated solution (SSKI, 38 mg
iodide per drop) or as Lugol solution, containing 6.3 mg of iodide
per drop.
• Typical starting dose of SSKI is 3 to 10 drops daily (120–400 mg)
in water or juice.
• When used to prepare a patient for surgery, it should be
administered 7 to 14 days preoperatively.
• As an adjunct to RAI, SSKI should not be used before but rather 3 to
7 days after RAI treatment so the RAI can concentrate in the thyroid.
IODID
• Adverse effects:
• hypersensitivity reactions (skin rashes, drug fever,
rhinitis, conjunctivitis)
• salivary gland swelling
• “iodism” (metallic taste, burning mouth and throat, sore teeth and
gums, symptoms of a head cold, and sometimes stomach upset
and diarrhea)
• gynecomastia.
ADRENERGIC
• β-Blockers are used to ameliorate thyrotoxic symptoms such
as palpitations, anxiety, tremor, and heat intolerance.
• Propranolol and nadolol partially block conversion of T4 to T3.
• β-Blockers are usually used as adjunctive therapy with antithyroid
drugs, RAI, or iodides when treating Graves’ disease or toxic
nodules; in preparation for surgery; or in thyroid storm
ADRENERGIC
• The only conditions for which β-blockers are primary therapy
for thyrotoxicosis are those associated with thyroiditis.
• Propranolol doses required to relieve adrenergic symptoms vary,
but an initial dose of 20 to 40 mg orally four times daily is effective
for most patients (heart rate <90 beats/min).
• Younger or more severely toxic patients may require 240 to
480 mg/day.
ADRENERGIC
• β-Blockers are contraindicated in decompensated heart failure
unless it is caused solely by tachycardia (high output).
• Other contraindications are sinus bradycardia, concomitant
therapy with monoamine oxidase inhibitors or tricyclic
antidepressants, and patients with spontaneous hypoglycemia
• Side effects include nausea, vomiting, anxiety, insomnia,
lightheadedness, bradycardia, and hematologic
disturbances.
• Centrally acting sympatholytics (eg, clonidine) and calcium channel
antagonists (eg, diltiazem) may be useful for symptom control
when contraindications to β-blockade exist.
RADIOACTIVE
• Sodium iodide–131 is an oral liquid that concentrates in the thyroid
and initially disrupts hormone synthesis by incorporating into
thyroid hormones and thyroglobulin.
• Over a period of weeks, follicles that have taken up RAI and
surrounding follicles develop evidence of cellular necrosis and
fibrosis of interstitial tissue.
• RAI is the agent of choice for Graves disease, toxic
autonomous nodules, and toxic multinodular goiters.
• Pregnancy is an absolute contraindication to use of RAI.
RADIOACTIVE
• β-Blockers are the primary adjunctive therapy to RAI because
they may be given anytime without compromising RAI therapy.
• Patients with cardiac disease and elderly patients are often
treated with thionamides prior to RAI ablation because thyroid
hormone levels transiently increase after RAI treatment due to
release of preformed thyroid hormone.
• If iodides are administered, they should be given 3 to 7 days after
RAI to prevent interference with uptake of RAI in the thyroid gland.
RADIOACTIVE
• The goal of therapy is to destroy overactive thyroid cells, and a
single dose of 4000 to 8000 rad results in a euthyroid state in 60% of
patients at 6 months or sooner.
• A second dose of RAI should be given 6 months after the first
RAI treatment if the patient remains hyperthyroid.
• Hypothyroidism commonly occurs months to years after RAI.
• The acute, short-term side effects include mild thyroidal
tenderness and dysphagia.
Treatment of Thyroid Storm
• Initiate the following therapeutic measures promptly:
(1) suppression of thyroid hormone formation and secretion
(2) antiadrenergic therapy
(3) administration of corticosteroids, and
(4) treatment of associated complications or coexisting factors
that may have precipitated the storm
Treatment of Thyroid
• Iodides, which rapidly block the release of preformed thyroid
hormone, should be administered after a thionamide is initiated
to inhibit iodide utilization by the overactive gland.
• Antiadrenergic therapy with the short-acting agent esmolol is
preferred because it can be used in patients with pulmonary
disease or at risk for cardiac failure and because its effects can be
rapidly reversed.
Treatment of Thyroid
• Corticosteroids are generally recommended; their benefits may
be attributed to their antipyretic action and stabilization of blood
pressure (BP).
• General supportive measures, including acetaminophen as an
antipyretic (aspirin or other nonsteroidal anti-inflammatory
drugs may displace bound thyroid hormone), fluid and
electrolyte replacement, sedatives, digoxin, antiarrhythmics,
insulin, and antibiotics should be given as indicated.
EVALUATION OF THERAPEUTIC
OUTCOMES
• After therapy (thionamides, RAI, or surgery) for hyperthyroidism has
been initiated, evaluate patients monthly until they reach a
euthyroid condition.
• Assess for clinical signs of continuing thyrotoxicosis or
development of hypothyroidism.
• After T4 replacement is initiated, the goal is to maintain both the free
T4 level and the TSH concentration in the normal range. Once a
stable dose of T4 is identified, monitor the patient every 6 to 12
months.
HYPOTHYROIDISM
• The vast majority of patients have primary hypothyroidism due
to thyroid gland failure from chronic autoimmune thyroiditis
(Hashimoto’s disease).
• Defects in suppressor T lymphocyte function lead to survival of a
randomly mutating clone of helper T lymphocytes directed
against antigens on the thyroid membrane. The resulting
interaction stimulates B lymphocytes to produce thyroid
antibodies.
PATHOPHYSIOL
• Iatrogenic hypothyroidism follows exposure to destructive
amounts of radiation, after total thyroidectomy, or with excessive
thionamide doses used to treat hyperthyroidism.
• Other causes of primary hypothyroidism include iodine
deficiency, enzymatic defects within the thyroid, thyroid
hypoplasia, and ingestion of goitrogens.
PATHOPHYSIOL
• Secondary hypothyroidism due to pituitary failure is
uncommon. Pituitary insufficiency may be caused by:
• destruction of thyrotrophs by pituitary tumors
• surgical therapy
• external pituitary radiation
• postpartum pituitary necrosis (Sheehan syndrome)
• Trauma
• infiltrative processes of the pituitary (eg, metastatic
tumors, tuberculosis).
CLINICAL
• Symptoms:
• dry skin
• cold intolerance
• weight gain & constipation,
• weakness, lethargy, fatigue, muscle cramps, myalgia, stiffness,
and loss of ambition or energy.
• In children, thyroid hormone deficiency may manifest as growth
or intellectual retardation.
CLINICAL
• Physical signs:
• coarse skin and hair
• cold or dry skin
• periorbital puffiness,
• Bradycardia
• slowed or hoarse speech.
• Objective weakness (with proximal muscles affected more than
distal muscles) and slow relaxation of deep tendon reflexesare
common.
• Reversible neurologic syndromes such as carpal tunnel
syndrome, polyneuropathy, and cerebellar dysfunction may also
occur.
CLINICAL
• Most patients with secondary hypothyroidism due to inadequate
TSH production have clinical signs of generalized pituitary
insufficiency, such as abnormal menses and decreased libido, or
evidence of a pituitary adenoma, such as visual field defects,
galactorrhea, or acromegaloid features.
CLINICAL
• Myxedema coma is a rare consequence of decompensated
hypothyroidism manifested by hypothermia, advanced stages of
hypothyroid symptoms, and altered sensorium ranging from
delirium to coma. Mortality rates of 60% to 70% necessitate
immediate and aggressive therapy.
DIAGNOSIS
• A rise in TSH level is the first evidence of primary hypothyroidism.
• Many patients have a free T4 level within the normal range
(compensated hypothyroidism) and few, if any, symptoms of
hypothyroidism.
• As the disease progresses, the free T4 drops below normal. The T3
concentration is often maintained in the normal range despite low
T4.
• Antithyroid peroxidase antibodies and antithyroglobulin antibodies
are usually elevated.
• Pituitary failure (secondary hypothyroidism) should be suspected in
patients with decreased T4 levels and inappropriately normal or low
TSH levels.
TREATMENT OF HYPOTHYROIDISM
• Goals of Treatment:
• Restore thyroid hormone concentrations in tissue
• Provide symptomatic relief
• prevent neurologic deficits in newborns and children
• Reverse the biochemical abnormalities of hypothyroidism.
Levothyroxin
• Levothyroxine (l-thyroxine, T4) is the drug of choice for thyroid
hormone replacement and suppressive therapy because it is
chemically stable, relatively inexpensive, free of antigenicity, and
has uniform potency.
• Once a particular product is selected, therapeutic interchange
is discouraged.
• Because T3 (and not T4) is the biologically active form, levothyroxine
administration results in a pool of thyroid hormone that is readily
and consistently converted to T3.
Levothyroxin
• In patients with long-standing disease and older individuals without
known cardiac disease start therapy with levothyroxine 50 mcg
daily and increase after 1 month.
• The recommended initial dose for older patients with known
cardiac disease is 25 mcg/day titrated upward in increments of 25
mcg at monthly intervals to prevent stress on the cardiovascular
system.
• The average maintenance dose for most adults is ~125 mcg/day,
but there is a wide range of replacement doses, necessitating
individualized therapy and appropriate TSH monitoring to
determine an appropriate dose.
Levothyroxin
• Although treatment of subclinical hypothyroidism is controversial,
patients presenting with marked elevations in TSH (>10 mIU/L)
and high titers of thyroid peroxidase antibody or prior treatment
with sodium iodide–131 may be most likely to benefit from
treatment.
• Levothyroxine is the drug of choice for pregnant women, and the
goal is to decrease TSH to the normal reference range for pregnancy.
Levothyroxin
• Cholestyramine, calcium carbonate, sucralfate, aluminum
hydroxide, ferrous sulfate, soybean formula, dietary fiber
supplements, and espresso coffee may impair the GI absorption of
levothyroxine.
• Drugs that increase nondeiodinative T4 clearance include
rifampin, carbamazepine, and possibly phenytoin.
• Amiodarone may block conversion of T4 to T3.
Other
• Thyroid USP (or desiccated thyroid) is usually derived from pig
thyroid gland.
• It may be antigenic in allergic or sensitive patients.
Inexpensive generic brands may not be bioequivalent.
• Liothyronine (synthetic T3) has uniform potency but has a
higher incidence of cardiac adverse effects, higher cost, and
difficulty in monitoring with conventional laboratory tests.
Other
• Liotrix (synthetic T4:T3 in a 4:1 ratio) is chemically stable, pure,
and has a predictable potency but is expensive. It lacks therapeutic
rationale because ~35% of T4 is converted to T3 peripherally.
• Excessive doses of thyroid hormone may lead to heart failure,
angina pectoris, and myocardial infarction (MI). Hyperthyroidism
leads to reduced bone density and increased risk of fracture.
TREATMENT OF MYXEDEMA
• Immediate and aggressive therapy with IV bolus levothyroxine,
300 to 500 mcg, has traditionally been used.
• Initial treatment with IV liothyronine or a combination of both
hormones has also been advocated because of impaired
conversion of T4 to T3.
• Give glucocorticoid therapy with IV hydrocortisone 100 mg every
8 hours until coexisting adrenal suppression is ruled out.
TREATMENT OF MYXEDEMA
• Consciousness, lowered TSH concentrations, and improvement in
vital signs are expected within 24 hours.
• Maintenance levothyroxine doses are typically 75 to 100 mcg IV
until the patient stabilizes and oral therapy is begun.
• Provide supportive therapy to maintain adequate ventilation,
euglycemia, BP, and body temperature. Diagnose and treat
underlying disorders such as sepsis and MI.
EVALUATION OF THERAPEUTIC
• Serum TSH concentration is the most sensitive and specific
monitoring parameter for adjustment of levothyroxine dose.
Concentrations begin to fall within hours and are usually
normalized within 2 to 6 weeks.
• Check both TSH and T4 concentrations every 6 weeks until a
euthyroid state is achieved. An elevated TSH level indicates
insufficient replacement. Serum T4 concentrations can be useful in
detecting noncompliance, malabsorption, or changes in
levothyroxine product bioequivalence.
• TSH may also be used to help identify noncompliance.
EVALUATION OF THERAPEUTIC
• In patients with hypothyroidism caused by hypothalamic or
pituitary failure, alleviation of the clinical syndrome and restoration
of serum T4 to the normal range are the only criteria available for
estimating the appropriate replacement dose of levothyroxine.