Thyroid disorder

Meaza Bulbula (M. pharm)

 Chief Complaint
“My heart feels like it is racing and beating out of my chest.”
 HPI
D.J is a 32-year-old woman who returns to her PCP with complaints of
worsening palpitations and continuing SOB with exertion. She saw the PCP 2
weeks ago for the SOB and was diagnosed with bronchitis. Despite treatment
with an antibiotic and an inhaler, the symptoms have not resolved.
• The palpitations started a few months ago and would come and go until the
past week when they began occurring more frequently, almost daily.
• She reports a 10-kg weight loss over the past 2 months, despite a good
appetite. She feels hot all of the time and becomes more irritable than usual.
• She notes that her hair has become more fine and thinner in distribution
recently. She has no visual changes. She has occasional N/V/D.
 FH
Father has HTN; mother has Graves’ disease and a history of ovarian cysts prior
to having a hysterectomy
 Physical Examination
VS
BP: 130/78, PR 120–160 irreg, RR 20, T 38.1°C; Wt 58 kg, Ht 5'6''
 Skin
Hyperpigmented on upper back and lower extremities; warm and moist. Hair is
fine and sparse in the frontal area
 HEENT
• Mild proptosis, mild lid retraction
 Neck/Lymph Nodes
symmetrically enlarged thyroid, (+) thyroid bruit, prominent pulsations in neck
vessels
• CV
Irregularly irregular rhythm, tachycardic without murmurs; (+) carotid bruits
bilaterally
 Neuro
fine tremor with outstretched hands; hyperreflexia at knees
 Labs

 Assessment
32-year-old white woman with goiter, probable hyperthyroidism, and
new onset atrial fibrillation. Most likely cause is Graves’ disease.
• Problem Identification
1.a. Create a list of the patient’s drug therapy problems.
1.b. What signs, symptoms, and laboratory values indicate the presence or
severity of hyperthyroidism?
• Desired Outcome
2. What are the goals of pharmacotherapy in this case?
• Therapeutic Alternatives
3.a. What nondrug therapies and instruction might be useful for this
patient?
3.b. What feasible pharmacotherapeutic alternatives are available for the
treatment of hyperthyroidism in this patient?
 Introduction
• The thyroid gland is the largest endocrine
gland in the body weighing 12-20g

• It has a butterfly-shape

• Located in neck,

• anterior to the trachea

• between the cricoid cartilage and

suprasternal notch
 Introduction
• The thyroid gland produces biologically active hormones,
thyroxine (T4)
triiodothyronine (T3 )
Calcitonin
• Thyroid hormones regulate the body's metabolic rate
Use energy
Control heart,
Stay warm,
Muscle and digestive function,
Keep brain development and bone maintenance
• It affect the function of virtually every organ in the body
 Synthesis of thyroid hormones
• Iodide Pump (Iodide Trapping)
• The transport of iodides from then blood into the thyroid glandular cells and
follicles
• Oxidation of the Iodide Ion
• It is conversion of the iodide ions to an oxidized form of iodine that is then
capable of combining directly with tyrosine. promoted by the enzyme
peroxidase
• “Organification” of Thyroglobulin and coupling
• The binding of iodine with the thyroglobulin molecule and formation of the
Thyroid Hormones
• Storage of Thyroglobulin. After synthesis, each thyroglobulin molecule stores up
to 30 T4 and a few T3 molecules
• Release of Thyroxine and Triiodothyronine from the Thyroid Gland
 Epidemiology
• Thyroid disorders are common. More than 2 billion people, or 38% of the world’s population, have
iodine deficiency, resulting in 74 million people with goiters.

• Undetected or improperly treated thyroid disease can result in long-term adverse sequelae, including
increased mortality.

• hypothyroidism was found in 3.7% (3.4% mild) and hyperthyroidism in 0.5%.

• The prevalence of hypothyroidism was higher in older age groups and in whites and Hispanics; blacks
had a lower prevalence of hypothyroidism.

• people aged 50 to 79 years had an almost twofold higher prevalence, and those aged 80 years and older
had a fivefold higher prevalence. Pregnant women also had a higher prevalence of hypothyroidism.

• The most common are hypothyroidism and hyperthyroidism, which often require long-term
pharmacotherapy
Iodide
Organification
Trapping

Oxidation of
the Iodide Ion
thiourea

Deiodinase
enzyme
PTU, amiodarone
Regulation of thyroid hormone
• The production and release of thyroid hormones are regulated by the
hypothalamic–pituitary–thyroid axis
• Hypothalamic thyrotropin-releasing hormone (TRH) stimulates the
release of TSH when there are physiologically inadequate levels of
thyroid hormones
• TSH promotes production and release of thyroid hormones
• As circulating thyroid hormone levels rise to needed levels, negative
feedback results in decreased release of TSH and TRH
• Release of TRH is also inhibited by somatostatin and its analogs, and
release of TSH can also be inhibited by dopamine, dopamine agonists,
and high levels of glucocorticoids.
Thyroid disorders
• Thyroid disorders encompass a variety of disease states affecting
thyroid hormone
• production or
• Secretion that result in alterations in metabolic stability
• Hyperthyroidism and hypothyroidism are the clinical and biochemical
syndromes
• More than 2 billion people, or 38% of the world’s population, have
iodine deficiency
• Undetected or improperly treated thyroid disease can result in long-
term adverse sequelae, including increased mortality
THYROTOXICOSIS (HYPERTHYROIDISM)
THYROTOXICOSIS (HYPERTHYROIDISM)
• Thyrotoxicosis results when tissues are exposed to excessive levels of
T4, T3, or both irrespective of the source.
• Hyperthyroidism, which is one cause of thyrotoxicosis, refers to
overproduction of thyroid hormone by the thyroid gland
Subclinical hyperthyroidism: TSH <0.1 milli IU/L, and T4 normal
Clinically significant hyperthyroidism: TSH <0.1 milli IU/L, and T4
>13.2 mcg/dL
• The prevalence of suppressed TSH values
• Peaked for people aged 20 to 39
• Declined in those 40 to 79, and
• Increased again in those 80 or older
Cause of thyrotoxicosis
 Primary hyperthyroidism  Thyrotoxicosis without
hyperthyroidism
• Graves’ disease
• Subacute thyroiditis
• Toxic adenoma
• Silent thyroiditis
• Toxic multinodular goiter
• Thyrotoxicosis factitia
• Thyroid cancer
• Painful subacute thyroiditis  Secondary hyperthyroidism
• Struma ovarii • Trophoblastic Diseases
• Drug induced (iodine excess) • Pituitary adenomas
• Gestational thyrotoxicosis
CONT…
a. Graves’ disease
• Most common hyperthyroid disorder (autoimmune)
• Thyroid-stimulating antibodies (TSAb) directed at
thyrotropin receptors mimic TSH and stimulate T3/T4)
production
b. Pituitary adenomas
• Produce biologically active hormone that is unresponsive
to normal feedback control mechanism
• Tumor may co-secrete prolactin or growth hormone
• Amenorrhea/galactorrhea or signs of acromegaly
CONT…
c. Toxic adenoma:
• discrete thyroid mass whose function is independent of pituitary
and TSH control
• Hyperthyroidism usually occurs with larger nodules (>3 cm in
diameter)
d. Toxic multinodular goiter (Plummer disease)
• Several autonomous follicles that, if large enough, cause excessive
thyroid hormone secretion
CONT…
e. Painful subacute thyroiditis

• Self-limiting inflammation of the thyroid gland caused by viral

invasion of the parenchyma, resulting in the release of stored
hormone
f. Drug induced
• e.g., excessive exogenous thyroid hormone doses, amiodarone
g. Painless (silent, lymphocytic, or postpartum) thyroiditis is a
common cause of thyrotoxicosis; its etiology is not fully understood;
autoimmunity may underlie most cases.
h. Trophoblastic Diseases
• hCG: a stimulator of the TSH receptor and may cause
hyperthyroidism
• hCG levels: > 300 units/mL
• The mean peak hCG level in normal pregnancy is 50 units/mL
Clinical presentation
• Symptoms
• nervousness, anxiety,
• palpitations,
• easy fatigability,
• heat intolerance,
• weight loss concurrent with increased appetite,
• proximal muscle weakness and
• scanty or irregular menses in women
Clinical presentation…
 Physical signs
• Warm/ smooth,
• Moist skin, and unusually fine hair;
• Tachycardia at rest,
• Widened pulse pressure, and systolic ejection murmur,
• Gynecomastia in men,
• Fine tremor of the protruded tongue and outstretched hands,
• Hyperactive deep tendon reflexes
• Thyromegaly is usually present
 Physical sign…

retraction of the eyelids and

lagging of the upper lid onycholysis Periorbital edema chemosis
behind the globe upon
downward gaze (lid lag);
 Thyroid function test
Total T4 Total T3 Free T4 TSH
Normal 4.5-10.9 mcg/dl 0.8-2.7 ng/dl 60-181 ng/dl 0.5-4.7mili-IU/L

Hyperthyroidism ↑↑ ↑↑ ↑↑↑ ↓↓˟

Hypothyroidism ↓↓ ↓↓ ↓ ↑↑˟

Increased TBG ↑ Normal ↑ Normal

Diagnosis
• Low TSH serum concentration
• Elevated free and total T3 and T4 serum concentrations
• Elevated radioactive iodine uptake (RAIU) by the thyroid gland when
hormone is being over produced
• Suppressed RAIU not by thyroid gland hyperfunction, this may seen in
painful thyroiditis, painless thyroiditis, Struma ovarii and follicular cancer.
• Almost all pts with Graves’ will have positive TSHR-Sabs and positive anti-
TPOAbs
Treatment
 Goals of Treatment:

• Eliminate excess thyroid hormone;

• Minimize symptoms and long-term consequences; and

• Provide individualized therapy based on the

type and severity of disease,
patient age and gender,
existence of nonthyroidal conditions, and
response to previous therapy.
Nonpharmacologic Therapy
• Surgical removal of the hypersecreting thyroid gland Should be
considered
• A large thyroid gland (>80 g)
• Severe ophthalmopathy and
• A lack of remission on antithyroid drug treatment

• Subtotal thyroidectomy: risk of recurrence

• Near total thyroidectomy: the procedure of choice for patients with

Graves’ disease
Nonpharmacological Therapy
• Surgical removal of the hypersecreting thyroid gland

Preparation of the patient

• Methimazole or PTU until the patient is biochemically euthyroid (usually
6 to 8 weeks)
• Add iodides (500 mg/day) for 10 to 14 days before surgery to decrease
the vascularity of the gland

• Propranolol for several weeks preoperatively and 7 to 10 days after surgery

to maintain pulse rate less than 90 beats/min.

• 10 to 14 days of potassium iodide also has been advocated

Nonpharmacological Therapy
• Complications of surgery include:
• Persistent or recurrent hyperthyroidism (0.6% to 18%),
• Hypothyroidism (up to about 49%),
• Hypoparathyroidism(up to 4%), and
• Vocal cord abnormalities (up to 5%).

• The frequent occurrence of hypothyroidism requires periodic follow-

up for identification and treatment.
 Pharmacologic Therapy
 Antithyroid Medications
1. Thiourea Drugs
Methimazole(MMI) and propylthiouracil (PTU)
• Mechanism of Action….prevent the biosynthesis of thyroid hormone
• It acts by inhibiting the enzyme thyroid peroxidase, which usually
functions to convert iodide to iodine molecule
• This prevents subsequent organification and Inhibit coupling
• PTU inhibits the peripheral conversion of T4 toT3 by inhibiting
Deiodinase enzyme
Thiourea drugs…
• Usual initial doses
MMI 30 to 60 mg daily (BID or TID)or
PTU 300 to 600 mg daily (TID or QID)
• both drugs can be given as a single daily dose

• Improvement in symptoms and laboratory abnormalities should occur

within 4 to 8 wks, at which time a tapering regimen to maintenance
doses can be started
Thiourea drugs…
• Make dosage change monthly because the endogenously produced T4 will
reach a new steady-state concentration in this interval
• Maintenance doses
• MMI 5 to 30 mg and PTU 50 to 300 mg

• Continue therapy for 12 to 24 months to induce long-term remission

• Pts should be monitored every 6 to 12 months after remission

If a relapse occurs, alternate therapy with RAI is preferred

Thiourea drugs
Pharmacologic Therapy
2. Iodides
• MOA
• Block thyroid hormone release

• by interfering with intrathyroidal iodide utilization by increasing the resistance

of thyroglobulin to proteolytic degradation

• Decrease the size and vascularity of the gland

• Symptom improvement within 2 to 7 days of initiating therapy

• Inhibitory effect decreases within 1 to 2 weeks by: decreased active transfer of

iodide into the gland
Iodides
• Used as adjunctive therapy
• To prepare a patient with Graves’ disease for surgery
• To quickly attain euthyroid state in severely thyrotoxic patients
with cardiac decompensation, or
• To inhibit thyroid hormone release following RAI therapy
• However, large doses of iodine may
• exacerbate hyperthyroidism or
• indeed precipitate hyperthyroidism in some previously euthyroid
individuals (Jod-Basedow disease)
Iodides
• Potassium iodide: 38 mg of iodide per drop
Dose: 3 to 10 drops daily (120 to 400 mg) in water or juice
• Preparation for surgery: 7 to 14 days preoperatively
• An adjunct to RAI: 3 to 7 days after RAI treatment

• Lugol’s solution: 6.3 mg of iodide per drop

Adverse effects Iodides include:
• Hypersensitivity rxns

• (skin rashes, drug fever, rhinitis,conjunctivitis); Salivary gland swelling;

• “Iodism”(metallic taste, burning mouth and throat, sore teeth and

gums, symptoms of aheadcold, and sometimes stomach upset and
diarrhea); and

• Gynecomastia
3. Adrenergic Blockers
• To ameliorate thyrotoxic symptoms such as palpitations, anxiety,
tremor, and heat intolerance
• Propranolol and nadolol partially block the conversion of T4 to T3
• Used as adjunctive therapy with antithyroid drugs, RAI, or iodides
• Used as a primary therapy for thyrotoxicosis associated with
thyroiditis
• Adrenergic Blockers
Dose
• Propranolol: initial dose of 20-40mg QID is effective for most
pts (HR<90)
• Younger or more severely toxic patients: 240 to 480 mg/day

Alternatives -therapy should be considered if pts has CI for BB

• Centrally acting sympatholytic (Clonidine 150 mcg twice daily)
• Diltiazem 120 mg given every 8 hours
4. Radioactive Iodine
• Sodium iodide 131 is an oral colorless and tasteless liquid that
concentrates in the thyroid & initially disrupts hormone synthesis by
incorporating in to thyroid hormones & thyroglobulin
• Over a period of wks, follicles that have taken up RAI & surrounding
follicles develop evidence of cellular necrosis and fibrosis of the interstitial
tissue
• Considered to be the agent of choice for Graves’ disease, toxic autonomous
nodules, and toxic MNGs
Radioactive Iodine

• The goal of therapy is to destroy overactive thyroid cells

• Single dose of 4,000 to 8,000 rad
• results in a euthyroid state in 60% of pts at 6 months or less.

• A second dose of RAI should be given 6 months after the first RAI
treatment if the patients remains hyperthyroid

• Hypothyroidism commonly occurs months to yrs after RAI

Thyroid Storm
Is a life-threatening medical emergency characterized by
decompensated thyrotoxicosis with mortality rate as high as 20%
• High fever (often >39.4°C [>103°F])

• Tachycardia

• Tachypnea

• Dehydration

• Delirium, coma

• Nausea, vomiting, and diarrhea

Treatment of Thyroid Storm
The following therapeutic measures should be instituted 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
Drug Dosages Used in the Management of Thyroid Storm
• PTU in large doses is the preferred thionamide b/c it interferes with the
production of thyroid hormones & blocks the peripheral conversion of T4 -T3.

• Iodides, which rapidly block the release of preformed thyroid hormone, should
be administered after PTU is initiated to inhibit iodide use by the overactive
gland.

• Antiadrenergic therapy with the short-acting agent esmolol is preferred b/c it

can be used in pts with pulmonary disease or at risk for cardiac failure & its
effects can be rapidly reversed.
• General supportive measures, including:
• Acetaminophen as anantipyretic (aspirin or other NSAIDs may
displace bound thyroid hormone),
• Fluid and electrolyte replacement,
• Sedatives, digoxin, antiarrhythmics, insulin, and antibiotics should
be given as indicated

• Corticosteroids are generally recommended, but there is no

convincing evidence of adrenocortical insufficiency in thyroid storm.
EVALUATION OF THERAPEUTIC OUTCOMES
• After therapy with thionamides, RAI, or surgery pts should be
evaluated on a monthly basis until they reach a euthyroid condition.

• Clinical signs of continuing thyrotoxicosis or the development of

hypothyroidism should be noted.

• After T4 replacement is initiated, the goal is to maintain both the free

T4 level & TSH in the normal range.

• Once a stable dose of T4 is identified, the pt may be followed every 6

-12 months.
Hypothyroidism
Hypothyroidism
• The clinical and biochemical syndrome resulting from decreased thyroid
hormone production Overt hypothyroidism occurs
• In 1.5% to 2% of women and
• 0.2% of men

• Incidence increases with age

• Mild-Subclinical hypothyroidism: serum TSH 4.5 to 10 mIU/L, and T4

normal

• Clinically significant hypothyroidism : TSH > 10 mIU/L, and T4 < 0.7 ng/dL
 Causes of Hypothyroidism
• Primary Hypothyroidism
Autoimmune thyroiditis (Hashimoto disease)
Iatrogenic (irradiation, surgery)
Drugs (amiodarone, radiocontrast media, lithium, interferon-α, tyrosine kinase inhibitors,
p-aminosalicylic acid, ethionamide, sulfonylureas, valproic acid, and amino glutethimide.
Silent thyroiditis (including postpartum)
Iodine deficiency and excess
• Secondary Hypothyroidism
Pituitary disease
Hypothalamic disease
• Tertiary: Hypothalamic dysfunction (rare)
• Peripheral resistance to the action of thyroid hormone
Clinical Presentation
 Symptoms

• Fatigue, Lethargy

• Cold intolerance

• Sleepiness, Depression,

• Mental impairment,

• Weight gain, Decreased appetite, Constipation

• Menorrhagia, infertility (female), Hoarseness,

• Arthralgia, Paresthesia
Clinical Presentation
 Signs
• Slow movements and speech
• Dry/Coarse/ skin and hair

• Non-pitting edema (myxedema)

• Galactorrhea (women)

• Hyporeflexia, Bradycardia, Delayed relaxation of reflexes

• In children, it may manifest as growth retardation

Diagnosis
• Primary hypothyroidism: elevated TSH

• Secondary hypothyroidism:
• TSH levels may be within or below the reference range
• Free and/or total T4 and T3 serum concentrations should be low

• Other tests
• TPOAbs and anti-TG antibodies are likely to be elevated in
autoimmune thyroiditis
Treatment
• Desired Outcomes
• To restore normal thyroid hormone concentrations in tissue
• To provide symptomatic relief
• To prevent neurologic deficits in newborns and children, and
• To reverse the biochemical abnormalities of hypothyroidism
Treatment
General Approach
1. Levothyroxine (L-thyroxine, synthetic T4 ): drug of choice
2. Desiccated thyroid : extract of bovine or porcine thyroid glands
• Preparations containing both T4 and T3 (liotrix,)
• High proportions of T4 than T3 (4:1)
3. Liothyronine (T3)
• a synthetic form of the natural thyroid hormone (T3) converted from T4
• Short -acting preparation (Requires TID dosing)
• higher incidence of cardiac adverse effects, and difficulty in
monitoring with conventional laboratory tests
Synthetic Thyroid Hormones
• L-Thyroxine (T4)
• Drug of choice for thyroid replacement
• Prohormone: converted peripherally toT3
• half-life: 7 days( monitor TSH andT4 every 6 days)

• Administered 125 mcg/day or 1.6 - 1.7 mcg/kg/day

• Bioavailability is approximately 80%

• Time to maximal absorption: 2 hours

Adverse Effects
• Excessive doses of thyroid hormone may lead to Heart failure, angina
pectoris, and myocardial infarction

• Allergic or idiosyncratic reactions: animal–derived products

• Reduced bone density: increase the risk of fracture

Special Conditions
 Myxedema Coma
• A rare consequence of decompensated hypothyroidism
• Hypothermia and altered sensorium ranging from delirium to
coma
• Mortality rates: 60% to 70%
• Initial treatment:
• IV bolus L-thyroxine 300 to 500 mcg or IV T3, or a combination
• Maintenance doses: 75 to 100 mcg IV until the patient stabilizes
and oral therapy is begun
• IV hydrocortisone 100 mg every 8 hours Until coexisting adrenal
suppression is ruled out
• Special Conditions

Congenital Hypothyroidism

• Maintenance therapy: to improve the prognosis for mental and

physical development

• Initiate therapy within 45 days of birth

Dose of 10 to 15 mcg/kg/day
Special Conditions
 Hypothyroidism in Pregnancy
• TSH should be targeted
• First trimester: < 2.5 milli–international units/L
• Reminder of pregnancy: < 3 milli–international units/L
• Dose of L-thyroxine had to be increased by 48% to decrease TSH into
the normal range
• Adjust dose 6 to 8 weeks after delivery
 EVALUATION OF THERAPEUTIC OUTCOMES
• Serum TSH is the most sensitive and specific monitoring parameter for
adjustment of levothyroxine dose. It begin to fall within hrs & are usually
normalized within 2 to 6 wks
• TSH & T4 should both be checked q6 wks until a euthyroid state is
achieved. An elevated TSH level indicates insufficient replacement.
• Serum T4 can be useful in detecting noncompliance, or malabsorption.
TSH may also be used to help identify noncompliance.
• In pts with hypothyroidism caused by hypothalamic or pituitary failure,
alleviation of the clinical syndrome & restoration of serum