Therapeutics IV

Endocrinology & Nephrology

Lecture (1)
 Normal
Physiology

Therapeutic
management Pathophysiology
(Medications)

Desired
outcomes
 Endocrinology
Thyroid Disorders
1. Normal Physiology
• The thyroid gland is the largest endocrine gland in the body, residing in the neck
anterior to the trachea between the cricoid cartilage and suprasternal notch.

• The thyroid gland produces two biologically active hormones, thyroxine (T4) and
triiodothyronine (T3).

• Thyroid hormones are essential for proper fetal growth and development,
particularly of the central nervous system (CNS).

• After delivery, the primary role of thyroid hormone is in regulation of energy

metabolism.

• Thyroid hormones can affect the function of virtually every organ in the body.

• The parafollicular C cells of the thyroid gland produce calcitonin.

• T4 and T3 are produced by the Organification of iodine in the thyroid gland.
➢ Iodine is actively transported into the thyroid follicular cells.

➢This inorganic iodine is oxidized by thyroid peroxidase and covalently bound to

tyrosine residues of thyroglobulin.
➢These iodinated tyrosine residues, monoiodotyrosine (MIT), and diiodotyrosine
(DIT), couple to form T4 and T3.

• About 80% of thyroid hormone is synthesized as T4 and stored in the thyroid bound to
thyroglobulin.

• Thyroid hormones are released from the gland when needed, primarily under the
influence of TSH, which is also known as thyrotropin, from the anterior pituitary.
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• T4 and T3 are transported in the blood by three proteins, 70% bound to thyroid-binding
globulin (TBG), 15% to transthyretin (thyroid-binding prealbumin), and 15% to
albumin.
• Most of the physiologic activity of thyroid hormones is from the actions
of T3.

• T4 can be thought of primarily as a prohormone.

• About 80% of needed T3 is derived from conversion of T4 to T3 in

peripheral tissue under the influence of tissue deiodinases.

• These deiodinases allow end organs to produce the amount of T3 needed

to control local metabolic functions.

• These enzymes also catabolize T3 and T4 to biologically inactive

metabolites. In order to be excreted
• Production and release of thyroid hormones are regulated by
HPT
the hypothalamic–pituitary–thyroid axis.

• Hypothalamic thyrotropin-releasing hormone (TRH)

Somatostatin plus negative
stimulates the release of TSH when there are physiologically feedback

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 the decreased release of TSH Negative feedback
Dopamine
and TRH. Dopamine Agonist
Glucocorti

• Release of TRH is also inhibited by somatostatin and its

analogs, and the release of TSH can also be inhibited by
dopamine, dopamine agonists, and high levels of
glucocorticoids.
2. Pathophysiology
• Thyroid disorders are common, with more than 2 billion people or 38%
of the world’s population having iodine deficiency, resulting in 74
million people with goiter. Thyroid disorders in general (Hyper and Hypo)

• Goiter: An enlargement of the thyroid gland, causing a swelling in the

front part of the neck.
Thyroid disorders due to iodine insufficiency

• Overt iodine deficiency is not a significant problem in developed

countries, a number of common thyroid conditions exist.

• The most common are hypothyroidism and hyperthyroidism, which

often require long-term pharmacotherapy.

• Undetected or improperly treated thyroid disease can result in long-term

adverse sequelae, including increased mortality.
• There are two general modes of presentation for thyroid disorders: changes
in size or shape of the gland and changes in secretion of hormone from the
gland.

• In some cases, structural changes can result in changes in hormone secretion.

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• Thyroid nodules and goiters in euthyroid patients are common problems.

• Patients with a goiter who are biochemically euthyroid do not often require
specific pharmacotherapy, unless the goiter is caused by iodine deficiency.

• In developing countries, iodized salt is the primary therapy in treating

goiter.

• Thyroid nodules, seen in 4% to 7% of adults, may be malignant, benign,

and/or may autonomously secrete thyroid hormones.
➢PATIENT ASSESSMENT AND MONITORING:

• Assessment of patients for thyroid disorders entails a history and physical

examination.

• In many patients with mild or subclinical thyroid disease, there may be an absence of
specific signs and symptoms, and physical examination findings may be normal.

• Various diagnostic tests can be used, including levels of serum thyroid hormone(s),
TSH 3aly hypo

TSH, thyroid antibody levels, and imaging techniques.

• Laboratory assessment of patients with suspected thyroid disorders must be based on

the continuum of disease from subclinical to mild to overt.

• In most patients with thyroid hormone disorders, measurement of serum TSH level is
adequate for initial screening and diagnosis of hypothyroidism and hyperthyroidism.
• Serum free thyroxine (FT4) and free triiodothyronine (FT3) levels may be helpful in
distinguishing mild (subclinical) thyroid disease from overt disease.

• TSH for most patients being treated for thyroid disorders should be the mean
normal value of 1.5 milli international units/L (mIU/L) or 1.5 micro international
units/mL (μIU/mL) (target range, 0.5–4.5 mIU/L or μIU/mL)

• Clinical laboratories use either unit of measurement, usually expressed as mIU/L or

μIU/mL), although patients must be individually titrated based on resolution of
signs and symptoms as well as biochemical tests.
Levothyroxine

• Target TSH may be different in the elderly and in patients being treated with LT4
for thyroid cancer.
Sub-clinical
• Serum T4 and T3 levels are used commonly to assess thyroid function. Older
screening tests of thyroid function measure total serum T4 or T3 levels.

• Because of the high degree of protein binding of these hormones, the free fraction
can be altered by changes in the levels of binding proteins or degree of protein
binding.

• Since a number of factors can alter protein binding, these older assays are very
insensitive and should no longer be used.

• FT4 and FT3 assays are readily available and more sensitive in identifying thyroid
dysfunction than older total assays.

• However, patients with mild hypothyroidism or hyperthyroidism have normal FT4

levels despite abnormal TSH levels.
➢Other Diagnostic tests:
• Global tests of thyroid gland function can be performed to assess
the rate of hormone synthesis. Radioactive iodine uptake (RAIU)
is elevated in those with hyperthyroidism and can aid in
identifying thyrotoxicosis due to non-thyroid gland sources.
Auto-immune may result in hypo or hyper
check three ABs

• Because many thyroid disorders are autoimmune, measurement

of various serum antithyroid antibodies can be performed.

• Antithyroid peroxidase antibodies (anti-TPOAb) and

antithyroglobulin antibodies (anti-TGAb) are present in many
patients with hypothyroidism. Prevent synthesis of hormone

• Most patients with Graves disease have TSH receptor-

stimulating antibodies (TSHR-SAb) as well as elevated anti-
TPOAb and anti-microsomal antibodies.
A. HYPOTHYROIDISM:

• Hypothyroidism is the most common clinical disorder of thyroid function and

results from inadequate secretion of thyroid hormones from the thyroid gland.

• The vast majority of hypothyroid patients have primary gland failure, but occasional

patients have pituitary or hypothalamic failure, resulting in secondary

hypothyroidism.

• Most studies define primary hypothyroidism based on a serum TSH level above the

upper limit of the laboratory reference range.

Women>Men

• In adults, 1.4% of women and 0.1% of men are biochemically hypothyroid.

However, incidence is highly age dependent.

• In the Colorado Thyroid Health Study, by age 64 years,
12% of women and 5% of men were hypothyroid,
and in the over 74 years age group, incidence in men
approached that of women.
➢Causes:
• The most common causes of hypothyroidism are
shown in the adjacent table.

• Up to 90% of patients with autoimmune thyroiditis

(Hashimoto disease) have circulating anti-TPOAbs.

• The autoimmune inflammatory response results in a

lymphocytic infiltration of the thyroid gland and its
eventual destruction.
➢Signs and Symptoms:
• Hypothyroidism can affect virtually any tissue or organ in the body.

• The most common symptoms, such as fatigue, lethargy, sleepiness,

cold intolerance, and dry skin, are nonspecific and can be seen with
many other disorders.

• The classic overt signs, such as myxedema and delayed deep tendon
reflexes, are seen uncommonly now because more patients are
screened or seek medical attention earlier.

• Patients with mild (also known as subclinical) hypothyroidism or

elderly patients may have subtle symptoms or may progress so
slowly they are not noticed easily by the patient or family.

• The lack of overt or specific signs and symptoms emphasizes the

importance of using serum TSH level to identify patients with
hypothyroidism.
➢Sequelae of Hypothyroidism: AGAINNNN

• Hypothyroidism is a chronic disease that may result in significant long-term sequelae.

• Hypercholesterolemia is associated with hypothyroidism, increasing long-term risk of

cardiovascular disease and cardiovascular mortality.

• The Colorado Thyroid Health Study showed a direct correlation between degree of TSH
T3,T4 olayel---Hypo

elevation and rise in serum cholesterol.

• Hypothyroidism also may result in increased systemic vascular resistance, decreased

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cardiac output, and increased diastolic blood pressure.

• Hypothyroidism can cause significant neuropsychiatric problems, including a dementia-like

state in the elderly that is reversible with LT4 therapy.

• Maternal hypothyroidism can have dire consequences for developing fetuses.

• Fetuses are almost completely dependent on maternal thyroid
hormones during the first trimester, a time crucial for
development of the CNS.

• Inadequately treated maternal hypothyroidism results in

increased risk of miscarriage and developmental impairment
in the child.

• Myxedema coma is seen in advanced hypothyroidism. These

patients develop CNS depression, respiratory depression,
cardiovascular instability, and fluid and electrolyte
disturbances.

• Myxedema coma often is triggered by an underlying acute

medical condition such as infection, stroke, trauma, or
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administration of CNS depressant drugs.
3. Desired Outcomes
➢There are three major goals in the treatment of
hypothyroidism:

I. Replace the missing hormones,

II. Relieve signs and symptoms,

III. and Achieve a stable biochemical euthyroid state.

• Although these goals should not be difficult to

achieve, 20% to 40% of treated patients are not
receiving optimal pharmacotherapy.
4. Therapeutic Management
(Medications)
 Hypothyroid disorders

A- Hashimoto D- Secondary
disease causes
- Most common B- Iatrogenic C- Iodine
hypothyroid disorder Thyroid resection or deficiency
in areas with iodine radioiodine ablative most common cause Pituitary insufficiency
sufficiency therapy for worldwide (failure to produce adequate
- Autoimmune-induced hyperthyroidism
TSH secretion, called by some a
thyroid injury resulting central or
in decreased thyroid
secretion secondary hypothyroidism)
- Disproportionately
affects women
Drug induced
(e.g., amiodarone, lithium)
A. Levothyroxine (drug of choice):
1. Mechanism of action: Synthetic T4
2. Dosing
• Initial

1. In otherwise healthy adults, 1.6 mcg/kg (use ideal body weight) per day

2. In patients age 50–60, consider 50 mcg/day.

3. In those with existing cardiovascular disease, consider 12.5–25 mcg/day.

• For optimal bioavailability, usually dosed in the morning on an empty stomach 30–60

minutes before breakfast or at bedtime 3–4 hours after last meal; dosed separately from

other medications (particularly calcium or iron supplements and antacids)

• Dosage titration depending on response (control of symptoms, normalization of TSH
and free T4).
 • Can increase or decrease in 12.5- to 25-mcg/day increments, or consider increase or
decrease in 10%–15% of weekly dose

• Daily requirements are higher in pregnancy (separate guidelines available for treating
thyroid disorders in pregnancy).

• For hospitalized patients already receiving levothyroxine but for whom oral
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administration not an option, the intravenous dose is 75% of the oral dose.

3. Monitoring
• 4–8 weeks is appropriate to assess patient response in TSH after initiating or changing therapy
(about a 7-day half-life for T4).
• May take longer for TSH to achieve steady-state concentrations.
• Use free T4 rather than TSH if central or secondary hypothyroidism; obtain sample before daily
dosing of levothyroxine.
4. Adverse effects
• Hyperthyroidism.
• Cardiac abnormalities (tachyarrhythmias, angina, myocardial infarction).
• Linked to risk of fractures (usually at higher dosages or over-supplementation).
5. Efficacy: If levothyroxine is properly dosed, most patients will maintain TSH and
free T4 in the normal ranges and experience symptomatic relief.
6. Considered drug of choice: because of its adverse effect profile, cost, lack of
antigenicity, and uniform potency.

7. Bioequivalence:
• Guidelines recommend brand-name levothyroxine or consistent use of specific generic
product.
• TSH concentrations in bioequivalence testing were never obtained; small changes in T4
between products can significantly change the TSH. Pharmacokinetic studies were
conducted in healthy subjects with normal thyroid function.
B. Liothyronine (synthetic T3), liotrix (synthetic T4/T3), and desiccated thyroid:

• Are not recommended by leading professional organizations or clinical

guidelines.

• If converting from dessicated thyroid preparation to levothyroxine, 60

mg of dessicated thyroid is about equal to 100 mcg of levothyroxine.

E. Subclinical Hypothyroidism
• Definition: Elevated TSH (above upper limit of reference range) with normal T4. Often the result of
early Hashimoto disease.
• Risk:
• TSH greater than 7 mIU/L in older adults associated with elevated risk of heart failure
• TSH greater than 10 mIU/L associated with elevated risk of coronary heart disease
• Treatment of subclinical hypothyroidism is controversial because benefits in identified patients are
inconclusive. An association between the use of levothyroxine and a reduction in heart disease in
younger patients (40–70 years of age) does appear to exist, but not in older patients (older than 70).
• Whom to treat:
• TSH 10 mIU/L or greater
• TSH 4.5–10 mIU/L and
• Symptoms of hypothyroidism
• Antithyroid peroxidase antibodies present
• History of cardiovascular disease, heart failure, or risk factors for such
➢ Initial daily doses of 25–75 mcg of levothyroxine recommended
• If untreated, screen regularly for the development of overt hypothyroidism (decreased free T4
concentrations).
F. Myxedema Coma
• Definition: Severe and life-threatening decompensated hypothyroidism; mortality rate
30%–60%
• Precipitating causes: Trauma, infections, heart failure, medications (e.g., sedatives,
narcotics, anesthesia, lithium, amiodarone)
• Presentation: Coma is not required and is uncommon, despite terminology; altered mental
state (very common); diastolic hypertension; hypothermia; hypoventilation
• Pharmacotherapy:
A. Intravenous thyroid hormone replacement:
i. T4: 200- to 400-mcg intravenous loading dose, followed by 1.6 mcg/kg daily.
Lower the initial dose in frail patients or patients with established cardiovascular
disease. Intravenous doses are around 75% of oral administration.
ii. Some advocate the use of T3 over T4, given that T3 is more biologically active
and that T4/T3 conversion may be suppressed in myxedema coma. Cost and
availability limit intravenous T3 use.
B. Antibiotic therapy: Given common infectious causes, some clinicians
advocate empiric therapy with broad spectrum antibiotics.

C. Corticosteroid therapy:
i. Hydrocortisone 100 mg every 8 hours (or equivalent steroid) or doses
appropriate for the stressed state.
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ii. Can be discontinued if random cortisol concentration not depressed.

D. Adjust levothyroxine dose on the basis of serum T3 measured every 1

or 2 days.