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Thyroid Physiology and Pharmacology
Overview
o
Thyroido Two hormones types released:
thyroxine and triiodothyronine
calcitonin
o Thyroxine and triiodothyronine are important in:
1 1 growth
1 1 development
1 1 maintaining normal body temperature
1 1 energy metabolism regulation
Receptors:
Thyrotropin (TSH, a pituitary hormone) modulates thyroid function by
binding to TSH receptors (TSH-R)
TSH-R: localization and properties:
o basolateral membrane of thyroid follicular cells.
Iodide:
Metabolism:
Iodide intake: gastrointestinal tract absorption from food, water, or
medication.
Iodide:
o rapid absorption
o enters extracellular pool
o thyroid removes amount required for hormone secretion
excess iodide: urinary excretion
Non-Physiological Thyroid Simulation:
o Graves' disease:
Greenspan, F.S., and Dong, B. J.. Histamine, Thyroid and Antithyroid Drugs, in Basic
and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 619-633.
8/23/2019 FKG3 Tambahan - Hormone Thyroid
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Wartofsky, L., Diseases of the Thyroid, In Harrison's Principles of Internal Medicine
14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S.
and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2012-
2034
Thyroid Hormones
Chemistry of thyroid hormones:
o Active isomer -- levo (L-form) -- thyroxine, triiodothyronine, reverse
iodothyronine (reverse T4)
Pharmacokinetics:
o T4 -- well absorbed from the ileum and duodenum following oral
administration-- about 80% absorbed on average
o Modification of absorption:
food
drugs (e.g., sucralfate, iron, aluminum-containing antacids)
o T3 -- almost completely absorbed (95%) following oral administration
o T4 and T3 absorption may be impaired by myxedema (may require parenteral
administration {IV}, as a result)
o Factors that alter T4 and T3 clearance:
hyperthyroidism: increases
hypothyroidism: decreases
Drugs (hepatic microsomal enzymes inducers): Clearance is enhanced;
Euthyroid state may be maintained because of thyroid hyperfunction.
phenobarbital
carbamazepine (Tegretol)
phenytoin (Dilantin)
rifampin
o Increases in the number of TBG binding sites (due to pregnancy, estrogen use,oral contraceptive use)
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more thyroid hormone is bound; elimination rate declines (only free
hormone can be eliminated); normal hormone concentration
would be eventually restored
Mechanism of Hormone Action:
1. Unbound T4 and T3 diffuse into the cell (passive diffusion, possibly active transport)
2. Inside cell:
3. T4 converted to T3
4. T3 is transported to the cell nucleus where T3 binds to a specific T3
nuclear receptor
Thyroid hormones: metabolic actions
o nuclear receptor activation results in increased RNA and protein synthesis:examples --
increased Na/K ATPase causes increased ATP turnover,
increased oxygen consumption --calorigenic effect
Thyroid Hormone Effects*
Physiological
system
Hyperthyroidism
(thyrotoxicosis)Hypothyroidism
skin --appendages
warm, moist skin;
sweating; fine, thin
hair; Plumber's
nails; pretibialdermopathy
(Graves' disease)
pale, cool, puffy skin; brittle
hair and nails
Eyes, face
Upper lid retraction
(wide stare);
periorbital edema;
exophthalmos,
diplopia (Graves'
disease)
Eyelid drooping; periorbital
edema; puffy, nonpitting
facies; large tongue
Cardiovascular decreased peripheral
resistance, increasedcardiac output,
increased peripheral
resistance, decreasedcardiac output, stroke
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stroke volume, heart
rate, pulse pressure;
congestive heart
failure (high-
output); increased
contractility,.arrhythmogenic;
angina
volume, heart rate, pulse
pressure; congestive heart
failure (low output);
bradycardia (low voltage
ECG with prolonged PRinterval, flat T wave);
pericardial effusion
Respiratorydyspnea; reduced
vital capacity
hypoventilation (CO2
retention) pleural effusions
Gastrointestinal
increased appetite;
increased bowel
movement
frequency;
hypoproteinemia
decreased appetite,
decreased bowel movement
frequency; ascites
CNS
Nervousness,
hyperkinesia,
variable emotional
states
lethargy, neuropathy
Musculoskeletal
Weakness; fatigue;
hypercalcemia,
osteoporosis,
increased deep
tendon reflex
muscle fatigue, reduced
deep tendon reflex,
increased alkaline
phosphatase, LDH, AST
Renal
Increased renal blood
flow; increased GFR;
mild polyuria
Decreased renal blood flow;
decreased GFR; reduced
water excretion
Hematopoietic
anemia (increased
RBC turnover);
increased
erythropoiesis
anemia (decrease
production rate, decreased
iron absorption, decreased
folate acid absorption,
autoimmune pernicious
anemia),decreased
erythropoiesis
Reproductive
decreased fertility;
menstrual
irregularity;
enhanced gonadal
steroid metabolism
infertility;hypermenorrhea,decreased libido; impotence,
decreased gonadal steroid
metabolism
Metabolic increased basal rate;
negative nitrogen
balance,
hyperglycemia;
increased free fatty
acids, decreased
cholesterol andtriglycerides;
decreased basal rate;
delayed insulin degradation,
with increased sensitivity;
enhanced cholesterol and
triglyceride levels;
decreased hormone
degradation; decreasedrequirements for fat-and
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increased hormone
degradation;
increased
requirement for fat-
and water-soluble
vitamins; enhanceddrug detoxification
water-soluble vitamins;
decreased drug
detoxification.
* * Adapted from Table 38-4, Greenspan, F.S., and Dong, B. J.. Histamine, Thyroid and
Antithyroid Drugs, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-
Lange, 1998, p 625.
Greenspan, F.S., and Dong, B. J.. Histamine, Thyroid and Antithyroid Drugs, in Basic
and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 619-633.
Wartofsky, L., Diseases of the Thyroid, In Harrison's Principles of Internal Medicine14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S.
and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2012-
2034
Thyroid preparations:
o Synthetic:
levothyroxine
liothyronine
liotrix
o Animal origin:
dessicated thyroid-- never justifiable; many disadvantages {protein
antigenicity; product instability and variable hormone concentration;
difficulty and lab assessment}
o Preparations of choice: synthetic levothyroxine:
Applications:
thyroid replacement suppression therapy
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Rationale:
11 low-cost
11 stability
11 non-allergenic (no foreign protein)
11 serum levels readily obtained
1 1 long half-life (seven days) -- supports once-daily dosing
1 1 since T4 is converted to T3 inside the cell, T4 administration produces both hormones
o Liothyronine -- more active than levothyroxine but not recommended because
of:
11
shorter half-life (multiple dosing)
11 more costly
11 higher hormonal activity enhances cardiotoxicity (T3 -- contraindicated in patients
with cardiac disease)
11 most appropriate use: short-term TSH suppression
Antithyroid Drugs:
Overview
o Purpose:
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reduction of thyroid activity
reduction of hormone effects
o Approach:
use drugs that change tissue response to thyroid hormones
destroy the the thyroid with surgical or radiation interventions
o Definition:
"goitrogens" --
1. compounds that suppress T3 and T4 secretion
2. thereby increasing TSH
3. increased TSH levels produces thyroid gland enlargement(goiter)
o Antithyroid drugs include:
thioamides
iodides
radioactive iodine
Thioamides:
o Major drugs for thyrotoxicosis:
Propylthiouracil
rapidly absorbed
bioavailability: 50 -- 80% (incomplete absorption/large first-
pass effect)
metabolism: glucuronidation by the liver; excreted by the
kidney
short half-life (1.5 hours) but accumulated by the thyroid
crosses placental barrier (increased protein binding compared
to methimazole makes propylthiouracil preferable for use in
pregnancy since less free drug is available to cross into the
fetus)
Methimazole
(about 10 times more active than propylthiouracil)
well absorbed
accumulated by the thyroid
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crosses the placental barrier
Mechanism of Action: thioamides
11 Major action: inhibits thyroidal peroxidase-catalyzed reactions, blocking iodine
organification: -- thus preventing hormone synthesis.
11 Propylthiouracil and methimazole (too a much reduced degree) inhibit peripheral
deiodination of T4 and T3
11 Slow onset of pharmacological effect
Toxicity:
Frequency of adverse effects: 3-12%.
Most common: maculopapular pruritic rash
Most serious potential reaction: agranulocytosis -- risk 0.3% -
0.6 % of patients; reversible upon discontinuation; cross
sensitivity between propylthiouracil and methimazole
possibly increased risk in:
o elderly
o patients receiving high-dose methimazole
Anion Inhibitors
o Competitive inhibition:
Perchlorate
Pertechnetate
Thiocyanate
o Major clinical use -- potassium perchlorate ( not often used because of the
possibility of causing aplastic anemia)
blockade of thyroid gland reuptake of I- in patients with iodide-induced
hyperthyroidism
Iodides
o rarely used now as monotherapy
o Actions on the thyroid:
inhibit organification
inhibit hormone release-- major action
Mechanism: perhaps inhibition of thyroglobulin proteolysis
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decreased thyroidal size and vascularity
may induce hyperthyroidism (jodbasedow)
may precipitate hypothyroidism
o Clinical Considerations:
may be useful in short-term management of thyroid storm
maybe helpful in preoperative preparation for surgery (due to reduction
in gland vascularity, size, and fragility)
Major disadvantages:
11 iodide therapy increases intraglandular iodine concentration
may delay initiation of thioamides treatment
may delay use of radioactive iodine treatment
11 chronic iodide used in pregnancy: avoid -- iodide crosses the placenta and may cause
fetal goiter
11 iodide as monotherapy: not appropriate; iodide block lasts only 2-8 weeks;
withdrawal at this time may exacerbate thyrotoxicosis
Iodide use, if at all, should be initiated only after thioamide treatment
and not used if radioactive iodine therapy is planned
Iodinated Radiographic Contrast Media
o Useful in management of hyperthyroidism (off label use)
o Ipodate and iopanoic acid inhibit T4 to T3conversion in:
kidney
liver
pituitary gland
brain
o additional mechanism: iodine release-mediated inhibition of hormone release
o Clinical Use:
11 adjunctive treatment of thyroid storm
11 alternatives if thioamides and iodides are contraindicated
o Toxicity:similar to iodides; relatively nontoxic.
Radioactive Iodine:
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o131I is the radioactive isotope used for treating thyrotoxicosis.
o Mechanism of Action:
rapidly absorbed, concentrated in the thyroid
incorporated into thyroid follicles
beta emission is the basis for therapeutic efficacy
Thyroid parenchymal destruction occurs within a few weeks.
o Therapeutic Advantages for radioiodine:
11 good efficacy
11 easy to administer
11 low expense
11 pain free treatment
o Contraindication:
131I-- not administered to pregnant women or nursing mother;131I
crosses placental barrier and excreted in breast milk.
Adrenergic receptor blocking drugs:
o
Rationale: reduction of sympathetic manifestations in thyrotoxicosis:
Applicable drugs:
beta adrenoceptor blockers
guanethidine
Agent of choice: propranolol (Inderal, nonselective beta-receptor
antagonist)
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Hypothyroidism
Overview: hypothyroidism1. cause: inadequate thyroid hormone synthesis
2. Cretinism -- when hypothyroidism is present from birth and accompanied by
developmental abnormalities
3. Myxedema: severe hypothyroidism associated with:
deposition of hydrophilic mucopolysaccharides in the dermis (ground
substance) and other tissues-- causing:
facial feature thickening
doughy skin induration
Pretibia myxedema
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Adult hypothyroidism: Pretibial myxedema in the foot and lower extremity skin
1999 KUMC Pathology and the University of Kansas, used with permission;courtesy of Dr. James Fishback, Department of Pathology, University of Kansas
Medical Center.
Hypothyroidism: Causes/Classification
Thyroid
Thyroprivic* Goitrous
Congenital development defect Biosynthesis defect (genetic)
Idiopathic (primary) Transmitted by the mother
(antithyroid drugs)
Postablative {postsurgical,131I} Iodine deficiency
Postradiation {e.g. for lymphoma} Drug-induced {e.g. salicylates,
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lithium,iodides,
phenylbutazone,iodoantipyrine}
chronic thyroiditis (Hashimoto's
disease); interleukin 2
Suprathyroid (Trophoprivic)
Pituitary Hypothalamic
Panhypopituitarism Congenital defect
Isolated low TSH levels Infection (e.g. encephalitis)
Neoplasm; Infiltrative (sarcoidosis)
Hypothyroidism: pathogenesis
1. inadequate thyroid hormone synthesis causes TSH hypersecretion which
results in goiter
2. if this compensatory physiological response is insufficient, goitrous
hypothyroidism occurs
o Causes of goitrous hypothyroidism (North America)
most common cause: Hashimoto's disease
Mechanism:
A. defective binding of iodide
B. abnormal secretion of iodoproteins
Iodide-induced goiter with or without hypothyroidism: intrinsic defect
inorganic binding mechanism
Euthyroid patients with Graves' disease {particularly
following surgery or radioiodine therapy}, patients with
Hashimoto's disease, and normal fetuses are particularlysusceptible to iodide-induced goiter.
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(Right) Struma lymphomatosa in Hashimoto thyroiditis, gross. Note: diffuse,
pale yellow infiltrate affecting the entire thyroid. The yellow infiltrate is caused
by an influx of lymphocytes, which may form follicles. Normal thyroid (Left)
1999 KUMC Pathology and the University of Kansas, used with permission;courtesy of Dr. James Fishback, Department of Pathology, University of Kansas
Medical Center.
Hypothyroidism: Clinical presentation
o Neonates (note that cretinism may be present at birth, but usually is
apparent within the first few months after birth as a function of the extent
of thyroid failure)
manifestations:
physiologic jaundice
constipation
somnolence
feeding problems
Since early clinical diagnosis may be difficult and early treatment is
necessary to ensure normal intellectual development,all neonates
should be screened for hypothyroidism by measuring serum T4 or TSH
o Young Children:
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coarse features, protruding tongue, broad, flat nose, widely set eyes,
dry skin, coarse hair. impaired mental development, retarded bone age,
epiphyseal dysgenesis, delayed dentition.
o Older Child:
retardation of linear growth, delayed puberty
poor school performance
o Adult:
fatigue, lethargy, constipation, cold intolerance,
slowing of intellectual and motor activity
lessened appetite; increased weight
dry skin; dry hair (may fall out)
deeper, hoarser voice
With Advanced Disease: (florid myxedema)
dull, expressionless facies, sparse hair, periorbital puffiness ,
large tongue, rough and doughy skin (cool, pale)
enlarged heart (dilation, pericardial effusion)
adynamic ileus
Without treatment: myxedema coma possible with respiratory
depression and increased PCO2
o Laboratory Tests :
single most useful: serum TSH
increased levels in thyroprivic and goitrous
normal or undetectable in pituitary or hypothalamic
hypothyroidism
in hypothalamic hypothyroidism: TSH
hypersecretion is associated with hypersecretion of
other pituitary hormones
All hypothyroidism:
decreased serum T4 and free T4I
serum T3 may be decreased less than serum serum T4
Some other abnormal laboratory results:
increase serum cholesterol (hypothyroidism of thyroid
origin)
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increased creatinine phosphokinase
increased aspartate transaminase
indications of pernicious anemia
Pharmacological treatment:
o Synthetic hormones:
levothyroxine, preferred
liothyronine
liotrix (combination of new L-thyroxine and liothyronine)
o Neonatal, infantile, and juvenile hypothyroidism : early full replacement
therapy vital to improve likelihood of:
normal intellectual development
normal growth
o If neonatal, infantile, and juvenile presentations result from pituitary and
hypothalamic hypothyroidism, treatment with hydrocortisone should precede
thyroid replacement therapy:
Rationale:acute adrenocortical insufficiency may because by the
increase in metabolic rate with increase glucocorticoid clearance
following thyroid hormonal treatment
o Adults:
rapid treatment desirable especially in patients with:
11 myxedema coma
1 1 hypothyroid patients needing to undergo emergency surgery (these patientshave extreme sensitivity to CNS depressants);
IV levothyroxine with hydrocortisone may be
appropriate
to patients with myxedema coma and systemic illness may have
reduced ability to convert T4 to T3. In these cases supplemental
liothyronine may be added to levothyroxine.
*- Thyroprivic: refering to lack of thyroidhormone (e.g. removal of the gland or
suppression of glandular function)
Thyrotoxicosis:
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Definition:clinical, physiological, biochemical consequences when tissues respond
to excess thyroid hormone
Most important causes: those associated with prolonged hormone
overproduction by the thyroid.
Causes:
o Extra-pituitary unregulated thyroid stimulation:
1. Graves' disease
2. Hashimoto's disease
3. trophoblastic tumor
o Chronic thyroiditis
o Excessive TSH secretion by pituitary tumor (rare)
o Autonomous thyroid gland hyperfunction
o Ingestion of meat contaminated with animal thyroids ("hamburger toxicosis")
Hyperthyroidism is only associated with conditions in which thyroidal hyperfunction
leads to thyrotoxicosis.
Graves' disease
Three major presentations:
o hyperthyroidism with diffuse goiter
o dermopathy
o ophthalmopathy
Thyroid Pathology :
o soft, enlarged, vascular
o Parenchymal hypertrophy/hyperplasia
o Lymphocytic infiltration (suggesting the immunological nature of thedisease)
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"Diffuse toxic goiter of Graves disease, gross, showing symmetric, non-nodular
hypervascular enlargement of the thyroid"
1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of
Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.
Graves' disease: other involvements
o generalized lymphoid hyperplasia and infiltration
o spleenic or thymic enlargement
o Thyrotoxicosis associated with:
skeletal muscle fiber degeneration
cardiac enlargement
diffuse liver fibrosis with fatty infiltration
skeletal decalcification
body tissue loss
Ophthalmopathy:characterized by --
1. inflammatory orbital content infiltrate (lymphocytes, mast cells, plasma cells)
2. enlargement of orbital musculature (lymphocytes infiltration, mucopolysaccharides,
edema, fat)
3. eventually -- muscle fiber degeneration; loss of striations; fibrosis
Dermopathy:
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o dermal thickening (lymphocytes infiltration; mucopolysaccharides)
Clinical Presentations:-- Thyrotoxicosis
o Common manifestations (thyrotoxicosis)
nervousness, insomnia, tremors, frequent bowel movements, heatintolerance, sweating, emotional instability
weight loss despite adequate or increased appetite
muscle weakness
oligomenorrhea/amenorrhea in premenstrual women
dyspnea
palpitations
exacerbation of angina/cardiac failure (older patients)
o Ocular Presentations: -- distinct from ophthalmopathy associated with
Graves' disease; ocular signs mainly due to excessive sympathetic stimulation
characteristics stare (widening palprebral fissures)
lid lag
infrequent blinking
failure to wrinkle brow upon upward gaze
o Cardiovascular effects:
wide pulse pressure
sinus tachycardia
atrial arrhythmias (particularly atrial fibrillation)
systolic murmurs
occasionally heart failure
Clinical Presentations: Graves' disease
o Common manifestations:
hyperfunctioning goiter
asymmetric, lobular
ophthalmopathy
Two components: spastic and mechanical
spastic-- stare, lid lag, lid retraction
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proptosis (sensitive to antiadrenergic agents)
including:
1. ophthalmoplegia
2. periorbital swelling
3. conjunctivitis
4. corneal ulceration, optic neuritis, optic
atrophy
Diagnosis:
in addition to physical manifestations described earlier:
undetectable TSH
Usually increased values of T4 and T3.
Thyroid Storm:
o Fulminating increase in symptoms of thyrotoxicosis
o "Medical storm" is now likely to be seen in undertreated patients.
o Precipitated by surgery or complicating illness, often sepsis.
o Presenting syndrome:
extreme irritability
coma or delirium
high fever, 41oC
tachycardia
hypotension
vomiting
diarrhea
o Treatment:
manage dehydration: IV glucose/Saline, vitamin B complex
glucocorticoids (possible reduction in adrenal reserve; increase
glucocorticoid requirement and thyrotoxicosis
digitalis may be required to control elevated ventricular rates in the
presence of atrial fibrillation
Block hormone synthesis by large dose propylthiouracil; followed by
large doses of iodine, oral or parenteral; sodium ipodate may be usedinstead of iodine
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Propranolol (adrenergic antagonist) important in the absence of CHF
Combination treatment with propylthiouracil, iodine, dexamethasone is
likely to result in serum T3 levels returning to normal within one to two
days.
Greenspan, F.S., and Dong, B. J.. Histamine, Thyroid and Antithyroid Drugs, in Basic
and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 619-633.
Wartofsky, L., Diseases of the Thyroid, In Harrison's Principles of Internal Medicine
14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S.
and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2012-
2034
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