Download Outline

Year Level 6 [Module 9: Endocrinology Module]
THYROID HORMONES AND ANTITHYROID DRUGS
Cecile A. Jimeno |[Pharmacology]
OUTLINE
I. Therapeutic Overview
II. Thyroid Physiology
III. Six major steps in Thyroid Hormone Synthesis
IV. Circulating Thyroid Hormone
V. Peripheral Metabolism of Thyroxine
VI. Effects of Drugs on Thyroid Hormone Production
VII. Summary of Thyroid Hormone Kinetics
VIII. Mechanisms for Thyroid Regulation
IX. Thyroid Hormone Mechanism of Action
X. Thyroid Hormone Effects
XI. Thyroid Preparations
XII. Hyperthyroidism
XIII. Clinical Features of Hyperthyroidism
XIV. Antithyroid Drugs
A. Thioamides
B. Iodides
C. Radioactive Iodine
D. Other Drugs
I. Therapeutic Overview
 Hypothyroidism
o Administer exogenous thyroxine (T4) or triidothyronine (T3)
 Hyperthyroidism
o Surgery
o Radioactive iodine
o Drugs: thioureylenes, beta adrenergic receptor blockers,
corticosteroids, iodides
II. Thyroid Physiology
 Thyroid gland maintains metabolic homeostasis by
regulating:
o growth and development,
o body temperature, and
o energy levels
 Multiple functions are accomplished through two hormones:
o triiodothyronine or T3, and
o tetraiodothyronine or T4
Hormones
triiodothyronine
tetraiodothyronine
Alias
T3
T4 or thyroxine
Molecular
composition
one MIT plus
one DIT
one DIT plus one
DIT
Iodine
content (%)
59
65
Thyroglobulin
ratio
1
5
Team 8| Anika, Anne, Archee, Francine, Greg, Jet, Kai, Kriska
December 10, 2009
III. Six major steps in Thyroid Hormone Synthesis
 Iodide (I-) is absorbed in the GIT enters an extracellular
pool from which the thyroid gland removes 75 mcg daily
1. Active Transport of Iodine across the basement membrane
into the thyroid cell (iodide trapping)
 I- is taken up by thyroid follicular cells via a membrane
Na+/I- transporter
2. Oxidation of iodide & iodination of tyrosyl residues in
thyroglobulin
3. Coupling of iodotyrosine molecules within thyroglobulin to
form T3 & T4
 I- is coupled to tyrosine residues on the thyroglobulin
molecule (organification)  formation of monoiodo(MIT) and diiodo-tyrosine (DIT)  thyroid peroxidase
catalyzes coupling of two molecules of DIT to form T4,
and one molecule each of MIT and DIT to form T3 
thyroglobulin stored as colloid in the lumen
Iodination of tyrosine & coupling
Tyrosine + I  MIT
Tyrosine + I2  3, 5 DIT
MIT + DIT
 3, 5, 3’ TIT (T3) or 3, 3’, 5’ TIT (rT3)
DIT + DIT
 3, 5, 3’, 5’ Tetraiodothyronine (T4)
4. Proteolysis of thyroglobulin - release of free iodothyronines
& iodotyrosines from colloid droplets (pinocytosis)
 TSH signals secretion to hydrolyze thyroglobulin to free
MIT, DIT, T3 & T4
5. Deiodination of iodotyrosines within the thyroid cells &
recycling of iodine
 MIT and DIT are deiodinated for recycling while T3 & T4
are released by exocytosis
6. Intrathyroidal 5’-deiodination of T4 to T3
Page 1 of 6
THYROID HORMONES AND ANTITHYROID DRUGS
Year Level 6 [Module 9: Endocrinology Module]|December 10, 2009
Steps in Thyroid Hormogenesis
IV. Circulating Thyroid Hormone
 T3 and T4 are mostly bound to thyroxin binding globulin
(TBG)
 Amounts of free or unbound hormones are minimal: 0.03%
T4 and 0.3% T3
 Only the unbound hormones have metabolic activity
 in peripheral tissues T4 is converted to T3 by iodothyronine
5’-deiodinase found mainly in liver, thyroid, and kidneys
 the active hormone in most target tissues is T3
V. Peripheral Metabolism of Thyroxine
VII. Summary of Thyroid Hormone Kinetics
Thyroid Hormones
T3
T4
Daily production (mg)
25
75
Daily Metabolic clearance (L)
24
1.1
Total Serum levels (nmol/L)
1.5-2.9
64-132
Biologic potency
3-4
1
Oral absorption (%)
95
80
Half Life (days)
1
7
VIII. Mechanisms for Thyroid Regulation
A. Hypothalamic-Pituitary Regulation
 paraventricular nuclei in the hypothalamus secrete
TRH TRH stimulates the anterior pituitary to release
TSH TSH acts on the thyroid to release T3 & T4 
T3 & T4 act by negative feedback to inhibit formation
of TRH and TSH
B.
Autoregulation within the thyroid modifies thyroid
hormone synthesis through blood iodine levels
 high iodine levels  inhibit iodide organification 
reduced T3 & T4 synthesis  hypothyroidism
 thyroid hormone released mostly as T4. T4 to T3 ratio in
thyroglobulin is 5:1
 peripheral metabolism of T4 is mainly by deiodination to
form:
o T3 which is 3-4 times more potent than T4, or
o reverse T3 which is metabolically inactive
 total serum levels for T4 are higher because more of it is
released and metabolic clearance of T3 is faster
VI. Effects of Drugs on Thyroid Hormone Production
METABOLIC STEP
INHIBITORS
Iodide Transport
Large amts of I-, Cl04-, SCN, TcO4Iodide Oxidation
Thionamide Drugs (PTU,
MMI)
Organification & coupling
Colloid Resorption &
Iodine, lithium
proteolysis (Release)
Team 4| Bia s Cliff. Karl. Chin. Harm. Joanna. Berto. Geno. Paula. Mica.
Page 2 of 6
THYROID HORMONES AND ANTITHYROID DRUGS
Year Level 6 [Module 9: Endocrinology Module]|December 10, 2009
IX. Thyroid Hormone Mechanism of Action
PB = plasma binding protein, F = transcription factor, R = receptor,
PP=proximal promoter proteins
 T3 receptors belong to a superfamily of nuclear receptors (cerb includes receptors for steroid hormones and vitamins A
and D)
 many T3 receptors are found in responsive tissues like
pituitary, liver, kidney, heart, skeletal muscle, lung, and
intestine
 T3 & T4 are dissociated from thyroid-binding proteins 
enter target cells by diffusion or transport  in the
cytoplasm 5’-deiodinase converts T4 to T3  T3 enters the
nucleus to bind to T3 receptors  more RNA formed 
increase protein synthesis
T3 Mechanism of Action
 T3 acts on Intracellular thyroid hormone receptors (TRs)
located in all cells of the body
 TR monomers interact with retinoic acid X receptor (RXR) to
form heterodimers
 in the absence of T3 the TR:RXR heterodimer associates with
a co-repressor complex that binds to DNA to inhibit gene
expression
 in the presence of T3, the co-repressor complex dissociates,
coactivators form to stimulate gene expression
 binding to TR dimers thus serves as a molecular switch from
inhibition
to
activation
of
gene
expression
X.
T
Thyroid Hormone Effects
 Generally responsible for optimal growth, development,
function, and energy levels in all tissues
o Excess  hyperthyroidism (thyrotoxicosis)
o Inadequacy  hypothyroidism (myxedema)
1. Nervous, musculoskeletal, and reproductive tissues:
nervousness, emotional lability, muscle weakness and
fatigue, osteoporosis, menstrual irregularities
2. Calorigenic effect: increased oxygen consumption, sweating
3. Sympathetic hyperactivity due to increased b-adrenergic
sensitivity ® dramatic cardiovascular effects including:
tachycardia, increased stroke volume and cardiac output,
high-output heart failure, arrhythmia, angina
4. Metabolic effects: decreased cholesterol and triglycerides;
increased basal metabolic rate, hyperglycemia, and appetite
XI. Thyroid Preparations
 Major clinical use of T3 & T4 is for hormone replacement
therapy in hypothyroidism
 Involves replacement of thyroid hormone adequate to meet
the patient’s needs
 Dose for replacement: 1.6-1.7 mcg/kg
 Indications
o Post-procedural hypothyroidism
o Endemic goiter
o Congenital hypothyroidism: cretinism
o Any cause of hypothyroidism i.e. thyroiditis
o Suppression of growth of nodules, thyroid CA
1. Synthetic levothyroxine [T4]: the preparation of choice for
replacement & suppression therapy because of its stability,
uniform content, low cost, long half-life (7 days), and
conversion to produce both T3 & T4
2. Desiccated thyroid, though inexpensive, is not recommended
for replacement therapy because of its antigenicity,
instability, and variable hormone content
Team 4| Bia s Cliff. Karl. Chin. Harm. Joanna. Berto. Geno. Paula. Mica.
Page 3 of 6
THYROID HORMONES AND ANTITHYROID DRUGS
Year Level 6 [Module 9: Endocrinology Module]|December 10, 2009
3. Liothyronine, [T3]
 3-4 times more active than levothyroxine
 Not recommended for routine replacement therapy
because of its higher cost, shorter half-life (24 hours), and
greater potential for cardiotoxicity
4. Liotrix, a 4:1 combination of synthetic T4 and T3,
expensive with the same disadvantages as liothyronine
XIV. Antithyroid Drugs
also
XII. Hyperthyroidism
 Is the consequence of excessive thyroid hormone action
 Causes
1. Diffuse toxic goiter (Graves’ disease)
2. Toxic adenoma
3. Toxic multinodular goiter (Plummer’s)
4. Painful subacute thyroiditis
5. Silent thyroiditis e.g. lymphocytic & postpartum
variations
6. Iodine-induced hyperthyroidism
7. Excessive pituitary TSH or trophoblastic disease
8. Excessive ingestion of thyroid hormones
XIII. Clinical Features of Hyperthyroidism
 Signs & symptoms are due to the effects of excess thyroid
hormone in the circulation
 Severity of signs & symptoms may be related to the duration
of the illness, magnitude of hormone excess & the age of the
patient
Symptoms
Weakness & Fatigue
Heat intolerance
Nervousness
Increased sweating
Tremor
Palpitations
Increased appetite
Weight loss
Hyperdefecation
Dyspnea
Menstrual a(N)
Hyperthyroidism
Signs
Goiter/thyroid bruit
Hyperkinesis
Ophthalmopathy
Lid retractions/stare
Lid lag
Tremor
Warm, moist skin
Muscle weakness
Hyperreflexia
Tachycardia/arrhythmia
Widened pulse pressure
1. Thioamides:
a. methimazole
b. propylthiouracil
Thioureylene or Thionamides
 Propylthiouracil, Methimazole/Thiamazole, Carbimazole
(pro-drug of methimazole)
 MOA: inhibit the thyroid peroxidase-mediated
iodination & coupling steps
 These drugs are preferentially iodinated, depriving
thyroglobulin of iodide and shutting down the synthesis
of thyroid hormones
 Accumulate readily in the thyroid gland for treatment of
thyrotoxicosis
 Methimazole is 10x more active than PTU
 Plasma half-lives: 6 hr for MMI & 1.5 hr for PTU
 Additional MOA: PTU but not methimazole, affects the
processing of T4 to T3 in the peripheral tissues
(inhibition of deiodinase enzyme)
 Since T3 is 10x as active as T4 this conversion step is
important
Thioamides: Methimazole & Propylthiouracil
 slow onset of action requiring 3-4 weeks to deplete T4
stores
 multiple mechanisms of action including:
o major action to prevent hormone synthesis by
inhibiting peroxidase reactions to block iodine
organification
o block iodotyrosine coupling
o inhibit peripheral deiodination of T3 & T4
Team 4| Bia s Cliff. Karl. Chin. Harm. Joanna. Berto. Geno. Paula. Mica.
Page 4 of 6
THYROID HORMONES AND ANTITHYROID DRUGS
Year Level 6 [Module 9: Endocrinology Module]|December 10, 2009
 adverse reactions occur in 3-12% of treated patients:
o most common: maculopapular pruritic rash
o rarely: urticarial rash, vasculitis, arthralgia, lupus-like
reaction, jaundice, hepatitis hypothrombinemia
o most dangerous – agranulocytosis
Side Effects of Thioureylenes
 Rash, urticaria – in as much as 20% of users; usually
transient even w/o treatment
 Auto-immune (lupus-like) nephritis, PAN
 Granulocytopenia,a granulocytosis:
RARE but
potentially fatal
o Watch out for sore throat, fever, diarrhea
2. Iodides: Potassium iodide Solution
 Many thyroid actions including:
o inhibition of hormone release by reducing
thyroglobulin proteolysis
o decrease in size and vascularity of the hyperplastic
gland
 Thyrotoxic symptoms improve within 2-7 days, but
should not be used alone because the gland “escapes’
from iodide block after 2-8 weeks and withdrawal may
result in severe thyrotoxicosis
 Avoid chronic use in pregnancy as iodides cross the
placenta and can cause fetal goiter
 Iodides: potassium iodide solution
 Advantages: simplicity, inexpensive, relatively nontoxic,
and absence of glandular destruction
 ADVERSE reactions, though uncommon, include:
acneiform rash, swollen salivary glands, mucous
membrane ulceration, conjunctivitis, rhinorrhea,
metallic taste, drug fever, bleeding disorders,
anaphylaxis
 DISADVANTAGES:
“escape”,
aggravation
of
thyrotoxicosis, allergic reactions, & increased
intraglandular iodine which can delay onset of
thioamide therapy or prevent use of radioactive iodine
therapy for several weeks
3. Radioactive Iodine (RAI)
 Given as oral solution, 131I is rapidly absorbed and
concentrated in the thyroid gland
 Thyroid parenchymal destruction becomes evident
within weeks in the form of epithelial swelling, necrosis,
follicular disruption, edema, and leukocyte infiltration
 Therapeutic effect depends on emission of beta rays
with:
o penetration range of 400-2000 mm and
o effective half-life of 5 days
 Advantages: easy administration, effectiveness, low
expense, & absence of pain
 Major disadvantage is induction of hypothyroidism
 Main contraindication is pregnancy as RAI crosses the
placenta and is excreted in breast milk
 Uses the ff radioisotopes: I123 or I131
 Side- effects are minimal: avoid in children (may inhibit
bone growth) and pregnant women or those intending
pregnancy
 Contraceptives are encouraged among those who are
sexually active
4. Other Anti-thyroid Drugs (Adjunct)
Anion Inhibitors & β-adrenergic Blockers
 Monovalent ions as perchlorate (ClO4-), pertechnetate
(TcO4-), and thiocyanate (SCN-) block iodide uptake
through competitive inhibition of the iodide transport
mechanism, but their effectiveness is unpredictable
 Potassium perchlorate is no longer used clinically because
it causes aplastic anemia
 Iodinated contrast media (ipodate and iopanoic acid by
mouth, or diatrizoate IV) though not FDA approved, act by
inhibiting conversion of T4 to T3 in liver, kidney, pituitary,
and brain
 Since many symptoms of thyrotoxicosis result from
sympathetic hyperactivity, guanethidine or b-adrenergic
blockers have also been used for treatment
1. Monocovalent Anions block thyroid hormone synthesis by
competitively inhibiting the active transport of iodide into
the thyroid gland
 Pertechnetate, Perchlorate: little clinical use
 High dose iodides: potassium iodide, SSKI, Lugol’s
solution, intravenous contrast agents
 Watch out for angioedema with iodides
2. Beta-adrenergic receptor blocking drugs
 Act peripherally rather than at the thyroid gland
 MOA: uncertain but may relate to inhibition of
deiodination= peripheral conversion of T4 to T3
 Also blocks the sympathetic (adrenergic) effects of
hyperthyroidism esp. on the heart
 Avoid in patient with ASTHMA
3. Corticosteroids
 Inhibit peripheral conversion of T4 to T3
 Immunosuppression of thyroid-stimulating antibodies
 Antipyretic
 May be used for treatment of adrenal insufficiency in
pts with thyroid storm
Radioactive Iodine Therapy
 Used for definitive therapy or ablation
 The only isotopes used for treatment of thyrotoxicosis
Team 4| Bia s Cliff. Karl. Chin. Harm. Joanna. Berto. Geno. Paula. Mica.
Page 5 of 6
THYROID HORMONES AND ANTITHYROID DRUGS
Year Level 6 [Module 9: Endocrinology Module]|December 10, 2009
Drugs Affecting T3-T4 Synthesis
 Anions (perchlorate, pertechnetate, & thiocyanate) compete
with I- uptake
 RAI causes selective thyroid destruction
 Iodide (high levels) reduce T3-T4 release by inhibiting
thyroglobulin proteolysis
 Thioamides inhibit peroxidase to block organification
Team 4| Bia s Cliff. Karl. Chin. Harm. Joanna. Berto. Geno. Paula. Mica.
Page 6 of 6