Thyroid and Antithyroid Agents
Dai Vo, D.V.M., M.S.c, Ph.D.
Department of Clinical Veterinary Sciences
Nong Lam University
To learn
– How thyroid hormones are
synthesized
– Factors that modulate the
synthesis pathway
– Fate of thyroid hormones
– Actions of thyroid hormones
– Classes of antithyroid agents
– Side effects of methimazole, a
widely used antithyroid agent
Thyroid Diseases
Hypothyroidism mostly in dogs and
horses (myxedema; lymphocytic
thyroiditis, an autoimmune disease)
Hyperthyroidism in cats
(hyperplasia, adenoma)
Hypothyroidism (Thyroiditis)
Lymphocytic (Hashimoto’s)
thyroiditis is the most prevalent form
of hypothyroidism
An autoimmune process
Detection of antibody vs.
thyroglobulin as a diagnostic tool
Hypothyroidism
Seen in older dogs & horses, rare in cats
Clinical signs:
– Lethargy, weakness, coma, obesity,
cold intolerance, skin lesion, poor hair
growth & loss (alopecia), infertility
Most of these signs may be
misinterpreted as senility
Hyperthyroidism in Cats
Seen in older cats, rare in other
species
Clinical signs: weight loss in spite
of ravenous appetite, hyperactivity,
polydipsia, polyuria, diarrhea,
vomiting, heat intolerance,
tachycardia and tachypnea, hair loss
In the end stage, lethargy &
anorexia may be seen
Thyroid hormone synthesis
pathway
Inorganic iodide (I-) is pumped into the follicular cell
Activation of TSH receptor stimulates the iodide pump
The iodide is oxidized by thyroid peroxidase (TPO) into
iodine (Iox)
Iox iodinates tyrosine residues of thyroglobulin (TG) to
form monoiodotyrosine (MIT) and diiodotyrosine (DIT)
The MIT and DIT residues on TG couple to form
triodothyronine (T3) and reverse T3. Two DIT residues
couple to form thyroxine (T4)
The TG complex undergoes proteolysis to release T 3,
rT3, T4, MIT and DIT. 7. MIT and DIT are deiodinated,
allowing recycling of I-.
Transport of Thyroid
Hormones in Blood
Inhumans, 99.98% of T4 & 99.8% of
T3 are bound by plasma proteins
Plasma protein binding of T4 & T3:
dogs < humans
– In dogs, ~99% of T4 & T3 are
bound by plasma proteins
Thyroid Hormone Binding
Plasma Proteins
Plasma protein binding activity affects
hormone actions and metabolism
Thyroxine-binding globulin (TBG): high
affinity, low capacity
– 4X higher in humans than dogs
– TBG not found in cats, rabbits, rats, birds
Albumin
Thyroid Hormone Binding
Plasma Proteins
Plasma protein bound T4:
primates, ruminants, rodents >
horses > dogs, cats, birds
Plasma T1/2 in humans:
T4 = 7 d, T3 = 1 d
Plasma T1/2 in dogs:
T4 = 8-16 hr, T3 = 5-6 hr
Plasma Binding Activity
Affects T4 Dosages
Do not use human T4 doses in
dogs
– In humans: 50-150 g/person/day
PO
– In dogs: 20 g/kg/day PO
Factors Affecting Plasma
Protein Levels and Bindings
Estrogens TBG synthesis
Liver and kidney diseases
plasma protein levels T1/2
Drugs compete on albumin binding
sites to free T3 & T4: NSAIDs, eg,
aspirin, phenylbutazone
Metabolism and Excretion of
Thyroid Hormones
Metabolism
– 30-40% of T4 T3
– 50% of T4 rT3
– 15-20% of T4 conjugates (in liver)
Excretion
– Conjugates enter the bile and into the
gut, and are excreted in feces
– Conjugates hydrolyzed in the gut
Metabolism of Thyroxine
Enzymes involved in the conversion:
– Type I deiodinase (5’DI): T3, found in liver and
kidney
– Type II deiodinase (5’DII): T3, found in brain,
pituitary, brown fat
– Type III deiodinase (5DI): rT3, found in
placenta and brain
Rate of T4 T3 : in hypothyroidism,
in hyperthyroidism
(compensation)
Regulation of Secretion
TSH, a glycoprotein hormone,
stimulates all steps involved in T4
synthesis pathway
TSH receptors are coupled to Gs,
leading to cAMP formation
Iodide is needed for synthesis
Regulation of Secretion
In
humans:
TSH-R[Stim] Ab, An IgG, which
activates TSH receptors
T4, T3 secretion
Hyperthyroidism
(Grave’s disease) - swelling of
extraocular muscles
Actions of Thyroid Hormones
T3 is 3-5X as active as T4, since T4 is
prohoromone of T3
on growth and development
on calorigenesis
on cardiovascular system
on lipid metabolism
on skin
on neuromuscular system
on GI & reproductive systems
Effects on Growth and
Development
GH secretion and action
Deficiency in newborn or young
animals leads to cretinism
T3 is critical for development and
maintenance of neural tissues,
esp. brain -mental retardation in
cretins
Activation of nuclear receptors
increases transcription, resulting in
protein synthesis
Calorigenic Action
This action includes heat
generation & O2 consumption
Seen in heart, skeletal muscle,
liver, kidney, but not in adult brain,
lymph nodes, spleen, or gonads
T3 is involved in body temperature
regulation
Cardiovascular Action
O2 consumption cardiac output
Expression of - & 1-receptors
Expression of -myosin heavy
chain and Ca2+ channels in
myocardium
Effects of T3 on Lipid
Metabolism
Facilitation of the effect of lipolytic
hormones
Conversion of cholesterol into
bile acids
High cholesterol levels in patients
with hypothyroidism (>400 mg/dl)
Dermatologic Effects
Needed for hair & skin turnover:
alopecia in hyperthyroidism
In hypothyroidism: thickened skin
(myxedema); hair coat dryness;
bilateral alopecia, keratin & sebum
production
Neuromuscular Effects
Synthesis of proteins associated with
neuromuscular activity, eg, Na+,K+-ATPase,
Ca2+ channels, -myosin heavy chain
Hypothyroid patients have:
– Myopathy
– Cranial nerve VII paralysis contributes to
“sad face”
– Cranial nerve VIII paralysis contributes to
hard-hearing
– CNS depression
GI and Reproductive Effects
Needed for normal GI motility and
reproductive activity
In hypothyroid patients:
– constipation and diarrhea
– galactorrhea
(TRH prolactin secretion)
– infertility, anestrus
– testicular atrophy, libido,
hypospermia in males
(prolactin actions of FSH & LH)
Mechanisms of Action
Activation of nuclear T3 receptors
leads to mRNA synthesis
Activation of mitochondrial T3
receptors ADP uptake ATP
Activation of plasma membrane
receptors - Gq-coupling activation
of phospholipase C
Use of Thyroid Hormones in
Hypothyroidism
T4 is preferred over T3 because T4
can maintain higher thyroid hormone
activity in brain than T3
Dosage adjustment
Thyroid agents
Levothyroxine is T4. Dose for dogs is
20 μg/kg/day, orally
Liothyronine is the drug name for T3.
The initial dose in dogs is 5 μg/kg
orally, 2-3 times daily
Antithyroid Agents
Thioureylenes, eg, methimazole
(reversible): MOA?
Large doses of iodide
Na I131 (SC)
-blockers, eg, propranolol, atenolol
Methimazole (Tapazole)
It
is very potent drug
Dosages:
– 2.5-5.0 mg, PO, bid; can be raised to 12.5
mg, bid, PO
– Metabolism: oxidation, conjugation
– Plasma T1/2 = 2-10 hr in cats
May need several days before the signs of
hyperthyroidism alleviate
Antithyroid Agents
Large doses of potassium iodide
– For short-term use, esp. for pre-thyroidectomy
control
– For blocking uptake of radioactive iodide
NaI131: Non-surgical thyroidectomy; T1/2=8 d
-blockers: For thyrotoxicosis & behavior
changes
Methimazole vs. Na131I
