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Hormones, Antagonists, and

Other Agents Affecting


Endocrine Function

Department of Pharmacology, medical school of


Xi’an Jiaotong University
Hu Hao
CHAPTER 33 Thyroid Hormones and Antithyroid Agents

CHAPTER 34 Insulin and Oral hypoglycemic Agents

CHAPTER 35 Corticotropin and Adrenal Corticosteroids

CHAPTER 36 Posterior Pituitary Hormones


Chapter 33
Thyroid hormones and
antithyroid agents
Thyroid Hormones
• Thyroid gland is located just
below the larynx. Weight?
• Thyroid is the largest of the pure
endocrine glands.
• Follicular cells secrete thyroxine
(T4) & T3.
• Parafollicular cells secrete
calcitonin.
– Decreases blood [Ca+2 ] by
increasing Ca+2 secretion in urine &
decreasing breakdown of bone.
Thyroid Hormones

Thyroid hormones — secreted by thyroid gland


triiodothyronine (T3)
tetraiodothyronine (T4, thyroxine)

Thyroid hormones — to maintain


normal growth and development,
normal body temperature,
normal energy levels.
【 Biosynthesis 】
(1) Uptake of iodide
(2) Oxidization and iodination: thyroperoxidase
monoiodotyrosine (MIT), diiodotyrosine (DIT)
(3) Formation of thyroxine(T4) and triiodothyronine(T3) from
iodotyrosines : DIT+DIT---T4 MIT+DIT ---T3
【 Storage 】
T4 and T3 are stored in the colloid droplets of thyroglobulin
after biosynthesis of thyroid hormones.
【 Release 】
Under the action of proteolytic enzymes, thyroglobulin is
hydrolyzed and releases T4, T3, MIT, and DIT into blood.
【 Regulation of thyroid function 】
TRH: thyrotropin-releasing hormone--- hypothalamus
TSH: thyroid-stimulating hormone--- pituitary gland

TRH stimulates the synthesis and release of TSH.


TSH increases the synthesis and release of T4 and T3.
T4 and T3 make a negative feedback fashion, acting on the
pituitary to block the action of TRH and in the hypothalamus to
inhibit the synthesis and secretion of TRH.
Large dose of iodine inhibit iodination.
In certain disease states (eg, hashimoto’s thyroiditis) can result
in an inhibition of thyroid hormone synthesis and hypothyroidism.
Thyroid hormone synthesis, release and regulation

blood

Iodide iodine
Iodide in blood

Iodine
Thyroid cell

pump Peroxidase MIT Peroxidase T3 Protease T3

Follicle
colloid
DIT T4 T4
Tyrosine residues on TG DIT

TSH
Pituitary gland

TRH
Hypothalamus
【 Relation of iodine to thyroid function 】
Normal thyroid function obviously requires an adequate intake
of iodine; Without it, normal amounts of hormone cannot be
made, TSH is secreted in excess, and the thyroid becomes
hyperplastic and hypertrophies.
The enlarged and stimulated thyroid becomes remarkably
efficient at extracting the residual traces of iodide from the blood.
The iodide-concentrating mechanism develops a gradient for the
ion that may be ten times normal, and in mild to moderate iodine
deficiency, the thyroid usually succeeds in producing sufficient
hormone. Adult hypothyroidism and cretinism may occur in
more severe iodine deficiency.
【 Pharmacokinetics 】

The primary kinetics varies of thyroid hormones are


(1) amount binding: T4 99.96%, T3 99.6 %;

(2) half-life (biologic): T4 5~7 days, T3 2 days;

(3) daily production: T4 75μg, T3 25μg;

(4) bioavailability: T4 50-75%, T3 90-95%.


【 Pharmacologic effects 】
(1) to maintain normal growth and development
The thyroid hormones are responsible for optimal growth, development,
function, and maintenance of all body tissues. It is generally believed that
thyroid hormones exert the effects on growth and development through control
of protein synthesis.
Thyroid hormone plays a critical role in brain development. The absence of
thyroid hormone during the period of active neurogenesis leads to irreversible
mental retardation (cretinism) and is accompanied by multiple morphological
alterations in the brain.
Thyroid hormone also plays an important role in fetus lung development. If
thyroid is cut out, the fetus lung will be hypoplastic.
【 Pharmacologic effects 】

(2) to increase metabolism


– to increase metabolic rate
A characteristic response of homeothermic animals to
thyroid hormone is increased oxygen consumption and
calorie production. Most peripheral tissues contribute to
this response; heart, skeletal muscle, liver, and kidney are
stimulated markedly by thyroid hormone.
【 Pharmacologic effects 】

(3) adrenergic facilitation


Many of the manifestations of thyroid hyperactivity resemble
sympathetic nervous system overactivity, though catecholamine
levels are not increased. The most dramatic effects of this
catecholamine hyperactivity are seen in the cardiovascular
system.
Other clinical symptoms reminiscent of excessive epinephrine
activity include lid lag and retraction, tremor, excessive sweating,
anxiety, and nervousness.
【 Therapeutic uses 】
1. Treatment of hypothyroidism: Cretinism

A 44 yr. old man who has always been cared


Cretinism—in infants and children, hypothyroidism is striking
for by his mother is presented. He is severely
retardation of growth and development that results in dwarfism
retarded and cannot communicate. He is only
and irreversible mental retardation.
40 inch
For treatment to be fully tall, his
effective, theepiphyses
diagnosisare
muststill
beopen,
made
long before these obviousalthough
changesseverely
have come about. Success
damaged. He has veryin
the treatment of cretinism depends
thick, uponHis
dry skin. thetongue
age at is
which
thick, and he
therapy is started. Treatment effectnose.
has a saddle : TheHe
earlier, thehis
still has better
primary
teeth; the secondary teeth have not erupted.
【 Therapeutic uses 】
2.Treatment of hypothyroidism: Myxedema

Myxedema frequently occurs in older persons, and it is often associated


with underlying coronary arteryAdisease.
43 y/o patient
In this with
situation,
the chief
the low
complaint
levels
of circulating thyroid hormone actually protect
of "decreased the heart
energy." Sheagainst
complains of
increasing demands that could result in angina pectoris or myocardial
fatigue, inability to finish tasks, sleeping
infarction.
more, yetcoma
The treatment of choice in myxedema always being
is to givetired. She has
a loading dosealso
of
noticedT3a can
thyroxine intravenously. Intravenous decreased
also becold
usedtolerance,
but may be
more cardiotoxic and more difficult to monitor.
constipation, and dryness of the skin. She
comments that she is always cold, even in
the summer.
【 Therapeutic uses 】
3. Simple goiter & nodular
goiter (who are deficient in the
secretion of thyroid hormone,
need rule out carcinoma).

【 Adverse effects 】
Toxicity is directly related to thyroxine levels ( excessive )
and manifests itself as nervousness, heart palpitations and
tachycardia, intolerance to heat and unexplained weight loss.
Antithyroid Agents

The antithyroid compounds used


clinically include :
Thioamides
Iodine and iodide
Radioiodine
Adrenoceptor-blocking agents
Thioamides

The thioamides methimazole and propylthiouracil are major


drugs for treatment of thyrotoxicosis. Carbimazole is converted
to methimazole in vivo, is widely used. Methimazole is about ten
times more active than propylthiouracil.

SH
S S
O
H3 C N N H3C N N C OCH2 CH3 HN NH
(CH2)2 CH3
O

Methimazole Carbimazole Propylthiouracil


Structure of thioamides
【 Pharmacokinetics 】
Propylthiouracil is rapidly absorbed, reaching peak serum levels after
2 hours. The bioavailability is 50-80%. The plasma half-life is 2 hours.
Methimazole is completely absorbed but at variable rates. It is readily
accumulated by the thyroid gland and has a volume of distribution
similar to that of propylthiouracil. Excretion is slower than with
propylthiouracil; 65-70% of a dose is recovered in the urine in 48 hours.
The plasma half–life is 6-13 hours.
Methimazole and Carbimazole can cross the placental barrier and
are concentrated by the fetal thyroid, so that caution must be employed
while using these drugs in pregnancy.
Propylthiouracil is preferable in pregnancy because it is more
strongly protein-binding and therefore crosses the placenta less readily.
【 Pharmacologic effects 】

Multiple mechanisms :
1. to block iodine organification (major action)
2. to block coupling of the iodotyrosines
3. to inhibit the peripheral deiodination of T4 and T3

Since the synthesis rather than the release of hormones is


affected, the onset of these agents is slow, often requiring 3-4
weeks before stores of T4 are depleted.
Peripheral tissue
T4
Thioamides

Deiodination
Iodide iodine
Iodide in blood

Iodine
Thyriod cell

pump Peroxidase MIT Peroxidase T3 Protease T3

Follicle
colloid
DIT T4 T4
Tyrosine residues on TG DIT blood
【 Therapeutic uses 】 Hyperthyroidism

A 32 years old man presents with heat intolerance


and weight loss. He has lost ten pounds in the last
six weeks but says his appetite is very good. He says
he is always hot, even in air-conditioned rooms.
After questioning, he also admits to having
increased nervousness, trouble concentrating, and
palpitations. He is having trouble doing fine motor
tasks because of a tremor. Physical exam reveals a
patient with warm, smooth, moist skin and a
diffuse goiter with a palpable thrill and bruit..
【 Therapeutic uses 】 Hyperthyroidism
Clinical features of hyperthyroidism
Distinctive features are weight loss in the setting of hyperphagia, tremor,
nervousness, and atrial tachyarrythmias (sinus tachycardia or atrial
fibrillation). Many symptoms and sign of hyperthyroidism are shared by
overactivity of the autonomic nervous system, including β-adrenergic
(tachycardia, tremor), sympathetic cholinergic (increased sweating), and
parasympathetic symptoms.
Treatment strategies of hyperthyroidism
• Remove gland and replace T4
• Irradiate gland and replace T4
• Prevent Iodide uptake (obsolete)
• Inhibit thyroperoxidase
• Prevent peripheral deiodination of T4
• Interfere with sympathetic nervous system
facilitating action of T3 and T4
【 Therapeutic uses 】 Hyperthyroidism

Treatment of hyperthroidism in the following


three ways :
(1) as definitive treatment, to control the disorder in
anticipation of a spontaneous remission in Graves’ disease;
(2) in conjunction with radioactive iodine, to hasten
recovery while awaiting the effects of radiation;
(3) to control the disorder in preparation for surgical
treatment.
【 Therapeutic uses 】 Preoperative Preparation

To reduce operative morbidity and mortality, patients must be


rendered euthyroid prior to subtotal thyroidectomy as definitive
treatment for hyperthyroidism. It is possible to bring virtually
100% of patients to a euthyroid state; the operative mortality in
these patients in the hands of an experienced thyroid surgeon is
extremely low.
Prior treatment with antithyroid drugs usually is successful in
rendering the patient euthyroid for surgery. Iodide is added to
the regimen for 7 to 10 days prior to surgery to decrease the
vascularity of the gland, making it less friable and decreasing the
difficulties for the surgeon.
【 Therapeutic uses 】 Thyroid Storm

Thyroid storm is an uncommon but life-threatening complication of


thyrotoxicosis. It occurs in untreated or partially treated thyrotoxic patients.
Clinical features are similar to those of thyrotoxicosis, but more exaggerated.
Cardinal features include fever ( temperature usually over 38.5℃ ) and
tachycardia out of proportion to the fever. Nausea, vomiting, diarrhea, agitation,
and confusion are frequent presentations. Coma and death may ensue in up to
20% of patients.
Treatment includes supportive measures such as intravenous fluids,
antipyretics, cooling blankets, and sedation. Antithyroid drugs are given in large
doses. Propylthiouracil is preferred over methimazole because of its additional
action of impairing peripheral conversion of thyroxine to triiothyronine.
Iodides, orally or intravenously, are used after the first dose of an antithyroid
drug has been administered.
【 Adverse effects 】
1. Anaphylactic maculopapular: pruritic rash,
urticarial rash, et al.
2. Agranulocytosis: an infrequent but potentially
fatal adverse reaction.
3. Goiter and hypothyroidism:
thyroid homones TSH
Iodides have been known since
the 1920s to have multiple effects
Iodides on the thyroid gland. Prior to the
introduction of the thioamides in
the 1940s, iodides were the major
antithyroid agents; today they are
【 Pharmacodynamics 】 rarely used as sole therapy.

Iodides inhibit thyroid hormones organification and release,


and decrease the size and vascularity of the hyperplastic gland.
In pharmacologic doses (>6mg daily), iodides inhibit
hormone release through inhibition of thyroglobulin
proteolysis. Rapid improvement in thyrotoxic symptoms occurs
within 2-7 days, hence the value of iodide therapy in thyroid
storm.
In addition, iodides decrease the vascularity, size, and
fragility of a hyperplastic gland, making the drugs valuable as
High dose I- Inhibit
Inhibit release
synthesis

blood

Iodide iodine
Iodide in blood

Iodine
Thyriod cell

pump Peroxidase MIT Peroxidase T3 Protease T3

Follicle
colloid
DIT T4 T4
Tyrosine residues on TG DIT

Increase synthesis of
thyroid hormones to Reduce the
TSH size of
treat simple goiter
thyroid
Pituitary gland

Low dose I - TRH High dose I-


Hypothalamus
Iodide is used frequently after the
hyperthyroidism has been controlled
by an antithyroid drug. It is then
【 Therapeutic uses 】 given for 7 to 10 days immediately
preceding the operation.

1. To be used in the preoperative period in preparation


for thyroidectomy.
2. To be used in the treatment of thyrotoxic crisis,
conjunction with antithyroid drugs and propranolol.
3. Another use of iodide is to protect the thyroid from
radioactive iodine fallout following a nuclear accident.
Because the uptake of radioactive iodine is inversely proportional to the serum
concentration of stable iodine, the administration of 30 to 100 mg of iodide daily will
markedly decrease the thyroid uptake of radioisotopes of iodine. Following the
Chernobyl nuclear reactor accident in 1986, approximately 10 million children and
adults in Poland were given stable iodide to block the thyroid exposure to radioactive
iodine from the atmosphere and from dairy products from cows that ate contaminated
grass. This prevented the occurrence of radiation-induced thyroid cancer, as observed
in children residing near Chernobyl.
【 Adverse effects 】
Adverse reactions include acneiform rash, swollen salivary
glands, mucous membrane ulcerations, conjunctivitis, metallic
taste, bleeding disorders, and rarely anaphylactoid reactions.
Iodide therapy include an increase in intraglandular stores of
iodine, which may delay onset of thioamides therapy or prevent
use of radioactive iodine therapy.
Iodide should not be used alone, because its withdrawal may
produce severe exacerbation of thyrotoxicosis in an iodine-
enriched gland.
Chronic use of iodides in pregnancy should be avoided, since
they cross the placenta and can cause fetal goiter…
Radioactive iodine
131
I is an isotope used for treatment of thyrotoxicosis. T1/2 is
8 days, therefore, more than 99% of its radiation is eliminated
within 56 days. Administered orally in solution as sodium 131 I,
it is rapidly absorbed, concentrated by the thyroid, and
incorporated into the colloid of the thyroid follicles.
【 Pharmacologic effects 】
Its therapeutic effect depends on emission of β-rays and a
penetration range of 0.4-2.0mm. Within a few weeks after
administration, destruction of the thyroid parenchyma is
evidenced by epithelial swelling and necrosis, follicular
disruption, edema, and leukocyte infiltration.
It is used in the patients who are not suitable to
thioamides with no effect or hypersusceptibility and
operation.
【 Therapeutic uses 】
1. Highly useful in the treatment of hyperthyroidism
2. A useful diagnostic tool
Tracer studies with radioactive iodine have found
wide application in studies of disorders of the thyroid
gland. Measurement of the thyroidal accumulation of
a tracer dose is helpful in the differential diagnosis of
【 Adverse effects 】thyrotoxicosis and nodular goiter.
1. high incidence of delayed hypothyroidism.
2. could induce genetic damage, leukemia and neoplasia.
3. not be administered to pregnant women or nursing
mothers, since its crosses the placenta and is excreted in
breast milk.
Adrenoceptor-blocking agents
• Antagonises thyroid hormone facilitation of
sympathetic activity
• Adjunct in managing hyperthyroid-related
tachyarrhythmias
• Suppresses sympathetic manifestations
• Tachycardia • Tremor • Eyelid retraction

【 Therapeutic uses 】
β-adrenoceptor-blocking drugs have been used in the therapy
of thyrotoxicosis patients who are not suitable to antithyroid
drugs, operation and therapy with 131 I.