Thyroid & Antithyroid Drugs

Fig 1

Fig 2

Thyroid follicles are the structural & functional units of the thyroid gland.
Each follicle is surround mainly by simple cuboidal epithelium and is

filled with a colloid which mainly composed by thyroglobulin.

Thyroid hormones are mainly synthesized in colloid while the simple
cuboidal epithelium undertaking thyroglobulin production, iodide intake &
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thyroid hormones release.

Synthesis of thyroid hormones

MIT: monoiodotyrosine

Thyroid hormones

DIT: diiodotyrosine

triiodothyronine (T3)

tetraiodothyronine (T4, thyroxine)

Materials
iodine & tyrosine
Steps

Thioamid
e drugs

1. Iodide is trapped by sodium-iodide symporter

2. Iodide is oxidized by thyroidal peroxidase to iodine
3. Tyrosine in thyroglobulin is iodinated and forms MIT & DIT
4. Iodotyrosines condensation
MIT+DITT3;

DIT+DITT4

Intra-thyroidal synthesis and processing of thyroidal hormones

1.

Iodide is taken up at the basolateral cell

membrane and transported to the apical
membrane

2.

Polypeptide chains of Tg (thyroglobulin) are

synthesized in the rough endoplasmic reticulum,
and posttranslational modifications take place in
the Golgi

3.

Newly formed Tg is transported to the cell

surface in small apical vesicles (AV)

4.

Within the follicular lumen, iodide is activated

and iodinates tyrosyl residues on Tg, producing
fully iodinated Tg containing MIT, DIT, T4 and a
small amount of T3 (organification and coupling),
which is stored as colloid in the follicular lumen

5.

Upon TSH stimulation, villi at the apical

membrane engulf the colloid and endocytose the
iodinated Tg as either colloid droplets (CD) or
small vesicles (MPV)

6.

Lysosomal proteolysis of the droplets or

vesicles hydrolyzes Tg to release its iodinated
amino acids and carbohydrates

7.

T4 and T3 are released into the circulation

8.

DIT and MIT are deiodinated, and the iodide

and tyrosine are recycled

thyroidal peroxidase

Regulation

of thyroid function

Physiological actions of thyroid hormones

To normalize growth and development, body
temperature, and energy levels
Insufficiency cretinism (infant & child), and

myxedema (adult);
Excesshyperthyroid
To enhance CNS excitability & sensitivity of CVS to NA
T3

is 3 to 4 times more potent than T4 in heat production;

T4 in colloid is about 4 times more numerous than T3 ;
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hyperthyroid

cretinism
myxedema
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Table 38-4. Manifestations of thyrotoxicosis and hypothyroidism.

System
Thyrotoxicosis
Warm, moist skin; sweating; heat intolerance;
Skin and appendages
fine, thin hair; Plummer's nails; pretibial
dermopathy (Graves' disease)
Retraction of upper lid with wide stare;
Eyes, face
periorbital edema; exophthalmos; diplopia
(Graves' disease)

Cardiovascular system

Decreased peripheral vascular resistance,

increased heart rate, stroke volume, cardiac
output, pulse pressure; high-output heart
failure; increased inotropic and chronotropic
effects; arrhythmias; angina

Respiratory system

Dyspnea; decreased vital capacity

Gastrointestinal system
Central nervous system
Musculoskeletal system
Renal system
Hematopoietic system
Reproductive system

Metabolic system

Hypothyroidism
Pale, cool, puffy skin; dry and brittle hair; brittle
nails
Drooping of eyelids; periorbital edema; loss of
temporal aspects of eyebrows; puffy, nonpitting
facies; large tongue
Increased peripheral vascular resistance;
decreased heart rate, stroke volume, cardiac
output, pulse pressure; low-output heart failure;
ECG: bradycardia, prolonged PR interval, flat T
wave, low voltage; pericardial effusion

Pleural effusions; hypoventilation and CO 2

retention
Increased appetite; increased frequency of
Decreased appetite; decreased frequency of
bowel movements; hypoproteinemia
bowel movements; ascites
Lethargy; general slowing of mental processes;
Nervousness; hyperkinesia; emotional lability
neuropathies
Stiffness and muscle fatigue; decreased deep
Weakness and muscle fatigue; increased deep
tendon reflexes; increased alkaline
tendon reflexes; hypercalcemia; osteoporosis
phosphatase, LDH, AST
Mild polyuria; increased renal blood flow;
Impaired water excretion; decreased renal blood
increased glomerular filtration rate
flow; decreased glomerular filtration rate
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Increased erythropoiesis; anemia
Decreased erythropoiesis; anemia1
Hypermenorrhea; infertility; decreased libido;
Menstrual irregularities; decreased fertility;
impotence; oligospermia; decreased gonadal
increased gonadal steroid metabolism
steroid metabolism
Increased basal metabolic rate; negative
nitrogen balance; hyperglycemia; increased
free fatty acids; decreased cholesterol and
triglycerides; increased hormone degradation;
increased requirements for fat- and watersoluble vitamins; increased drug metabolism

Decreased basal metabolic rate; slight positive

nitrogen balance; delayed degradation of
insulin, with increased sensitivity; increased
cholesterol and triglycerides; decreased
hormone degradation; decreased requirements
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for fat- and water-soluble vitamins; decreased
drug metabolism

Mechanism

of actions
of thyroid hormones

Some of T4 are converted to

T3 in kidney and liver

The actions of T3 on several

organ systems are shown

BMR: basal metabolic rate;

CNS: central nervous system

T3, via its nuclear

receptor, induces
new proteins
generation which
produce effects

Thyroid drugs
Representative

drugs

levothyroxine (L-T4, levoxyl, synthroid)

liothyronine (T3, cytomel, triostat)
liotrix (T4 plus T3) (euthyroid, thyrolar)

Pharmacokinetics
po easily absorbed; the bioavailablity of T4 is 80%, and T3 is

95%.
Drugs that induce hepatic microsomal enzymes (e.g., rifampin,
phenbarbital, phenytoin, and etc) improve their metabolism.
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Table 38-1. Summary of thyroid hormone kinetics.

T4

Variable

T3

Volume of distribution

10 L

40 L

Extrathyroidal pool
Daily production

800 mcg
75 mcg

54 mcg
25 mcg

Fractional turnover per day

10%

60%

Metabolic clearance per day

1.1 L

24 L

Half-life (biologic)
Serum levels

7 days

1 day

Total

5-12 mcg/dL (64164 nmol/L)

70-132 ng/dL (1.12.0 nmol/L)

Free

0.7-1.86 ng/dL (9-24 0.23-0.42 ng/dL

pmol/L)
(3.5-6.47 pmol/L)

Amount bound
Biologic potency
Oral absorption

99.96%
1
80%

99.6%
4
95%

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Pharmacological

effect
see physiological effect

Clinical

use

1. Hypothyroidism: cretinism & myxedema;

2. simple goiter: for pathogeny remaining unclear
(endemic goiter directly supply iodine)
3. Others:
Adverse

reactions

Overmuch leads to thyrotoxicosis;

Angina or myocardial infarction usually appears in
ageds
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Inhibition of TRH or TSH secretion without

induction of hypothyroidism or hyperthyroidism

Dopamine, levodopa, corticosteroids, somatostatin, metformin,

bexarotene

Inhibition of thyroid hormone synthesis or release

Iodides (including amiodarone), lithium, aminoglutethimide,
with the induction of hypothyroidism (or
thioamides, ethionamide
occasionally hyperthyroidism)
Alteration of thyroid hormone transport and serum total T 3 and T4 levels, but usually no modification of FT4 or
TSH
Increased TBG

Estrogens, tamoxifen, heroin, methadone, mitotane, fluorouracil

Decreased TBG
Androgens, glucocorticoids
Displacement of T3 and T4 from TBG with transient
Salicylates, fenclofenac, mefenamic acid, furosemide
hyperthyroxinemia
Alteration of T4 and T3 metabolism with modified serum T3 and T4 levels but not FT4 or TSH levels
Induction of increased hepatic enzyme activity

Nicardipine, imatinib, protease inhibitors, phenytoin,

carbamazepine, phenobarbital, rifampin, rifabutin

Inhibition of 5-deiodinase with decreased T3,

increased rT3

Iopanoic acid, ipodate, amiodarone, blockers, corticosteroids,

propylthiouracil, flavonoids

Other interactions
Interference with T4 absorption

Cholestyramine, colestipol, ciprofloxacin, aluminum hydroxide,

sucralfate, sodium polystyrene sulfonate, raloxifene, ferrous
sulfate, calcium carbonate, bran, soy

Induction of autoimmune thyroid disease with

hypothyroidism or hyperthyroidism

Interferon-, interleukin-2, interferon-, lithium, amiodarone

Effect of thyroid function on drug effects

Anticoagulation

Lower doses of warfarin required in hyperthyroidism, higher

doses in hypothyroidism

Glucose control

Increased hepatic glucose production and glucose intolerance in

hyperthyroidism; impaired insulin action and glucose disposal in
hypothyroidism

Cardiac drugs

Higher doses of digoxin required in hyperthyroidism; lower

doses in hypothyroidism

Sedatives; analgesics

Increased sedative and respiratory depressant effects from

sedatives and opioids in hypothyroidsim; converse in

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Antithyroid drugs
Drugs
Class

Representative
propylthiouracil

Thioamides

methylthiouracil
methimazole
carbimazole

Iodides
Radioactive iodine
-adrenoceptor blockers

KI, NaI
131
I
propranolol
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14

. Thioamides
Structure

The thiocarbamide
group is essential for
antithyroid activity

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Pharmacological action
Inhibition of the synthesis of T3 & T4
Mechanism
All thioamides inhibit peroxidase-catalyzing reactions
Iodine organification
First choice for
Iodotyrosines condensation
thyroid crisis
Propylthiouracil also inhibit T4 converting to T3
Characteristics
Result appears slowly: in 3-4 w hyperthyroid
ameliorated, and in 2-3 months BMR normalized;
Long-term use leads to thyroid hyperplasia
Methimazole is 10 times as potent as propylthiouracil
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17

Clinical use
treatment of hyperthyroid
1. Mild hyperthyroid and those surgery & 131I
not permitted;
2. Operation preparation;
3. Thyroid crisis (comprehensive therapy).
Adverse reactions
1. Long-term use leads to thyroid hyperplasia;
2. Pruritic maculopapular rash is the most common
adverse raaction
3. The severe adverse reaction is agranulocytosis
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Iodides (NaI, KI)

Pharmacological action
Inhibition of T3 & T4 release and synthesis
Decrease of size & vascularity of the hyperplastic gland

Clinical use
Ministrant treatment of hyperthyroid
1. Operation preparation;
2. Thyroid crisis.
Adverse reactions
1. Acneiform rash (similar to that of bromism);
2. Swollen salivary glands, mucous membrane ulcerations, and etc.
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20

Radioactive iodine (131I)

I is the only isotope for treatment of thyrotoxicosis.
Its therapeutic effect depends on emission of rays with an
131

effective half-life of 5 days & a penetration range of 0.4-2 mm.

Woman in pregnancy or lactation is forbidden!

-adrenoceptor blockers
blockers are effective in treatment of thyrotoxicosis.
Propranolol is the most widely studied and used.
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