8.

THYROID THERAPY

Class Mechanism Drugs

Thyroid Hormones Levothyroxine#
Liothyronine
Liotrix
Tiratricol
Thyroid gland preparations
Antithyroids Thyroid peroxidase Thiouracils

inhibitors (thioamide) Sulfur containing imidazoles

Block conversion Propylthiouracil#

of Ipodate
T4 to T3

Sodium-iodide symporter Perchlorate

inhibitor Pertechnetate
Diiodotyrosine
Halogenated aminoacids Dibromotyrosine
Others
LECTURE 8. THYROID HORMONES

8.4 Biosynthesis of thyroid hormones:

Thyroid hormones are iodinated tyrosine derivatives; after ingestion, iodine is concentrated in
the thyroid -iodide trapping
The iodide is oxidized to iodine by H2O2 under the catalysis of thyroid peroxidase. The actual
iodinating entity is iodosulfonyl cysteine protein, which iodinates tyrosine at
the o-position to yield the 3- and 3,5-iodotyrosil residues (MIT& DIT)

Thyroglobulin is a glycoprotein whose function is under thyrotropin influence:

1. Iodine organification
2. Tyrosyl coupling
3. Storage of T3/T4

Thyroid hormones
Thyroid hormones are the active principles of the thyroid gland + their synthetic analogs.

8.5 Uses of thyroid hormones:

1. Treatment of simple goiter - hypothyroidism/ myxedemia
2. Diagnosis of hyperthyroidism and thyrotropic dependent carcinoma of the thyroid and in
fibrous or lymphocytic thyroiditis
They are life long replacement therapy for hypothyroid patients.

8.6 Thyroid hormone preparations of natural thyroid hormones

Natural thyroid hormone preparations include desiccated thyroid and thyroglobulin. They are
derived from thyroid glands of domesticated animals that are used for food by human. Fresh or
desiccated gland is extracted with dilute NaOH and then acidified with HCl to generate the crude
thyroxine. Purification is by means of solubilization with NaOH and re-precipitation in HCl. For
example, ‘Thyroid USP’ is an acetone powder of bovine or porcine thyroid glands that are
compressed into tablets, often with a diluent. The dessicated thyroid preparation contains
iodinated tyrosyl and thyronyl residues of the precipitated thyroglobulin and its efficacy is as a
result of the hormones that are liberated by intestinal proteases.

8.7 Synthetic thyroid hormones

Synthetic thyroid hormones include levothyroxine, liothyronine, liotrix and tiratricol. Synthetic,
crystalline thyroid hormones have the following advantages over biological thyroid hormones:
They are more uniformly absorbed
They contain more precisely measured amounts of active ingredients per unit dose

8.7.1 LEVOTHYROXINE SODIUM

8.7.1.1 Structure of levothyroxine sodium:

8.7.1.2 Physical Properties of levothyroxine sodium:
Whitish, odorless, hygroscopic crystalline powder; Assumes a pink color upon exposure to light;
Slightly soluble in water, alcohol; Insoluble in CHCl3, acetone, ether.

8.7.1.3 Uses of levothyroxine sodium:

Drug of choice in replacement therapy in hypothyroidism and related conditions. Should be used
with caution in patients with cardiac disease and hypertension and geriatrics.

8.7.1.4 Biotransformation of levothyroxine sodium:

Absorption from GIT is incomplete & variable. Completely protein bound. t½ = 1 week.
Partially metabolized in the liver to triodothyronine (T3). Peripheral deiodination also occurs.
Excreted in urine as the unchanged drug, deiodinated metabolites and their conjugates.

8.7.1.5 Incompatibilities of levothyroxine sodium:

1. Enhances the effect of coumarin anticoagulants by increasing catabolism of vitamin K-
dependent factors.
2. Cholestyramine & colestipol interfere with absorption of levothyroxine sodium.
Administration should be spaced 4 hours apart.
3. When taken with antidiabetic agents an increase in dosage of the later is required.
8.7.1.6 Metabolism of of levothyroxine sodium

1. Deiodination : Is a reductive process catalyzed by the iodothyronine deiodinases (D); (a)

Activation of T4 (pro-hormone) to triiodothyronine,T3 (active); (b) Inactivation of T4 to rT3
and 3,3'-T2
2. (a) Conjugation of the deiodinized metabolites- glucuronide or sulphate. The conjugates are
excreted in bile and partly undergoes enterohepatic circulation; (b) Side chain degradation-
transamination, oxidative deamination, decarboxylation to the thyroacetic acid and
thyroethane thiol; (c) Cleavage of the diphenyl ether linkage

8.7.1.7Analysis:
A) Tests for Identity
1. IR and UV spectroscopy
2. Specific optical rotation
3. TLC

B) Related substances are controlled through HPLC under conditions of the assay. Liothyronine
arises from synthesis.

C) Assay: HPLC

8.7.1.8 Stability of levothyroxine sodium:

The ether bond is cleaved in acid. In the presence of light autoxidation occurs via a radical
mechanism to produce colored products.
8.7.1.9 Synthesis of Levothyroxine Sodium:
 o Liothyronine sodium is crystalline T3. It has a rapid onset and short duration and
is suitable when rapid onset or cessation is required, as is the case in patients with
heart disease.
o Liotrix is a mixture of the sodium salts of levothyroxine (T4) and liothyronine
(T3) in ratios 4:1..

8.7.1.10 Structure activity relationships

1. A central lipophilic core of 2 aromatic rings linked by O, S or C atom forming an interring

bond of 120o and resting approx. perpendicular to each other.
2. Non-polar groups e.g. X (mainly I) and Me in the 3 & 5 positions of the inner (Ala- bearing)
ring. These groups aid maintain the Ar- rings mutually perpendicular. In addition they share
in the hydrophobic interactions with the receptor.
3. An -amino acid or anionic side chain of 2-3C attached at p-position to the bridging of the
inner Ar- ring. This side chain contributes in drug receptor interactions.
4. A phenolic OH group in the 4'- position of the outer ring. It supplies a H- bonding site near
the 5- position of the hormone. The 4'-phenates provides strong binding of the hormone with
transport proteins.
5. The activity of the structures 1-4 above is enhanced by a lipophilic halogen (I atom) or alkyl
or aryl subsistent adjacent to the 4-OH group.

8.7.1.11 Adverse effects:

a) Proper dosage free from S/E
b) Overdose causes thyrotoxicosis manifesting as palpitations, tachycardia, tremor, nervousness
and insomnia.
Lecture Nine: ANTI THYROID DRUGS

B. Antithyroid drugs are substances that inhibit synthesis or release of thyroid hormones or
interference with their metabolic actions at the cellular level. They are used for treatment of
hyperthyroidism. The alternative is surgery for which patients are prepared by admn of
antithyroid drugs.

9.3 Mechanism of action of anti thyroid drugs:They inhibit biosynthesis of thyroid hormones
thus decreasing levels of the same in circulation. Consequently, by feedback mechanism pituitary
thyrotropin is secreted to stimulate circulation & tissue development of the thyroid. The thyroid
gland is them enlarged (goiter) in which hormone synthesis is inhibited. For this reason anti
thyroid drugs can be called goitrogens or intrathyroid inhibitors.

9.4 Use of anti thyroid drugs:

Treatment of hyperthyroidism (excess secretion of thyroid hormones).

9.5 Thyroid peroxidase inhibitors

These group consists of two broad categories:
a) Sulfur containing imidazole derivatives like methimazole and carbimazole.
b) Thiouracils like propylthiouracil, methylthiouracil and benzylthiouracil.

9.5.1 Mechanism of action of thyroid peroxidase inhibitors:

1. Inhibition of thyroid peroxidases that catalyze iodination of tyrosine and subsequent ether
formation e.g. thiouracil, propylthiourea, methimazole (2-thioimidazole). These agents have
no effect on iodide-trap or thyroid hormone release
2. PTU and iopanoic acid also interferes with the peripheral deiodination of T4 through
inhibition of the enzyme 5'-deiodinase.

A) Halogenated amino acids: Dibromotyrosine, Diiodotyrosine

B) Inorganic compounds: I2, KI, NaI, Lugols solution (strong Iodine solution).
C) Oral cholecystographic agents: Iopanoic acid, Iopanate sodium
D) Thioureylenes & Isosteres: Carbimazole, Methimazole, Goitrin, Methylthiouracil,
Propylthiouracil.
Most of the compounds contain the thioureylene moiety – NH-CS-NH-

9.5.2 Structures of thyroid peroxidase inhibitors:

Carbimazole is a prodrug, which undergoes ester hydrolyses to form methimazole.

9.5.3 Structure action relationships of thyroid peroxidase inhibitors:

1. The C2-thioketo/thioenol is necessary for activity. This moiety undergoes keto-thioenol
tautomerism.

2. The C4 enolic OH in PTU and the C5/C6 alkyl group enhance the inhibitory potency
3. Unsubstituted N1 is essential for PTU activity with respect to inhibition of 5'-deiodinase.
4. Replacing the pyrimidine ring with imidazole ring yields compounds with more potent
thyroid peroxidase inhibition e.g. methimazole. However these compounds are not able to
inhibit 5'-deiodinase due to N1-CH3 substitution. The thioureylene is maintained.
5. Replacing the thioureylene moiety with –NH-CS-O- gives more potent compounds e.g.
goitrin. Goitrin occurs naturally in Brassica spp and is held responsible for mild goiter
observed in Brassica eating communities.
 9.5.4 Sulfur containing imidazole derivatives
These include methimazole and carbimazole.

9.5.4.1 Carbimazole

Carbimazole is a derivative and prodrug of methimazole. Methimazole is bitter and is rapidly

eliminated t1/2 = 3–5h. It is carbamoylated to carbimazole to improve on the taste &
pharmacokinetic parameters.

9.5.4.1.1Physical properties of carbimazole: White/yellow crystalline powder; slightly soluble

in water; soluble in acetone and alcohol

9.5.4.1.2Synthesis of carbimazole:
Condensation and de-ethanolation of (methylamino)acetaldehyde diethylacetal with thiocyanic
acid yields methimazole. Thiamazole is then reacted with ethylchloroformate in base to form
carbimazole.
9.5.4.1.3Uses of carbimazole: Management of hyperthyroidism; thyrotoxic crisis.

9.5.4.1.4Biotransformation of carbimazole: Carbimazole is a methimazole prodrug, which

undergoes ester hydrolyses thereby releasing CO2. A minor metabolite is 3-methyl-2-
thiohydantoin (I). The compound is not significantly PP bound.

9.5.4.1.5Incompatibilities of carbimazole: Oral anticoagulants enhance the anticoagulant effect

due to the hypothrombinemic effect of thioamide group

9.5.4.1.6Analysis of carbimazole:

A) Tests for Identity

1. IR spectroscopy against a CRS
2. TLC

B) Related substances are controlled by HPLC.

Thiamazole arises from synthesis and acid/base hydrolysis.
C) Assay; UV spetrophotometry at 291 nm, A1%1cm = 557.

9.5.4.1.7 Stability of carbimazole: Acid and base labile

9.5.5 PROPYLTHIOURACIL (PTU)

9.5.5.1Properties of propylthiouracil:
White odorless crystalline powder with bitter taste; Slightly soluble in water, alcohol; Soluble in
NH3 (aq) & alkalis

9.5.5.2Uses of propylthiouracil: Management of hyperthyroidism; thyrotoxic crisis.

9.5.5.3Biotransformation of propylthiouracil: Rapidly absorbed and highly protein bound;
Undergoes hepatic metabolism; Excreted in urine & breast milk.

9.5.5.4Incompatibilities of propylthiouracil: Oral anticoagulants enhance the anticoagulant

effect due to the hypothrombinemic effect of thioamide group

9.5.5.5Assay of propylthiouracil: Titration with standard NaOH. Solution.

9.5.5.6Synthesis of of propylthiouracil:
9.5.5.7Mechanism of action of propylthiouracil:
The thioureynes inhibit peroxidase enzymes that catalyze iodination of tyrosine and subsequent
ether formation i.e. they prevent incorporation of I- into the tyrosine residues of thyroglobulin
and the coupling iodothyronines.

9.5.5.8Analysis of propylthiouracil:
A) Tests for Identity
1. IR spectroscopy
TLC
B) Related substances controlled through TLC
E.g. Thiourea
C) Assay:
Boil sample in NaOH followed. Add AgNO 3 and boil. Then titrate using 0.1N NaOH to a
potentiometric EP.

9.6Drugs that Block conversion of T4 to T3

9.6.1 Propylthiouracil#
9.6.2 Ipodate

Ipodate sodium
 sodium 3-(3-{[(dimethylamino)methylidene]amino}-
2,4,6-triiodophenyl)propanoate
Although not FDA approved, ipodate sodium has been used to treat Graves' disease and thyroid
storm, an extreme form of hyperthyroidism.

9.7 Sodium-iodide symporter inhibitors

Sodium-iodide symporter inhibitors
 Perchlorate (Potassium perchlorate)
 Pertechnetate (Sodium pertechnetate)

Perchlorate is a potent competitive inhibitor of the thyroid sodium-iodide symporter. Thus, it has
been used to treat hyperthyroidism since the 1950s. At very high doses (70,000–300,000 ppb) the
administration of potassium perchlorate was considered the standard of care in the United States,
and remains the approved pharmacologic intervention for many countries.

The structure of the technetate(VII) ion.

9.8Halogenated amino acids

9.8.1Diiodotyrosine

Diiodotyrosine

Identifiers

9.8.2Dibromotyrosine

Dibromotyrosine

(2S)-2-amino-3-(3,5-dibromo-4-hydroxyphenyl)
propanoic acid

Dibromotyrosine
 (2S)-2-amino-3-(3,5-dibromo-4-hydroxyphenyl)
propanoic acid
Dibromotyrosine is an antithyroid preparation and a derivative of the natural amino acid
tyrosine. It is formed by eosinophil peroxidase.

9.9 Others
9.9.1 Goitrin is a sulfur-containing oxazolidine, a cyclic thiocarbamate, that reduces the
production of thyroid hormones such as thyroxine. It is found in cruciferous vegetables
such as cabbage, brussels sprouts and oil-seed rape, and is formed by the hydrolysis of a
glucosinolate: progoitrin or 2-hydroxy-3-butenyl glucosinolate.
Goitrin

5-ethenyl-1,3-oxazolidine-2-thione

9.9.2 Inorganic compounds

9.9.2.1RADIOACTIVE IODINE:
9.9.2.1.1 Use:
1. Treatment of hyperthyroidism caused by Graves’s disease, multinodular goiter or single toxic
adenoma.
2. Treatment of metastatic thyroid carcinoma when the lesions have affinity for iodine

9.9.2.1.2 Adverse reactions: Hypothyroidism

Isotopes of Radioactive I- available 131I, 125I, 123I, whereby 131I is the most commonly used.

9.9.2.1.3 Pharmacokinetics:
131
I is reality absorbed from GIT and selectively contributes and binds to tyrosyl residues of
thyroglobulin in the thyroid gland. t1/2 = 138 days. Onset of therapeutic action = 2-4 weeks, peak
= 2-4 months. Excreted in urine, breast milk, saliva. Uptake of 131
I is increases by concomitant
admin of thyrotropin IM, SQ.

9.9.2.1.4 Mechanism of action:

131
I is selectively accumulated by thyroid. Causes localized damage & destruction to thyroid cells
without injuring surrounding tissues or organs. The radiation responsible is by –particles.

9.9.3 Drugs for thyroid imaging

9.9.3.1 Ipodate
9.9.3.2 I-123
o 9.9.3.3 Tc-99