Download Thyroid function and thyroid drugs


IN THE NAME OF
GOD
Thyroid function and thyroid
drugs
Introduction:
The thyroid is a butterfly shaped gland which wraps around
the front part of the windpipe just below the Adam's apple.
It produces hormones which influence
essentially every organ, every tissue and
every cell in the body.
Thyroid hormones (Thyroxine T4 and
Triiodothyronine T3) regulate the body's
metabolism and organ function, affecting heart
rate, cholesterol level, body weight, energy level,
muscle strength, skin condition, menstrual
regularity,memory and many other conditions.
•13 million Americans suffer from a thyroid disorder,
but 8 million of them don't know it?
•Approximately 1 of 8 women will develop
a thyroid disorder during her lifetime?
•More than half of American women over 40 experience
three or more common symptoms of thyroid disorder,
but 75% haven't discussed them with a doctor?
Your thyroid gland produces hormones that influence
essentially every organ, every tissue and every cell
in your body?
Thyroid Disease
Hypothyroidism :
Definition:
The purpose of the thyroid gland is to make, store, and release
thyroid hormones, which help control many of the body's
functions. If there is too little thyroid hormone in the blood, you
have a condition called hypothyroidism. Symptoms may include
tiredness, forgetfulness, brittle nails, dry skin, puffy face and
eyes, depression, unexplained weight gain, and cold intolerance.
However, the number and type of symptoms vary from patient to
patient.
Hypothyroidism diseases:
It is a common thyroid disorder, occurring five times
more often in women than in men, and with greater
frequency in older individuals.
Hypothyroidism may affect 4% to 8% of the general
population.
It may affect 9% to 16% of the population over age 60.
Hypothyroidism diseases:
Goiter
Cretinism
Myxedema
Treatment
Fortunately, Hypothyroidism is very easily treated
The type of thyroid hormone replacement therapy most often
prescribed is called levothyroxine sodium.
Hyperthyroidism:
Definition:
•If there is too much thyroid hormone in the blood,
you have a condition called hyperthyroidism.
Symptoms of hyperthyroidism include:
weight loss, nervousness, and irritability.
However, the number and type of symptoms vary from
patient to patient.
Hyperthyroidism:
Hashimoto’s disease
Grave’s disease
Hyperthyroidism is a common disorder ,occurring
five times more often in women than in men.
*
Treatment for Hyperthyroidism
 Anti-thyroid drugs—Inhibits thyroid hormone synthesis by
irreversibly binding to TPO inhibiting its ability to break
down iodine (I2→I-) and covalently attach it to the tyrosine
residue of thyroglobulin.
– Propylthiouracil
– Methimazole
– Carbamizole─Degraded to methimazole in the body.
 Radioactive Iodine
 Thyroidectomy
 β-Blockers used in the treatment of thyroiditis to treat
symptoms.
Thyroid Cancers :
Thyroid cancers are rare and often curable
Thyroid cancer is a malignant tumor or growth
located in the thyroid gland. Thyroid cancer is
very rare, accounting for little more than 1% of all
cancers in the US.
20,000 case in USA each year,
 More common in women than in men,
Background:
T4 ( L-thyroxine or 3,5,3’,5’ tetraiodo-L-thyronine ) was
the first biologically active compound derived from thyroid
extract.
25 years later T3 ( 3,5,3’-triiodo-L-thyronine) was identified.
Two other compounds called DIT and MIT were discovered
later.
These two are precursors of T3 (DIT+MIT) and T4 (DIT+DIT ).
I
COOH
DIT
NH2
HO
I
HO
I
I
COOH
T3
NH2
O
I
98.5% T4
1.5% T3
I
HO
I
I
COOH
NH2
O
T4
I
I
HO
I
I
O
COOH
In blood:
rT3
NH2
Structure of the iodinated compounds of the
thyroid glands.
Biosynthesis of thyroid hormones:
Figure 2. Synthesis of Thyroxine and Triiodothyronine.
In Panel A, thyroid peroxidase (TPO), a heme-containing glycoprotein, is anchored within the thyroid follicular-cell
membrane at the luminal side of the thyroid follicle. In Panel B, the first step in thyroid hormone synthesis involves
generation of an oxidized enzyme promoted by endogenously produced hydrogen peroxide. In Panel C, the oxidized enzyme
reacts with trapped iodide to form an "iodinating intermediate" (TPO–Iox), the nature of which is not entirely understood.
Some investigators favor the formation of a heme-linked iodinium ion (TPO–I+), whereas others suggest the formation of
hypoiodite (TPO–O–I–).
. Panel D, in the absence of an antithyroid drug, the iodinating intermediate reacts with specific tyrosine residues in
thyroglobulin (Tg) to form monoiodotyrosine and diiodotyrosine. Subsequent intramolecular coupling of MIT and DIT forms
triiodothyronine, and the coupling of two DIT molecules forms thyroxine. In the presence of an antithyroid drug (e.g.,
methimazole, shown in Panel E), the drug serves as an alternative substrate for the iodinating intermediate, competing with
thyroglobulin-linked tyrosine residues and diverting oxidized iodide away from hormone synthesis. The drug intermediate
with a sulfur-linked iodide is a theoretical reaction product.6 In Panel F, the oxidized drug forms an unstable drug disulfide 7
that spontaneously degrades to an inactive desulfurated molecule, shown as methylimidazole. Antithyroid drugs also impair
the coupling reaction in vitro, but it is uncertain whether this occurs in vivo.
Thyroid hormone
biosynthesis
T4(tetra-iodinated tyrosine molecules)
-biosynthesis from thyroid gland
T3(tri-iodinated tyrosine molecules)
-produced by peripheral tissues or
small fraction from thyroid
Iodide Metabolism:
Dietary
Uptake
Thyroid 1 -
Plasma 1 -
Leak
Hormones
Urinary 1
-
1 from
Deiodinations
Tissue 1 -
Simplified scheme of
iodide metabolism.
Simplified scheme of Iodide metabolism
Metabolism and Excretion:
Deiodination of T4
Metabolic pathway of Thyroxine:
Metabolic pathways for Thyroxine
Control of Thyroid hormone biosynthesis:
Anterior Pituitary release TSH;
TSH: 2 large polypeptide chains
(α- chain which present in other peptide as well
& β-chain, specific in TSH).
TSH
Release of TSH
LH
FSH
Increase Iodide Uptake,
Iodination of thyroglobulin, and endocytosis
of colloid.
Second Messenger
Examples of Hormones Which Utilize This System
Cyclic AMP
Epinephrine and norepinephrine, glucagon, luteinizing
hormone, follicle stimulating hormone, thyroidstimulating hormone, calcitonin, parathyroid hormone,
antidiuretic hormone
Protein kinase activity
Insulin, growth hormone, prolactin, oxytocin, erythropoietin,
several growth factors
Calcium and/or phosphoinositides
Epinephrine and norepinephrine, angiotensin II, antidiuretic
hormone, gonadotropin-releasing hormone, thyroid-releasing
hormone.
Cyclic GMP
Atrial naturetic hormone, nitric oxide
Structure of Cell Surface Receptors
Extracellular domains
 Transmembrane domains
Cytoplasmic or intracellular domains
Several distinctive variations in receptor
structure have been identified. As depicted
below, some receptors are simple, single-pass
proteins; many growth factor receptors take this
form. Others, such as the receptor for insulin, have
more than one subunit. Another class, which
includes the beta-adrenergic receptor, is threaded
through the membrane seven times.
Thyroid Hormone
receptor
َA Nuclear Receptors
Large number of organic and inorganic compounds
Stimulate or prevent thyroid hormone formation by:
*Interfering with iodide uptake into follicular cells,
*Inhibiting thyroid peroxidase(TPO),
*Preventing thyroid hormone binding to plasma
proteins, or
*Acting as effectors of thyroid deiodinases.
*From the complete absence of thyroid function
seen in Myxedema to the simple Goiter and
Cretinism treatment was natural extract of thyroid.
Question 1:
Thyroid total weight
20g
From which 1/3 thyroglobulin (MW= 670,000 D)
MIT = 6 residue
DIT = 5
T3 = 0.3
T4 = 1
How many mg T3 and T4 are in the thyroid gland?
1) T4(Levothyroxine)
2) T3(Liothyronine)
3) dT4(dextrothyroxine)
4) T3-T4 mixture(liotrix)
I
HO
I
I
O
COOH
NH2
T4
I
Has a slower onset of action because bind to
carrier proteins firmer,
Greater increase in serum T4 and lesser
increase in serum T3
Dose: tablet from 25 - 300 mcg.
HO
I
I
COOH
NH2
O
T3
I
Has a rapid onset and short duration therefore
in
patients
recommended.
with
heart
disease
is
more
Synthetic isomer of T4.
Introduced in hypocholesteremic-hypolipidemic
therapy.
SAR
concentrated in:
1)
2)
3)
4)
5)
Alanine side chain
3- and 5-positions of the inner ring
The bridging atom
3’- and 5’-positions of the outer ring
The 4’-phenolic OH group
SAR
Lipophilic link between 2 rings are necessary
(O,S,C) so that 2 rings are perpendicular.
Non polar groups like halogen (I) and methyl in
position 3 & 5 of internal ring are necessary.
The order in halogens is: F<Cl<Br<I
The order for alkyl is: CH3< CH3CH2< iPropyl
α-amino acidic side chain or L-amino acids with 2 or
3 carbons in para positions of lipophilic link on
position 1 of internal ring increase activity.
A phenolic group in position 4` of external ring
increase activity.
Lipophilic group such as halogens (I) And alkyl or
aryl groups on outer ring increase activity, although
the 3’ position is more important, removal of 5’ even
increase the antithyroid activity.
Activity order:
II>I>IV>III
Compounds
Dose (mg/kg/day)
% T4 Activity
I
0.025
50
II
0.013
>100
III
2.3
<1
IV
0.5
2
•All isotopes of iodine are rapidly taken up in
thyroid follicles.
•131I and 125I so far have been used in
Thyrotoxicosis.
•131I has a half-life of 8 days.
•125I has a half- life of 60 days.
-Radioiodine therapy is alternative to surgery.
simple procedure,
applicable to all patients,
avoidance of surgical complications such as
Hypoparathyroidism.
may chromosomal damage in patients under 20
years.
In pregnancy
With radioiodine, whole body scan and serum
thyroglobulin measurement are commonly
used as the follow–up testing in thyroid cancer
patients.
Thyrotropin available (supply by pituitary)
Body must be free of T3 and T4,
Patients must stop taking all medication for
several weeks before the scan day.
This condition results in severe hypothyroidism,
to avoid this: FDA recommended using Thyrogen
(Thyrotropin alfa for injection)
Perchlorate & pertechnetate
Large anions taken up into the thyroid by iodide
pump.
ClO4- & TcO4- competitively inhibits the uptake of
iodide and have been used in diagnosis and
treatment of thyroid disease (for surgical
preparation and in the long term treatment of
Thyrotoxicosis)
Antithyroid drugs for the
treatment of Hyperthyroidism
Introduction
 use for more than half a century
 the treatment of choice for most young
people with Graves' disease
Mechanism of Action
 simple molecules :thionamides, contain a sulfhydryl
group and a thiourea moiety within a heterocyclic
structure
 Propylthiouracil and methimazole: United States
 Methimazole: Europe and Asia
 Carbimazole: United Kingdom
 actively concentrated by thyroid gland against a
concentration gradient.
 inhibit thyroid hormone synthesis by interfering with
thyroid peroxidase–mediated iodination of tyrosine
residues in thyroglobulin
Figure 2. Synthesis of Thyroxine and Triiodothyronine.
In Panel A, thyroid peroxidase (TPO), a heme-containing glycoprotein, is anchored within the thyroid follicular-cell
membrane at the luminal side of the thyroid follicle. In Panel B, the first step in thyroid hormone synthesis involves
generation of an oxidized enzyme promoted by endogenously produced hydrogen peroxide. In Panel C, the oxidized enzyme
reacts with trapped iodide to form an "iodinating intermediate" (TPO–Iox), the nature of which is not entirely understood.
Some investigators favor the formation of a heme-linked iodinium ion (TPO–I+), whereas others suggest the formation of
hypoiodite (TPO–O–I–).
. Panel D, in the absence of an antithyroid drug, the iodinating intermediate reacts with specific tyrosine residues in
thyroglobulin (Tg) to form monoiodotyrosine and diiodotyrosine. Subsequent intramolecular coupling of MIT and DIT forms
triiodothyronine, and the coupling of two DIT molecules forms thyroxine. In the presence of an antithyroid drug (e.g.,
methimazole, shown in Panel E), the drug serves as an alternative substrate for the iodinating intermediate, competing with
thyroglobulin-linked tyrosine residues and diverting oxidized iodide away from hormone synthesis. The drug intermediate
with a sulfur-linked iodide is a theoretical reaction product.6 In Panel F, the oxidized drug forms an unstable drug disulfide 7
that spontaneously degrades to an inactive desulfurated molecule, shown as methylimidazole. Antithyroid drugs also impair
the coupling reaction in vitro, but it is uncertain whether this occurs in vivo.
Iodide
Inhibit the release of thyroid hormone in
Hyperthyroidism,
lugol`s solution (strong iodine solution) or
saturated KI solution administered for 2 weeks.
Methimazole, propylthiouracil (PTU) and
related compounds
O
4
HN
2
S
6
N
H
R
Thiouracil: R=H
Methylthiouracil: R=CH3
Propylthiouracil(PTU): R=n-C3H7
N
2N
R
CH3
S
Methimazole(MMI),R=H)
Carbimazole(R=C2H5CO)
These are potent inhibitors of the thyroid
peroxidase enzymes(TPO),
TPO Responsible for iodination of tyrosine residue
of thyroglobulin,
Thioamide
R-CS-N
Also called thionamide or thiocarbamide
S
C N
R
Thioamide
N
N
S
HS
N
Thioketo
N
Thioenol(SH FORM)
Thioureylene tautomers
Mechanism of Action
 PTU block the conversion of T4 to T3 within the
thyroid and in peripheral tissues
 immunosuppressive effects:
1) antithyrotropin-receptor antibodies
2) intracellular adhesion molecule 1
3) soluble interleukin-2 and interleukin-6 receptors
decrease with time
 may induce apoptosis of intrathyroidal
lymphocytes, and decrease HLA (human
leukocyte antigen) class II expression
 circulating suppressor T cells
  helper T cells, natural killer cells and activated
intrathyroidal T cells
Figure 3. Effects of
Antithyroid Drugs.
inhibition of thyroid hormone
synthesis and a reduction in
both intrathyroidal immune
dysregulation and the
peripheral conversion of T4 to
T3.
Tyrosine-Tg denotes tyrosine
residues in thyroglobulin,
I+ the iodinating intermediate,
TPO thyroid peroxidase.
6-propylthiouracil shows maximal activity.
6-methylthiouracil has less than one- tenth
the activity of PTU.
PTU inhibit peripheral deiodination of T4 to
T3.
Methimazole has more thyroid peroxidase
Inhibitory activity and is longer acting than
PTU,but is not able to inhibit the peripheral
deiodination of T4 because of the presence
of the methyl group at N position.
Enolic hydroxyl at C4 in PTU and presence of
alkyl group at C5 and C6 enhance inhibitory
potency.
Carbimazole (prodrug) change to Methimazole.
Ca is a weak goitrogen cause hypothyroidism.
Li used for the treatment of thyrotoxicosis, inhibition of
hormone secretion,
Li concentrated by thyroid gland (thyroid to serum ratio is
2:1),
Li inhibits adenylyl cyclase which forms cAMP,
cAMP is formed in response to TSH and is a stimulator of
the process of hormone release, so Li is useful in
hyperthyroidism by inhibition of hormone secretion.
Most naturally occurring sulfur compounds
(glucosinolates) are present in foods such as
cabbage, turnip, mustard seed, salad greens &
radishes.
Thiocyanate (CNS-)
-
Isothiocyanate (SCN )
Nitriles (RCN)
Thiooxazolidones
thiocyanates competes with iodide for uptake by
the thyroid gland.
Goitrin is a potent thyroid peroxidase (TPO)
inhibitor
HN
S
O
Goitrin
H
sulfonamides (e.g diamox & carbutamide)
SO2
H2N
NHC4H9
HN
O
Acetazolamide
Carbutamide
anticoagulants (e.g warfarin & dicomarol)
O
O
CH3
OH
Warfarin
O
Oxygenated compounds (e.g resorcinol & phloretin)
HO
OH
OH
OH
O
Phloretin
 Iodinated aromatic compounds( e.g amiodarone,
Iopanoic Acid & Ipodoic acid)
I
CH3
CH3
N
O
I
C4H9
CH3
O
I
I
COOH
O
I
Amiodarone
NH2
lopanoic acid
Amiodarone, used in the treatment of cardiac
arrhythmias, is associated with thyroid
dysfunction. In usual doses, it may generate 6mg
iodine a day, much higher than the optimal iodine
intake recommended by WHO (0.3 mg/day).
increases T4 & rT3 and decrease T3 in
serum.
All interfere with peripheral deiodination of T4 and
used in the treatment of hyperthyroidism.
O
I
O
C4H9
HO
I
O
HO
I
COOH
NH2
I
Butyl 3,5-diiodo-4-hydroxybenzoate (BDHB)
DHDB
2`,6`-Diiodothyronine
only compounds like phenyl-x-phenyl
nucleus have thyroid hormonal activity; cis
and trans are not too important in activity.
*Most SAR discussed in the following
positions in T4:
(1) Alanine side chain
(2) 3-& 5- positions of the inner ring
(3) the bridging atom.
(4) 3`& 5` positions of the outer ring
(5) the 4` phenolic hydroxyl group.
L-Isomers of T4 & T3 are more active than the
D – isomers.
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