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Thyroid and Antithyroid
Drugs
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Chemistry
3
5
3
5
I
INH2
I
I
OHO
CH2CH C OH
O
3,5 Tetra iodothyromine (Thyroxine, T4)
INH2
I
I
OHO CH2CH C OH
O
3,5,3 Triodothyromine (T3)
All of these naturally occurring molecules are levo (L) isomers. The synthetic dextro
(D) isomer of thyroxine, has 4% of the biologic activity of the L-isomer as
evidenced by its lesser ability to suppress TSH secretion and correct
hypothyroidism.
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MOA
act thro nuclear receptors to affect metabolic processes
Large # of thyroid hormone receptors are found in the most
hormone-responsive tissues (pituitary, liver, kidney, heart,
skeletal muscle, lung, and intestine) while few receptor sites occur in hormone-unresponsive
tissues (spleen, testes).
The brain, which lacks an anabolic response to T3, contains
an intermediate number of receptors.
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Pharmacokinetics
Thyroxine is absorbed best in the duodenum and ileum
Absorption is modified by intraluminal factors such as food, drugs, and
intestinal flora.
Oral bioavailability of current preparations of L-thyroxine averages
80%. In contrast, T3is almost completely absorbed (95%).
T4and T3absorption appears not to be affected by mild
hypothyroidism but may be impaired in severe myxedema with ileus.
These factors are important in switching from oral to parenteral
therapy.
For parenteral use, the IV route is preferred for both
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Pharmacokinetics
In hyperthyroidism, the metabolic clearances of T4and
T3are increased and the t decreased (the reverse is
true in patients with hypothyroidism)
Drugs that induce hepatic microsomal enzymes (eg,rifampin, phenobarbital, carbamazepine, phenytoin,
imatinib, protease inhibitors) increase the metabolism of
both T4and T3
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Indication
1. Replacement therapy in Hypothyroidism/ Myxedema coma
Although T3is 3-4 times more potent than T4, it is not
recommended for routine replacement therapy because of
its shorter t (24 hrs)
2. Suppression therapy (TSH)
3. Drug induced hypothyroidism - levothyroxine therapy
NB: amiodarone (used in arrrthymias can cause both hyper
or hypothyroidism)may need to be discontinued (long t)
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ADRs
Caution:
Panhypopituitarism or pre disposition to adrenal insufficiency
(initiate corticosteroids B4 T4, CVS disorders (HT, MI), Diabetes
insipidus
C/I: thyrotoxicosis
S/E: most are due to overdose & include GIT ( diarrhea, Heat
Intolerance , Palpitation, Tremor, Sweating, insomnia
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Thioamides,
Anion Inhibitors,
Iodides,
Iodinated Contrast Media,
Radioactive Iodine,
Adrenoceptor-blocking Agents
ANTITHYROID AGENTS
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Chemistry
1. Thioamides: Carbimazole, Methimazole
and Propylthiouracil
The thiocarbamide
moiety is shown in color
carbimazole, is converted
to methimazole in vivo, is
widely used. Methimazole
is about ten times more
potent than
propylthiouracil.
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Pharmacokinetics
Propyl thiouracil is rapidly absorbed, reaching peak serum levels
after 1 hr. The bioavailability of 50-80% may be due to incomplete
absorption or a large 1stpass effect in the liver. Most of an
ingested dose of propylthiouracil is excreted by the kidney as the
inactive glucuronide within 24 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.
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Pharmacokinetics
Excretion is slower than with propylthiouracil; 65-70% of a dose
is recovered in the urine in 48 hours.
The short plasma t of these agents (1.5 hours for
propylthiouracil and 6 hours for methimazole) has little influence
on the duration of the antithyroid action or the dosing interval
since both agents are accumulated by the thyroid gland.
For propylthiouracil, giving the drug every 6-8 hours is
reasonable since a single 100 mg dose can inhibit iodine
organification by 60% for 7 hours.
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Pharmacokinetics
Since a single 30 mg dose of methimazole exerts an
antithyroid effect for longer than 24 hours, a single daily
dose is effective in the management of mild to moderate
hyperthyroidism.
Both thioamides cross the placental barrier and are
concentrated by the fetal thyroid, so that caution must be
employed when using these drugs in pregnancy.
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Pharmacokinetics
Because of the risk of fetal hypothyroidism, both thioamides have
evidence of human fetal risk based on adverse reaction data from
investigational or marketing experience).
Of the 2, propylthiouracil is preferable in pregnancy because it is
more strongly protein-bound and, therefore, crosses the placenta less
readily. In addition, methimazole has been, albeit rarely, associated
with congenital malformations.
Both thioamides are secreted in low concentrations in breast milk but
are considered safe for the nursing infant.
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MOA
Inhibits thyroid peroxidase-catalyzed reactions & blocking
iodine organification
block coupling of the iodotyrosines
Propylthiouracil and (to a much lesser extent) methimazoleinhibit the peripheral deiodination of T4and 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 T4are depleted.
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ADRs
Gastrointestinal; distress & Nausea.
Altered sense of taste or smell may occur with methimazole
Maculopapular pruritic rash (4-6%), at times accompanied by systemic signs
such as fever.
Rare adverse effects include an urticarial rash, vasculitis, a lupus-like reaction,
lymphadenopathy, hypoprothrombinemia, exfoliative
Hepatitis (more common with propylthiouracil) & cholestatic jaundice (more
common with methimazole) can be fatal; although asymptomatic elevations in
transaminase levels also occur.
most dangerous complication is agranulocytosis (granulocyte count < 500
cells/mm3), an infrequent but potentially fatal adverse reaction
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Anion Inhibitors
Monovalent anions such as perchlorate (clo4-), pertechnetate
(tco4-
), and thiocyanate (SCN-
) Formulation: as a potassium e.g., Potassium perchlorate
MOA:
Block thyroidal reuptake of I-ion through competitive inhibition
of the iodide transport mechanism,
Indication:
Iodide-induced hyperthyroidism (eg, amiodarone-induced
hyperthyroidism).
BUT rarely used clinically because it is associated with aplastic
anemia
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Iodides
E.g., Potassium iodide
Were used prior to the introduction of the thioamides in
the 1940s, today they are rarely used as sole therapy
MOA
Inhibit organification & hormone release
Decrease the size and vascularity of the hyperplastic
gland.
In susceptible individuals, iodides can induce
hyperthyroidism (jodbasedow phenomenon)or precipitate
hypothyroidism.
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Iodides (MOA)
In pharmacologic doses (> 6 mg/d), the major action of
iodides is to inhibit hormone release, possibly through
inhibition of thyroglobulin proteolysis. Improvement in
thyrotoxic symptoms occurs rapidly-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 preoperative preparation for surgery.
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Clinical Use of Iodide
Drawback to its use
It delay onset of thioamide therapy or prevent use of radioactiveiodine therapy for several weeks ( due to intragradular iodine
storage)
Only effective for 2-8 weeks
Withdrawal may produce severe exacerbation of thyrotoxicosis in
an iodine-enriched gland
C/I in pregnancy: cross the placenta and can cause fetal goiter.
Note: in radiation emergencies, the thyroid-blocking effects of canprotect the gland from subsequent damage if administered before
radiation exposure.
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ADRs
ADR to iodine (iodism) are uncommon and in most
cases reversible upon discontinuance.
Include acneiform rash (similar to that of bromism),
swollen salivary glands, mucous membrane
ulcerations, conjunctivitis, rhinorrhea, drug fever,
metallic taste, bleeding disorders
Rarely, anaphylactoid reactions.
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Iodinated Contrast Media
Include diatrizoate orally (Diatrizoate sodium(Hypaque))&
iohexol orally or intravenously Omnipaque )
MOA
1. Inhibition of hormone release
2. Rapidly inhibit the conversion of T4to T3in the liver, kidney,
pituitary gland, and brain
Account for dramatic improvement of both subjective &
objective parameters e.g.,
decrease in HR after only 3 days of admin of 0.5-1 g/d of oral
contrast media & T3 normalizes
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Iodinated Contrast Media
Clinical use
Are non labeled Rx of hyperthyroidism
Useful adjunctive therapy in the treatment of thyroid storm
Offer valuable alternatives when iodides or thioamides arecontraindicated
No interaction with Iodine 131 isotope (131 I), i.e., no
interference with its retention
Relatively nontoxic
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Radioactive Iodine
Iodine 131 isotope (131 I) used for treatment of thyrotoxicosis
(others for diagnosis).
Pharmacokinetics
Admin orally in solution as sodium 131I
Rapidly absorbed, concentrated by the thyroid, and incorporated
into storage follicles
MOA
Emission of rays destroys thyroid parenchyma evidenced by
epithelial swelling and necrosis, follicular disruption, edema,
and leukocyte infiltration
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Radioactive Iodine
C/I: Pregnant women or nursing mothers, since it crosses
the placenta to destroy the fetal thyroid gland and is
excreted in breast milk.
ADRs:
No radiation-induced genetic damage, leukemia, and
neoplasia have been reported after more than 50 years of
clinical experience with radioiodine
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Adrenoceptor-Blocking Agents
blockers without intrinsic sympathomimetic activity (eg,
metoprolol, propranolol, atenolol)
Effective therapeutic adjuncts in the management of
thyrotoxicosis since many of these symptoms mimic those
associated with sympathetic stimulation.
Propranolol has been the blocker most widely studied and
used in the therapy of thyrotoxicosis.
NOTE: blockers cause clinical improvement of hyperthyroid
symptoms but do not alter thyroid hormone levels.
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