Lesson 6 Thyroid and Antithyroid Drugs

8/13/2019 Lesson 6 Thyroid and Antithyroid Drugs

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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.

Lesson 6 Thyroid and Antithyroid Drugs

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