Thyroid and Antithyroid Drugs

Chemistry
I
H O

3
5

I
O

3
5 CH2 CH C OH NH2 O

3,5 Tetra iodothyromine (Thyroxine, T4)

I
HO O CH2 CH C OH

NH2

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.

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.

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, T3 is almost completely absorbed (95%). T4 and T3 absorption 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

Pharmacokinetics
In hyperthyroidism, the metabolic clearances of T4 and T3 are 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 T4 and T3

Indication
1. Replacement therapy in Hypothyroidism/ Myxedema coma Although T3 is 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)

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

ANTITHYROID AGENTS
Thioamides, Anion Inhibitors, Iodides, Iodinated Contrast Media, Radioactive Iodine, Adrenoceptor-blocking Agents

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.

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 1st pass 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.

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.

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.

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.

MOA
Inhibits thyroid peroxidase-catalyzed reactions & blocking iodine organification block coupling of the iodotyrosines Propylthiouracil and (to a much lesser extent) methimazole inhibit the peripheral deiodination of T4 and 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 T4 are depleted.

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

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

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.

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.

Clinical Use of Iodide

Drawback to its use It delay onset of thioamide therapy or prevent use of radioactive iodine 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 can protect the gland from subsequent damage if administered before radiation exposure.

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.

Iodinated Contrast Media

Include diatrizoate orally (Diatrizoate sodium (Hypaque)) & iohexol orally or intravenously Omnipaque )

MOA
1. 2. Inhibition of hormone release Rapidly inhibit the conversion of T4 to T3 in 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

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 are

contraindicated
No interaction with Iodine 131 isotope (131 I), i.e., no interference with its retention

Relatively nontoxic

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

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

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.