12/8/2015C.A. JIMENO, M.D. UPCM PHARMACOLOGY1 THYROID HORMONES and ANTI-THYROID DRUGS CECILE A....

04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 1

THYROID HORMONES and ANTI-THYROID DRUGS

CECILE A. JIMENO, M.DSlides adapted from the presentation of visiting

Professor DR. RUBEN BUNAG, University of Kansas

(Katzung Chapter 38 pp. 625-639)

Therapeutic Overview HYPOTHYROIDISM

Administer exogenous thyroxine (T4) or triidothyronine (T3)

HYPERTHYROIDISM Surgery Radioactive iodine Drugs: thioureylenes, beta adrenergic receptor

blockers, corticosteroids, iodides

THYROID PHYSIOLOGY

Thyroid gland maintains metabolic homeostasis by regulating: growth and development, body temperature, and energy levels

Multiple functions are accomplished through two hormones:

[1] triiodothyronine or T3, and [2] tetraiodothyronine or T4

Two Thyroid Hormones

Hormones triiodothyronine tetraiodothyronine

Alias T3 T4 or thyroxine

Molecular composition

one MIT plus one DIT

one DIT plus one DIT

MIT= monoiodotyrosine DIT= diiodotyrosine

Iodine content (%)

Thyroglobulin ratio

THYROID HORMONE SYNTHESIS SIX MAJOR STEPS:

1. Active Transport of Iodine - across the basement membrane into the thyroid cell (iodide trapping) 2. Oxidation - of iodide & iodination of tyrosyl residues in thyroglobulin

3. Coupling - of iodotyrosine molecules within thyroglobulin to form T3 & T4

3. Iodination of tyrosine & coupling

Tyrosine + I -------> MIT

Tyrosine + I2 -------> 3, 5 DIT

MIT + DIT -------> 3, 5, 3’ TIT (T3) or

3, 3’, 5’ TIT (rT3)

DIT + DIT -------> 3, 5, 3’, 5’

Tetraiodothyronine (T4)

THYROID HORMONE SYNTHESIS

4. Proteolysis of thyroglobulin - release of free iodothyronines & iodotyrosines from colloid droplets (pinocytosis)

T3, T4Lysosomes (hydrolyzed)

(proteases, peptidases)

MIT, DIT dehalogenation recycling

5. Deiodination of iodotyrosines within the thyroid cells & recycling of iodine

6. Intrathyroidal 5’-deiodination of T4 to T3

Circ‘n

THYROID HORMONE SYNTHESIS

04/21/23 11

iodide (I-) absorbed in the GIT enters an extracellular pool from which the thyroid gland removes 75 mg daily

I- is taken up by thyroid follicular cells via a membrane Na+/I- transporter

I- is coupled to tyrosine residues on the thyroglobulin molecule (organification)

formation of monoiodo- (MIT) and diiodo-tyrosine (DIT)

Thyroid Hormone Biosynthesis

thyroid peroxidase catalyzes coupling of two molecules of DIT to form T4, and one molecule each of MIT and DIT to form T3 --------------

thyroglobulin stored as colloid in the lumen -----

TSH signals secretion to hydrolyze thyroglobulin to free MIT, DIT, T3 & T4 -------

MIT and DIT are deiodinated for recycling while T3 & T4 are released by exocytosis

Peripheral Metabolism of Thyroxine

Pharmacokinetics of Thyroid Hormone

T3 & T4 are mostly bound to thyroxin binding globulin (TBG)

Amounts of free or unbound hormones are minimal: 0.03% T4 and 0.3% T3

Only the unbound hormones have metabolic activity

in peripheral tissues T4 is converted to T3 by iodothyronine 5’-deiodinase found mainly in liver, thyroid, and kidneys

the active hormone in most target tissues is T3

Thyroid hormone released mostly as T4 because T4 to T3 ratio in thyroglobulin is 5:1

peripheral metabolism of T4 is mainly by deiodination to form:

[1] T3 which is 3-4 times more potent than T4, or

[2] reverse T3 which is metabolically inactive total serum levels for T4 are higher because

more of it is released and metabolic clearance of T3 is faster

Kinetics: Peripheral Metabolism of Thyroxine

STEPS IN THYROID HORMONOGENESIS

Iodidetransport

Peroxidase(organification)

Thyroglobulinproduction

Coupling Dehalogenase

T3 & T4

release

RECYCLED IODINE

Effects of Drugs on Thyroid Hormone Production

METABOLIC STEP

A. Iodide Transport

B. Iodide OxidationC. Organification &

coupling

D. Colloid Resorption & proteolysis (Release)

INHIBITORS

A. Large amts of I-, Cl04-,

SCN-, TcO4-

B & C. Thionamide Drugs (PTU, MMI)

D. Iodine, lithium

Summary of Thyroid Hormone Kinetics

Thyroid Hormones T3 T4 Daily production (mg) 25 75

Daily Metabolic clearance (L) 24 1.1

Total Serum levels (nmol/L) 1.5-2.9 64-132

Biologic potency 3-4 1

Oral absorption (%) 95 80

Half Life (days) 1 7

04/21/23 24

Hypothalamic-Pituitary Regulation[1] paraventricular nuclei in the hypothalamus secrete TRH

[2] TRH stimulates the anterior pituitary to release TSH

[3] TSH acts on the thyroid to release T3 & T4

[4] T3 & T4 act by negative feedback to inhibit formation of TRH and TSH

mechanisms for thyroid regulation

C.A. JIMENO, M.D. UPCM PHARMACOLOGY

04/21/23 25

Autoregulation within the thyroid modifies thyroid hormone synthesis through blood iodine levels:

high iodine levels

inhibit iodide organification

reduced T3 & T4 synthesis hypothyroidism

mechanisms for thyroid regulation

C.A. JIMENO, M.D. UPCM PHARMACOLOGY

04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY26

PB = plasma binding protein F = transcription factor R = receptor PP=proximal promoter proteins

T3 receptors belong to a superfamily of nuclear receptors (c-erb includes receptors for steroid hormones and vitamins A and D) many T3 receptors are found in responsive tissues like pituitary, liver, kidney, heart, skeletal muscle, lung, and intestine

Thyroid Hormone Mechanism of Action

PB = plasma binding protein F = transcription factor R = receptor PP=proximal promoter proteins

T3 & T4 are dissociated from thyroid-binding proteins nter target cells by diffusion or transport in the cytoplasm 5’-deiodinase converts T4 to T3 T3 enters the nucleus to bind to T3 receptors more RNA formed increase protein synthesis

04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY28

T3 Mechanism of Action

T3 acts on Intracellular thyroid hormone receptors (TRs) located in all cells of the body

TR monomers interact with retinoic acid X receptor (RXR) to form heterodimers

in the absence of T3 the TR:RXR heterodimer associates with a co-repressor complex that binds to DNA to inhibit gene expression

T3 Mechanism of Action

in the presence of T3, the co-repressor complex dissociates, coactivators form to stimulate gene expression

binding to TR dimers thus serves as a molecular switch from inhibition to activation of gene expression

Thyroid hormone effects

Generally responsible for optimal growth, development, function, and energy levels in all tissues Excess hyperthyroidism

(thyrotoxicosis) Inadequacy hypothyroidism

(myxedema)

Thyroid Hormone Effects

1. Nervous, musculoskeletal, and reproductive tissues: nervousness, emotional lability, muscle weakness and fatigue, osteoporosis, menstrual irregularities

2. Calorigenic effect: increased oxygen consumption, sweating

3. Sympathetic hyperactivity due to increased -adrenergic sensitivity dramatic cardiovascular effects including: tachycardia, increased stroke volume and cardiac output, high-output heart failure, arrhythmia, angina

4. Metabolic effects: decreased cholesterol and triglycerides; increased basal metabolic rate, hyperglycemia, and appetite

Thyroid Hormone Effects

Thyroid Preparations Major clinical use of T3 & T4 is for hormone

replacement therapy in hypothyroidism Involves replacement of thyroid hormone adequate

to meet the patient’s needs Dose for replacement: 1.6-1.7 mcg/kg SLOW replacement for the elderly, CAD, arrhythmia Indications?

Post-procedural hypothyroidism Endemic goiter Congenital hypothyroidism: cretinism Any cause of hypothyroidism i.e. thyroiditis Suppression of growth of nodules, thyroid CA (dose is

higher: 2.2-3.0 mcg/kg)

Thyroid Preparations

1. Synthetic levothyroxine [T4]: the preparation of choice for replacement & suppression therapy because of its stability, uniform content, low cost, long half-life (7 days), and conversion to produce both T3 & T4

2. Desiccated thyroid, though inexpensive, is not recommended for replacement therapy because of its antigenicity, instability, and variable hormone content

3. Liothyronine, [T3] 3-4 times more active than levothyroxine Not recommended for routine replacement

therapy because of its higher cost, shorter half-life (24 hours), and greater potential for cardiotoxicity

4. Liotrix, a 4:1 combination of synthetic T4 and T3, also expensive with the same disadvantages as liothyronine

Thyroid Preparations

Thyrotoxicosis (vs hyperthyroidism)

Is the consequence of excessive thyroid hormone action due to

Causes:

1. Diffuse toxic goiter (Graves’ disease)

2. Toxic adenoma

3. Toxic multinodular goiter (Plummer’s)

4. Painful subacute thyroiditis

5. Silent thyroiditis e.g. lymphocytic &

postpartum variations

6. Iodine-induced hyperthyroidism

7. Excessive pituitary TSH or trophoblastic

disease

8. Excessive ingestion of thyroid hormones

Clinical Features

Signs & symptoms are due to the effects of excess thyroid hormone in the circulation

Severity of signs & symptoms may be related to the duration of the illness, magnitude of hormone excess & the age of the patient

Signs & Sx of Hyperthyroidism

SYMPTOMS Weakness & Fatigue Heat intolerance Nervousness Increased sweating Tremor Palpitations Increased appetite Weight loss Hyperdefecation Dyspnea Menstrual a(N)

SIGNS Goiter/thyroid bruit Hyperkinesis Ophthalmopathy Lid retractions/stare Lid lag Tremor Warm, moist skin Muscle weakness Hyperreflexia Tachycardia/arrhythmia Widened pulse pressure

Hyperthyroidism

Antithyroid Drugs

[1] Thioamides: methimazole propylthiouracil

[2] Iodides: potassium iodide solution [3] Radioactive Iodine (RAI)[4] Other Drugs:

anion inhibitors -adrenergic blockers

Anti-thyroid Drugs THIOUREYLENE or THIONAMIDES

Propylthiouracil, Methimazole/Thiamazole, Carbimazole (pro-drug of methimazole)

MOA: inhibit the thyroid peroxidase-mediated iodination & coupling steps

These drugs are preferentially iodinated, depriving thyroglobulin of iodide and shutting down the synthesis of thyroid hormones

Accumulate readily in the thyroid gland for treatment of thyrotoxicosis

Thioanamide/Thioureylene Drugs

Methimazole is 10x more active than PTU Plasma half-lives: 6 hr for MMI & 1.5 hr for PTU Additional MOA: PTU but not methimazole, affects

the processing of T4 to T3 in the peripheral tissues (inhibition of deiodinase enzyme)

Since T3 is 10x as active as T4 this conversion step is important

04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY

Thioamides: methimazole & propylthiouracil slow onset of action requiring 3-4 weeks to deplete T4 stores multiple mechanisms of action including:

major action to prevent hormone synthesis by inhibiting peroxidase reactions to block iodine organification

block iodotyrosine coupling inhibit peripheral deiodination of T3 & T4

adverse reactions occur in 3-12% of treated patients: most common: maculopapular pruritic rash rarely: urticarial rash, vasculitis, arthralgia, lupus-

like reaction, jaundice, hepatitis hypothrombinemia most dangerous – agranulocytosis

Side Effects of Thioureylenes

Rash, urticaria – in as much as 20% of users; usually transient even w/o treatment

Auto-immune (lupus-like) nephritis, PAN Granulocytopenia,a granulocytosis: RARE

but potentially fatal Watch out for sore throat, fever, diarrhea

Other anti-thyroid Drugs (Adjunct)

Monocovalent anions: block thyroid hormone synthesis by competitively inhibiting the active transport of iodide into the thyroid gland Pertechnetate, Perchlorate: little clinical use High dose iodides: potassium iodide, SSKI,

Lugol’s solution, intravenous contrast agents Watch out for angioedema with iodides

Anion Inhibitors & -adrenergic

Blockers Monovalent ions as perchlorate (ClO4-),

pertechnetate (TcO4-), and thiocyanate (SCN-) block iodide uptake through competitive inhibition of the iodide transport mechanism, but their effectiveness is unpredictable

Potassium perchlorate is no longer used clinically because it causes aplastic anemia

Iodinated contrast media (ipodate and iopanoic acid by mouth, or diatrizoate IV) though not FDA approved, act by inhibiting conversion of T4 to T3 in liver, kidney, pituitary, and brain

Since many symptoms of thyrotoxicosis result from sympathetic hyperactivity, guanethidine or -adrenergic blockers have also been used for treatment

Anion Inhibitors & B-adrenergic Blockers

Iodides: potassium iodide solution

Many thyroid actions including: inhibition of hormone release by reducing

thyroglobulin proteolysis decrease in size and vascularity of the

hyperplastic gland Thyrotoxic symptoms improve within 2-7 days,

but should not be used alone because the gland “escapes’ from iodide block after 2-8 weeks and withdrawal may result in severe thyrotoxicosis

Avoid chronic use in pregnancy as iodides cross the placenta and can cause fetal goiter

Iodides: potassium iodide solution

Advantages: simplicity, inexpensive, relatively nontoxic, and absence of glandular destruction

ADVERSE reactions (uncommon): acneiform rash, swollen salivary glands, mucous membrane ulceration, conjunctivitis, rhinorrhea, metallic taste, drug fever, bleeding disorders, anaphylaxis

DISADVANTAGES: “escape”, aggravation of thyrotoxicosis, allergic reactions, & increased intraglandular iodine which can delay onset of thioamide therapy or prevent use of radioactive iodine therapy for several weeks

Beta-adrenergic receptor blocking drugs Act peripherally rather than at the thyroid gland MOA: uncertain but may relate to inhibition of

deiodination= peripheral conversion of T4 to T3 Also blocks the sympathetic (adrenergic) effects of

hyperthyroidism esp. on the heart Avoid in patient with ASTHMA

Corticosteroids Inhibit peripheral conversion of T4 to T3 Immunosuppression of thyroid-stimulating

antibodies Antipyretic May be used for treatment of adrenal insufficiency

in pts with thyroid storm

IODIDETRANSPORT

HORMONESYNTHESIS

HORMONESECRETION

I- TPOI-H2O2

DITMIT

T4, T3

DIT, MIT

Tyr I-

STEPS IN THYROID HORMONOGENESIS

Iodidetransport

Peroxidase(organification)

PTU, MMZ

Thyroglobulinproduction

Coupling

PTU, MMZ

Release

T3 & T4

release

RECYCLED IODINE

Iodides Iodides, Li

Radioactive Iodine Therapy

Used for definitive therapy or ablation The only isotopes used for treatment of thyrotoxicosis Uses the ff radioisotopes: I123 or I131

Side- effects are minimal: avoid in children (may inhibit bone growth) and pregnant women or those intending pregnancy

Contraceptives are encouraged among those who are sexually active:

Radioactive Iodine (RAI) Given as oral solution or capsulized, 131I is

rapidly absorbed and concentrated in the thyroid gland

Thyroid parenchymal destruction becomes evident within weeks in the form of epithelial swelling, necrosis, follicular disruption, edema, and leukocyte infiltration

Therapeutic effect depends on emission of beta rays with:

(a) penetration range of 400-2000 mm and

(b) effective half-life of 5 days

Advantages: easy administration, effectiveness, low expense, & absence of pain

Major disadvantage is induction of hypothyroidism

Main contraindication is pregnancy as RAI crosses the placenta and is excreted in breast milk

Radioactive Iodine (RAI)

04/21/23 58

Drugs Affecting T3-T4 Synthesis

Anions (perchlorate, pertechnetate, & thiocyanate)

compete with I- uptake

RAI causes selective thyroid destruction

Iodide (high levels) reduce T3-T4 release by inhibiting thyroglobulin proteolysis

Thioamides inhibit peroxidase to block organificationC.A. JIMENO, M.D. UPCM PHARMACOLOGY

THANK VERY

12/8/2015C.A. JIMENO, M.D. UPCM PHARMACOLOGY1 THYROID HORMONES and ANTI-THYROID DRUGS CECILE A....

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