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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)
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 2
Therapeutic Overview HYPOTHYROIDISM
Administer exogenous thyroxine (T4) or triidothyronine (T3)
HYPERTHYROIDISM Surgery Radioactive iodine Drugs: thioureylenes, beta adrenergic receptor
blockers, corticosteroids, iodides
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 3
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 4
Two Thyroid Hormones
Hormones triiodothyronine tetraiodothyronine
Alias T3 T4 or thyroxine
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 5
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 6
Two Thyroid Hormones
Hormones triiodothyronine tetraiodothyronine
Alias T3 T4 or thyroxine
Molecular composition
one MIT plus one DIT
one DIT plus one DIT
Iodine content (%)
59 65
MIT= monoiodotyrosine DIT= diiodotyrosine
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 7
Two Thyroid Hormones
Hormones triiodothyronine tetraiodothyronine
Alias T3 T4 or thyroxine
Molecular composition
one MIT plus one DIT
one DIT plus one DIT
Iodine content (%)
59 65
Thyroglobulin ratio
1 5
MIT= monoiodotyrosine DIT= diiodotyrosine
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 8
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 9
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 10
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 12
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 13
Peripheral Metabolism of Thyroxine
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 14
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 15
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 16
STEPS IN THYROID HORMONOGENESIS
Iodidetransport
I
Peroxidase(organification)
I
MIT
DIT
Thyroglobulinproduction
Coupling Dehalogenase
T3
and
T4
T3 & T4
release
RECYCLED IODINE
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 17
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 18
Summary of Thyroid Hormone Kinetics
Thyroid Hormones T3 T4 Daily production (mg) 25 75
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 19
Summary of Thyroid Hormone Kinetics
Thyroid Hormones T3 T4 Daily production (mg) 25 75
Daily Metabolic clearance (L) 24 1.1
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 20
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 21
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 22
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 23
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
Reproduced with permission from McGraw-Hill Companies, Inc. “Basic & Clinical Pharmacology” 9th ed. by Katzung, Copyright © 2004, Figure 38-3, p. 629.
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
Reproduced with permission from McGraw-Hill Companies, Inc. “Basic & Clinical Pharmacology” 9th ed. by Katzung, Copyright © 2004, Figure 38-3, p. 629.
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 27
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 29
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 30
Thyroid hormone effects
Generally responsible for optimal growth, development, function, and energy levels in all tissues Excess hyperthyroidism
(thyrotoxicosis) Inadequacy hypothyroidism
(myxedema)
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 31
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 32
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 33
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)
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 34
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 35
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 36
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 37
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 38
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 39
Hyperthyroidism
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 40
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 41
Antithyroid Drugs
[1] Thioamides: methimazole propylthiouracil
[2] Iodides: potassium iodide solution [3] Radioactive Iodine (RAI)[4] Other Drugs:
anion inhibitors -adrenergic blockers
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 42
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 43
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
44
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 45
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 46
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 47
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 48
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 49
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 50
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 51
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
Other anti-thyroid Drugs (Adjunct)
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 52
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
Other anti-thyroid Drugs (Adjunct)
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 53
IODIDETRANSPORT
HORMONESYNTHESIS
HORMONESECRETION
I- TPOI-H2O2
Io
T4
T3
DITMIT
Tg
T4, T3
DIT, MIT
Tyr I-
Tg
T4 T3
Tyr I-
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 54
STEPS IN THYROID HORMONOGENESIS
Iodidetransport
I
Peroxidase(organification)
PTU, MMZ
I
MIT
DIT
Thyroglobulinproduction
Coupling
PTU, MMZ
Release
T3
and
T4
T3 & T4
release
RECYCLED IODINE
Iodides Iodides, Li
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 55
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:
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 56
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 57
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
04/21/23 C.A. JIMENO, M.D. UPCM PHARMACOLOGY 59
THANK VERY
MUCH!