Thyroid Drugs for IDM1 2024-Lymperopoulos.pdf

3/22/2024 Drugs used in Thyroid Disorders Dr. A. Lymperopoulos Department of Pharmaceutical Sciences NSU COP, Main Campus (Davie) 1 1 3/22/2024 Thyroid Physiology  The thyroid gland secretes three main hormones: thyroxine (T4), tri-iodothyronine (T3), and calcitonin (involved in the control of plas...

3/22/2024 Drugs used in Thyroid Disorders Dr. A. Lymperopoulos Department of Pharmaceutical Sciences NSU COP, Main Campus (Davie) 1 1 3/22/2024 Thyroid Physiology  The thyroid gland secretes three main hormones: thyroxine (T4), tri-iodothyronine (T3), and calcitonin (involved in the control of plasma [Ca2+], used to treat osteoporosis and other metabolic bone diseases).  Both T3 and T4 circulate in the blood tightly bound (>99%) to plasma proteins, mainly thyroxine-binding globulin (TBG).  The majority (~85%) of the secreted thyroid hormones is T4. Circulating T4 is converted to T3 (3-5-fold more active than T4) in a tissue-specific manner.  Both hormones are critically important for normal growth and development and for controlling energy metabolism. 2 2 3/22/2024 (T4) (T3) (reverse T3, rT3) (DIT) (MIT) 3 3 3/22/2024 Thyroid Physiology  The functional unit of the thyroid gland is the follicle or acinus. Each follicle consists of a single layer of epithelial cells surrounding a cavity, the follicle lumen, filled with a thick colloid rich in thyroglobulin (TG).  TG is a large glycoprotein, with each TG molecule containing ~115 Tyr residues. It is synthesized and glycosylated inside the follicle cell, then secreted into the follicle lumen, wherein Tyr residue iodination occurs.  The main steps in the thyroid hormone synthesis, storage and secretion are: a) Uptake of plasma I- by the follicle cell; b) Oxidation of I- (to I. radical) and iodination of TG`s Tyr residues; c) Secretion of thyroid hormones (mainly T4) 4 4 3/22/2024 Thyroid Physiology I- uptake is very rapid (i.v. injected 125I is found in the follicle lumen within seconds) and occurs against a concentration gradient (normally ~25:1): energy-dependent process carried out by a Na+/I− symporter (NIS), located in the basolateral membrane of the follicle cell (secondary active transport using the energy provided by Na+/K+ATPase), and pendrin (PDS), a I−/Cl− antiporter (exchanger) in the apical membrane of the follicle. I- oxidation and its incorporation into the TG-incorporated Tyr residues (I- organification) is catalyzed by thyroperoxidase (TPO), an enzyme that uses hydrogen peroxide (H2O2) as the oxidizing agent. 5 5 3/22/2024 Thyroid Physiology The iodinated Tyr residues of TG serves as a large store of thyroid hormones within the gland, with a relatively slow turnover. This is in contrast to other hormones released (e.g., adrenocortical steroids, catecholamines from adrenal medulla), which are NOT stored but synthesized and released on demand.  TG is taken up into the follicle cell by endocytosis, followed by lysosomal proteolysis which releases T4 and T3 to be secreted into blood. Surplus MIT and DIT, released together with T4 and T3, are scavenged and their I- removed enzymatically (via deiodinases, Dio`s) and reused. Plasma total [T4] is ~50 times higher than plasma total [T3]. The half-life of T3 is a few hours, whereas that of T4 between 3-4 days in hyperthyroidism and 9-10 days in hypothyroidism. 6 6 3/22/2024 Thyroid Physiology 7 7 3/22/2024 8 8 3/22/2024 9 9 3/22/2024 10 10 3/22/2024 I - I I I - I 11 11 3/22/2024 Thyroid Physiology TBG is the major carrier of thyroid hormones. A glycoprotein of ~63 kDa, it binds T4 tightly at 1:1 stoichiometry. T3 is bound less avidly. Other plasma proteins (transthyretin, albumin) also bind T4.  Plasma-protein bound hormone is protected from metabolism/excretion, so its half-life is increased. Free (unbound) hormone is a very small percentage (~0.02% of total T4 and ~0.3% of total T3) of total hormone in plasma. The much higher affinity of T4 for TBG than T3 is the reason for the much higher total circulating concentration and longer half-life vs. T3.  Because only free (unbound) hormone has metabolic activity, changes in plasma protein levels or in their affinities for thyroid hormones result in changes in free T4 (or T3) levels causing hyper- or hypothyroidism. Indeed, certain drugs (e.g., estrogens) and states (e.g., pregnancy) increase plasma protein binding of T4 causing hypothyroidism, whereas other drugs (e.g., antiepileptics) decrease it and cause hyperthyroidism. 12 12 3/22/2024 Thyroid Physiology  Although both T4 and T3 are secreted by the thyroid, metabolism of T4 by 5′-deiodination of the outer ring in peripheral tissues accounts for ~80% of circulating T3. 5′-deiodination of the inner ring produces the metabolically inactive 3,3′,5′-triiodothyronine (reverse T3 [rT3]. Normally ~40% of T4 is converted to each of T3 and rT3, and the rest ~20% is metabolized via other pathways, such as glucuronidation in the liver and excretion in the bile. T3 has a much higher affinity for the nuclear thyroid hormone receptor (TR) than T4 and is much more potent biologically on a molar basis. Thus, T4 is considered a precursor and T3 the active form of thyroid hormones.  There are three iodothyronine deiodinases, produced by the genes DIO1, DIO2, and DIO3: Dio1 & Dio2 convert T4 to T3. Dio1 is a plasma membrane protein expressed primarily in the liver, kidney, thyroid, and pituitary. It is upregulated in hyperthyroidism, downregulated in hypothyroidism, and inhibited by propylthiouracil. 13 13 3/22/2024 Thyroid Physiology  Dio2 is primarily in the CNS, brown adipose tissue, thyroid, and at low levels in skeletal muscle and heart. Dio2 is in the ER, facilitating access of Dio2-generated T3 to the nuclear TR, and unaffected by propylthiouracil. Its expression is affected by T4 and T3. Dio2 also displays polymorphisms that affect its activity, thus affecting T3 production & thyroid hormone responses.  Dio1 is estimated to account for ~1/3 and Dio2 for ~2/3 of the circulating T3 in euthyroid individuals.  Dio3 catalyzes inner ring or 5-deiodination, the main metabolic inactivation pathway of T3. Dio3 is found at highest levels in the CNS and placenta and can be induced locally by inflammation and hypoxia (also highly expressed in certain tumors).  Both Dio2 and Dio3 are expressed in time- and spatially restricted patterns during development, in which they play important roles by regulating local levels of T3. 14 14 3/22/2024 I I I I I I I 15 15 3/22/2024 16 16 3/22/2024 17 17 3/22/2024 18 18 3/22/2024 Thyroid Physiology  TSH (thyroid-stimulating hormone or thyrotropin): TSH increases synthesis and secretion of thyroid hormones through its specific plasma membrane receptor (TSHR, a GPCR) in thyroid follicle cells. TSHR couples to the Gs protein-adenylyl cyclase–cyclic AMP pathway, although higher TSH concentrations activate the Gq protein-phospholipase C-calcium signaling pathway. Inactivating and activating mutations of the TSHR have been described and result in thyroid dysfunction.  Iodine intake and thyroid function: Adequate iodine intake is essential for normal thyroid function. When low, hormone production is reduced, TSH goes up, and the thyroid becomes hypertrophic to markedly increase its efficiency at extracting the residual traces of iodide from the blood (gland-to-blood iodine gradient can increase up to ~10 times the normal). In mild-to-moderate deficiency, production is usually sufficient, almost like normal. In severe iodine deficiency, hypothyroidism or congenital iodine deficiency syndrome may occur. 19 19 3/22/2024 Thyroid Physiology  Iodine intake and thyroid function: High iodine levels inhibit thyroid function. The addition of iodate to table salt (NaCl) provides convenient iodine supplementation. Vegetables, meat, and poultry contain minimal amounts, whereas dairy products and fish are relatively high in iodine.  Thyroid hormone receptors (TRs): Three TRs in humans: TRα1, TRβ1, and TRβ2. All are nuclear receptors, i.e., ligand (T3)-stimulated transcription factors. TRα1 is in most tissues and regulates heart rate, body temperature, skeletal muscle function, and bone development. Patients with TRα1 gene mutations have short stature, bone abnormalities, and chronic constipation. TRβ1 is ubiquitous and mediates specific effects in liver metabolism (including the hypocholesterolemic effect of T3). TRβ2 is restricted in only certain tissues, such as pituitary and hypothalamus, where it mediates the negative feedback by T3 on hypothalamic TRH and pituitary TSH. 20 20 3/22/2024 Thyroid Physiology  Thyroid hormone receptors (TRs): TRs have also non-genomic actions, since they can be located outside the nucleus. These are far more rapid than their genomic actions. TRα1 can get palmitoylated and localize to the plasma membrane, and, from there, it causes rapid T3-dependent nitric oxide production. The rapid vasodilation observed upon T3 administration might be due to this non-genomic effect of TRα1 (NO is a major endogenous vasodilator). 21 21 3/22/2024 22 22 3/22/2024 Thyroid Physiology  Major clinical effects of thyroid hormones: 1) Growth and Development (both physical and mental): Central in amphibian metamorphosis (transformation of tadpoles into frogs). Development of limbs, lungs, and other features required for life on land are driven by T3. Similarly, T3 is required for active neurogenesis (up to 6 months postpartum) in humans. Its absence leads to irreversible intellectual disability and multiple morphological alterations in the brain (can be rescued with T4 supplementation during first 2 weeks of postnatal life). T3 (via TRα1) is essential for linear bone growth. Hypothyroidism causes short stature, delayed ossification, and skeletal dysplasia (childhood thyrotoxicosis also decreases final height, but that is because of premature epiphyseal fusion). Adult hyperthyroidism accelerates bone turnover and increases the risk of osteoporosis, especially in postmenopausal women with estrogen deficiency (similarly to glucocorticoids). 23 23 3/22/2024 Thyroid Disorders-Pathophysiology Thyroid deficiency during development, affecting 1 in 3000–4000 births, causes congenital hypothyroidism, characterized by gross retardation of growth (dwarfism) and mental deficiency (cretinism). 24 24 3/22/2024 Thyroid Physiology  Major clinical effects of thyroid hormones: 2) Thermogenesis: T3 is necessary for both obligatory thermogenesis (heat from vital processes) and adaptive thermogenesis. Only brain, gonads, and spleen are unresponsive to its thermogenic effects. Small changes in T4 replacement doses significantly alter resting energy expenditure in the hypothyroid patient. The capacity of T3 to stimulate thermogenesis has evolved along with ancillary effects to support this action, such as stimulation of appetite and lipogenesis. 25 25 3/22/2024 Thyroid Physiology  Major clinical effects of thyroid hormones: 3) Cardiovascular System: Hyperthyroid patients have tachycardia, increased stroke volume & cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance (hypotension, due to T3-induced NO-dependent vasodilation). Hyperthyroidism is a common cause of atrial fibrillation. Hypothyroid patients have bradycardia, decreased cardiac index, and higher peripheral vascular resistance (hypertension). T3 (mainly via TRα1) accelerates diastolic relaxation (lusitropic effect) by inducing SERCA2 activity of the SR. T3 increases contractility (inotropic effect) via ryanodine receptor (RyR2) induction, a Ca2+-releasing channel of the SR, and α-myosin heavy chain (α-MHC) induction, a myosin isoform with higher ATPase activity (increased contraction velocity). T3 increases heart rate (chronotropic effect) by increasing the pacemaker ion current If in the SA node (increases expression of hyperpolarization-activated, cyclic nucleotide–gated (CNG) channels HCN2 and HCN4). 26 26 3/22/2024 Thyroid Physiology  Major clinical effects of thyroid hormones: 4) Lipid Metabolism: T3 stimulates the expression of hepatic LDL receptors and reduces apolipoprotein B levels through non-LDL receptor pathways, thereby reducing circulating LDL-cholesterol levels. Hypercholesterolemia is a characteristic feature of hypothyroidism. T3 stimulates lipid metabolism in the liver via TRβ1 and resmetirom (Rezdiffra®), a selective TRβ agonist, just (in March 2024) became the first FDA-approved drug specifically for non-alcoholic steatohepatitis (NASH) and NASH-associated liver fibrosis. 27 27 3/22/2024 28 28 3/22/2024 Thyroid Disorders-Pathophysiology Thyroid disorders are among the most common endocrine diseases in all age groups, including children.  Accompanied by many extra-thyroidal symptoms, particularly in the heart, GI tract and skin. One rare cause of thyroid dysfunction is thyroid cancer. Many thyroid disorders have an autoimmune basis: autoimmune thyroid disease is the commonest autoimmune disease. Two main types of autoimmune thyroid disorder: Graves` disease and Hashimoto’s disease. Both are caused by thyroid autoantibody production (usually against TSHR) and involve immune damage to the gland itself, but: Graves` disease results in thyrotoxicosis (hyperthyroidism), while Hashimoto’s thyroiditis leads to hypoactive thyroid (hypothyroidism). 29 29 3/22/2024 Thyroid Disorders-Pathophysiology Thyroid dysfunction in both is associated with typical gross enlargement of the gland (goiter). Like many autoimmune diseases, thyroid disorders are more common in women than in men and occur with increased frequency during pregnancy. Hyperthyroidism (thyrotoxicosis): Excessive thyroid hormone secretion and activity resulting in high metabolic rate, increased skin temperature and sweating, and heat intolerance. Nervousness, tremor, tachycardia and increased appetite associated with loss of weight occur. Two common subtypes: exophthalmic or diffuse toxic goiter (Graves` disease) and toxic nodular goiter. 30 30 3/22/2024 Thyroid Disorders-Pathophysiology Diffuse toxic goiter or Graves` disease: organ-specific autoimmune disease caused by activating (agonistic) antiTSH receptor autoantibodies, increasing T4 secretion. Patients have protrusion of the eyeballs (“exophthalmos”), due to antibodies against TSH receptor-like proteins in orbital tissues. Enhanced sensitivity to catecholamines. 31 31 3/22/2024 Thyroid Disorders-Pathophysiology Toxic nodular goiter: caused by a benign tumor, usually NO concomitant exophthalmos. The class III anti-arrhythmic drug amiodarone is rich in iodine and can cause either hyperthyroidism (in people with mild-moderate iodine deficiency, in whom it will stimulate NIS-dependent I- uptake) or hypothyroidism (in people with normal or slightly high iodine intake, in whom the additional amiodarone-derived I- amount will block NIS-dependent Iuptake). Importantly, amiodarone-precipitated hyperthyroidism might be masked by the bradycardia caused by the drug. Dronaderone (Multaq®) is a good alternative to amiodarone in thyroid patients (same drug class but contains no iodine). Simple, non-toxic goiter: dietary deficiency of iodine, if prolonged, causes a rise in plasma TRH and eventually thyroid gland enlargement. Ingestion of goitrogens (e.g., cassava root) can cause this type of goiter also. 32 32 3/22/2024 Thyroid Disorders-Pathophysiology Hypothyroidism Decreased thyroid activity results in hypothyroidism, and in severe cases myxedema. Also immunological in origin; symptoms include low metabolism, slow speech, lethargy, bradycardia, sensitivity to cold, mental impairment. Patients develop a characteristic thickening of the skin (caused by subcutaneous glycosaminoglycan deposition), which gives myxedema its name. Hashimoto`s thyroiditis: immune reaction against TG or some other thyroid component. Genetic factors play an important role. Can be caused by radioiodine treatment of thyroid tumors. Some drugs (anti-epileptics) and environmental EDCs (endocrine disruptive chemicals) may interfere with normal thyroid hormone production, as well. Lithium decreases T4 & T3 secretion, which can cause overt hypothyroidism in some bipolar disorder/mania patients on this drug. 33 33 3/22/2024 Drug Therapy of Thyroid Disorders Radio-iodine Thiourylenes (thionamides): Methimazole (Thiamazole, Tapazole®) & Propylthiouracil Iodide & anionic inhibitors Other drugs (b-blockers) Synthetic T3 (Liothyronine, Triostat®) Synthetic T4 (Levothyroxine, Synthroid®) 34 34 3/22/2024 Drug Therapy of Thyroid Disorders Radio-iodine First-line treatment for hyperthyroidism. The isotope used is 131I (usually as the sodium salt), and the dose generally 5–15 mCi. 131I is one of the most common radioactive products in nuclear reactors. Given orally, taken up and processed by the thyroid exactly as non-radioactive I−, eventually incorporated into TG. Emits both β and γ radiation: γ rays (high energy UV radiation) pass through the tissue without causing damage (used for diagnostic imaging of the gland), but the β particles (high energy electrons) have a very short range, so they are absorbed by the thyroid and destroy its follicles (therapeutic effect in thyroid cancer). 131I has a half-life of 8 days; by 2 months radioactivity has effectively disappeared. 35 35 3/22/2024 Drug Therapy of Thyroid Disorders Radio-iodine (cont`d) o Hypothyroidism will eventually develop with radioiodine, esp. in Graves` disease patients, which is managed by replacement therapy with T4. o Should be avoided in children and in pregnancy (risk of potential damage to the fetus). Theoretically, thyroid cancer risk is elevated with radioiodine treatment but this has not been seen in clinical practice. o 131I and other iodine radio-isotopes are also used diagnostically to test thyroid function. A tracer isotope dose is given orally or iv and the amount accumulated by the thyroid is measured by a γ-scintillation counter placed over the thyroid gland. 36 36 3/22/2024 Drug Therapy of Thyroid Disorders Thiourylenes (thionamides): methimazolepropylthiouracil Chemically related to thiourea; the thiocarbamide (S=C–NH-) group is essential for anti-thyroid activity. Cabbage is rich in SCN-containing compounds; excessive consumption can cause thyroid problems. 37 37 3/22/2024 Drug Therapy of Thyroid Disorders Thiourylenes (thionamides) (cont`d):  Mechanism of action: Not completely understood; they reduce Tyr iodination of TG by inhibiting TPO. Possibly substrate analogs (pseudo-substrates) competitively inhibiting the interaction of TPO with tyrosine.  Propylthiouracil has the additional effect of reducing the de-iodination of T4 to T3 in peripheral tissues (inhibits tissue 5`-deiodinase).  Pharmacokinetics: given orally. Methimazole`s prodrug, carbimazole, available in Europe, is rapidly converted to the active metabolite methimazole. Rapid inhibition of iodine incorporation into the thyroid but full clinical response may take several weeks, due to long half-life of T4 and the large hormone stores of the thyroid gland. Propylthiouracil acts more rapidly thanks to its additional effect of T4 to T3 peripheral conversion inhibition (preferred over methimazole in acute thyroid storm treatment). 38 38 3/22/2024 Drug Therapy of Thyroid Disorders Thiourylenes (cont`d):  Adverse effects: The most dangerous unwanted effects are neutropenia and agranulocytosis, although relatively rare (incidence of 0.1%–1.2%) and reversible upon treatment discontinuation. More common symptoms include rashes (2%–25%), headaches, nausea, jaundice, and arthralgia. Methimazole is safer than propylthiouracil and has longer half-life requiring less frequent dosing, so it is preferred for regular Graves disease treatment.  Pregnancy: Rare cases of fetal abnormalities have been reported with methimazole, so propylthiouracil is preferred during the first trimester of pregnancy. After that however, the patient should switch to methimazole for the last two trimesters, due to the hepatotoxicity/liver failure risk of propylthiouracil. 39 39 3/22/2024 Drug Therapy of Thyroid Disorders Iodine/iodide: o Iodine (I2) is converted in vivo to iodide (I−), temporarily inhibiting release of thyroid hormones. Over 10–14 days, marked reduction in vascularity of the gland, becoming smaller and firmer, occurs. o Strong iodine solution (Lugol solution) consists of 5% iodine and 10% potassium iodide (KI), yielding a dose of ~8 mg of iodine per drop. Potassium iodide saturated solution (KISS) is also available, containing 50 mg per drop. MOA is not entirely clear; may inhibit iodine organification by reducing H2O2 availability to TPO. o KI products (Thyroshield, various generics) are available OTC for the event of a radiation emergency (block uptake of radioactive iodine into the thyroid). Adult dose is 130 mg every 24 h, as directed by public health officials. 40 40 3/22/2024 Drug Therapy of Thyroid Disorders Iodine/iodide (cont`d): o Main uses: preparation of hyperthyroid subjects for surgical resection of the gland, and as part of the treatment of severe thyrotoxic crisis (“thyroid storm”). Also used following exposure to a nuclear accident. o Adverse effects: allergic reactions, including angioedema, rashes and drug fever. Lacrimation, conjunctivitis, pain in the salivary glands and a cold-like syndrome may also develop due to iodide concentration in tears and saliva. o Other anions resembling I− (monoanions with similar size) that inhibit NIS (i.e., I− uptake into the thyroid): thiocyanate (SCN−), perchlorate (ClO4−), and fluoroborate (FB4−). Perchlorate can be used to control hyperthyroidism and is used for Graves disease in some countries. 41 41 3/22/2024 Drug Therapy of Thyroid Disorders Other drugs:  The β-adrenoceptor antagonists (β-blockers) without ISA decrease many signs and symptoms of hyperthyroidism, including all cardiovascular ones: tachycardia, arrhythmias, tremor, and agitation. Non-selective βblockers like propranolol are usually preferred, because they can partially inhibit tissue 5`-deiodinase (reduce T4 to T3 conversion). However, β1-selective blockers (e.g., metoprolol, atenolol) are also useful thanks to their lower risk of diabetic and asthma complications.  Used during the preparation of thyrotoxicosis patients for surgery, in most hyperthyroidism patients during the initial treatment period while anti-thyroid drugs take effect, and for acute hyperthyroid crisis. 42 42 3/22/2024 AC cAMP AC cAMP 43 43 3/22/2024 Drug Therapy of Thyroid Disorders b-blockers:  Non-selective without ISA: Propranolol, bucindolol (also blocks α1-adrenergic receptors), carteolol, carvedilol (also blocks α1adrenergic receptors), nadolol, and timolol.  Non-selective with ISA (contraindicated in hyperthyroidism): Labetalol (also blocks α1-adrenergic receptors), oxprenolol, penbutolol, and pindolol.  b1-selective without ISA: Atenolol, metoprolol, betaxolol, bisoprolol, nebivolol (also activates b3-adrenergic receptors), and esmolol (ultra-short acting).  b1-selective with ISA (contraindicated in hyperthyroidism): Acebutolol & celiprolol. 44 44 3/22/2024 Aryloxypropanolamine 45 45 3/22/2024 Drug Therapy of Thyroid Disorders Thyroid eye disease (TED):  Eye drops containing guanethidine, a noradrenergic-blocking agent, are used to mitigate the exophthalmos of hyperthyroidism (NOT relieved by anti-thyroid drugs). Guanethidine relaxes the sympathetically innervated smooth muscle that causes eyelid retraction. β-blockers are NOT useful for exophthalmos (because eyelid retraction is a1adrenoceptor-dependent).  Glucocorticoids, e.g. prednisolone, hydrocortisone, & surgical decompression needed in severe TED (ocular autoimmune swelling/inflammation) of Graves` disease.  Teprotumumab (Tepezza®), an anti-IGF-1R (insulin-like growth factor-1 receptor) inhibitory human monoclonal antibody, is FDA-approved specifically for TED treatment (infused every 3 weeks, up to 8 infusions total). 46 46 3/22/2024 47 47 3/22/2024 Drug Therapy of Thyroid Disorders Synthetic T3-T4:  No drugs to augment synthesis or release of thyroid hormones. Thus, the only effective treatment for hypothyroidism, unless it is caused by iodine deficiency (treated with iodide), is to administer synthetic thyroid hormones themselves as replacement therapy.  Synthetic T4 (levothyroxine) & T3 (liothyronine), identical to the natural hormones, are given orally. T4 sodium salt is the usual first-line drug of choice. T3 has faster onset of, but shorter duration of action; generally reserved for acute emergencies (myxedema coma). 48 48 3/22/2024 Drug Therapy of Thyroid Disorders Synthetic T3-T4: Structure-activity relationship:  The backbone of the two phenyl rings coupled through an oxygen (X must be an O atom) is necessary for activity (forming a phenoxy-phenyl pharmacophore).  R1 must be an alanine moiety (CH2-CH(NH2)-COOH).  R5, R3, and R3` must be I and R4` must be OH.  If R4` is OH, R1 is alanine, R5`, R3, and R3` are I, and R5 is H, the molecule is reverse T3 (biologically inactive).  I at R5` is NOT needed for activity (in fact, activity is lower if R5` is I (as in T4) than if R5` is H (as in T3). 49 49 3/22/2024 Drug Therapy of Thyroid Disorders Synthetic T3-T4:  Adverse effects: may occur with overdose upon chronic treatment and include hyperthyroidism, risk of precipitating angina, osteoporosis, cardiac arrhythmias (atrial fibrillation), even heart failure. Effects of less severe overdose are insidious: patient feels well overall but bone resorption is increased & osteoporosis develops.  A mixture of levothyroxine and liothyronine at 4:1 w/w, as well as desiccated thyroid preparations with a similar T4:T3 ratio, are also available. A 60 mg (1-grain) desiccated thyroid tablet is approximately equivalent to 65 μg of levothyroxine in terms of TSH-lowering capacity. 50 50 3/22/2024 Drug Therapy of Thyroid Disorders Recombinant TSH:  Recombinant human thyrotropin (TSH) (Thyrogen®) is available for injection for diagnostic purposes following surgery, to test the capacity of normal or malignant thyroid tissue to take up radioactive iodine and to secrete thyroid hormones (i.e., test for residual activity following thyroidectomy).  It can also be used, in lieu of levothyroxine withdrawal, to prepare a patient for radioiodine ablation/destruction of thyroid remnant tissue (rhTSH stimulates radioiodine uptake by the thyroid via the NIS). 51 51