Endocrine Pharmacology Notes (2022)

Joongkyu Park, Ph.D. Pharmacology January 14, 2022 Endocrine Pharmacology Many of the body’s major hormones are used as medicines. This first part of this lecture provides an overview of the use of these hormones in modifying the disease state. The second part of...

Joongkyu Park, Ph.D. Pharmacology January 14, 2022 Endocrine Pharmacology Many of the body’s major hormones are used as medicines. This first part of this lecture provides an overview of the use of these hormones in modifying the disease state. The second part of the lecture drills into two hormonally controlled homeostases to examine the challenges of hormone replacement therapy. First, we will look at how the tightly controlled blood glucose homeostasis is re-established in the absence of insulin in type 1 diabetes mellitus. Next, we will examine how the deranged levels of thyroid hormone levels in thyroid patients, both hypo- and hyperthyroidism, are rectified. _______________________ Learning Objectives: 1. Understand the general use of hormonal medicine in treating hormonal deficiency disorders. 2. Understand the tight control of blood glucose levels by insulin and glucagon. 3. Understand the challenges of insulin replacement therapy for type 1 diabetes mellitus. 4. Understand how thyroid hormone controls the basal metabolic rate. 5. Understand pharmacologic treatments for hypo- and hyperthyroidism Lecture Outline: I. Overview of endocrine disorders A. Disorders associated with either excess or diminished hormone production – glucocorticoids, growth hormone, thyroid hormone, insulin B. Treatment 1. Deficiency – hormone replacement 2. Excess – tumor excision II. Pharmacology of type 1 diabetes mellitus (T1DM) – insulin replacement A. Pancreatic control of blood glucose homeostasis by insulin and glucagon 1. Reasons for tight homeostatic control a. Hypoglycemia b. Hyperglycemia B. Diabetes mellitus (DM) overview 1. T1DM – etiology and treatment 2. T2DM a. insulin resistance – obesity b. treatment overview 3. Long-term complications of T1DM and T2DM C. Banting and Best – insulin replacement therapy – T1DM “cure” D. Insulin – normal physiology E. Insulin replacement therapy for T1DM 1. Euglycemia goal 2. Insulin preparations 3. Insulin self-injection regimens a. Insulin pump b. Glucose testing (1) HbA1c 4. Adverse reactions – hypoglycemia a. Glucagon treatment  2 III. Pharmacology of thyroid disorders A. Overview of hypo- and hyperthyroidism B. Thyroid hormone background 1. Thyroid hormone actions – control of basal metabolic rate 2. Thyroid hormone mechanism 3. Thyroid hormone pharmacokinetics 4. Thyroid hormone biosynthesis a. Iodide trapping 5. Thyroid-stimulating hormone (TSH) C. Hypothyroidism 1. Causes 2. Hashimoto’s thyroiditis a. Treatment – thyroid hormone replacement D. Hyperthyroidism – Graves’ disease ____________________ Endocrine Disorders Below, we examine disorders of some of the major endocrine systems. At the root of these disorders is the production of either too much or too little hormone. Some examples: 1. Glucocorticoids Deficiency – Addison’s disease Excess – Cushing’s disease or syndrome 2. Growth hormone (GH) Deficiency - from birth – projected short stature; pituitary dwarfism - in adults – deficiency → reduced muscle mass and bone density with possible effects on cognition and mood - in the elderly – GH drop with aging – possible “longevity” treatment? Excess – gigantism; acromegaly 3. Thyroid hormone Deficiency – hypothyroidism Excess – hyperthyroidism 4. Insulin Deficiency – diabetes mellitus Excess – insulinoma – rare; low blood glucose  3 Treating Endocrine Disorders Hormone deficiencies typically are treated through hormone replacement therapy. 1. Addison’s disease is well-treated with cortisol and its derivatives. 2. Pituitary dwarfism treated from infancy with bi-weekly growth hormone injections. 3. The symptoms of hypothyroidism are reversed by daily ingestion of a thyroid hormone pill. 4. Type 1 diabetes mellitus is treated with multiple insulin self-injections per day. Hormone excesses usually are caused by endocrine tumors – i.e. tumors deriving from particular endocrine-producing cells. The definitive treatment typically then is tumor excision. Pituitary adenomas – typically, these are benign – clonal expansion of cells dedicated to the secretion of particular hormone For instance: 1. Tumors of pituitary corticotrophs produce excess adrenocorticotropic hormone (ACTH) → excess glucocorticoid production by adrenal glands = Cushing’s disease 2. Tumors of pituitary somatotrophs produce excess growth hormone → excess liver release of insulin-like growth factor-1 (IGF-1) → gigantism (in children); acromegaly (in adults) 3. Tumors of pituitary lactotrophs produce excess prolactin → broad dysfunction in both males and females: hypogonadism, amenorrhea, infertility, etc. 4. Rare tumors of pituitary thyrotrophs produce excess thyrotropin or thyroid- stimulating hormone (TSH) → stimulates the synthesis and release of thyroid hormone = hyperthyroidism. More typically, hyperthyroidism is the result of autoimmune disorder known as Graves’ disease. In addition to surgical excision, some drugs are available that can inhibit hormone production. Often, these are drugs build on the natural hypothalamic regulatory mechanisms. For instance, administration of dopamine agonists inhibits prolactin release. Likewise, somatostatin analogs inhibit growth hormone release. ___________________________________ The rest of the lecture will drill more deeply into two endocrine systems and their associated disorders: 1. Insulin/glucagon control blood glucose levels 2. Thyroid hormone control of the basal metabolic rate (BMR) The blood glucose homoeostasis is tightly controlled on a minute-by-minute basis, with only small deflections from the 90 mg/dL baseline seen following meals or during overnight sleep (when no food is ingested). In sharp contrast, the thyroid hormone-controlled BMR is a very stable homeostasis that is altered only slowly. Treating disorders of these two endocrine systems is quite different. In thyroid conditions, either hypo- or hyperthyroidism, restabilizing the disordered BMR is easily achieved, while treating the disordered glucose levels of diabetes mellitus remains more difficult. INSULIN and the BLOOD GLUCOSE HOMEOSTASIS Glucose is the body’s circulating energy source. It is controlled by a tight homeostasis, which keeps it at its 90 mg/dL baseline throughout the day and night. With ingested food at mealtimes, there are slight deflections. Overnight, when no food is being consumed, glucose levels are maintained through glycogenolysis and gluconeogenesis.  4 Two hormones secreted by pancreatic islet cells control this homeostasis: 1. Glucagon – peptide hormone secreted from α cells – is released into circulation when blood glucose levels are low – for instance, between meals or while you are asleep. Glucagon acts to increase glucose levels by stimulating both the breakdown of glycogen and new glucose synthesis. 2. Insulin – peptide hormone that is secreted by β cells when glucose levels are high, for instance, after a meal. Insulin causes this ingested glucose to be taken up into cells, to be stored and to be saved for future needs through the synthesis of glucose polymer glycogen. The release of both hormones is exquisitely sensitive to blood glucose levels, so that as blood glucose levels fall below 90 mg/dL, glucagon is released, which drives glucose levels back towards 90 mg/dL. Likewise, after a big pasta meal, where ingested starch is rapidly broken down to glucose and glucose levels rise, insulin is released → glucose is rapidly removed from circulation and thus, there is just this blip of increased glucose levels that rapidly returns to the 90 mg/dL baseline. Glucagon/insulin half-lives. Both glucagon and insulin have very short half-lives in circulation, in the 5-10 min range. Obviously, longer half-lives would complicate homeostatic control – for instance, a long-lived insulin, secreted under hyperglycemic conditions would end up over-correcting, pushing the body into a dangerous hypoglycemic state. Why the tight control? What are the dangers of the hypo- and hyperglycemic states? 1. Hypoglycemic state can be acutely dangerous since glucose is normally the main energy source for the brain. The primary symptoms of the hypoglycemia are neurologic – initially: sweating, tremor, confusion, blurred vision → then, if unremedied: coma, death. Indeed, hypoglycemia is the most concerning side effect of insulin replacement therapy for diabetes mellitus. 2. Hyperglycemia – The reasons why high blood glucose might be a problem are less obvious. Clearly, it is a problem, since hyperglycemia is the most salient symptom of both type 1 and type 2 diabetes mellitus (T1DM and T2DM). Failure to treat these two diseases leads to early death for T1DM and premature death for T2DM. Glucose toxicity. The current thinking is that chronically high levels of blood glucose are somehow toxic, likely a consequence of the glucose’s capacity to chemically react with, and modify, proteins, thereby perhaps, degrading protein function. [Note: the chemical modification of hemoglobin by glucose provides the basis for the HbA1c test, an important measure of glucose level control in diabetes.]  5 Type 1 and Type 2 Diabetes mellitus (T1DM and T2DM) – two diseases of different origins that both lead to hyperglycemia and thus, to shared pathologies. Type 1 diabetes mellitus (T1DM) – auto-immune destruction of pancreatic β cells → no insulin is produced, thus, the level circulating glucose remains high as it is not taken up into cells. - typically begins in children and young adults - Treatment: insulin replacement therapy – lifelong daily regimen of self-injections - prior to the development of insulin replacement therapy (Banting and Best, 1922), T1DM was always fatal – being unable to utilize circulating glucose, patients essentially starved to death Type 2 diabetes mellitus (T2DM) – makes up 90-95% of diabetes mellitus – closely linked to obesity - pathophysiology – insulin resistance coupled with β cell insufficiency. Insulin resistance – cells are less sensitive to insulin – thus, more insulin is required to store glucose – many insulin-resistant individuals show normal glucose levels as they are able ramp up insulin secretion sufficiently to overcome the resistance – individuals that lack this capacity, i.e. those with an insufficient β-cell response, are T2DM. - obesity is tightly linked to insulin resistance Treatments include diet and exercise, insulin, plus a wide variety of other anti-diabetic medications that either: 1. increase insulin levels 2. decrease insulin resistance 3. act to reduce circulating glucose levels [Note: The pharmacology of T2DM is beyond the scope of the present lecture and is reserved for Year 2 Pharmacology.] Long-Term Complications – both under-treated T1DM and T2DM, where blood glucose levels remain too high, associate with the same set of long-term complications: 1. Cardiovascular disease – dysregulated lipid metabolism – atherosclerosis – hugely increased risk of heart attack and stroke 2. Retinopathy – blindness – major cause of adult onset blindness 3. Nephropathy – kidney failure – accounts for ~1/3 of patients requiring kidney dialysis 4. Peripheral neuropathy – deterioration of peripheral motor and sensory neurons – most pronounced for the long neurons innervating the feet – consequent bacterial ulceration and gangrene – major cause of amputation Evidence indicates long-term complications to be the consequence of the high blood glucose levels in poorly treated diabetes.  6 Banting and Best – Insulin Replacement Therapy for T1DM Insulin replacement therapy introduced by Banting and Best in 1922 provided a miraculous cure of an otherwise fatal disease. While once daily injections of partially purified bovine pancreatic insulin proved lifesaving, this therapy obviously is unable to replicate the fine minute-by-minute regulation that normally controls blood glucose levels. The consequence of this under-treatment is that average glucose levels remain well above normal, which ultimately leads to the above long-term complications that may present 20 or 30 years down the road. Insulin (background) Insulin is comprised of two peptides – the 30-residue B peptide, which is disulfide bonded to the 21-residue A peptide. Released into circulation by pancreatic b cells, insulin acts upon the cell surface insulin receptors to rapidly activate downstream signaling to effectuate a panel of insulin- dependent changes. Prominent among these are: 1. uptake of glucose into cells – driven by the transposition of GLUT4 glucose transporters to the cell surface (from the Golgi) 2. downregulation of gluconeogenesis. The liver is a major site where new glucose is synthesized for release into blood. 3. downregulation of glycogenolysis. Again, the liver is a major site that makes glucose available to body through glycogen hydrolysis. Insulin Turnover. Insulin is largely turned over through normal endocytic degradation mechanisms, i.e. liganded receptor is endocytosed to endosomal compartments where ligand and receptor dissociate, with the receptor recycling back to the surface and with the insulin ligand traveling on to the lysosome for degradation. The liver, being a major locus of gluconeogenesis and glycogenolysis, plays a central role in glucose control and thus, is an important insulin target. Due to the way the circulatory system is “plumbed”, insulin, newly released from the pancreas, acts upon the liver first. Thus, in the natural situation, the liver sees high insulin levels, which are depleted, prior to insulin action on downstream peripheral tissues. It is often pointed out that these different pre- and post-liver insulin concentrations, are not replicated by subcutaneous insulin injections in the leg or buttocks. Insulin Therapy The euglycemia goal of restoring glucose levels to the ranges seen in normal physiological control is a difficult goal, given the minute-by-minute control normally exerted by glucagon and insulin. In the normal individual, high levels of insulin are induced at meals, with reduced basal levels of insulin secretion serving to maintain blood glucose levels between meals and during sleep. Obviously, Banting and Best’s once daily insulin injections cannot recapitulate this. Relatively good control, however, is achievable today with multiple daily injections with different insulin preparations (discussed below). Insulin Preparations – the different preparations have different duration of actions when injected subcutaneously, being either short- or long-acting. In the past, this has largely involved mixing purified insulin with various compounds, often either zinc or the peptide protamine, to reduce solubility.  7 An additional, more recent approach involves introducing amino acid changes into insulin that perturb its monomer- hexamer equilibrium. Since only monomeric insulin is able to bind to and activate the insulin receptor, mutations that favor the monomer are rapid-acting (acting more quickly than regular, soluble insulin). Conversely, amino acid changes that favor self-association into the hexamer result in long-acting insulins. These mutations do not affect binding to, or action on, the insulin receptor. Insulin Preparations: 1. Soluble or regular insulin – purified insulin – short-acting – human recombinant insulin, over-produced in either E. coli or yeast, has supplanted prior versions purified from porcine pancreas, 2. NPH insulin – intermediate-acting – regular insulin mixed with zinc and protamine to slow absorption. 3. Lente insulin – slow absorption – amorphous insulin zinc suspension. 4. Lispro insulin and aspart insulin – most soluble and most rapid-acting forms – mutations introduced into the human insulin diminish self-association of monomeric insulin into hexamers. 5. Glargine insulin – 'peakless' insulin – ultra-long acting – insulin mutations, which cause the injected insulin to precipitate at the subcutaneous injection site. A mixture of different preparations is typically injected. Insulin Self-Adminstration Regimens. A number of different regimens, with different numbers of daily injections are used by T1DM, which largely differ in how aggressively blood glucose is to be managed. A typical regimen might involve self-administered subcutaneous injections just before each meal. Each injection would utilize a mixture preparations – a rapid-acting insulin (e.g., lispro insulin) to accommodate the post-prandial glucose surge, as well as a long- acting insulin (e.g., NPH insulin) to maintain basal glucose levels. Frequent glucose monitoring should be used to fine-tune the regimen. Insulin pumps – Even with the different insulin preparations and frequent self glucose testing, achievement of the perfect euglycemic state remains elusive. Currently, the best regulation is achieved by continuous insulin infusion. The patient wears a small pump, which continuously administers a rapid-acting insulin into a subcutaneous site in the abdomen. At mealtime, the patient administers an extra bolus of insulin. Monitoring Blood Glucose Levels – the goal of both T1 and T2 DM treatment is to come as close as possible to achieving normal blood glucose levels. The normal baseline (fasting) blood glucose level is 90 mg/dL, with post-prandial levels peaking up to 130-150 mg/dL. In untreated diabetes, baseline levels may be as high as 300-350 mg/dL, with further post-prandial rises that fail to be rapidly down-regulated as they are in normal individuals.  8 Frequent blood glucose monitoring is the crux of good diabetes treatment – allowing patient and physician to individually scale treatment. The goal is to reduce levels throughout the day into the normal range. The potential danger, however, is the potential dropping levels too low, where the patient transitions into a hypoglycemic state with the consequence of coma and death resulting. Thus, good treatment requires a rigorous fine-tuning of drugs and life-style by patient and physician. Self-Monitoring – patient applies blood from lancet fingerstick to test strip, which is inserted into monitor for readout. Allows patient to monitor condition and make appropriate adjustment to medication. Glycated Hemoglobin – HbA1c – laboratory blood test. Glucose chemically reacts with N-termini of hemoglobin α and β chains. Due to long lifetime of hemoglobin in the body (erythrocyte lifetime = ~120 days), HbA1c allows a long-term measure of average blood glucose levels, providing a good one- or two-month-long measure of treatment efficacy. Useful for following courses of both T1 and T2 DM. Increased blood glucose levels correlate with HbA1c: HbA1c 4-5.6% normal range 5.6-6.4% pre-diabetes >6.5% diabetes Typical treatment goal – reduce HbA1c to 99%) of circulating hormone is in this bound form. This accounts for the long half-lives of T3 and T4 as the bound hormone is not subject to metabolic degradation. Indeed, the longer half-life of T4 relative to T3 is a consequence of its tighter binding to TBG. 4. Peripheral conversion of T4 to T3 -- Deiodinase enzymes in target tissues convert T4 to T3. Also, in a dead-end side reaction, the same enzymes convert equal amounts of T4 to the inactive T3-isomer reverse T3. Though T3 is the main active form, T4 is the major form synthesized and released into circulation. T4 is also more stable. As T4 is converted to T3, greater activity is assumed. Thus, T4 can be thought of as a storage form of the active hormone T3 -- in a sense, a prohormone.  11 Thyroid Hormone Biosynthesis -- this is main site of action of the major anti- thyroid pharmacologic agents. Note in the adjacent image, that the thyroid is composed of follicles – i.e. spheres of endothelial cells enclosing an interior luminal space. The exterior surface of these follicular endothelial cells is exposed to the blood. Most of the key events of thyroid hormone biosynthesis take place within the follicular lumen. 1. Iodide Trapping -- Iodine plays a key role in thyroid hormone biosynthesis (see structures above). Indeed, the body's main requirement of iodine is for thyroid hormone synthesis. It is the iodide form (I-) of iodine that is absorbed from circulation by thyroid follicular cells. Uptake, which is energy-dependent, is extremely rapid and efficient with follicular cells capable of a 250-fold concentration of iodide from blood. Note: radioisotopes of iodine are common byproducts of nuclear reactor accidents or nuclear explosion. The iodine radioisotopes also are efficiently absorbed into thyroid → thyroid cancer. In the event of such a catastrophe, thyroidal uptake of these radioisotopes can be largely prevented through the ingestion of massive quantities of sodium iodide (competes with the radioisotopes for thyroidal uptake). Iodide uptake also is inhibited by thiocyanate (SCN-) or by perchlorate (ClO4-) ions. Dietary Iodine. Main natural source of dietary iodide is from salt-water seafood. In the recent past (and still in some parts of the world), iodide deficiency has been a frequent endemic cause of hypothyroidism and goiter (an enlargement of the thyroid gland that occurs as the gland tries to scavenge more iodide from circulation). Today, table salt is generally supplemented with sodium iodide. 2. Iodide Organification -- Once absorbed, iodide is further oxidized and then attached to tyrosine. These reactions require the thyroidal enzyme, thyroperoxidase. The tyrosine substrates for iodination are the tyrosine residues resident in the protein thyroglobulin. Both thyroperoxidase and thyroglobulin reside extracellularly within the follicular lumen. Thyroglobulin -- a huge 300 kDal protein containing about 100 tyrosine residues. A subset of these tyrosyl residues serve as the substrate for thyroxine (T4) synthesis. On average, one to three T4 molecules are produced per molecule of thyroglobulin. Iodination of tyrosine is a two-step reaction, mediated by the l In the first step an iodine is added at the 3 position giving monoiodotyrosine (MIT). Then a second iodine is added to the 5 position giving diiodotyrosine (DIT). These steps that are the target for inhibition by the main anti-thyroid drugs, the thioureylenes (see description below).  12 To form T4, two DIT residues are combined in a condensation reaction. This takes place while residues remain attached to the thyroglobulin backbone. Finally, the iodine-modified thyroglobulin is secreted out of the follicular cells into an enclosed extracellular space -- the colloid. 3. Thyroid Hormone Secretion – Newly synthesized T3 and T4 moieties remain as amino acids within thyroglobulin that is stored within the extracellular colloid. Release of active thyroid hormone requires endocytosis of this thyroglobulin from the extracellular lumenal space with delivery to the lysosome for proteolysis. Finally, the released T3 and T4 molecules are secreted into the blood stream. Thyrotropin or Thyroid-Stimulating Hormone (TSH) secreted by anterior pituitary is the main controller of thyroid hormone and the BMR homeostasis. TSH stimulates all aspects of thyroid hormome biosynthesis – iodide uptake and organification, as well as its lysosomal release from thyroglobulin. TSH also stimulates growth of the thyroid gland itself, contributing thus to the development of goiter, the pathological enlargement of the thyroid gland which can accompany both hypo- and hyperthyroidism. In hypothyroidism → decreased levels of circulating T3 and T4 → increased release of TSH → goiter. In Graves disease – an auto-immune disorder that is the predominant form of hyperthyroidism – auto-antibodies against the TSH receptor activate this receptor → increased release of T3 and T4 (hyperthyroidism) and thyroid hyperplasia (i.e. goiter). The presence of goiter indicates excessive stimulation of the TSH receptor. ________________________________ HYPOTHYROIDISM – Reduced BMR due to reduced levels of circulating T3 and T4. Three causes: 1. Dietary iodine insufficiency – treated by supplementing diet with sodium or potassium iodide. 2. Idiopathic failure of thyroid development – newborns are tested for T3/T4 and if found to be deficient are treated by T4 replacement therapy. 3. Hashimoto’s thyroiditis – auto-immune disorder – immune attack on thyroid → reduced thyroid function. Note: In addition to its adult role in regulating BMR, thyroid hormone also plays a big role in development – stimulating both muscle and bone growth and also importantly, brain development. Thus, hypothyroidism present from birth, either due to iodine deficiency or developmental failure, leads to mental retardation if untreated → cretinism. Hashimoto’s Thyroiditis – reduced levels of circulating thyroid hormone – most common form of hypothyroidism in the developed world. cause – auto-immune attack on thyroid.  13 occurrence – 0.1-0.2% –women more frequently affected symptoms – may be difficult to diagnose due to the generalized features of the presentation: feeling cold; changes to skin, hair, nails; reduced appetite coupled to weight gain; lethargy; depression; bradycardia; goiter (early in disease process, prior to ongoing immune destruction of thyroid) diagnosis – low blood levels of T3 and T4, coupled high TSH levels Treatment – T4 replacement therapy – oral medication – taken daily in pill-form. Medications: 1. levothyroxine – synthetic T4 – best choice 2. Armour thyroid (produced by the company that makes Spam and Vienna sausages) – thyroid homogenate from pig – still available for use, but largely supplanted by levothyronine, which allows more precise dosing (homogenates may vary in terms of T3/T4 ratio). 3. liothyronine – synthetic T3 – not used much – unnecessary, since T3 is generated by the patient’s peripheral deiodinases from levothyroxine (i.e. T4). Hypothyroid symptoms begin to ameliorate in 3-5 days, but several weeks are required for the newly T3/T4 equilibrium to be reached. This slow rebalancing likely reflects both the slow conversion of T4 → T3, coupled to the serum large binding capacity for thyroid hormones (e.g. thyroxine-binding globulin). Monthly monitoring of TSH levels is used to make dose adjustments. Side Effects – T4 dosing that is too high causes hyperthyroidal symptoms (elevated BMR, tachycardia, tremor, etc.). The treatment of hypothyroidism is generally simple, easy and satisfying (unlike the prior- discussed insulin replacement for T1DM). ______________________________________ HYPERTHYROIDISM – GRAVES’ DISEASE Like Hashimoto’s thyroiditis, the hyperthyroidism caused Graves’ disease also is autoimmune in origin. Indeed, some think that these two disorders, opposite in their symptomology, may share the same etiology, i.e. anti-thyroidal antibodies. The distinguishing feature of Graves’ disease is the presence of autoantibodies that bind to, and activate the TSH receptors. These antibodies mimic TSH causing thyroid hyperplasia (i.e. goiter), plus the excess production and secretion of T3 and T4. cause – auto-immune activation of thyroid (TSH-mimetic autoantibodies) occurrence – 0.2-0.4% –women more frequently affected symptoms – generalized symptomology complicates diagnosis: heat intolerance; increased appetite coupled to weight loss; muscle tremor; osteoporosis; anxiety, insomnia, and paranoia; goiter (activation of TSH receptors). One unique symptom that is often seen is exophthalmos. exophthalmos – slight or extreme protrusion of eyeball from socket due to immune infiltrate of peri-orbital tissue. Successful treatment of core hyperthyroidal symptoms may or may not reduce progression of the exophthalmos. diagnosis – elevated levels of free T3 and T4, coupled with low TSH levels  14 Treatments – aim to reduce thyroidal release of T3 and T4. 1. thyroid resection – difficult surgery 2. radioiodine ablation of thyroid with 131I – rapid and specific uptake of isotope by thyroid → thyroid destruction – most widely used treatment – surprisingly safe (low risks of cancer, infertility or birth defects) – however, generally not used with children or women of child-bearing age. Typically, the goal of these two thyroid destruction approaches is to render patient hypothyroid, allowing easy, lifelong treatment with T4. 3. thionamides – methimazole and propylthiouracil – inhibitors of the thyroperoxidase enzyme