2. Drugs for Thyroid Disorders Burchum & Rosendahl, Chapter 58

3. Thyroid

4. Thyroid Hormone Actions Thyroid hormones have three principal actions: Stimulation of energy use (metabolism) Stimulation of the heart (increase force and rate of cardiac contraction) Promotion of growth & development −normal levels of thyroid hormone are essential to the development of the fetal and neonatal brain

5. Thyroid Hormones The thyroid gland produces: Tri-iodothyronine (T 3 ) - highly active Tetra-iodothyronine (T 4 ) - more abundant, but much less active (prohormone) 99.5% plasma-protein bound T4  T3 in cells Most abnormalities of thyroid function can be treated effectively

6. Figure 58-2 Steps in thyroid hormone synthesis.

7. Regulation of thyroid function: when levels of T3 and T4 hormones rise in the bloodstream, negative feedback inhibits production of more T3 and T4. (Figure 58-3)

8. Hypothalamus is the major neuroendocrine gland. Hypothalamus produces a variety of “Releasing Factors” which cause the pituitary, in turn, to secrete hormones.

9. Lab Tests Thyroid Stimulating Hormone (TSH) is an exquisitely sensitive indicator of thyroid status (when hypothalamus and anterior pituitary function are normal.) The free T4 (thyroxin) assay is usually done at the same time as the TSH assay. Thyroxine level is used to confirm a thyroid disorder in the event that the TSH is abnormal.

10. Thyroid Problems Hypo Weakness/ Fatigue Skin changes (dry, coarse, cold) Slowed speech Eyelid (or facial) edema Increased sensitivity to cold Constipation Low HR Weight gain Hoarseness Depression Forgetfulness Hyper Increased sensitivity to heat Skin warm and moist Elevated HR Weight loss Increased BM Increased appetite Nervousness, anxiety, irritability, INSOMNIA Possible tremor Possible sweating Irregular menstruation

11. GOITER A goiter can occur in a gland that is producing: – too much hormone (hyperthyroidism) – too little hormone (hypothyroidism) –or the correct amount of hormone (euthyroidism). A goiter indicates there is a condition present which is causing the thyroid to grow abnormally. “Beauty” in ancient times

12. TOO LITTLE thyroid hormone

13. #2 most common endocrine disorder in US Prevalence 0.5% in the general US population. increasingly common with advancing age, affecting about 2 to 3 percent of older women May be misdiagnosed as depression, post- partum “blues”, constipation, etc Hypothyroidism: epidemiology

14. Hypothyroidism Top Causes –Autoimmune (Hashimoto’s thyroiditis) –Iodine deficiency (goiter) in countries without iodinated salt, and where soil doesn’t get rainfall from ocean clouds

15. Thyroid Hormone Replacement: Preparations Therapeutic strategy for hypothyroid: hormone replacement –Most common treatment is T4 replacement –Levothyroxine = synthetic preparation of thyroxine (T 4 ) –Liothyronine (T 3 ) –“Armor thyroid” “natural”, from animal source (?)) –Historically, dessicated animal thyroid was used Before After

16. Thyroid Hormone Therapy Levothyroxine (T 4 ) [Synthroid] –Used for all forms of hypothyroidism Use caution in elderly or if heart disease monitor vital signs –Half-life is 6-7 days –Takes FIVE WEEKS for plateau to be reached –Starting dose titrated up/down based on TSH –Recheck TSH 6 - 8 weeks after every dose change –Absorption decreased with food (varies 40-80%): Give 30 - 60 minutes before breakfast with a full glass of water (empty stomach) –best for patients to not switch brands Adverse effects?

17. Levothyroxine: interactions Many drugs, including cholestyramine [Questran], colestipol [Colestid], sucralfate [Carafate], H 2 receptor blockers, proton pump inhibitors, aluminum-containing antacids, iron supplements, and calcium supplements can significantly reduce levothyroxine absorption. ***At least 4 hours should separate administration of levothyroxine and these drugs. Levothyroxine can intensify the anticoagulant effects of warfarin.

18. Hypothyroidism Severe deficiency of thyroid hormone –Myxedema (adults) –Cretinism (infancy) –Extremes help teach hormone functions Puffy face

19. TOO MUCH thyroid hormone

20. Hyperthyroidism: two forms Much less common Two major forms: –Graves’ disease (most common) Symptoms can often be unnoticed, resulting in severe hyperthyroid manifestation of “thyroid storm” –Toxic nodular goiter (Plummer’s disease)

21. Hyperthyroidism: Grave’s Disease Cause of Grave’s disease: autoimmune –Thyroid-stimulating immunoglobulins (TSIs) –Attack TSH receptors on thyroid gland resulting in overstimulation Treatment –Suppression of thyroid hormone synthesis (eg drug therapy with methimazole, PTU) –Surgical removal of thyroid tissue –Destruction of thyroid tissue –Followed by hormone replacement therapy

22. Methimazole First line drug Inhibits thyroid hormone synthesis Is safer and more convenient than PTU Oral med taken once daily, minimal plasma protein binding, crosses membranes more easily, Half life is 6 – 13 hours Full benefits of methimazole may take 6 to 12 months to develop contraindicated during pregnancy and breastfeeding Main adverse effect is agranulocytosis

23. Propylthiouracil (PTU) “antithyroid medication”: Inhibits thyroid hormone synthesis and release Short half-life (about 75 minutes) Drug is given with radiation treatment (thyroid destroyed); pt becomes hypothyroid; then thyroid replacement therapy Therapeutic uses –Graves’ disease –Adjunct to radiation therapy –Preparation for thyroid gland surgery Adverse effects –Skin problems = most common –Agranulocytosis (loss of granulocytes, decreased ability to fight infection) = most serious –Hypothyroidism  Caution in Pregnancy and lactation (Category D) ; evidence of risk

24. Radioactive Iodine-131 ( 131 I) Radioactive isotope of stable iodine –Emits gamma and beta rays Half-life is 8 days Full effects of 131 I require 2 to 3 months to develop. 131 I is contraindicated during pregnancy and lactation. Used in Graves’ disease Action –Produces clinical remission with destruction of thyroid gland

25. Exophthalmos (Uncommon) & Goiter (common)

26. Case A 25-year-old, previously healthy woman presents with 1 month of anxiety, palpitations, loose stools, fine tremors, and hair loss. She has had a 20-pound weight loss over past 4 months, despite increased appetite. HR 115 to 130 BPM, T 37.5C. Exam notable for mild bilateral proptosis, thin hair, and moist skin. Goiter visible with audible bruit. Hyperreflexia and fine tremors. EKG – normal sinus tachycardia.

27. Question A client is prescribed levothyroxine (Synthroid) daily. The most important instruction to give her is… Taper dose & dc if mental or emotional states stabilize Take it at bedtime to avoid side effects of nausea and flatus. Call the doctor immediately at the onset of palpitations or nervousness. Decrease intake of juices and fruits with high potassium and calcium contents.

29. Drugs for Disorders of the Adrenal Cortex Chapter 60: Endocrine Gland Dysfunction - hypERsecretion or hypOsecretion Chapter 72: Glucocorticoids for Non-endocrine Disorders

30. Corticosteroids are key regulators of whole-body homeostasis; provide capacity to resist environmental changes and invasion of foreign substances

31. Physiology of the Adrenocortical Hormones The adrenal cortex produces over 20 hormones “Corticosteroids” refers to the glucocorticoids and the mineralocorticoids. NURS 310 will examine the following three classes of adrenocortical steroid hormones: 1.Glucocorticoids- cortisol  Homeostasis (metabolism, immune, inflammation and more  In times of stress, glucocorticoids are essential for survival. 2.Mineralocorticoids- aldosterone →Salt and water balance 3.Androgens- androstenedione →Sexual hormones and sexual balance

32. 1. Glucocorticoids: Physiologic Effects and mechanism of production Affect all of the major systems of the body Carbohydrate, protein and lipid metabolism Inflammation, immunity, wound healing Myocardial and skeletal muscle integrity Central nervous system Cardiovascular system Musculoskeletal system Stress response Respiratory system in neonates

33. Negative feedback regulation of glucocorticoid synthesis and secretion. Figure 60-2 Glucocorticoids: Physiologic Effects and mechanism of production

34. Mineralocorticoids –Circulatory balance; Hemodynamic stability –Retention of sodium (Na+) & water –Excretion of potassium (K+) 2. Mineralocorticoids: Physiologic Effects and mechanism of production

35. Androgens are male hormones. Androgens are used for several reasons, such as: To replace the hormone when the body is unable to produce enough on its own. To stimulate the beginning of puberty in certain boys who are late starting puberty naturally. To treat certain types of breast cancer in females. Development of male features in transsexuals Lichen sclerosus (a skin problem of the vulva) Microphallus (underdevelopment of the penis) 3. Androgens: Physiologic Effects and mechanism of production

36. Exogenous corticosteroids (ie glucocorticoids with or without mineralocorticoids) are used to treat seemingly “opposite” conditions: excessive and insufficient hormone secretion by the adrenal cortex. Why?

37. Excess or Insufficiency of Adrenocortical Hormones Two most familiar forms of adrenocortical dysfunction Adrenal hormone excess = Cushing’s syndrome Adrenal hormone deficiency = Addison’s disease

38. TOO MUCH ADRENAL HORMONE

39. Cushing’s syndrome

42. Adrenal Hormone Excess = Cushing’s Syndrome Cushing’s syndrome –Causes Hypersecretion of adrenocorticotropic hormone (ACTH) Hypersecretion of glucocorticoids Administering glucocorticoids in large doses –Treatment Surgical removal of the adrenal gland Replacement therapy

43. TOO LITTLE ADRENAL HORMONE

44. Addison’s Disease

46. Primary Adreno-cortical Insufficiency:  Causes — most often caused by autoimmune disease Acute adrenal insufficiency (adrenal crisis) Causes –Adrenal failure –Pituitary failure –Inadequate doses of corticosteroids Adrenal Hormone Insufficiency (Addison’s Disease): causes

47. Symptoms Hypoglycemia Malaise Loss of appetite Reduced capacity to respond to stress Treatment: lifelong Replacement of fluid, salt, and glucocorticoids Hydrocortisone is the drug of choice –Increase in time of physiologic stress – 3x3 rule In adrenal insufficiency: –All people require glucocorticoid replacement –Some people require mineralocorticoid Adrenal Hormone Insufficiency (Addison’s Disease): Symptoms & Tx

48. Synthetic steroid –Primarily glucocorticoid effects, but also has some mineralocorticoid effects –Must take entire daily dose upon wakening –Doses for endocrine hormones are SMALLER than when dosed for anti-inflammatory or other purposes. In times of stress, MUST increase dose by a magnitude of 3, for 3 days (otherwise potentially fatal) Therapeutic uses –Adrenal insufficiency –Allergic reactions to inflammation to cancer Adverse effects –Adrenal suppression –Cushing’s syndrome Glucocorticoids in tx of adreno-cortical hormone insufficiency : hydrocortisone is drug of choice

49. Mineralocorticoid: Fludrocortisone [Florinef] Potent mineralocorticoid Therapeutic uses –Addison’s disease –Primary hypoaldosteronism –Congenital adrenal hyperplasia Adverse effects –Hypertension –Edema –Cardiac enlargement –Hypokalemia

50. Question A nurse knows the clinical manifestations of a client with Addison’s disease include which of the following? Weight gain Hypertension Melanosis Hypotension Hyponatremia

51. Answer A nurse knows the clinical manifestations of a client with Addison’s disease include… Weight gain Hypertension Melanosis Hypotension Hyponatremia

52. CASE Ms. J is diagnosed with primary adrenocortical insufficiency, or Addison’s disease. She is prescribed corticosteroid therapy. She wonders how she will fit taking pills into her busy schedule. Glucocorticoid replacement therapy may be done by (1) giving the entire daily dose in the morning or (2) splitting the daily dose, giving two-thirds in the morning and one- third in the afternoon. She asks the nurse if she really has to take pills for this condition for the rest of her life. She insists that she works hard and loves to go on vacation and that she will not take pills every day for the rest of her life. What is the nurse’s most appropriate response?

53. Same case, one week later Ms. J is started on corticosteroid replacement therapy. One week later, she is admitted to the emergency department with hypotension, dehydration, hypoglycemia, weakness, lethargy, vomiting, and diarrhea. What is the most probable cause of these signs and symptoms? Which treatment measures are likely to be used to resolve the cause of Ms. J’s signs and symptoms?

54. Glucocorticoids in non-endocrine disorders Burchum & Rosenthal, Chapter 72

55. Pharmacology of Glucocorticoids: therapeutic uses → Effects on metabolism and electrolytes (physiologic dose- LOW) → Anti-inflammatory and immunosuppressant effects (pharmacologic dose- HIGH) Therapeutic uses in non-endocrine disorders: −Rheumatoid arthritis –Systemic lupus erythematosus –Inflammatory bowel disease –Miscellaneous inflammatory disorders –Allergic conditions –Asthma –Dermatologic disorders –Neoplasms –Suppression of allograft rejection –Prevention of respiratory distress syndrome

56. Pharmacology of the Glucocorticoids: adverse effects Adverse effects –Thinning of the skin- pts notice –Adrenal insufficiency with prolonged use- next slide –Osteoporosis –Increased risk of infection, cancers –Glucose intolerance  increased BG, may develop diabetes –Myopathy –Fluid and electrolyte disturbance –Growth retardation –Psychologic disturbances- insomnia, racing thoughts  steroid-induced psychosis (“wig out”) –Cataracts and glaucoma –Peptic ulcer disease –Iatrogenic Cushing’s syndrome –Potassium loss

57. Pharmacology of the Glucocorticoids: (to decrease risk of adverse effects) Prolonged glucocorticoid use (may) cause adrenal insufficiency/ adrenal suppression –Due to negative feedback/ suppression –Exogenous vs. endogenous When GC are discontinued, withdrawal of therapy must allow time for adrenal glands to regain function: TAPERING DOSE TO OFF will ↓risk of adrenal insufficiency. Taper depends on duration and dose of GC therapy: might be very slow taper over a LOOONG time –Taper the dosage to 50% of physiologic values –Monitor for adrenal crisis: nausea, vomiting, shock  People with adrenal suppression MUST have supplemental GC during physiologic stress (surgery, trauma); potentially fatal if no increased dose

58. Things to Know Similarities among corticoids are striking: no prototype Doses are highly individualized Duration of treatment & withdrawal/ taper of therapy are somewhat subjective Some degree of glucocorticoid effect and some degree of mineralocorticoid effect. See comparison tables. GC vary in half-lives; potency; degree of GC vs MC  Short-acting (typically acute, time-limited conditions; Intermediate acting  Long-acting (typically used for chronic conditions) Different steroids (eg topical) vary considerably in strength of effect/potency. Concentration differences/ doses meaningful if comparing the SAME medication.

59. Glucocorticoids DrugPhysiologic dose Non- endocrine dose Relative GC efficacy Relative MC efficacy Hydrocortisone (half-life 8-12 hours) 20-25 mgUp to 240 mg (up to 800 mg in MS!) Prednisone (half-life 18 – 36 hours) 5-10 mgUp to 60-80 mg Dexamethasone (half-life 36-54 hours) 0.25- 0.75 mgUp to 9 mg GC = glucocorticoid MC = mineralocorticoid

60. widely used through many routes: PO IV IM SUBCUT TOPICAL INHALE INTRANASAL INTRA-ARTICULAR RECTAL and more TEACH: do not stop taking suddenly; confer with PCP TEACH: psyche effects Daily therapy: administer before 9:00 am –Minimizes SE such as insomnia –Often tolerated better if taken with food Multiple drug intx: examples –GC + NSAIDS  PUD –Hypokalemia  ↑risk of digoxin toxicity, some diuretics PK: −Oral absorption is rapid and complete –Metab by liver, metabolites are not active –Excreted by kidneys Pharmacology of Glucocorticoids: General

61. Prednisone: oral synthetic corticosteroid Effects similar to other corticosteroids; mimic the action of cortisol (hydrocortisone) Used in low doses to treat symptoms of low corticosteroid levels More commonly used at higher doses (to tx acute, chronic, or remit/relapse conditions) for its potent anti-inflammatory effects: −arthritis, colitis, asthma, bronchitis, skin conditions, allergies, or inflammatory conditions of the nose and eyes; −multiple sclerosis ; lupus; and a multitude of other conditions that affect the lungs, skin, eyes, kidneys blood, thyroid, stomach, and intestines; including symptoms of certain types of cancer −these patients may have normal adrenocortical function Prednisone is inactive; must be converted to prednisolone by hepatic enzymes. May not be effective in people with liver disease.

62. Case: 30 yr old man post-transplant As a nursing student, you are assigned to the transplant clinic. Mr. M, 30 years old, received a heart and lung transplant 6 weeks ago. He is single with a large extended family. He tells you, “I have six nieces and nephews. The oldest is 10, and the youngest is 8 months. I was so glad to see all of them when I went home. They really cheer me up.” Mr. M is taking multiple drugs to manage his health, including glucocorticoids. Develop a plan of care to minimize adverse effects of long-term glucocorticoid therapy. What do you identify as a priority teaching points related to glucocorticoid therapy? What side effects should you inform Mr. O about?

63. References and resources for further learning National Institute of Diabetes and Digestive and Kidney Diseases- excellent endocrine section http://www.niddk.nih.gov/health-information/health- topics/endocrine/Pages/default.aspx Medline Plus: library on drugs, herbs and supplements. See also videos and cooltools https://www.nlm.nih.gov/medlineplus/druginform ation.htmlhttps://www.nlm.nih.gov/medlineplus/druginform ation.html https://www.nlm.nih.gov/medlineplus/videosand cooltools.html