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Drugs for Thyroid Disorders Burchum & Rosendahl, Chapter 58 Thyroid 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 Thyroid Hormones • The thyroid gland produces: • Tri-iodothyronine (T3) - highly active • Tetra-iodothyronine (T4) - 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 Figure 58-2 Steps in thyroid hormone synthesis. 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) Hypothalamus is the major neuroendocrine gland Hypothalamus produces a variety of “Releasing Factors” which cause the pituitary, in turn, to secrete hormones. 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. 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 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 TOO LITTLE thyroid hormone Hypothyroidism: epidemiology • #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, postpartum “blues” , constipation, etc 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 Thyroid Hormone Replacement: Preparations • Therapeutic strategy for hypothyroid: hormone replacement – Most common treatment is T4 replacement – Levothyroxine = synthetic preparation of thyroxine (T4) – Liothyronine (T3) – “Armor thyroid” “natural”, from animal source (?)) – Historically, dessicated animal thyroid was used Before After Thyroid Hormone Therapy Levothyroxine (T4) [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? Levothyroxine: interactions • Many drugs, including cholestyramine [Questran], colestipol [Colestid], sucralfate [Carafate], H2 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. Hypothyroidism • Severe deficiency of thyroid hormone – Myxedema (adults) – Cretinism (infancy) – Extremes help teach hormone functions Puffy face TOO MUCH thyroid hormone 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) 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 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 • • • • 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 Radioactive Iodine-131 (131I) • Radioactive isotope of stable iodine – Emits gamma and beta rays • Half-life is 8 days • Full effects of 131I require 2 to 3 months to develop. • 131I is contraindicated during pregnancy and lactation. • Used in Graves’ disease • Action – Produces clinical remission with destruction of thyroid gland Exophthalmos (Uncommon) & Goiter (common) 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. 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. Drugs for Disorders of the Adrenal Cortex Chapter 60: Endocrine Gland Dysfunction - hypERsecretion or hypOsecretion Chapter 72: Glucocorticoids for Non-endocrine Disorders Corticosteroids are key regulators of whole-body homeostasis; provide capacity to resist environmental changes and invasion of foreign substances 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 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 Figure 60-2 Negative feedback regulation of glucocorticoid synthesis and secretion. Physiologic Effects and mechanism of production Glucocorticoids: 2. Mineralocorticoids: Physiologic Effects and mechanism of production Mineralocorticoids – Circulatory balance; Hemodynamic stability – Retention of sodium (Na+) & water – Excretion of potassium (K+) 3. Androgens: Physiologic Effects and mechanism of production 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) 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? 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 TOO MUCH ADRENAL HORMONE Cushing’s syndrome Cushing’s syndrome Cushing’s syndrome 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 TOO LITTLE ADRENAL HORMONE Addison’s Disease Addison’s Disease Addison’s Disease Adrenal Hormone Insufficiency (Addison’s Disease): causes 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): Symptoms & Tx 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 Glucocorticoids in tx of adreno-cortical hormone insufficiency: hydrocortisone is drug of choice • 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 Mineralocorticoid: Fludrocortisone [Florinef] • Potent mineralocorticoid • Therapeutic uses – Addison’s disease – Primary hypoaldosteronism – Congenital adrenal hyperplasia • Adverse effects – Hypertension – Edema – Cardiac enlargement – Hypokalemia 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 Answer A nurse knows the clinical manifestations of a client with Addison’s disease include… • Weight gain • Hypertension • Melanosis • Hypotension • Hyponatremia 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 onethird 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? 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 Glucocorticoids in non-endocrine disorders Burchum & Rosenthal, Chapter 72 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 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 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 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. Glucocorticoids Drug Physiologic dose Nonendocrine dose Hydrocortisone (half-life 8-12 hours) 20-25 mg Up to 240 mg (up to 800 mg in MS!) Prednisone (half-life 18 – 36 hours) 5-10 mg Up to 60-80 mg Dexamethasone (half-life 36-54 hours) 0.25- 0.75 mg Up to 9 mg GC = glucocorticoid MC = mineralocorticoid Relative GC efficacy Relative MC efficacy Pharmacology of Glucocorticoids: General • 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 diuretic • PK: − Oral absorption is rapid and complete – Metab by liver, metabolites are not active – Excreted by kidneys 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. 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? 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/healthtopics/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.html • https://www.nlm.nih.gov/medlineplus/videosand cooltools.html