-Prescribed when there are excess thyroid hormones

-2 thyroid hormones: Triiodothyronine (T3) and Thyroxine (T4)

-Synthesis of thyroid hormones take in inorganic iodide hormones from the blood along with 2 Na+ molecules (iodide trap), the iron is pumped into the colloid of the thyrocyte to become organic iodide which then binds to tyrosine in thyroglobulin (Iodination step), this process will ultimately produce T3 and T4

-T4 (less active, half-life 6-8 days)

-T3 (more active, the half-life is 1-2 days)

-Once released from the thyroid gland, thyroxine binds to globulin (TBG) to travel in the blood to reach the target cell but a small portion stays unbound (free thyroid hormone)

-Free thyroid hormone (physiologically active) and able to enter the cell)

-Once in the cell, T4 converted to T3 (by 5'-Deiodinase)---> T3 binds to thyroid hormone receptor (regulates gene expression)----> Metabolic and physiologic effects occur

-Increase in metabolism uses up sugars and fats (otherwise used for energy) and increases body heat

-Increase in metabolism stimulates the sympathetic nervous system (fight or flight response)---> increased cardiac output, increased resp rate, and increased mental alertness---> also contributes to neuronal development and increased GI motility

1) Grave's disease (autoimmune most common): B-cells produce autoantibodies against thyroid-stimulating hormone receptors on follicular cells---> autoantibodies bind to thyroid-stimulating hormone receptors and activate them which results in the production of more thyroid hormones

2)Toxic multinodular goiter may result in increased release of thyroid hormones

3)Thyroiditis may result in increased release of thyroid hormones

*** Fewer than 2% of hyperthyroid cases in cats involve malignant thyroid gland tumors. Specific mechanisms are not known in felines however exposure to high levels of dietary iodine may cause susceptible cats to develop hyperthyroidism.

***Siamese, Burmese, Persian, Abyssinian and Himalayan breeds appear to have a somewhat decreased risk compared to other breeds

-Increased metabolic rate (weight loss, increased appetite)

-increased production of heat (heat intolerance)

-Effect of thyroid hormones on the sympathetic nervous system (tachycardia, sweating, hyperactivity, anxiety, and insomnia)

***Untreated hyperthyroidism (combined with infection or illness) may lead to thyroid storm. Symptoms become exaggerated (severe tachyarrhythmia, high fever, delirium, coma)

-Target the thyroid gland (decrease synthesis and prevent release)

-Target tissue peripherally (decrease effectiveness)

-Radioiodine ablation therapy (I131 is taken orally) and is taken up by the thyroid and collects in the colloid, over a few weeks it emits Beta radiation and damages the thyroid

-Tx of choice for Grave's disease and multinodular goiter

-Need to supplement with thyroid hormone replacement to prevent hypothyroidism

***Radiation side effects include infertility, thyroiditis, radiation toxicity (neoplasia, hematopoietic suppression, and salivary/lacrimal toxicity)

-Methimazole and Propylthiouracil (or PTU) are given oral where they inhibit thyroid peroxidase---> stops oxidation/iodination and coupling phases---> unable to form T3 and T4

-These medications do not inhibit the release of thyroid hormones therefore they require several weeks for therapeutic effect

***Side effects include skin rash, vasculitis, hypothyroidism, lupus-like syndrome, agranulocytosis (decreased neutrophils which makes more susceptible to infection), hypoprothrombinemia (increase risk of bleeding), hepatotoxicity (more common with propylthiouracil)

-Saturated potassium iodide solution

-Lugol's solution- Potassium iodide (10%) and iodine (5%)

-At increased concentrations, these medications inhibit the synthesis and release of T3/T4 (rapid onset of action and treat thyroid storms)

-Decrease vascularity and size of the thyroid (used before thyroid surgery)

***These medications are not used to treat hyperthyroidism because the thyroid gland can adapt and resume hormone synthesis after the initial few weeks of treatment

***Side effects include skin rash, drug fever, metallic taste, irritation of gastric mucosa, bleeding disorders, anaphylactic reactions, may also result in Fetal goiter (if given during pregnancy)

-occurs when too little production of thyroid hormones

-Thyroid supplements are provided (tyrosine-based)

-Triiodothyronine (T3) and Thyroxine (T4)

-T4 is created in greater amounts than T3 (more active form but shorter half-life)

-Production of thyroid hormone is under the production of hypothalamus/pituitary axis at the base of brain to release TRH---> stimulates Anterior Pituitary gland to release TSH ---> travels to cells of the thyroid gland and binds to TSH receptor on follicular cell--->promotes every aspect of T3 and T4 production (iodide trapping and release of thyroid hormones into thyroid gland)

-When T3 and T4 are released from the thyroid gland, most of the T3 and T4 bind to Thyroxine binding globulin in the blood to reach target cells (small amounts stay unbound and are known as physiologically active free T4)

-T4 is converted to T3---> T3 binds to thyroid hormone receptors (regulate gene expression)---> results in metabolic and physiologic effects in the body

-Increased metabolism uses up sugars and fats in metabolism and increases body heat

-T3 also activates the sympathetic nervous system responsible for 'fight or flight' response), neuronal development, increased GI motility

1)Primary- thyroid gland not making enough thyroid hormones (iodine deficiency, immune-mediated thyroiditis, or after treatment for hyperthyroidism such as radiation therapy)

2)Secondary- the body doesn't produce enough TSH (needed to stimulate the thyroid gland to produce T3 and T4), usually secondary to tumor in pituitary gland

3)Tertiary- hypothalamus does not produce enough thyroid producing hormone or TRH- results in decreased TSH and decreased T3/T4

***Congenital hypothyroidism may also occur via thyroid dysgenesis or thyroid dyshormonogenesis

-Cold, dry skin

-Cold intolerance

-Hair loss

-Weight gain

-Constipation

-Lethargy and fatigue

-Results from Infection or Heart Attack that lead to an acute drop in T3 and T4

-Sudden decrease in body temperature, decrease heart rate, decreased blood pressure, hypoventilation, confusion, and coma

-Primary, Secondary, Tertiary, or Congenital are treated with synthetic thyroid hormone replacements

(T3---> Liothyronine and T4---> Levothyroxine)

-Liothyronine is shorter acting but more potent (T3 analog so can enter the cell and take effect very rapidly therefore given IV for myxedema coma). More side effects in this drug

-Levothyroxine is less potent but longer acting, may require 6-8 weeks of therapy (needs to be converted to T3 when it enters the cell). Treatment of choice in long-term treatment and in pregnancy. Less side effects

***Dose of thyroid medication needs to be increased in pregnant patients because increased Estrogen--->increases thyroxine-binding globulins---> decreased free T4

-Drugs decrease levothyroxine absorption (Iron, calcium, aluminum hydroxide, PPIs, Sucralfate, Bile acid-binding agents (e.g.Cholestyramine)----> need to increase doses of Levothyroxine

-Drugs increase thyroid hormone metabolism (Rifampin, Phenytoin, Carbamazepine)----> need to increase doses of Levothyroxine

-Drugs increase thyroglobulin in the blood (decrease free T4) (Estrogen, Raloxifene, Tamoxifen, Heroin, Methadone)---> increase doses of Levothyroxine

-Drugs decrease thyroglobulin in the blood (increase free T4) (Androgens, glucocorticoids, anabolic steroids, slow-release nicotinic acid)----> decrease dose of levothyroxine

-Propranolol also inhibits 5'-Deiodinase to decrease conversion T4 to T3 therefore need to increase doses of Levothyroxine

-synthetic hormones that inhibit the release of TRH (from Hypothalamus) thereby decreasing TSH production (from anterior Pituitary gland)

-Liothyronine (T3) can be used to prevent the growth of thyroid nodules

-Levothyroxine (T4) can be used to prevent the recurrence of thyroid cancer

-Should not be used in patients with uncorrected adrenal insufficiency (thyroid hormones increase metabolism of glucocorticoids which are hormones produced by adrenal glands)

-In adrenal gland insufficiency, adrenals are unable to compensate for increased turnover (may lead to adrenal crisis therefore must treat adrenal insufficiency before hypothyroidism)

-Inhibit the synthesis of adrenocortical hormones (cortisol produced in zona fasciculata of the adrenal cortex)

-AHSIs include: Ketoconazole, Metyrapone, aminoglutethimide, etomidate

-Hypothalamus secretes CRH (corticotropin-releasing hormone)---> stimulates Pituitary gland production of ACTH ---> adrenocortical cells take up cholesterol from blood (and stimulates cholesterol desmolase inside cells)

--> conversion of cholesterol to pregnenolone occurs

--->enzyme 3-Beta-HSD turns some of the pregnenolone into progesterone

-Synthesis of Cortisol begins when Pregnenolone and Progesterone move into the Zona fasciculata of the Adrenal gland---> 17alpha-hydroxylase turns pregnenolone into 17-alpha-hydroxypregnenolone and it turns progesterone into 17-alpha-hydroxyprogesterone (17-alpha-hydroxypregnenolone then is converted to 17-alpha hydroxyprogesterone by 3-B-HSD enzyme)

-17-alpha-hydroxyprogesterone (converted by 21 hydroxylase) into 11-Deoxycortisol--->converted to cortisol (via enzyme 11 B-hydroxylase)

-stress hormone

-results in increased gluconeogenesis, proteolysis, lipolysis

-Maintains blood pressure (via catecholamines: epinephrine and NE and narrows blood vessel lumen)

-Dampens inflammatory and immune response (reduces production and release of prostaglandins and interleukins and inhibits proliferation of T-lymphocytes)

-Receptors are also present in the brain (may affect mood and memory)

-Cushing's syndrome: Increased cortisol levels over a long period of time

-Cushing's disease: Benign pituitary adenoma, too much ACTH

-Adrenocortical carcinoma: Overproduce cortisol results in muscle and skin breakdown, osteoporosis, increased blood glucose levels, and high insulin levels

-antifungal drug (oral)

-First-line treatment for Cushing's syndrome

-inhibits several enzymes:

1) inhibits cholesterol desmolase (decreases the conversion of cholesterol to pregnenolone and prevents the synthesis of all adrenal hormones

2) inhibits 17-alpha-hydroxylase (blocks conversion of pregnenolone to 17-alpha-hydroxypregnenolone and conversion of progesterone to 17-alpha-hydroxyprogesterone which decreases cortisol synthesis)

3) inhibits 17,20 lyase (which decreases synthesis of androgens)

***Ketoconazole is useful for the following conditions:

-adrenocortical carcinomas which increase the production of all adrenocortical hormones (cortisol and androgens)

-Breast and prostate cancer

-Decreases androgenic symptoms (ie. Hirsutism and acne)

-Side effects include GI, hepatotoxicity, sedation

-Potent CYP3A4 Inhibitor (Ketoconazole with other medications will decrease metabolism, increase blood levels and lead to toxicity)

-Enters adrenal gland and inhibits enzyme 11-B-hydroxylase which inhibits the conversion of 11-deoxycortisol to cortisol

-Does not block synthesis androgens (so Hirsutism and acne may worsen), often used with ketoconazole

-Side effects include acne, hirsutism, nausea, vomiting, edema, acute adrenal insufficiency (in individuals with decreased secretory capacity of adrenal glands)

-in healthy individuals decreased cortisol will stimulate hypothalamus to produce more CRH which causes the anterior pituitary gland to produce more ACTH and results in increased cortisol production of adrenal gland

-metyraPONE stimulation test: can be used to evaluate Hypothalmic-Pituitary axis (mP inhibits 11 B-hydroxylase which converts 11-deoxycortisol to cortisol (enzyme blocked so adrenal glands cannot produce cortisol). Therefore 11-deoxycortisol increases

-In healthy individuals, metyraPONE stimulation test will show high ACTH and high 11-Deoxycortisol. In patients with primary adrenal insufficiency, they show high ACTH but low 11-deoxycortisol. In patients with secondary or tertiary adrenal insufficiency, they will have low levels of ACTH and 11-Deoxycortisol

-oral drug

-selectively destroys all adrenocortical cells by inhibiting their mitochondria

-reserved for adrenocortical carcinoma

-synthetic corticosteroid replacement therapy needed

-Side effects include GI issues, hypercholesterolemia, rash, low white blood cell count

-Potent CYP3A4 inducer so medications given with this drug can lead to increased metabolism, decreased blood levels, and decreased efficacy

-inhibits the production of corticosteroids such as cortisol and aldosterone in the adrenal glands

-produces suppression of the adrenal cortex by preventing the enzymatic conversion of steroids by inhibiting 3-beta-hydroxysteroid dehydrogenase