💊Intro to Pharmacology Unit 9 – Endocrine & Metabolic Drug Therapies

Key Hormones and Glands

• Major endocrine glands include the hypothalamus, pituitary, thyroid, parathyroid, adrenal, pancreas, and gonads (ovaries and testes)
• Hypothalamus secretes releasing hormones (CRH, TRH, GnRH) that stimulate the anterior pituitary to release its hormones
• Anterior pituitary releases hormones such as ACTH, TSH, FSH, LH, GH, and prolactin which target various endocrine glands
• Thyroid gland produces thyroid hormones (T3 and T4) that regulate metabolism, growth, and development
  • Calcitonin from the thyroid helps regulate calcium levels
• Parathyroid glands secrete parathyroid hormone (PTH) which increases blood calcium levels
• Adrenal cortex produces glucocorticoids (cortisol), mineralocorticoids (aldosterone), and androgens while the adrenal medulla secretes catecholamines (epinephrine and norepinephrine)
• Pancreas contains islet cells that secrete insulin and glucagon to regulate blood glucose levels
• Gonads produce sex hormones such as estrogen, progesterone, and testosterone which are essential for reproductive function and secondary sexual characteristics

Endocrine System Basics

• Endocrine system consists of glands that secrete hormones directly into the bloodstream to regulate various physiological processes
• Hormones are chemical messengers that travel through the blood to target specific cells or organs
• Endocrine glands are ductless and release hormones in response to stimuli such as blood levels of specific substances, neuronal input, or other hormones
• Hormone receptors on target cells bind to specific hormones, initiating a cascade of cellular responses
• Negative feedback loops help maintain homeostasis by adjusting hormone secretion based on the levels of the regulated substance (glucose, calcium, thyroid hormones)
  • For example, high blood glucose levels stimulate insulin secretion, which then lowers blood glucose by promoting uptake into cells
• Positive feedback loops are less common but can be seen in situations such as oxytocin release during childbirth, leading to increased uterine contractions
• Endocrine disorders can result from hyposecretion (too little) or hypersecretion (too much) of hormones, or from the target cells' inability to respond appropriately to hormones

Common Endocrine Disorders

• Diabetes mellitus is characterized by high blood glucose levels due to insufficient insulin production (Type 1) or insulin resistance (Type 2)
• Hypothyroidism results from an underactive thyroid gland, leading to symptoms such as fatigue, weight gain, and cold intolerance
• Hyperthyroidism occurs when the thyroid gland produces excessive amounts of thyroid hormones, causing weight loss, heat intolerance, and rapid heartbeat
• Cushing's syndrome is caused by prolonged exposure to high levels of cortisol, leading to weight gain, muscle weakness, and skin changes
• Addison's disease is a rare disorder characterized by insufficient production of cortisol and aldosterone, causing fatigue, weight loss, and low blood pressure
• Hyperparathyroidism results from overactive parathyroid glands, leading to high blood calcium levels and an increased risk of osteoporosis
• Hypogonadism occurs when the gonads produce insufficient levels of sex hormones, leading to delayed puberty, infertility, and decreased libido
• Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women, characterized by excessive androgen production, irregular menstrual cycles, and ovarian cysts

Types of Endocrine Drugs

• Insulin and insulin analogs are used to treat diabetes mellitus by lowering blood glucose levels
  • Examples include short-acting (regular insulin), intermediate-acting (NPH insulin), and long-acting (glargine, detemir) insulins
• Oral hypoglycemic agents help manage Type 2 diabetes by increasing insulin sensitivity (metformin, thiazolidinediones) or stimulating insulin secretion (sulfonylureas, meglitinides)
• Thyroid hormone replacements (levothyroxine) are used to treat hypothyroidism
• Antithyroid drugs (methimazole, propylthiouracil) inhibit thyroid hormone synthesis and are used to treat hyperthyroidism
• Corticosteroids (prednisone, hydrocortisone) are used to replace deficient cortisol in conditions like Addison's disease or to suppress inflammation in various disorders
• Gonadotropins (FSH, LH, hCG) and sex hormone replacements (estrogen, progesterone, testosterone) are used to treat hypogonadism and infertility
• Bisphosphonates (alendronate, risedronate) and calcitonin are used to treat osteoporosis by inhibiting bone resorption
• Somatostatin analogs (octreotide) are used to treat acromegaly and neuroendocrine tumors by inhibiting growth hormone and other hormone secretion

Mechanism of Action

• Insulin and insulin analogs bind to insulin receptors on target cells, promoting glucose uptake and utilization while inhibiting glucose production in the liver
• Oral hypoglycemic agents work by various mechanisms:
  • Metformin reduces hepatic glucose production and increases insulin sensitivity in peripheral tissues
  • Sulfonylureas and meglitinides stimulate insulin secretion from pancreatic beta cells
  • Thiazolidinediones increase insulin sensitivity by activating PPAR-gamma receptors
• Levothyroxine (T4) is converted to the active form, triiodothyronine (T3), which binds to thyroid hormone receptors and regulates gene expression
• Antithyroid drugs inhibit thyroid peroxidase, an enzyme essential for thyroid hormone synthesis
• Corticosteroids bind to glucocorticoid receptors and regulate gene expression, leading to anti-inflammatory and immunosuppressive effects
• Gonadotropins (FSH, LH) bind to their respective receptors in the gonads, stimulating sex hormone production and gametogenesis
• Bisphosphonates inhibit osteoclast activity, reducing bone resorption and increasing bone mineral density
• Calcitonin binds to receptors on osteoclasts, inhibiting their activity and decreasing bone resorption

Pharmacokinetics

• Insulin is typically administered subcutaneously, with the onset, peak, and duration of action varying depending on the type of insulin
  • Regular insulin: Onset 30-60 min, peak 2-4 h, duration 6-8 h
  • NPH insulin: Onset 2-4 h, peak 4-10 h, duration 12-18 h
  • Glargine and detemir: Onset 2-4 h, minimal peak, duration 20-24 h
• Oral hypoglycemic agents are administered orally and have varying half-lives and durations of action
  • Metformin: Half-life 6.2 h, duration 24 h
  • Sulfonylureas: Half-life 3-7 h, duration 12-24 h
  • Thiazolidinediones: Half-life 3-7 h, duration 24 h
• Levothyroxine is administered orally, with a half-life of 7 days and a duration of action of several weeks
• Antithyroid drugs are administered orally, with half-lives ranging from 4-6 hours (propylthiouracil) to 4-6 days (methimazole)
• Corticosteroids can be administered orally, intravenously, or topically, with half-lives ranging from 1-5 hours and durations of action varying based on the specific drug and formulation
• Gonadotropins are administered subcutaneously or intramuscularly, with half-lives ranging from a few hours to several days
• Bisphosphonates are administered orally or intravenously, with varying half-lives and durations of action depending on the specific drug and route of administration

Clinical Uses and Indications

• Insulin and oral hypoglycemic agents are used to manage diabetes mellitus and maintain blood glucose levels within a target range
• Levothyroxine is indicated for the treatment of hypothyroidism, goiter, and cretinism
• Antithyroid drugs are used to treat hyperthyroidism, including Graves' disease and toxic nodular goiter
• Corticosteroids are used to replace deficient cortisol in conditions like Addison's disease and to treat various inflammatory and autoimmune disorders (rheumatoid arthritis, asthma, inflammatory bowel disease)
• Gonadotropins and sex hormone replacements are used to treat hypogonadism, delayed puberty, and infertility
  • FSH and LH are used to stimulate follicle development and ovulation in assisted reproductive techniques
• Bisphosphonates and calcitonin are used to treat osteoporosis, Paget's disease, and hypercalcemia of malignancy
• Somatostatin analogs are used to treat acromegaly, neuroendocrine tumors, and refractory diarrhea associated with certain conditions (AIDS, short bowel syndrome)

Side Effects and Precautions

• Insulin and oral hypoglycemic agents can cause hypoglycemia, which may present with symptoms such as shakiness, sweating, confusion, and seizures
  • Patients should be educated on the signs and symptoms of hypoglycemia and how to manage it
• Levothyroxine may cause symptoms of hyperthyroidism if the dose is too high, such as tachycardia, tremors, and heat intolerance
• Antithyroid drugs can cause agranulocytosis, a serious condition characterized by a severe decrease in white blood cells, leading to an increased risk of infections
  • Patients should be monitored for signs of infection and have their blood counts checked regularly
• Corticosteroids can cause a wide range of side effects, including weight gain, osteoporosis, hypertension, and impaired wound healing
  • Long-term use may lead to adrenal suppression, requiring careful tapering of the dose when discontinuing therapy
• Gonadotropins and sex hormone replacements may cause side effects related to their specific hormonal actions, such as bloating, breast tenderness, and mood changes
• Bisphosphonates can cause gastrointestinal side effects, such as nausea, vomiting, and abdominal pain
  • Rarely, they may cause osteonecrosis of the jaw or atypical femoral fractures
• Somatostatin analogs may cause gastrointestinal side effects, such as diarrhea, abdominal pain, and gallstone formation

Drug Interactions

• Insulin and oral hypoglycemic agents may interact with other medications that affect glucose metabolism, such as corticosteroids, thiazide diuretics, and beta-blockers
• Levothyroxine absorption may be reduced by medications that bind to it in the gut, such as calcium carbonate, iron supplements, and cholestyramine
  • Levothyroxine should be taken on an empty stomach, at least 4 hours apart from these medications
• Antithyroid drugs may interact with medications that can cause agranulocytosis, such as clozapine and carbamazepine, increasing the risk of this serious side effect
• Corticosteroids may interact with a wide range of medications due to their effects on drug metabolism and their immunosuppressive properties
  • Examples include increased risk of gastrointestinal bleeding with NSAIDs and decreased effectiveness of vaccines
• Gonadotropins and sex hormone replacements may interact with medications that affect hormone metabolism or binding, such as anticonvulsants and thyroid hormone replacements
• Bisphosphonates may interact with medications that can cause esophageal irritation, such as NSAIDs and iron supplements, increasing the risk of gastrointestinal side effects

Patient Education and Monitoring

• Patients should be educated on the proper administration, storage, and disposal of their endocrine medications
  • For example, insulin should be stored in the refrigerator and discarded 28 days after opening
• Patients should be taught how to monitor their blood glucose levels and adjust their insulin doses accordingly
  • They should also be educated on the signs and symptoms of hypoglycemia and how to manage it
• Patients taking levothyroxine should be instructed to take it on an empty stomach, at least 30 minutes before breakfast, and to avoid taking it with medications that can interfere with its absorption
• Patients on antithyroid drugs should be advised to report any signs of infection, such as fever, sore throat, or mouth ulcers, as these may indicate agranulocytosis
• Patients taking corticosteroids should be monitored for side effects, such as weight gain, hypertension, and osteoporosis
  • They should also be educated on the importance of not discontinuing the medication abruptly and the need for stress-dose steroids during illness or surgery
• Patients undergoing treatment with gonadotropins or sex hormone replacements should be monitored for side effects and have their hormone levels checked regularly
• Patients taking bisphosphonates should be instructed to take them with a full glass of water and to remain upright for at least 30 minutes after administration to reduce the risk of esophageal irritation

Special Considerations

• Pregnancy and lactation: Many endocrine medications can cross the placenta or be excreted in breast milk, potentially affecting the fetus or infant
  • The risks and benefits of using these medications during pregnancy or lactation should be carefully considered and discussed with the patient
• Elderly patients may be more sensitive to the effects of endocrine medications and may require lower doses or more frequent monitoring
  • They may also be at increased risk for side effects, such as hypoglycemia with insulin or oral hypoglycemic agents
• Patients with renal or hepatic impairment may require dose adjustments or more frequent monitoring when taking endocrine medications, as these conditions can affect drug metabolism and elimination
• Patients with a history of adrenal insufficiency or hypothalamic-pituitary disorders may require stress-dose steroids during illness, surgery, or other stressful events
• Patients with diabetes should be monitored for complications, such as retinopathy, neuropathy, and nephropathy, and should receive regular foot exams and eye exams
• Patients with thyroid disorders should have their thyroid function monitored regularly and their medication doses adjusted as needed
  • Those with a history of thyroid cancer may require more frequent monitoring and may need to maintain TSH levels at the lower end of the reference range