2.8.8 Endocrine Drugs

Overview

Endocrine drugs are medications that mimic, replace, or block the actions of endogenous hormones. For USMLE preparation, the key is to connect each drug to the specific hormone axis it affects, the clinical indications, and the characteristic adverse effects or contraindications. This chapter focuses on the pharmacology specific to endocrine therapies, not on general pharmacologic principles or on detailed pathophysiology of each endocrine disease, which are treated elsewhere.

Thyroid Drugs

Thyroid Hormone Replacement

The primary drug for hypothyroidism is levothyroxine, a synthetic form of thyroxine, or T4. In the body, T4 is converted to the more active triiodothyronine, or T3, in peripheral tissues. Levothyroxine is orally administered, has a long half life of about 7 days, and is dosed once daily. It is protein bound and slow to reach steady state, so dose changes require several weeks before you see full clinical effect.

Levothyroxine is used for primary hypothyroidism, including Hashimoto thyroiditis and post thyroidectomy replacement, and also to suppress TSH in some cases of thyroid cancer. Adverse effects occur when the dose is excessive, producing symptoms similar to hyperthyroidism. Patients can develop tachycardia, palpitations, heat intolerance, tremor, and anxiety. Long term overtreatment can worsen angina or precipitate arrhythmias, especially atrial fibrillation, and can increase bone resorption and osteoporosis.

Important drug interactions occur through altered absorption and altered binding. Iron, calcium, cholestyramine, and some antacids decrease levothyroxine absorption and should be separated from it in time. Enzyme inducers such as carbamazepine and phenytoin increase metabolism, and estrogen increases thyroid binding globulin, which can increase levothyroxine requirements.

Liothyronine is synthetic T3. It acts faster and is more potent, but with a shorter half life and greater risk of cardiotoxicity. USMLE typically emphasizes levothyroxine as standard therapy, while liothyronine is reserved for specific cases such as myxedema coma along with IV T4 or when a rapid onset of action is needed.

Antithyroid Drugs

Thionamides, namely methimazole and propylthiouracil, or PTU, inhibit thyroid hormone synthesis. Both act by blocking thyroid peroxidase, which normally catalyzes iodide oxidation, organification, and coupling of iodotyrosine residues needed to form T3 and T4. PTU also inhibits peripheral conversion of T4 to T3, which methimazole does not.

Methimazole is usually the first-line drug for hyperthyroidism due to once daily dosing and fewer severe hepatic effects. PTU is preferred in the first trimester of pregnancy because methimazole is associated with specific congenital anomalies such as aplasia cutis. After the first trimester, patients are typically switched to methimazole because of PTU associated hepatotoxicity.

Both drugs can cause skin rash, arthralgia, and gastrointestinal upset. A serious but rare toxicity is agranulocytosis, which presents with sudden fever and sore throat.

PTU carries a black box warning for severe hepatotoxicity. Methimazole is contraindicated in the first trimester and in patients with life threatening methimazole induced reactions. In thyroid storm, PTU is often used acutely because of its additional inhibition of peripheral T4 to T3 conversion.

Other antithyroid therapies include iodide and radioiodine. High dose potassium iodide acutely inhibits thyroid hormone release and synthesis. This is used short term, such as preoperatively, or in thyroid storm, often combined with beta blockers and thionamides. Radioactive iodine, usually I 131, is taken up by the thyroid and causes gradual gland destruction. It is a definitive treatment for Graves disease but is contraindicated in pregnancy and breastfeeding. Hypothyroidism is a common long term consequence that then requires levothyroxine replacement.

Beta blockers, particularly propranolol, are not antithyroid per se but are very important in symptomatic control of hyperthyroidism. They reduce adrenergic symptoms such as tremor and tachycardia, and propranolol at higher doses also reduces peripheral conversion of T4 to T3.

Insulin and Antidiabetic Drugs

Insulin Preparations

Insulin therapies are central in type 1 diabetes and often required in advanced type 2 disease. On exam, you must recognize their onset, peak, and duration.

Rapid acting insulins, such as lispro, aspart, and glulisine, are injected before meals. They have an onset of about 15 minutes and a peak around 1 hour, with duration of 3 to 4 hours. They mimic the normal prandial insulin spike and are useful to control postprandial glucose.

Short acting regular insulin has an onset of 30 to 60 minutes, peaks at 2 to 3 hours, and lasts 5 to 8 hours. It is still used for IV therapy in diabetic ketoacidosis and in hyperkalemia to drive potassium into cells. For meal coverage, it must be injected about 30 minutes before eating.

Intermediate acting NPH insulin is a suspension that has delayed absorption, with a peak at about 4 to 10 hours and duration up to 16 hours. It is used for basal coverage but has a pronounced peak so it can cause nighttime hypoglycemia.

Long acting insulins, such as glargine and detemir, provide relatively peakless basal insulin coverage with duration up to 24 hours. Degludec is ultra long acting. These are commonly given once daily.

Insulin adverse effects center on hypoglycemia. Symptoms include sweating, tremor, confusion, palpitations, and in severe cases seizures or coma. Weight gain is common. Local reactions such as lipohypertrophy or lipoatrophy can occur at injection sites if rotation is inadequate.

Non Insulin Antidiabetic Drugs

The major non insulin drug classes for type 2 diabetes differ by their mechanism of glucose lowering and their impact on weight and hypoglycemia risk. Recognizing these patterns is high yield.

Biguanides are represented by metformin. Metformin decreases hepatic gluconeogenesis, increases peripheral insulin sensitivity, and may modestly reduce intestinal glucose absorption. It does not stimulate insulin secretion, so hypoglycemia is rare. It often causes gastrointestinal upset like nausea and diarrhea. A serious but rare adverse effect is lactic acidosis, especially in renal insufficiency. For this reason, metformin is contraindicated in severe chronic kidney disease and is typically held temporarily before iodinated contrast studies in patients with reduced renal function.

Sulfonylureas, such as first generation tolbutamide and chlorpropamide and second generation glyburide, glipizide, and glimepiride, stimulate insulin release from pancreatic beta cells. They close ATP sensitive potassium channels, causing depolarization and insulin exocytosis. They can cause hypoglycemia and weight gain. First generation agents can cause disulfiram like reactions, while second generation agents are more potent and more commonly used. Use is risky in elderly patients and in those with renal or hepatic impairment.

Meglitinides, such as repaglinide and nateglinide, have a similar mechanism of closing beta cell potassium channels, but they are shorter acting and mainly target postprandial glucose when taken before meals. Hypoglycemia and weight gain remain adverse effects.

Thiazolidinediones, TZDs, include pioglitazone and rosiglitazone. They activate PPAR gamma, a nuclear receptor that regulates genes for adipocyte differentiation and glucose metabolism. They increase insulin sensitivity in adipose tissue, muscle, and liver. Adverse effects include weight gain, fluid retention, and an increased risk of heart failure exacerbation. They can also cause bone fractures and may increase the risk of bladder cancer, especially with pioglitazone. Liver toxicity was a concern with earlier agents, so liver function monitoring is important.

Dipeptidyl peptidase 4, DPP 4, inhibitors, such as sitagliptin and saxagliptin, inhibit the enzyme that breaks down incretins like GLP 1. This increases endogenous GLP 1 and GIP, which enhance glucose dependent insulin secretion and reduce glucagon. They are weight neutral and have a low hypoglycemia risk when used alone. Reported adverse effects include mild infections, nasopharyngitis, and, rarely, pancreatitis and joint pain.

Glucagon like peptide 1 receptor agonists, such as exenatide, liraglutide, and semaglutide, directly activate GLP 1 receptors. They enhance glucose dependent insulin secretion, suppress glucagon, slow gastric emptying, and promote satiety. This can lead to weight loss. They commonly cause nausea and vomiting and carry a risk of pancreatitis. Some are associated with an increased risk of medullary thyroid carcinoma in rodent studies, so they are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or MEN 2.

Sodium glucose cotransporter 2, SGLT2, inhibitors, such as canagliflozin, dapagliflozin, and empagliflozin, block glucose reabsorption in the proximal tubule, causing glycosuria and lowered blood glucose. They promote modest weight loss and lower blood pressure. Adverse effects include urinary tract infections, genital mycotic infections, volume depletion, and risk of euglycemic ketoacidosis. Canagliflozin has been associated with increased risk of fractures and amputations. These drugs require adequate kidney function.

Alpha glucosidase inhibitors, such as acarbose and miglitol, inhibit brush border alpha glucosidases in the intestine. This slows carbohydrate digestion and glucose absorption, particularly affecting postprandial hyperglycemia. They cause flatulence, diarrhea, and abdominal pain. Because they act in the gut, they are less effective with low carbohydrate intake.

A comparison of selected features is useful:

Adrenal Drugs

Glucocorticoids

Glucocorticoids are synthetic analogs of cortisol that act at intracellular glucocorticoid receptors and alter gene transcription. Common agents include hydrocortisone, prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, and betamethasone. Hydrocortisone is the most mineralocorticoid like, while dexamethasone and betamethasone have almost pure glucocorticoid effect and long duration.

In endocrine contexts, glucocorticoids are used for adrenal insufficiency replacement, as in Addison disease, and for congenital adrenal hyperplasia to suppress ACTH and reduce adrenal androgen production. Dexamethasone is also used diagnostically in the dexamethasone suppression test for Cushing syndrome.

Systemic glucocorticoids have broad adverse effects. Metabolic effects include hyperglycemia, muscle wasting, fat redistribution with central obesity and moon facies, and osteoporosis. They cause skin thinning, poor wound healing, and increase susceptibility to infection through immunosuppression. Cardiovascular effects include hypertension and fluid retention, especially with glucocorticoids that have mineralocorticoid activity. Psychiatric effects include mood changes, insomnia, and psychosis.

Mineralocorticoids and Antagonists

Fludrocortisone is a synthetic mineralocorticoid with potent aldosterone like activity and some glucocorticoid activity. It is used as replacement in primary adrenal insufficiency and in some forms of congenital adrenal hyperplasia. Adverse effects resemble aldosterone excess, such as hypertension, edema, hypokalemia, and metabolic alkalosis.

Mineralocorticoid receptor antagonists, such as spironolactone and eplerenone, block aldosterone receptors in the collecting duct. They are primarily used as diuretics and in heart failure, but in endocrine conditions spironolactone is also used for hyperaldosteronism and to treat androgen excess, for example in hirsutism and polycystic ovary syndrome, because it also antagonizes androgen receptors and inhibits steroid synthesis. Spironolactone can cause hyperkalemia, gynecomastia, decreased libido, and menstrual irregularities. Eplerenone is more selective for mineralocorticoid receptors and has fewer endocrine side effects.

Adrenal steroid synthesis inhibitors such as ketoconazole and metyrapone also have endocrine relevance. Ketoconazole, an antifungal, at high doses inhibits several cytochrome P450 enzymes in steroid synthesis and is used in some cases of Cushing syndrome. It can cause hepatotoxicity and antiandrogen effects, with gynecomastia and decreased libido. Metyrapone blocks 11 beta hydroxylase, reducing cortisol synthesis and increasing 11 deoxycortisol and ACTH. It is used diagnostically to test HPA axis function and sometimes therapeutically.

Pituitary and Hypothalamic Drugs

Anterior Pituitary Related Drugs

Prolactin secretion is inhibited by dopamine, so dopamine agonists treat hyperprolactinemia. Bromocriptine and cabergoline are D2 receptor agonists that lower prolactin levels, shrink prolactinomas, and restore fertility. Cabergoline is more selective and longer acting, with a lower risk of nausea. Adverse effects include nausea, orthostatic hypotension, and, with chronic use at high doses, valvular heart disease.

Somatostatin analogs, such as octreotide and lanreotide, bind somatostatin receptors and inhibit secretion of growth hormone, TSH, and several gastrointestinal hormones. In endocrine practice, octreotide is used for acromegaly and for hormone secreting tumors including some pituitary tumors. Adverse effects include gastrointestinal disturbances, gallstones due to reduced gallbladder contractility, and possible vitamin B12 deficiency.

Growth hormone analogs such as somatropin are used in growth hormone deficiency and some non endocrine growth failure syndromes. Adverse effects can include edema, arthralgia, and intracranial hypertension. Conversely, growth hormone receptor antagonists like pegvisomant block GH receptors and are used in acromegaly when somatostatin analogs are insufficient. Pegvisomant can cause liver function abnormalities.

Posterior Pituitary Related Drugs

Vasopressin, also called antidiuretic hormone, ADH, and its analogs are central in the treatment of diabetes insipidus. Desmopressin, DDAVP, is a synthetic analog with selective V2 receptor activity in the kidney and minimal vasoconstrictive V1 activity. It increases water reabsorption in the collecting duct and is used in central diabetes insipidus, nocturnal enuresis, and some bleeding disorders such as von Willebrand disease. Excessive dosing can cause water retention and hyponatremia, leading to headache, confusion, or seizures.

Vasopressin itself activates both V1 and V2 receptors and is used intravenously in some shock states and for variceal bleeding, but its strong vasoconstrictive actions can cause ischemia.

Drugs that antagonize vasopressin receptors, the vaptans such as conivaptan and tolvaptan, block V2 receptors in the kidney to promote free water excretion. They are used in certain cases of SIADH and euvolemic or hypervolemic hyponatremia. Overly rapid correction of chronic hyponatremia is dangerous and can lead to osmotic demyelination.

Gonadal and Reproductive Hormones

Estrogens and Selective Estrogen Receptor Modulators

Exogenous estrogens, such as ethinyl estradiol and conjugated estrogens, act at estrogen receptors and are used in contraception, hormone replacement therapy, and certain gynecologic conditions. Estrogen adverse effects include nausea, breast tenderness, and increased risk of thromboembolism, stroke, and some cancers, especially with long term unopposed estrogen which increases the risk of endometrial carcinoma. Combined estrogen progestin therapy mitigates that endometrial risk but can still increase breast cancer risk in some populations.

Selective estrogen receptor modulators, SERMs, have tissue specific agonist or antagonist activity. Tamoxifen is an estrogen receptor antagonist in breast tissue and an agonist in bone and endometrium. It is used for estrogen receptor positive breast cancer treatment and prevention. It increases the risk of endometrial carcinoma and thromboembolism but protects bone density. Raloxifene is an estrogen agonist in bone and antagonist in breast and endometrium. It is used in osteoporosis prevention and treatment and in breast cancer risk reduction. Raloxifene does not increase endometrial cancer risk but still increases thrombotic risk.

Clomiphene is another SERM that acts as an estrogen antagonist at hypothalamic receptors. It blocks negative feedback of estrogen on the hypothalamus, increasing GnRH, FSH, and LH, and thereby stimulating ovulation. It is used in some cases of infertility, including anovulation in polycystic ovary syndrome. Multiple pregnancies, hot flashes, and visual disturbances can occur.

Aromatase inhibitors, such as anastrozole, letrozole, and exemestane, block conversion of androgens to estrogens in peripheral tissues. They are used in estrogen receptor positive breast cancer in postmenopausal women. They can cause osteoporosis, arthralgias, and menopausal symptoms.

Progestins and Antiprogestins

Progestins, including progesterone and synthetic derivatives like medroxyprogesterone, levonorgestrel, and norethindrone, act at progesterone receptors. They reduce endometrial proliferation, increase cervical mucus viscosity, and inhibit ovulation at higher doses. They are used in contraception, abnormal uterine bleeding, endometriosis, and hormone replacement therapy. Adverse effects include weight gain, depression, irregular bleeding, and changes in lipid profiles.

Antiprogestins, especially mifepristone, are progesterone receptor antagonists. Mifepristone is used in combination with a prostaglandin analog like misoprostol for medical termination of early pregnancy. It leads to decidual breakdown and detachment of the embryo. Misoprostol then induces uterine contractions to expel the products of conception. Mifepristone can cause heavy bleeding, cramping, and gastrointestinal symptoms. It is also used in some cases of Cushing syndrome because at higher doses it antagonizes glucocorticoid receptors.

Combined Hormonal Contraceptives

Combined oral contraceptives, COCs, contain estrogen, most often ethinyl estradiol, and a progestin. Their primary contraceptive mechanism is suppression of ovulation through negative feedback on the hypothalamic pituitary gonadal axis, which decreases FSH and LH and prevents the LH surge. Progestin also thickens cervical mucus and makes the endometrium less suitable for implantation.

Non oral combined methods, such as the transdermal patch and vaginal ring, use the same hormones. Typical adverse effects include nausea, breast tenderness, and breakthrough bleeding. More serious risks include venous thromboembolism and, in some women, hypertension and increased stroke risk.

Progestin only methods, including the progestin only pill, injectables such as depot medroxyprogesterone acetate, implants, and some intrauterine devices, primarily act through thickening cervical mucus and creating an atrophic endometrium. They are preferred when estrogen is contraindicated. Irregular bleeding is common.

Androgens and Antiandrogens

Testosterone and synthetic androgens like methyltestosterone are used for male hypogonadism and some types of delayed puberty. They promote development of male secondary sexual characteristics, increase muscle mass, and stimulate erythropoiesis. Adverse effects include premature closure of epiphyseal plates in adolescents, testicular atrophy, decreased fertility through suppression of LH and FSH, acne, and virilization in women. Androgen abuse can cause liver toxicity and cardiovascular risk.

Antiandrogen therapies include several mechanisms. 5 alpha reductase inhibitors such as finasteride and dutasteride block conversion of testosterone to dihydrotestosterone, DHT, particularly in prostate and hair follicles. They are used in benign prostatic hyperplasia and male pattern baldness. Adverse effects include decreased libido, erectile dysfunction, and rare gynecomastia.

Androgen receptor antagonists, such as flutamide, bicalutamide, nilutamide, and enzalutamide, block androgen receptors in target tissues. They are used in prostate cancer, usually along with GnRH analogs. Spironolactone, already discussed, also has antiandrogen effects and is used for hirsutism and some cases of androgen excess.

Gonadotropin releasing hormone, GnRH, analogs such as leuprolide have different effects depending on dosing pattern. In pulsatile dosing, they can stimulate FSH and LH and support fertility treatments. In continuous dosing, they cause downregulation of GnRH receptors and decrease LH and FSH, leading to medical castration levels of sex hormones. Continuous leuprolide is used in prostate cancer, endometriosis, uterine fibroids, and precocious puberty. Adverse effects reflect hypoestrogenism in women or hypogonadism in men, including hot flashes, decreased libido, and bone loss.

Bone Mineral and Calcium Regulating Drugs

Vitamin D Analogs and Calcimimetics

Vitamin D analogs, such as calcitriol, cholecalciferol, and ergocalciferol, are used to treat vitamin D deficiency, hypocalcemia, and some forms of secondary hyperparathyroidism. Calcitriol is the active form and is particularly important in chronic kidney disease, where conversion of vitamin D to its active form is impaired. Excessive vitamin D can cause hypercalcemia, hyperphosphatemia, and nephrocalcinosis.

Calcimimetics such as cinacalcet activate calcium sensing receptors on parathyroid cells, making them more sensitive to circulating calcium. This reduces PTH secretion and is used in secondary hyperparathyroidism in chronic kidney disease and in some cases of parathyroid carcinoma. Hypocalcemia and gastrointestinal symptoms are the main adverse effects.

Bisphosphonates and Other Osteoporosis Drugs

Bisphosphonates, such as alendronate, risedronate, ibandronate, and zoledronic acid, are analogs of pyrophosphate that bind hydroxyapatite and are taken up by osteoclasts. They inhibit osteoclast mediated bone resorption, improving bone density and reducing fracture risk in osteoporosis, Paget disease of bone, and some malignancy associated hypercalcemias. Oral agents must be taken with water on an empty stomach, and the patient must remain upright for at least 30 minutes to reduce esophageal irritation.

Adverse effects include esophagitis, esophageal ulcers, and, with long term use, rare osteonecrosis of the jaw and atypical femoral fractures.

Denosumab is a monoclonal antibody that targets RANKL, preventing activation of RANK on osteoclast precursors and thereby reducing bone resorption. It is used for osteoporosis in high risk patients. Hypocalcemia and increased risk of infections are possible side effects.

Teriparatide is a recombinant PTH analog given intermittently. Unlike continuous PTH elevation which causes bone resorption, intermittent low dose teriparatide increases osteoblastic activity and bone formation. It is used for severe osteoporosis. Long term use beyond two years is generally avoided because of osteosarcoma risk seen in animal studies. Hypercalcemia and hypercalciuria can occur.

Summary

Endocrine drugs target specific hormone pathways and frequently rely on feedback mechanisms that are characteristic of the endocrine system. For USMLE purposes, it is essential to connect each drug with the hormone axis affected, remember the direction of effect on hormone levels, and associate characteristic adverse reactions that often mirror either excess or deficiency of the hormone involved.