Endocrine

Insulin binds a tyrosine-kinase receptor that moves GLUT4 to the surface of muscle and fat cells, stores glucose as glycogen in liver and muscle, and switches off lipolysis and ketogenesis. The insulins are the same hormone engineered to absorb at different speeds — rapid analogs for meals, NPH, glargine and degludec as basal depots — and the two classic dangers are hypoglycemia and a fall in potassium as insulin drives it into cells.

Metformin, a biguanide, lowers blood glucose mainly by cutting the liver’s glucose output, with less intestinal glucose absorption and better peripheral glucose uptake. Insulin secretion stays unchanged, so on its own it is unlikely to cause hypoglycemia and is weight-neutral. Its boxed danger, lactic acidosis, follows from its handling: the kidneys clear it unchanged, and at toxic levels it blocks mitochondrial respiration and the liver’s use of lactate — so anything that stops its excretion or adds lactate tips the balance.

Sulfonylureas bind the sulfonylurea receptor (SUR1) of the ATP-sensitive potassium channel on pancreatic β cells and close it. Less potassium leaves, the cell depolarizes, voltage-gated calcium channels open, and insulin is released — whatever the blood glucose. That is why they work only while β cells still function, and why their signature harms are hypoglycemia and weight gain, worst with the long-acting glyburide in older adults or renal impairment.

DPP-4 is the enzyme that inactivates the gut’s incretin hormones, GLP-1 and GIP, within minutes of their release. The -gliptins inhibit it, so the patient’s own incretins last longer: insulin release rises and glucagon falls, but only when glucose is high — hence little hypoglycemia on their own and no weight change. The four drugs differ mainly in how they are cleared, which predicts their renal dosing and interactions, and the class shares pancreatitis, joint pain, bullous pemphigoid and hypersensitivity warnings, with a heart-failure signal for saxagliptin and alogliptin.

GLP-1 is a gut incretin that makes the β cell release insulin only when glucose is high, lowers glucagon, slows gastric emptying and increases satiety — but native GLP-1 is degraded within minutes. Semaglutide, liraglutide and dulaglutide are GLP-1 analogs engineered to resist that breakdown and last from hours to a week, and tirzepatide also activates the GIP receptor. The class lowers glucose with little hypoglycemia and with weight loss, and its harms follow from its actions: GI effects (with kidney injury when fluid is lost), a boxed rodent thyroid C-cell tumor signal that rules out medullary thyroid carcinoma and MEN 2, and pancreatitis.

Four smaller groups with four mechanisms. Pioglitazone activates the nuclear receptor PPAR-γ and sensitizes fat, muscle and liver to insulin — at the price of fluid retention and heart failure. Acarbose and miglitol block the brush-border enzymes that free glucose from dietary carbohydrate, so the after-meal rise is blunted and the leftover sugar ferments in the colon. Repaglinide and nateglinide close the β-cell K-ATP channel briefly at mealtimes. Pramlintide replaces amylin, the hormone co-secreted with insulin, slowing gastric emptying and suppressing glucagon.

Glucagon is the α-cell hormone that defends against hypoglycemia. It binds a Gs-coupled receptor, mainly on hepatocytes, raises cAMP and activates protein kinase A, which turns on glycogen breakdown and gluconeogenesis and turns off glycogen synthesis. Given as an injection or a nasal powder, it rescues severe hypoglycemia when sugar cannot be taken by mouth — but only if the liver still has glycogen.

Empagliflozin and dapagliflozin block SGLT2, the proximal-tubule transporter that reclaims most filtered glucose, so glucose and sodium leave in the urine. The glucosuria lowers blood glucose; the natriuresis lowers cardiac preload and intraglomerular pressure — the basis of the heart-failure and kidney indications — while the same glucose-rich urine and ketone shift explain genital infections, Fournier’s gangrene and euglycemic ketoacidosis. (on the Cardiovascular pages)

Thyroid hormone is built in four steps the drugs can target: the sodium-iodide symporter traps iodide, thyroid peroxidase oxidizes it and couples iodinated tyrosines on thyroglobulin into T4 and T3, proteolysis releases them, and deiodinases turn T4 into the more active T3 in tissues. Methimazole and PTU block thyroid peroxidase (PTU also blocks peripheral deiodination); pharmacologic iodide blocks release and, briefly, organification; radioactive iodine is trapped like dietary iodide and destroys the gland from inside; levothyroxine replaces T4 with a long half-life and a narrow window.

Competitive β-adrenergic antagonists that blunt Gs–cAMP signalling in the heart and kidney. β1 selectivity, partial agonism (ISA), α1 or nitric-oxide vasodilation and the route of elimination tell the ten drugs apart. (on the Cardiovascular pages)

Glucocorticoids diffuse into cells and bind a cytoplasmic receptor that moves to the nucleus: it switches on anti-inflammatory genes such as lipocortin-1, which inhibits phospholipase A2, and switches off inflammatory transcription factors such as NF-κB. The same genomic action raises glucose, breaks down muscle and bone, and feeds back on the HPA axis, so long courses suppress ACTH and must be tapered. The drugs differ mainly in duration and in how much they also stimulate the mineralocorticoid receptor — cortisol about equally, the synthetic steroids hardly at all.

The adrenal cortex runs two hormone lines: cortisol under ACTH, and aldosterone under the renin–angiotensin system. Fludrocortisone replaces the missing mineralocorticoid when the gland itself fails, and it is judged by blood pressure, potassium and renin. Osilodrostat and metyrapone block 11β-hydroxylase, the last step of cortisol synthesis, so precursors build up behind the block — the reason for osilodrostat’s hypokalemia, hypertension and androgen effects. Mifepristone blocks cortisol at its receptor instead, so cortisol rises and adrenal insufficiency has to be recognized clinically.

Two routes to the same channel: mineralocorticoid-receptor antagonists (spironolactone, eplerenone) and ENaC blockers (amiloride, triamterene). Both shut down electrogenic sodium entry in the aldosterone-sensitive distal nephron, so K⁺ and H⁺ secretion fall. (on the Cardiovascular pages)

Three anterior-pituitary levers. Somatostatin switches off growth hormone, insulin, glucagon, TSH and gut hormones; its long-acting analogs octreotide and lanreotide treat acromegaly, carcinoid and VIPoma — and, like a somatostatinoma, cause gallstones and glucose swings. Growth hormone acts through IGF-1: somatropin replaces it, while pegvisomant blocks its receptor and is judged by IGF-1 alone. Dopamine tonically inhibits prolactin, so the ergot D2 agonists cabergoline and bromocriptine treat prolactinomas and hyperprolactinemia, at the price of valve and fibrosis risks.

Vasopressin (ADH) acts on two receptors: V2 on the collecting duct (Gs → cAMP → aquaporin-2 insertion → water reabsorption) and V1 on vascular smooth muscle (Gq → calcium → vasoconstriction). Desmopressin is a V2-selective analog with little pressor effect — it replaces ADH in central diabetes insipidus, distinguishes central from nephrogenic DI, and releases von Willebrand factor and factor VIII; its defining risk is water intoxication. Vasopressin itself is a V1 pressor for vasodilatory shock. (on the Renal pages)

Antagonists of vasopressin’s V2 receptor in the collecting duct, which signals through Gs, cAMP and aquaporin-2. Blocking it causes aquaresis — free-water loss without sodium loss — which raises serum sodium in euvolemic and hypervolemic hyponatremia and lowers the cAMP that drives cyst growth in ADPKD. Conivaptan also blocks the vascular V1a receptor. (on the Renal pages)

Bisphosphonates are pyrophosphate analogs that bind bone hydroxyapatite where bone is being resorbed. When an osteoclast resorbs that bone it releases the drug, and the nitrogen-containing agents — alendronate, risedronate, ibandronate, pamidronate and zoledronic acid — inhibit farnesyl pyrophosphate synthase and drive the osteoclast into apoptosis. They treat osteoporosis, Paget disease and, given IV, hypercalcemia of malignancy. Their risks follow where they act: the esophagus on the way in, the jaw and femur after years in bone, and calcium and the kidney with IV use.

Parathyroid hormone (PTH) raises serum calcium through bone, kidney and, via calcitriol, the gut. Given continuously it resorbs bone, but intermittent PTH-receptor stimulation by teriparatide or abaloparatide builds it. Romosozumab builds bone by blocking sclerostin, a brake on Wnt signaling. Denosumab blocks RANKL, so its effect fades and turnover rebounds when it is stopped. Raloxifene is an estrogen agonist in bone and an antagonist in breast and uterus. Cinacalcet sensitizes the parathyroid calcium-sensing receptor, and calcitriol replaces the active vitamin D that failing kidneys cannot make.