Step 1 · Endocrine

Endocrine Pharmacology

Name: Endocrine Pharmacology
Creator: Veli Bakalov, MD

Diabetes agents, thyroid drugs, steroids, and bone therapies by mechanism

Endocrine·Pharmacology·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Rapid-acting insulins (lispro, aspart, glulisine) cover meals, NPH is intermediate and glargine/detemir/degludec are basal; regular insulin is the IV insulin for DKA and hyperkalemia, and all insulins risk hypoglycemia, weight gain and hypokalemia.
Metformin activates AMPK to cut hepatic gluconeogenesis; it is first-line, causes no hypoglycemia or weight gain, and risks lactic acidosis (hold in advanced CKD and before iodinated contrast) and B12 deficiency.
Sulfonylureas and meglitinides close the β-cell K-ATP channel, require functioning β cells, and cause hypoglycemia and weight gain; chlorpropamide causes a disulfiram-like reaction.
TZDs (pioglitazone, rosiglitazone) are PPAR-γ agonists that cause weight gain, edema and heart-failure exacerbation (contraindicated in HF), fractures and hepatotoxicity.
GLP-1 agonists (-tides) cause weight loss, nausea and pancreatitis and are contraindicated with medullary thyroid carcinoma or MEN2; DPP-4 inhibitors (-gliptins) are oral and weight-neutral.
SGLT2 inhibitors (-gliflozins) cause glucosuria, weight loss and cardiorenal protection but also genital mycotic infections, UTIs, volume depletion and euglycemic DKA.
Methimazole and PTU block thyroid peroxidase and both cause agranulocytosis; PTU also blocks peripheral T4 → T3 and is used in the first trimester and thyroid storm despite hepatotoxicity; methimazole is teratogenic.
Chronic glucocorticoids cause iatrogenic Cushing syndrome, osteoporosis, cataracts, avascular necrosis and adrenal suppression, so taper rather than stopping abruptly.
Bisphosphonates inhibit osteoclast farnesyl pyrophosphate synthase and must be taken upright on an empty stomach (pill esophagitis); watch for jaw osteonecrosis and atypical femoral fractures; continuous leuprolide suppresses the gonadal axis after an initial testosterone flare.

Insulin

Mechanism. All insulins act on the insulin receptor tyrosine kinase to lower glucose by recruiting GLUT4 into muscle and fat membranes, promoting glycogen and fat storage, and suppressing hepatic glucose output. They also shift K+ into cells. The main risks are hypoglycemia and weight gain, plus hypokalemia when large doses are given.

Rapid-acting: lispro, aspart, glulisine; given with meals for postprandial control.
Short-acting: regular insulin; the standard IV insulin, used for DKA and, with glucose, for hyperkalemia.
Intermediate-acting: NPH.
Long-acting (basal): glargine, detemir, degludec; a flat, near-peakless background level.

Regular insulin is the one given IV for DKA and hyperkalemia; intermediate and long-acting insulins are subcutaneous only.

Non-insulin diabetes drugs

Metformin. This biguanide is first-line in type 2 diabetes. It activates AMPK, cutting hepatic gluconeogenesis and improving insulin sensitivity, and it causes neither hypoglycemia nor weight gain. Adverse effects are GI upset, vitamin B12 deficiency and rare but serious lactic acidosis, so it is held in advanced renal failure and before iodinated contrast.

Sulfonylureas and meglitinides. Sulfonylureas (glyburide, glipizide, glimepiride) close the β-cell ATP-sensitive K+ channel, depolarizing the cell to release insulin. Because they need working β cells, they fail in type 1 diabetes. They cause hypoglycemia and weight gain, and the first-generation drug chlorpropamide causes a disulfiram-like reaction with alcohol. Meglitinides (repaglinide, nateglinide) close the same channel through a different binding site, with rapid onset and short duration for postprandial control; they share the hypoglycemia and weight gain.

Thiazolidinediones. Pioglitazone and rosiglitazone are PPAR-γ nuclear-receptor agonists that alter gene transcription to raise insulin sensitivity and adiponectin, so their onset is slow. They cause weight gain, fluid retention with edema that can precipitate or worsen heart failure (contraindicated in heart failure), fractures and hepatotoxicity.

Incretin drugs. GLP-1 receptor agonists (exenatide, liraglutide, semaglutide; the injected -tides) mimic the gut incretin: they increase insulin release only when glucose is high, suppress glucagon, slow gastric emptying and promote satiety, producing weight loss. Adverse effects are nausea and pancreatitis, and they are contraindicated with a history of medullary thyroid carcinoma or MEN2. DPP-4 inhibitors (sitagliptin and the other -gliptins) block the enzyme that degrades endogenous GLP-1 and GIP; they are oral and weight-neutral, with nasopharyngitis, joint pain and pancreatitis as adverse effects.

Meal releases GLP-1Gut incretin
Insulin up, glucagon downGlucose-dependent
Slowed emptying, satietyWeight loss
DPP-4 degrades GLP-1Gliptins block this step

The incretin (GLP-1) axis

SGLT2 inhibitors. Empagliflozin, canagliflozin and dapagliflozin block proximal-tubule glucose reabsorption, causing glucosuria with weight loss, lower blood pressure and proven cardiorenal protection. Adverse effects: genital mycotic infections and UTIs, volume depletion, and euglycemic DKA, in which ketoacidosis develops with a near-normal glucose, often during fasting or illness.

Other agents. α-Glucosidase inhibitors (acarbose, miglitol) slow brush-border carbohydrate digestion to blunt postprandial glucose, at the cost of flatulence and diarrhea. Pramlintide, an amylin analog given with insulin, suppresses glucagon and slows gastric emptying.

Non-insulin diabetes drugs

Class	Mechanism	Hypoglycemia	Weight	Signature adverse effect
Metformin	AMPK; ↓hepatic gluconeogenesis	No	Neutral	Lactic acidosis, B12 deficiency, GI upset
Sulfonylureas	Close β-cell K-ATP channel	Yes	Gain	Hypoglycemia; chlorpropamide disulfiram-like reaction
Meglitinides	Close K-ATP (different site), short-acting	Yes	Gain	Hypoglycemia
TZDs	PPAR-γ agonist; ↑insulin sensitivity	No	Gain	Edema, heart failure, fractures, hepatotoxicity
GLP-1 agonists	Glucose-dependent insulin, ↓glucagon, slow emptying	No	Loss	Nausea, pancreatitis; avoid with MTC/MEN2
DPP-4 inhibitors	Block GLP-1/GIP breakdown	No	Neutral	Nasopharyngitis, joint pain, pancreatitis
SGLT2 inhibitors	Block proximal glucose reabsorption	No	Loss	Genital infections, UTI, volume depletion, euglycemic DKA

Only insulin, sulfonylureas and meglitinides push insulin regardless of glucose, so only they carry a real hypoglycemia risk on their own.

Thyroid drugs

Replacement. Levothyroxine (T4) treats hypothyroidism; it is taken on an empty stomach and separated from calcium and iron, which impair absorption, and excess dosing produces iatrogenic thyrotoxicosis with atrial fibrillation and bone loss.

Thionamides. Methimazole and propylthiouracil (PTU) both block thyroid peroxidase, stopping organification and coupling; PTU additionally blocks peripheral T4-to-T3 conversion (5′-deiodinase). Both can cause agranulocytosis, so sore throat and fever call for a white count.

Methimazole vs PTU

Feature	Methimazole	PTU
Thyroid peroxidase	Blocks	Blocks
Peripheral T4 → T3	No effect	Blocks
Pregnancy	Teratogenic (aplasia cutis); avoid in first trimester	Preferred in first trimester
Signature toxicity	Agranulocytosis	Hepatotoxicity; agranulocytosis
Default use	Preferred outside the first trimester	First trimester and thyroid storm

Adjuncts. β-Blockers (propranolol) control adrenergic symptoms, and potassium iodide blocks hormone synthesis (Wolff-Chaikoff effect) and release, given only after a thionamide. Radioactive iodine ablates the gland and is contraindicated in pregnancy.

Glucocorticoids and bone therapies

Glucocorticoids. Prednisone, dexamethasone and hydrocortisone act on intracellular receptors to alter transcription, inhibiting phospholipase A2, NF-κB and cytokine production; they are anti-inflammatory and immunosuppressive. Chronic use gives iatrogenic Cushing syndrome: hyperglycemia, osteoporosis, weight gain, hypertension, cataracts, avascular necrosis (femoral head), infections and adrenal suppression. Fludrocortisone is the mineralocorticoid used to replace aldosterone.

Never stop long-term glucocorticoids abruptly: the suppressed HPA axis cannot respond, so taper to avoid adrenal crisis.

Bisphosphonates. Alendronate and the other -dronates are pyrophosphate analogs that bind bone mineral and inhibit osteoclast farnesyl pyrophosphate synthase, triggering osteoclast apoptosis. They treat osteoporosis, Paget disease and hypercalcemia of malignancy. Oral forms are taken upright with water on an empty stomach to prevent pill esophagitis; other adverse effects are osteonecrosis of the jaw and atypical femoral fractures.

Denosumab: a monoclonal antibody against RANKL that blocks osteoclast formation.
Teriparatide: a PTH analog that builds bone when given intermittently; transient hypercalcemia is a side effect.
Raloxifene: a SERM that acts as an estrogen agonist on bone and an antagonist on breast, but raises the risk of venous thromboembolism.

GnRH analogs

Pulses stimulate, steady suppresses. Leuprolide is a GnRH analog. Given in pulses it mimics native GnRH and stimulates FSH and LH release, which is used to treat infertility. Given continuously it downregulates pituitary GnRH receptors and shuts down the gonadal axis, which treats prostate cancer, endometriosis, uterine fibroids and central precocious puberty.

The flare. Continuous therapy first stimulates the receptors, so LH and testosterone rise transiently during the first week or two, before receptor downregulation brings testosterone to castrate levels; in prostate cancer an androgen-receptor blocker such as flutamide is added to cover this flare. GnRH antagonists such as degarelix suppress the axis immediately without a flare.

Same drug, opposite effects: pulsatile leuprolide acts as an agonist; continuous leuprolide acts as a functional antagonist.