Preparatory Mindset
Endocrine pharmacology covers two major topics: glucocorticoids and antidiabetic agents. For glucocorticoids: the anti-inflammatory effect is non-specific, anti-inflammatory but NOT antibacterial. Requires gradual withdrawal to avoid HPA axis suppression. For antidiabetics: insulin is the ONLY treatment for T1DM; metformin is first-line for T2DM. Know the mechanism of each oral class.
Core Concepts
Ch06: Endocrine
Examination Overview for the Entire Endocrine Drugs Module
This module covers two core chapters in the endocrine system:
- Adrenocortical Hormones (Glucocorticoids): Typically accounts for 2–4 points in final exams at general universities. Test frequency: ★★★.
- Insulin and Oral Hypoglycemic Agents: Typically accounts for 2–3 points in final exams. Test frequency: ★★★.
PART 1: ADRENOCORTICAL HORMONES (GLUCOCORTICOIDS)
Examination Status
This chapter is a core mandatory examination focus within the endocrine system. Test frequency: ★★★. The core assessment areas are the classification and representative drugs (matching questions), pharmacological effects, clinical applications, adverse reactions, and contraindications, and their corresponding relationships.
I. Classification and Representative Drugs (Test Frequency ★★★, must-know for matching questions)
| Category | Representative Drugs |
| --- | --- |
| Short-acting | Hydrocortisone, Cortisone |
| Intermediate-acting | Prednisone, Prednisolone, Methylprednisolone |
| Long-acting | Dexamethasone, Betamethasone |
| Topical | Fluocinolone acetonide, Beclomethasone |
II. Core Pharmacological Effects (Test Frequency ★★★, must-know for short-answer/multiple-choice questions)
| Effect | Characteristics / Details |
| --- | --- |
| Anti-inflammatory | Non-specific anti-inflammatory action; anti-inflammatory but not antibacterial. Effective against inflammation of various causes (physical, chemical, biological, immune). In early stages: reduces redness, swelling, heat, and pain. In later stages: prevents adhesion and scar formation. Also delays wound healing. |
| Immunosuppression | Inhibits multiple steps of the immune response. Small doses inhibit cellular immunity; large doses inhibit humoral immunity. |
| Antitoxic | Increases the body's tolerance to endotoxins; does not neutralize or destroy endotoxins; ineffective against exotoxins. |
| Anti-shock | Extra-large doses used for various severe shocks, especially septic shock (first choice). |
| Metabolic effects | Raises blood glucose (hyperglycemia); promotes protein catabolism (proteolysis); redistributes body fat (central obesity); causes sodium and water retention (edema, hypertension); promotes potassium and calcium excretion (hypokalemia, osteoporosis). |
III. Clinical Applications
| Application Area | Specific Indications |
| --- | --- |
| Replacement Therapy | Acute and chronic adrenocortical insufficiency (Addison's disease); after subtotal adrenalectomy. |
| Severe Infections / Inflammation | Used only for severe infections with marked toxemia; must be combined with adequate and effective antimicrobial agents; generally not used for viral/fungal infections. Can prevent inflammatory sequelae (e.g., tuberculous meningitis, keratitis, etc.). |
| Autoimmune & Allergic Diseases | Autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis), allergic diseases (e.g., severe asthma, urticaria), organ transplant rejection. |
| Shock | Septic shock: requires early, high-dose, short-course administration under antimicrobial coverage. Also effective for anaphylactic, cardiogenic, and hemorrhagic shock. |
| Hematological Disorders | Acute lymphoblastic leukemia, aplastic anemia, immune thrombocytopenia, etc. |
| Topical Applications | Eczema, contact dermatitis, psoriasis; inhaled administration for asthma; ophthalmic use for inflammation. |
IV. Adverse Reactions (Test Frequency ★★★, must-know)
A. Adverse Reactions from Long-term, High-dose Use
- Cushing's syndrome (Hypercorticism): Moon face, buffalo hump, central obesity, thinning skin, acne, hirsutism, edema.
- Metabolic disturbances: Hypertension, hyperglycemia, hypokalemia, osteoporosis.
- Induction or exacerbation of infections: Due to immunosuppression.
- Induction or exacerbation of peptic ulcers: Increased gastric acid secretion and decreased mucosal protection.
- Psychiatric/neurological effects: Insomnia, euphoria, depression, psychosis, precipitation of epilepsy.
- Musculoskeletal effects: Osteoporosis, avascular necrosis of bone, muscle weakness, growth suppression in children.
- Other: Delayed wound healing, increased intraocular pressure (glaucoma), posterior subcapsular cataracts.
B. Withdrawal Reactions
| Reaction | Description |
| --- | --- |
| Iatrogenic Adrenocortical Insufficiency | Long-term use suppresses the hypothalamic-pituitary-adrenal (HPA) axis; abrupt withdrawal may precipitate adrenal crisis (hypotension, shock, coma) under stress. |
| Rebound Phenomenon | Relapse or exacerbation of the original disease due to the patient's dependence on the hormone or incomplete control of the underlying condition. |
V. Contraindications
| Contraindications | Details |
| --- | --- |
| Severe psychosis / epilepsy | May precipitate or exacerbate psychiatric symptoms or seizures. |
| Active peptic ulcer | May induce or exacerbate bleeding and perforation. |
| Recent gastrointestinal anastomosis | Impairs wound healing. |
| Fractures / wound healing phase | Delays bone and tissue repair. |
| Corneal ulcer | May worsen infection and delay healing. |
| Severe hypertension / diabetes mellitus | May exacerbate hypertension and hyperglycemia. |
| Pregnancy | May cause fetal growth retardation, cleft palate, etc. (especially in first trimester). |
| Infections not controllable by antimicrobial agents | Chickenpox, fungal infections, viral infections (may cause dissemination). |
VI. Must-Know Details
Alternate-Day Therapy
- Purpose: To reduce suppression of the HPA axis and minimize adverse reactions.
- Administration time: Around 8:00 AM (coinciding with the physiological secretion peak of endogenous glucocorticoids).
- Method: The total two-day dose is given as a single morning dose on alternate days.
Withdrawal Precautions
- Withdrawal must be gradual; abrupt discontinuation is strictly prohibited to avoid adrenal crisis and rebound phenomenon.
- Doses should be tapered slowly over weeks to months, depending on the duration and dose of previous therapy.
PART 2: INSULIN AND ORAL HYPOGLYCEMIC AGENTS
Examination Status
This chapter is a secondary core focus within the endocrine system. Test frequency: ★★★. Core assessment areas are the mechanisms of action, clinical applications, and characteristic adverse reactions of various hypoglycemic agents, and their corresponding relationships.
Section A: Insulin
I. Pharmacological Effects
| Effect Category | Specific Effects |
| --- | --- |
| Carbohydrate metabolism | Accelerates glucose utilization (uptake and glycolysis); inhibits glycogenolysis and gluconeogenesis; lowers blood glucose. |
| Fat metabolism | Promotes fatty acid and triglyceride synthesis; inhibits lipolysis; reduces free fatty acids and ketone bodies. |
| Protein metabolism | Promotes amino acid uptake and protein synthesis; inhibits protein breakdown (anti-catabolic effect). |
| Other | Promotes cellular uptake of potassium (used in polarizing solution). |
II. Clinical Applications
| Indication | Details |
| --- | --- |
| Type 1 Diabetes Mellitus | The only therapeutic agent (absolute indication). |
| Type 2 Diabetes Mellitus | Uncontrolled by diet and oral hypoglycemic agents (secondary failure). |
| Acute Diabetic Complications | Diabetic ketoacidosis (DKA); hyperosmolar nonketotic diabetic coma (HONK/HHS). |
| Diabetes Complicated by Stress | Severe infection, major surgery, trauma, pregnancy, high fever, myocardial infarction, etc. |
| Intracellular Potassium Deficiency | Combined with glucose and potassium chloride as polarizing solution (GIK solution) for prevention and treatment of arrhythmias caused by myocardial infarction. |
III. Adverse Reactions
| Adverse Reaction | Description |
| --- | --- |
| Hypoglycemia | Most common. Caused by insulin overdose, missed meals, or excessive exercise. Mild cases: oral glucose; severe cases: intravenous glucose (50% dextrose) for rescue. |
| Allergic Reactions | Mostly due to impurities in the preparation (animal-derived insulin). Local: redness, swelling, itching; systemic: urticaria, anaphylaxis (rare with human insulin). |
| Insulin Resistance (Tolerance) | Acute resistance: mainly due to stress (infection, trauma, surgery); chronic resistance: mainly due to anti-insulin antibodies or reduced insulin receptor numbers. |
| Local Reactions | Lipoatrophy, lipohypertrophy, or induration at subcutaneous injection sites (rotate injection sites to minimize). |
IV. Must-Know Details
- Antagonists (weaken hypoglycemic effect): Glucocorticoids, epinephrine, thiazide diuretics, oral contraceptives.
- Enhancers (potentiate hypoglycemic effect): Phenylbutazone, ethanol (alcohol), salicylates, sulfonamides.
- Dose adjustments are needed when used concomitantly.
Section B: Oral Hypoglycemic Agents
Overview
Oral hypoglycemic agents are classified into 5 main classes, each with distinct mechanisms, indications, and adverse reaction profiles.
1. Sulfonylureas
Representative Drugs: Glibenclamide (Glyburide), Gliclazide, Chlorpropamide, Glipizide
| Aspect | Details |
| --- | --- |
| Mechanism of Action | Directly stimulate pancreatic β-cells to release insulin. Effective only in type 2 diabetic patients with preserved β-cell function (≥30% residual function). Also reduce hepatic glucose output and increase peripheral insulin sensitivity. |
| Clinical Applications | Type 2 diabetes mellitus uncontrolled by diet and exercise; Chlorpropamide can also be used for diabetes insipidus (due to ADH-like effect). |
| Adverse Reactions | Most serious: Persistent hypoglycemia (requires repeated glucose supplementation for rescue). Also: gastrointestinal reactions, liver damage (cholestatic jaundice), granulocytopenia, allergic reactions (skin rashes). |
| Drug Interactions | Enhancers (may cause hypoglycemia): Sulfonamides, salicylates, coumarins, penicillins (competitive plasma protein binding). Antagonists: Chlorpromazine, thiazide diuretics, glucocorticoids. |
2. Biguanides
Representative Drug: Metformin (Phenformin is now rarely used due to lactic acidosis risk)
| Aspect | Details |
| --- | --- |
| Mechanism of Action | Promotes peripheral glucose uptake and anaerobic glycolysis; inhibits gluconeogenesis (hepatic glucose production); does not depend on islet function and does not stimulate insulin secretion. Also improves insulin sensitivity. |
| Clinical Applications | First choice for obese type 2 diabetic patients; can be used alone or in combination with other hypoglycemic agents (sulfonylureas, insulin, etc.). Also used in polycystic ovary syndrome (PCOS). |
| Adverse Reactions | Most serious: Lactic acidosis (risk is low with Metformin, higher with Phenformin). Common: Gastrointestinal reactions (nausea, diarrhea, abdominal discomfort, metallic taste) – can be minimized by starting with a low dose and taking with meals. |
| Must-Know Details | Metformin alone does NOT cause hypoglycemia (does not stimulate insulin secretion). Contraindicated in renal insufficiency, hepatic disease, and conditions predisposing to lactic acidosis (severe infection, heart failure, alcohol abuse). |
3. α-Glucosidase Inhibitors
Representative Drug: Acarbose, Miglitol, Voglibose
| Aspect | Details |
| --- | --- |
| Mechanism of Action | Inhibits intestinal mucosal α-glucosidase, delaying the hydrolysis and absorption of carbohydrates (starch, sucrose, maltose); reduces glucose absorption, primarily lowers postprandial blood glucose. |
| Clinical Applications | All types of diabetes (type 1 and type 2), especially suitable for patients with predominant postprandial hyperglycemia. |
| Adverse Reactions | Common: Gastrointestinal reactions (abdominal distension, diarrhea, flatulence, borborygmi) – due to undigested carbohydrates fermenting in the colon. Can be minimized by starting with a low dose and gradually titrating. |
| Must-Know Details | If hypoglycemia occurs when combined with other agents, treat with glucose (sucrose or starch will not reverse hypoglycemia because α-glucosidase is inhibited). |
4. Insulin Sensitizers (Thiazolidinediones / Glitazones)
Representative Drugs: Rosiglitazone, Pioglitazone
| Aspect | Details |
| --- | --- |
| Mechanism of Action | Activates PPAR-γ (peroxisome proliferator-activated receptor gamma), increasing peripheral tissue sensitivity to insulin (in adipose, muscle, and liver); improves insulin resistance. |
| Clinical Applications | Type 2 diabetic patients with insulin resistance; used alone or in combination with other hypoglycemic agents (except insulin in some regions due to safety concerns). |
| Adverse Reactions | Weight gain, fluid retention (edema), increased risk of heart failure; Pioglitazone may increase bladder cancer risk; Rosiglitazone may increase cardiovascular risk (restricted in some countries). |
| Must-Know Details | Contraindicated in patients with heart failure or hepatic impairment. Requires monitoring of liver function. |
5. Glinides (Meglitinides)
Representative Drugs: Repaglinide, Nateglinide
| Aspect | Details |
| --- | --- |
| Mechanism of Action | Stimulates pancreatic β-cells to release insulin (binds to a different site than sulfonylureas); rapid onset, short duration – classified as a prandial glucose regulator. |
| Clinical Applications | Type 2 diabetes, especially for controlling postprandial hyperglycemia. Can be used in patients with sulfonylurea secondary failure. |
| Adverse Reactions | Hypoglycemia (less common and less severe than sulfonylureas); weight gain; gastrointestinal reactions. |
| Must-Know Details | Taken immediately before meals (within 15–30 minutes). Doses are skipped if meals are skipped. |
Comprehensive Comparison Table of Oral Hypoglycemic Agents
| Drug Class | Representative Drug | Mechanism | Clinical Application | Most Serious AE | Key Points |
| --- | --- | --- | --- | --- | --- |
| Sulfonylureas | Glibenclamide | Stimulates β-cells → ↑ insulin | Type 2 DM with residual β-cell function | Persistent hypoglycemia | Requires ≥30% β-cell function; Chlorpropamide used for DI |
| Biguanides | Metformin | ↑ Glucose uptake, ↓ Gluconeogenesis | Obese type 2 DM (first choice) | Lactic acidosis | No hypoglycemia alone; GI reactions common |
| α-Glucosidase Inhibitors | Acarbose | Inhibits carbohydrate digestion/absorption | Postprandial hyperglycemia | GI reactions (flatulence, diarrhea) | Treat hypoglycemia with glucose, not sucrose |
| Insulin Sensitizers | Pioglitazone | PPAR-γ agonist → ↑ insulin sensitivity | Type 2 DM with insulin resistance | Edema, heart failure risk | Monitor liver function; avoid in heart failure |
| Glinides | Repaglinide | Stimulates β-cells (short-acting) | Postprandial hyperglycemia | Hypoglycemia (mild) | Take immediately before meals |
Important Exam Tips & Key Distinctions
For Glucocorticoids:
- Anti-inflammatory but not antibacterial – always combine with antibiotics for severe infections.
- Does NOT neutralize endotoxins – only increases tolerance.
- Alternate-day therapy at 8 AM reduces HPA axis suppression.
- Rebound phenomenon vs. adrenal crisis – both are withdrawal-related but have different mechanisms.
- Cushing's syndrome is reversible upon drug withdrawal.
For Insulin & Hypoglycemics:
- Insulin is the ONLY treatment for type 1 DM – must be injected.
- Metformin is the first choice for obese type 2 DM – does NOT cause hypoglycemia alone.
- Sulfonylureas require functioning β-cells – ineffective in type 1 DM.
- Acarbose lowers postprandial glucose – treat hypoglycemia with glucose, not sucrose.
- Polarizing solution = Insulin + Glucose + KCl – for intracellular K⁺ deficiency and arrhythmias.
Core Teacher & Past Paper Content
Part A: Glucocorticoids
Pharmacological Effects
| Effect | Mechanism | Clinical Implication |
|--------|-----------|---------------------|
| Anti-inflammatory | ↑ Lipocortin-1 → ↓ PLA2 → ↓ AA → ↓ PGs + ↓ LTs | All phases of inflammation |
| Immunosuppressive | ↓ Cytokine production, ↓ lymphocyte function | Autoimmune diseases, allergy, transplant |
| Anti-shock | ↑ Response to catecholamines, ↓ capillary permeability, stabilize lysosomes | Septic shock (with antibiotics) |
| Antipyretic | ↓ Thermoregulatory center response to pyrogens | Fever in certain conditions |
| Metabolic | ↑ Gluconeogenesis, ↓ glucose uptake (insulin resistance), ↑ protein catabolism, ↑ lipolysis, redistribute fat | Hyperglycemia, moon face, buffalo hump, osteoporosis |
Adverse Effects (Long-term)
| System | Effect |
|--------|--------|
| Metabolic | Hyperglycemia (steroid diabetes), central obesity, osteoporosis, muscle wasting |
| Cardiovascular | Hypertension (↑ aldosterone-like effect), fluid retention |
| GI | Peptic ulcer (↓ protective PGs) |
| Immunologic | Immunosuppression → increased infection risk |
| CNS | Insomnia, mood changes, euphoria, psychosis |
| HPA Axis | Adrenal suppression (HPA axis feedback inhibition) |
Withdrawal Guidelines
- ★ NEVER stop abruptly after >2-3 weeks. Taper 10-20% every 3-7 days.
- Alternate-day dosing for medium-acting GCs → less HPA suppression.
- Morning dosing for short-acting GCs (mimics circadian cortisol rhythm).
Endotoxin vs External Toxin
- GCs enhance tolerance to bacterial endotoxins but cannot neutralize them.
- GCs have no protective effect against external toxins.
Part B: Antidiabetic Drugs
Insulin Types
| Type | Onset | Peak | Duration | Key Features |
|------|-------|------|----------|-------------|
| Rapid-acting (Lispro/Aspart) | 5-15 min | 30-90 min | 3-5 h | Monomeric → fast absorption; taken with meals |
| Short-acting (Regular) | 30 min | 2-4 h | 5-8 h | Hexameric → must dissociate to monomers (delayed onset) |
| Intermediate (NPH) | 1-2 h | 6-12 h | 16-24 h | Cloudy suspension |
| Long-acting (Glargine) | 2-4 h | No peak | ~24 h | Forms crystals at pH 7.4; NEVER MIX with other insulin |
Oral Antidiabetic Agents
| Class | Drug | MOA | Key Side Effects | Notes |
|------|------|-----|-----------------|-------|
| Biguanide | Metformin | ↓ Hepatic gluconeogenesis, ↑ insulin sensitivity | Lactic acidosis (rare but dangerous), GI upset | First-line for T2DM; weight neutral; CV benefit |
| Sulfonylurea | Glyburide, Glipizide | ↑ Insulin secretion (block K-ATP channels) | Hypoglycemia, weight gain | Glibenclamide → severe/prolonged hypoglycemia in elderly |
| α-Glucosidase Inhibitor | Acarbose | ↓ Carb digestion in gut | Flatulence, abdominal bloating, diarrhea | Postprandial glucose control |
| Thiazolidinedione (TZD) | Pioglitazone | ↑ Insulin sensitivity (PPARγ agonist) | Weight gain, edema, bone fracture | Contraindicated in HF |
| Meglitinide | Repaglinide | ↑ Insulin secretion (fast onset, short duration) | Hypoglycemia (less than sulfonylureas) | Taken with meals |
| GLP-1 RA | Exenatide, Liraglutide | ↑ Glucose-dependent insulin, ↓ glucagon, slow gastric emptying | Nausea, vomiting | Weight loss; low hypo risk; CV benefit |
| DPP-4 Inhibitor | Sitagliptin | ↑ GLP-1 (by preventing GLP-1 degradation) | Well-tolerated | Modest HbA1c reduction; weight neutral |
| SGLT2 Inhibitor | Empagliflozin | ↓ Renal glucose reabsorption | UTI, genital infections, dehydration | CV and renal benefit |
High-Yield Points
- Glucocorticoid anti-inflammatory: NON-SPECIFIC, NOT antibacterial → must combine with antibiotics for severe infections
- GC withdrawal: gradual taper needed — abrupt withdrawal → adrenal crisis (hypotension, shock, coma)
- Alternate-day therapy at 8 AM: reduces HPA suppression
- Insulin: ONLY treatment for T1DM — must be injected (protein, destroyed orally)
- Metformin: first-line for T2DM — does NOT cause hypoglycemia alone
- Sulfonylureas: HIGHEST risk of prolonged hypoglycemia (especially glyburide)
- Acarbose: treats hypoglycemia with GLUCOSE, not sucrose
Topic Summary
Glucocorticoids: powerful anti-inflammatory but require careful withdrawal. Antidiabetics: metformin is first-line for T2DM (does NOT cause hypoglycemia alone), insulin is only option for T1DM. Sulfonylureas carry highest risk of hypoglycemia. Acarbose causes flatulence. SGLT2 inhibitors increase UTI risk.