Oral Hypoglycemic Agents (OHA)

Classification and Mechanisms

1. Biguanides - Metformin

• Mechanism: Reduces hepatic gluconeogenesis (main effect), slows intestinal glucose absorption, and improves peripheral insulin sensitivity. Does NOT stimulate insulin secretion - hence low risk of hypoglycemia.
• Pharmacokinetics: Well absorbed orally, excreted unchanged in urine.
• Adverse effects: GI (diarrhea, nausea, vomiting) - mitigated by slow dose titration with meals. Risk of lactic acidosis (rare but fatal). Long-term use causes vitamin B12 deficiency.
• Contraindications: eGFR <30 mL/min/1.73 m², IV contrast procedures, severe hepatic failure, acute MI/sepsis/decompensated heart failure.

2. Sulfonylureas (2nd generation: Glipizide, Glyburide, Glimepiride)

• Mechanism: Block ATP-sensitive K+ channels on pancreatic β-cells → membrane depolarization → Ca²⁺ influx → insulin exocytosis. They are insulin secretagogues.
• Duration: 12-24 hours.
• Adverse effects: Hypoglycemia (most significant), weight gain, hyperinsulinemia.
• Caution: In renal impairment - glipizide/glimepiride are safer; glyburide accumulates and worsens hypoglycemia risk. Also use cautiously in the elderly.

3. Meglitinides (Repaglinide, Nateglinide)

• Mechanism: Similar to sulfonylureas (stimulate insulin secretion) but with rapid onset and shorter duration - act primarily on postprandial glucose.
• Taken before meals.
• Adverse effects: Hypoglycemia (less than sulfonylureas), weight gain.
• Should NOT be combined with sulfonylureas (overlapping mechanism, serious hypoglycemia risk).

4. Thiazolidinediones / TZDs (Pioglitazone, Rosiglitazone) - "Glitazones"

• Mechanism: PPAR-γ (peroxisome proliferator-activated receptor gamma) agonists → increase peripheral insulin sensitivity (especially in adipose tissue and muscle). Do not directly stimulate insulin release.
• Adverse effects: Weight gain, fluid retention/edema, increased risk of fractures, heart failure (contraindicated in NYHA class III-IV).
• Rarely cause significant hypoglycemia alone.

5. DPP-4 Inhibitors (Gliptins: Sitagliptin, Saxagliptin, Alogliptin)

• Mechanism: Inhibit dipeptidyl peptidase-4, which degrades GLP-1 and GIP → increased incretin levels → glucose-dependent insulin release and reduced glucagon.
• Adverse effects: Upper respiratory infections, nasopharyngitis; low hypoglycemia risk.

6. SGLT2 Inhibitors (Gliflozins: Empagliflozin, Dapagliflozin, Canagliflozin)

• Mechanism: Inhibit sodium-glucose cotransporter-2 in the proximal renal tubule → increased urinary glucose excretion.
• Added benefits: Cardiovascular and renal protection (major trials).
• Adverse effects: Genital mycotic infections, UTIs, euglycemic DKA (especially perioperatively - must be held before surgery), volume depletion.

7. Alpha-glucosidase Inhibitors (Acarbose, Miglitol)

• Mechanism: Inhibit intestinal brush border enzymes → delayed carbohydrate digestion and absorption → blunts postprandial hyperglycemia.
• Adverse effects: Flatulence, diarrhea, abdominal bloating (due to colonic fermentation of unabsorbed carbohydrates).
• No systemic hypoglycemia risk when used alone.

8. GLP-1 Receptor Agonists (Exenatide, Liraglutide, Semaglutide) - Injectable but classified with OHAs

• Mechanism: Mimic GLP-1 → stimulate insulin release (glucose-dependent), suppress glucagon, slow gastric emptying, promote satiety and weight loss.

Corticosteroids and Steroid Withdrawal Syndrome

Corticosteroids - Overview

• Glucocorticoids (e.g., hydrocortisone, prednisolone, dexamethasone, methylprednisolone) - primarily anti-inflammatory and metabolic effects.
• Mineralocorticoids (e.g., fludrocortisone, aldosterone) - primarily salt and water regulation.

Relative Potencies (Goodman & Gilman)

Mechanisms of Action

• Glucocorticoids bind intracellular receptors → translocate to nucleus → alter gene transcription → suppress inflammatory mediators (IL-1, IL-6, TNF-α, prostaglandins, leukotrienes).
• They also suppress the HPA (hypothalamic-pituitary-adrenal) axis via negative feedback - the key basis of withdrawal problems.

Adverse Effects of Chronic Supraphysiologic Use

• Metabolic: Hyperglycemia, hypokalemic alkalosis, dyslipidemia.
• Cardiovascular: Hypertension, fluid retention.
• Musculoskeletal: Osteoporosis, proximal myopathy (weakness of proximal limbs, can impair ambulation - type II fiber atrophy), growth arrest in children.
• Immunologic: Increased infection susceptibility, reactivation of latent TB.
• GI: Gastritis, peptic ulceration (especially when combined with NSAIDs).
• Ophthalmologic: Cataracts, glaucoma.
• CNS/Behavioral: Insomnia, mood changes, psychosis.
• Cutaneous: Striae, easy bruising (ecchymoses), fat redistribution (Cushingoid habitus - buffalo hump, moon face, central obesity).

Steroid Withdrawal Syndrome

1. HPA Axis Suppression (Most Serious)

• Prolonged exogenous corticosteroids suppress pituitary ACTH and hypothalamic CRH via negative feedback.
• On withdrawal, the HPA axis cannot mount a sufficient cortisol response.
• Result: Acute adrenal insufficiency (adrenal crisis) - the most severe and life-threatening complication.
• Risk: Patients who received supraphysiologic doses for 2-4 weeks within the preceding year, or those with Cushingoid appearance, should be presumed to have some degree of HPA impairment.
• Recovery time: Several weeks to months; in some individuals up to 1 year or longer.

2. Glucocorticoid Withdrawal Syndrome (Steroid Pseudorheumatism)

• Fever
• Myalgia
• Arthralgias (joint pain - can mimic the underlying disease for which steroids were started)
• Malaise
• Fatigue

Management of Steroid Withdrawal

1. Gradual tapering - most important principle. Protocols involve either gradual daily dose reduction or transition to alternate-day regimens before final taper.
2. Never abruptly stop steroids after prolonged therapy.
3. If signs of acute adrenal insufficiency (hypotension, nausea, vomiting, altered consciousness) develop - immediately return to a higher dose.
4. If withdrawal syndrome symptoms (myalgia, arthralgia, fever, malaise) appear without evidence of adrenal crisis, slow the rate of taper.
5. Stress dosing - patients on chronic steroids or recently tapered need supplemental "stress doses" during surgery, infection, or major physiologic stress.

Key Rule: The most frequent problem with steroid withdrawal is flare-up of the underlying disease for which steroids were prescribed - always consider this before diagnosing true withdrawal syndrome.

• Goodman & Gilman's Pharmacological Basis of Therapeutics
• Lippincott Illustrated Reviews: Pharmacology
• Rheumatology, 2-Volume Set (Elsevier, 2022)