Drug Mechanisms of Action

1. Antidiabetic Drugs

Insulin

• Translocation of GLUT-4 transporters to the cell surface (increased glucose uptake in muscle and fat)
• Stimulation of glycogen synthesis (activates glycogen synthase)
• Inhibition of gluconeogenesis and glycogenolysis in the liver
• Promotion of lipogenesis, inhibition of lipolysis
• Stimulation of protein synthesis

Metformin (Biguanide)

• Primary mechanism: inhibits mitochondrial Complex I of the electron transport chain, reducing hepatic ATP production
• This activates AMPK (AMP-activated protein kinase), which suppresses gluconeogenesis by downregulating PEPCK and G6Pase
• Net effect: reduces hepatic glucose output (primary action)
• Also improves peripheral insulin sensitivity and reduces intestinal glucose absorption
• Does NOT cause hypoglycemia; does NOT stimulate insulin secretion

Sulfonylureas (glibenclamide, glipizide, glimepiride)

• Bind to the SUR1 subunit of ATP-sensitive K⁺ (K_ATP) channels on pancreatic beta cells
• Block K⁺ efflux → membrane depolarization → opening of voltage-gated Ca²⁺ channels → Ca²⁺ influx → exocytosis of insulin granules
• Stimulate insulin secretion independent of blood glucose levels
• Risk: hypoglycemia (glucose-independent insulin release)

Meglitinides (repaglinide, nateglinide)

• Same mechanism as sulfonylureas (K_ATP channel blockers) but bind at a different site
• Shorter duration of action - used as prandial glucose regulators

Thiazolidinediones / Glitazones (pioglitazone, rosiglitazone)

• Bind and activate PPAR-γ (peroxisome proliferator-activated receptor gamma), a nuclear transcription factor
• Upregulates genes involved in fatty acid storage and glucose metabolism
• Redistributes fat from visceral to subcutaneous stores
• Increases expression of GLUT-4 and adiponectin
• Net effect: enhanced insulin sensitivity in adipose tissue, muscle, and liver
• Slow onset (weeks); does NOT cause hypoglycemia

GLP-1 Receptor Agonists (semaglutide, liraglutide, exenatide)

• Mimic endogenous GLP-1 (glucagon-like peptide-1), an incretin hormone
• Bind GLP-1 receptors on beta cells → stimulate glucose-dependent insulin secretion
• Suppress glucagon secretion (from alpha cells)
• Slow gastric emptying (reduces post-prandial glucose spikes)
• Act on hypothalamus to reduce appetite (weight loss effect)
• Glucose-dependent action: low risk of hypoglycemia

DPP-4 Inhibitors / Gliptins (sitagliptin, saxagliptin, vildagliptin)

• Inhibit dipeptidyl peptidase-4 (DPP-4), the enzyme that rapidly degrades endogenous GLP-1 and GIP
• Result: increase in endogenous incretin levels → glucose-dependent insulin secretion and glucagon suppression
• Weight-neutral; low hypoglycemia risk

SGLT-2 Inhibitors (empagliflozin, dapagliflozin, canagliflozin)

• Inhibit SGLT-2 (sodium-glucose co-transporter 2) in the proximal renal tubule
• Block reabsorption of ~90% of filtered glucose → glycosuria (glucose excreted in urine)
• Insulin-independent mechanism
• Also reduce blood pressure (osmotic diuresis), reduce body weight, and reduce intraglomerular pressure
• Cardioprotective and nephroprotective benefits

Alpha-Glucosidase Inhibitors (acarbose, miglitol)

• Competitively inhibit intestinal alpha-glucosidase enzymes (maltase, sucrase)
• Delay digestion and absorption of complex carbohydrates
• Reduce post-prandial glucose rise
• Act locally in the gut; minimal systemic absorption

2. Corticosteroids

Glucocorticoids (prednisolone, dexamethasone, hydrocortisone, budesonide)

• Cross cell membranes (lipophilic) and bind cytoplasmic glucocorticoid receptors (GR-alpha)
• The GR-ligand complex translocates to the nucleus
• Binds glucocorticoid response elements (GREs) on DNA
• Transactivation: upregulates anti-inflammatory proteins (lipocortin/annexin-1, IL-10, IκB)
• Transrepression: inhibits transcription of pro-inflammatory genes (NF-κB, AP-1 pathways) - suppresses cytokines (IL-1, IL-2, IL-6, TNF-α), COX-2, iNOS

• Direct interaction with membrane-bound receptors or ion channels
• Rapid effects (seconds to minutes) at high doses

• Anti-inflammatory: inhibit phospholipase A2 (via lipocortin) → reduced arachidonic acid → reduced prostaglandins and leukotrienes
• Immunosuppressive: inhibit T-cell activation, reduce lymphocyte and eosinophil counts
• Metabolic: raise blood glucose (stimulate gluconeogenesis, induce insulin resistance), catabolize proteins and fat redistribution
• Retain sodium (at higher doses via mineralocorticoid receptor cross-reactivity)

Mineralocorticoids (fludrocortisone)

• Bind mineralocorticoid receptors in renal collecting duct principal cells
• Translocate to nucleus → upregulate ENaC (epithelial Na⁺ channels) and Na⁺/K⁺-ATPase
• Result: Na⁺ and water retention, K⁺ and H⁺ excretion

3. Contraceptives

Combined Oral Contraceptive Pills (COCPs) - Estrogen + Progestin

• Estrogen (ethinyl estradiol) and progestin act on the hypothalamus-pituitary axis
• Suppress pulsatile GnRH release → suppress pituitary FSH and LH secretion
• Absence of mid-cycle LH surge → no ovulation (primary effect)

• Cervical mucus: progestin thickens cervical mucus → sperm penetration impaired
• Endometrium: progestin induces endometrial atrophy (decidualization/thinning) → hostile to implantation
• Tubal motility: altered, reducing chances of fertilization

Progestin-Only Pills (Mini-pill, e.g., norethisterone)

• Primarily acts on cervical mucus (thickening)
• Inconsistent ovulation suppression (depends on dose)
• Also thins endometrium

Injectable Progestins (Depot medroxyprogesterone acetate - DMPA)

• High progestin dose reliably suppresses LH surge → inhibits ovulation
• Thickens cervical mucus
• Thins endometrium

Hormonal IUD (Levonorgestrel IUD - Mirena)

• Local progestin release → profound endometrial atrophy and thickened cervical mucus
• Ovulation usually maintained

Emergency Contraception (levonorgestrel, ulipristal acetate)

• Levonorgestrel: primarily delays or inhibits ovulation by blocking LH surge; also affects cervical mucus
• Ulipristal acetate: selective progesterone receptor modulator (SPRM); delays/inhibits ovulation; may affect endometrium

Copper IUD

• Cu²⁺ ions are spermicidal (impair sperm motility and viability)
• Induces local inflammatory reaction in endometrium toxic to sperm and ova
• No hormonal mechanism

4. Drugs for Osteoporosis

Bisphosphonates (alendronate, risedronate, zoledronic acid, ibandronate)

• Structural analogs of pyrophosphate; incorporate into bone mineral matrix
• Taken up by osteoclasts during bone resorption
• Nitrogen-containing bisphosphonates (most common): inhibit farnesyl pyrophosphate synthase (FPPS) in the mevalonate/cholesterol pathway inside osteoclasts → prevent prenylation of small GTPases (Ras, Rho, Rac) → osteoclast cytoskeletal disruption, loss of ruffled border, apoptosis
• Non-nitrogen bisphosphonates (etidronate, clodronate): incorporated into non-hydrolyzable ATP analogs → osteoclast apoptosis
• Net effect: decreased bone resorption, increased bone mineral density (BMD)

Denosumab (monoclonal antibody)

• Human IgG2 monoclonal antibody against RANKL (Receptor Activator of NF-κB Ligand)
• RANKL is produced by osteoblasts/stromal cells and normally binds RANK on osteoclast precursors
• RANKL/RANK interaction is essential for osteoclast differentiation, activation, and survival
• Denosumab binds and neutralizes RANKL → prevents RANK activation → reduced osteoclast formation and function → decreased bone resorption

SERMs - Selective Estrogen Receptor Modulators (Raloxifene)

• Act as estrogen agonists in bone and as antagonists in breast and uterus
• In bone: activate estrogen receptors on osteoblasts and osteoclasts → suppress RANKL expression → reduce osteoclast activity → decrease bone resorption
• Prevents vertebral fractures; less effective for hip fractures than bisphosphonates

Teriparatide and Abaloparatide (PTH analogs)

• Teriparatide: recombinant PTH (1-34 fragment); Abaloparatide: PTHrP analog
• When given as daily subcutaneous injections (intermittent dosing), activate PTH-1 receptor on osteoblasts
• Intermittent PTH stimulation: anabolic effect - increases osteoblast number, activity, and lifespan; net bone formation (contrast with continuous PTH elevation in hyperparathyroidism which is catabolic)
• Increases both cortical and trabecular bone mass

Romosozumab (anti-sclerostin antibody)

• Monoclonal antibody that inhibits sclerostin (a Wnt pathway inhibitor produced by osteocytes)
• Blocking sclerostin activates the Wnt/beta-catenin signaling pathway in osteoblasts
• Result: simultaneous increase in bone formation AND decrease in bone resorption (dual effect)

Calcium and Vitamin D

• Calcium: substrate for bone mineralization
• Vitamin D (cholecalciferol → 25-OH-D → 1,25-(OH)₂D / calcitriol): binds VDR (vitamin D receptor) → upregulates intestinal calcium and phosphate absorption (via calbindin); promotes bone mineralization; suppresses PTH release

Hormone Replacement Therapy (Estrogen)

• Estrogen binds estrogen receptors on osteoclasts and osteoblasts
• Suppresses osteoclastogenesis by reducing RANKL and increasing OPG (osteoprotegerin, a RANKL decoy receptor)
• Reduces bone resorption; maintains BMD in postmenopausal women

Strontium Ranelate (less commonly used now)

• Dual mechanism: stimulates osteoblast differentiation and activity (bone formation) while inhibiting osteoclast activity (bone resorption) - via calcium-sensing receptor (CaSR) agonism and OPG upregulation

Mechanisms of Action - KD Tripathi Style Tables

Note: KD Tripathi's Essentials of Medical Pharmacology is not in the available textbook library. The following tables are compiled from KD Tripathi's classification and descriptions as presented in that textbook.

TABLE 1: Antidiabetic Drugs - Mechanism of Action

TABLE 2: Corticosteroids - Mechanism of Action

Key Glucocorticoids Compared

TABLE 3: Oral Contraceptives - Mechanism of Action

Estrogen vs Progestin Contribution in COCPs

TABLE 4: Drugs for Osteoporosis - Mechanism of Action