3.3 Pathophysiological Bases of Diseases

Pathophysiology describes the functional changes that accompany disease. The FPGEE expects you to link cellular injury, inflammation, hemodynamic disorders, and neoplasia to the clinical presentations you will encounter in pharmacy practice.

Cellular Injury

Cells are injured when oxygen, nutrients, or waste removal fail. Ischemia blocks blood flow; hypoxia reduces oxygen delivery. Both collapse aerobic ATP generation, causing Na/K ATPase failure, cellular swelling, and calcium influx. Reperfusion injury worsens damage when oxidative phosphorylation restarts and generates reactive oxygen species (ROS). Oxidative stress overwhelms endogenous antioxidants such as glutathione, superoxide dismutase, and catalase. Persistent injury triggers apoptosis (programmed, energy-requiring, caspase-driven, no inflammation) or necrosis (pathologic, ATP-depleted, membrane rupture, inflammation). Liquefactive necrosis occurs in brain infarcts and abscesses; coagulative necrosis in myocardial and kidney infarcts; caseous necrosis in tuberculosis; fat necrosis in acute pancreatitis.

Inflammation

Acute inflammation is the early vascular and cellular response to injury. Vascular changes (vasodilation, increased permeability) deliver plasma proteins; neutrophils emigrate via margination, rolling, adhesion, and diapedesis. Mediators include histamine (vasodilation, bronchoconstriction), bradykinin (pain, vasodilation), prostaglandins (fever, pain, vasodilation via COX), leukotrienes (bronchoconstriction, vascular permeability via 5-lipoxygenase), and cytokines (IL-1, IL-6, and TNF-alpha for systemic effects such as fever and acute-phase reactants).

Chronic inflammation features macrophages, lymphocytes, and plasma cells. Granulomatous inflammation (tuberculosis, sarcoidosis, Crohn disease) organizes activated macrophages into epithelioid cells with multinucleated giant cells. Fibroblast activation leads to fibrosis, the scar tissue that replaces parenchyma when regeneration fails.

Tissue Repair

Repair proceeds through hemostasis, inflammation, proliferation (fibroblast and angiogenic), and remodeling. Labile cells (epithelium, bone marrow) regenerate continuously. Stable cells (liver, kidney) regenerate when injured but are otherwise quiescent. Permanent cells (neurons, cardiac myocytes) cannot divide, so injury heals by scarring rather than regeneration. Wound healing phases are tightly regulated: platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) drive fibroblast migration and collagen synthesis, while vascular endothelial growth factor (VEGF) initiates angiogenesis. Vitamin C is required for collagen cross-linking (scurvy causes impaired wound healing), and zinc deficiency delays epithelialization. Chronic wounds (diabetic foot ulcers, pressure injuries) stall in the inflammatory phase because of repeated ischemia, infection, or biofilm.

Hemodynamic Disorders

Edema is excess interstitial fluid from increased hydrostatic pressure, decreased oncotic pressure, lymphatic obstruction, or sodium retention. Hyperemia is active arteriolar dilation (inflammation, exercise); congestion is impaired venous outflow (right heart failure, cirrhosis). Hemorrhage is blood escaping the vasculature. Thrombosis forms clots in intact vessels via Virchow's triad: endothelial injury, abnormal blood flow (stasis or turbulence), and hypercoagulability. Embolism is a detached intravascular mass — pulmonary embolism, fat embolism, air embolism, or septic embolism. Infarction is ischemic necrosis of tissue; red infarcts occur with venous occlusion or loose tissue (lung, intestine), while white infarcts occur in solid organs with end-arterial supply (heart, kidney, spleen).

Neoplasia

Neoplasms are autonomous new growths. Benign tumors remain localized, grow expansively, and rarely recur. Malignant tumors invade surrounding tissue, metastasize, and recur. The hallmarks of cancer (Hanahan and Weinberg) include sustained proliferative signaling, evading growth suppressors, resisting apoptosis, enabling replicative immortality (telomerase), inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism (Warburg effect), and evading immune destruction.

Tumor suppressors (p53, Rb, APC) restrain cell division; their loss removes the brakes. Oncogenes (Ras, MYC, HER2) drive proliferation when mutated or amplified. Metastasis occurs via lymphatic spread (typical of carcinomas), hematogenous spread (sarcomas, renal cell, hepatocellular), seeding of body cavities (ovarian), and direct extension. Common metastatic sites include liver, lung, bone, and brain.

Chemotherapy and targeted therapy exploit these mechanisms: antimetabolites (methotrexate, 5-FU) disrupt DNA synthesis in rapidly dividing cells; alkylating agents (cyclophosphamide) cross-link DNA; platinum compounds (cisplatin) form adducts; anthracyclines (doxorubicin) intercalate DNA and generate ROS but are cardiotoxic; taxanes (paclitaxel) stabilize microtubules; vinca alkaloids (vincristine) inhibit microtubule polymerization causing peripheral neuropathy; tyrosine kinase inhibitors (imatinib for BCR-ABL, erlotinib for EGFR, sorafenib and sunitinib for VEGFR/PDGFR) block oncogenic signaling; monoclonal antibodies (trastuzumab for HER2, rituximab for CD20, cetuximab for EGFR) bind surface antigens; immune checkpoint inhibitors (nivolumab, pembrolizumab block PD-1; ipilimumab blocks CTLA-4) release T-cell responses but cause immune-related adverse events (colitis, pneumonitis, hepatitis, endocrinopathies).

Genetic and Systemic Pathophysiology

Genetic disease ranges from single-nucleotide mutations (sickle cell disease, cystic fibrosis) to chromosomal aneuploidies (trisomy 21, Turner syndrome) to polygenic disorders. Shock is systemic circulatory failure with several forms: hypovolemic (hemorrhage, burns, dehydration), cardiogenic (myocardial infarction, heart failure), septic (infection-driven vasodilation and capillary leak), and anaphylactic (Type I hypersensitivity causing massive vasodilation). The systemic inflammatory response underlies sepsis, severe trauma, and pancreatitis through a cytokine cascade (TNF-alpha, IL-1, IL-6) that can progress to multi-organ dysfunction syndrome.

Amyloidosis results from misfolded proteins depositing as beta-pleated sheets in tissues; AL amyloidosis arises from monoclonal light chains (plasma cell dyscrasia), AA amyloidosis from chronic inflammation (serum amyloid A), and hereditary forms from transthyretin mutations. Presentation includes nephrotic syndrome, restrictive cardiomyopathy, and macroglossia; diagnosis is Congo-red-positive biopsy. Atherosclerosis begins with endothelial injury, LDL infiltration, foam cell formation, fatty streaks, fibrous plaque, and ultimately ruptured plaque with thrombosis — the substrate of most myocardial infarctions and ischemic strokes. Risk factor modification (statins, antihypertensives, smoking cessation, glycemic control) targets the modifiable drivers of plaque progression.