Anatomy and Histology of the Esophagus

The esophagus is a muscular tube extending from the epiglottis to the gastroesophageal junction (GEJ).
It is lined by stratified squamous epithelium.

Causes: Congenital or Acquired, Atresia, Fistulas, Duplications, Agenesis (very rare), Stenosis
Atresia: characterized by a thin, non-canalized cord replacing a segment of the esophagus, typically near the tracheal bifurcation
Esophageal Stenosis: results from fibrous thickening of the submucosa and atrophy of the muscularis propria due to inflammation and scarring
Clinical Presentation of Atresia: regurgitation during feeding shortly after birth, requires prompt surgical correction
Complications of Atresia: aspiration, suffocation, pneumonia, and severe fluid and electrolyte imbalances
Clinical Presentation of Esophageal Stenosis: progressive dysphagia, initially affecting solids and later liquids

Characterized by esophageal dysmotility, with discoordinated peristalsis or muscular spasms
Achalasia: most significant cause, characterized by a triad of incomplete LES relaxation, increased LES tone, and esophageal aperistalsis
Primary Achalasia: often idiopathic, involving degeneration of distal esophageal inhibitory neurons
Secondary Achalasia: results from damage to the esophagus, vagus nerve, or dorsal motor nucleus of the vagus
Clinical Presentation of Achalasia: difficulty swallowing (dysphagia), regurgitation, occasionally chest pain

Tortuous dilated veins within the submucosa of the distal esophagus and proximal stomach
Pathogenesis: portal hypertension leads to the development of collateral channels in the distal esophagus, creating varices
Causes of Portal Hypertension: cirrhosis, hepatic schistosomiasis
Clinical Features: often asymptomatic until rupture, massive hematemesis and death, first bleed has a 20% mortality rate, rebleeding occurs in 60% of cases

Types: Esophageal Lacerations (Mallory-Weiss tears), Chemical Esophagitis, Infectious Esophagitis
Clinical Features and Morphology: ulceration and acute inflammation, symptoms include pain, odynophagia (painful swallowing), hemorrhage, stricture, or perforation in severe cases

Pharmacokinetics describes the movement of drugs within the body and is characterized by four key processes: absorption, distribution, metabolism, and excretion (ADME).
Understanding these processes is critical for determining appropriate drug dosages and selecting the most effective routes of drug administration.

Overview: Absorption is the process by which a drug enters the bloodstream from its administration site (e.g., oral, intravenous).
Factors affecting absorption: Drug formulation, route of administration, and physicochemical properties like solubility, ionization, and molecular size play crucial roles.
Mechanisms:
- Passive Diffusion: The most frequent mechanism where drugs move from areas of high concentration (e.g., GI tract) to lower concentration (e.g., bloodstream) without energy expenditure. Lipid-soluble and non-ionized drugs readily undergo passive diffusion.
- Facilitated Diffusion: Drugs move along a concentration gradient but require carrier proteins (e.g., glucose transport via GLUT transporters).
- Active Transport: Energy-dependent transport that moves drugs against their concentration gradient, using carriers like P-glycoprotein (important in the gut and brain).
- Endocytosis: Larger molecules (e.g., proteins or antibodies) are engulfed by cell membranes in vesicles for cellular uptake (e.g., vitamin B12 absorption in the intestines).
Example: Aspirin (a weak acid) is primarily absorbed in the stomach due to the acidic environment, favoring its non-ionized form for passive diffusion.

Overview: Distribution describes how drugs move from the bloodstream into tissues and organs.
Factors influencing distribution: Blood flow, tissue permeability, drug binding to plasma proteins (like albumin), and the drug's lipid solubility all play significant roles.
Volume of Distribution (Vd): A theoretical volume representing a drug's distribution into body tissues relative to the blood. Vd helps determine the loading dose.
- Low Vd: Drugs that primarily remain in the bloodstream (e.g., heparin).
- High Vd: Drugs that distribute widely into tissues (e.g., lipophilic drugs like chloroquine).
Example: Warfarin, an anticoagulant, extensively binds to albumin, resulting in a low Vd, as only the free (unbound) fraction exerts its effects.

Overview: Metabolism, mainly occurring in the liver, converts lipophilic drugs into more water-soluble metabolites for excretion. It is divided into two phases:
- Phase I (Functionalization Reactions): Introduces or exposes functional groups on the drug molecule through oxidation (often via cytochrome P450 enzymes), reduction, or hydrolysis. These reactions generally increase the drug's polarity.
- Phase II (Conjugation Reactions): The drug or its Phase I metabolite is conjugated with a larger polar molecule (e.g., glucuronide, sulfate) to increase solubility and facilitate renal excretion.
Example:
- Diazepam (Valium) is metabolized through oxidation by CYP3A4 enzymes (Phase I).
- Morphine undergoes glucuronidation (Phase II) to increase its solubility for excretion.
Cytochrome P450 (CYP) Enzymes: A group of enzymes responsible for many Phase I reactions.
- Inducers (e.g., rifampin) can increase enzyme activity, leading to faster drug clearance.
- Inhibitors (e.g., ketoconazole) slow down metabolism, increasing drug levels.

Overview: Drugs are removed from the body through metabolism and excretion (mainly through renal and biliary routes). Elimination kinetics determine how drug levels decrease over time.
First-Order Kinetics: The majority of drugs follow first-order kinetics, where a constant fraction of the drug is eliminated per unit time. The rate of elimination is proportional to the drug concentration.
Example: Most antibiotics follow first-order elimination, where higher concentrations result in faster clearance.
Zero-Order Kinetics: In zero-order kinetics, a constant amount of the drug is eliminated per unit time, regardless of concentration. This occurs when elimination pathways become saturated.
Example: Ethanol exhibits zero-order kinetics, meaning a constant amount is cleared per hour, regardless of total ethanol intake.
Half-life (t½): The time required for the drug concentration to decrease by half in the body. It is crucial for determining appropriate dosing intervals.