The Gastrointestinal Tract

Oral Administration Advantages

• Oral route is convenient and cost-effective.
• Offers sustained release.
• Easy to administer.

GI Epithelium Mucus

• Role: Protects the GI tract, facilitates nutrient absorption, and defends against pathogens.
• Main Components: Glycoproteins, mucins, electrolytes, and water.
• Turnover Time: Constant renewal, ensuring continuous protection.

Stomach

• Volumes: Fed state: significantly larger than fasting state.
• Roles: Digestion of food, storage of food, mixing of food, and initiating the digestion of proteins.
• pH: ~2.
• Secretions: Hydrochloric acid, mucus, pepsinogen, intrinsic factor.
• MMC Phase III: Occurs in the fasting stomach.

Small Intestine and Colon

• Roles: Small intestine: major site of nutrient absorption. Colon: water absorption and fermentation.
• Length: Small intestine: ~6-8 meters. Colon: ~1.5 meters.
• pH: Small intestine: ~6-7. Colon: ~7-8.
• Drug Absorption Factors: Surface area, motility, pH, presence of food.

Gastric Motility

• Fasted Stomach: Migrating motor complex (MMC), primarily for cleansing of stomach and digestive debris.
• Fed Stomach: Increased mixing and peristaltic activity.
• Factors Affecting Gastric Residence Time: Dosage form size, meal size.
• Pyloric Sphincter Role: Regulates the flow of chyme from stomach to small intestine, influencing drug transit time.

Gastric Residence Times

• Dosage Form Size/Meal Size: Larger dosage forms/larger meals result in longer gastric residence times.
• Water vs. Food: Administration with water results in faster transit to the intestine than administration with food, or on an empty stomach.

Drug Transit Times (Small & Large Intestine)

• Transit times vary between the different intestinal segments and are drug and subject dependent.

Barriers to Drug Absorption

• Gut Lumen: Drugs may interact with food particles, enzymes, or other constituents.
• Unstirred Water Layer: Slows down drug diffusion to absorption sites.
• GI pH, Food, and Disease: Can affect drug ionization and solubility, impacting absorption.
• Luminal Enzymes: May degrade drugs before absorption.
• Excipients Vulnerable to Lipases: Can be digested, affecting drug performance and delivery.

GI Membrane and Drug Transport Mechanisms

• Active transport is mostly efficient for drug absorption.

Passive Diffusion

• Suitable Drugs: Small, lipophilic molecules.
• Factors Affecting Rate: Drug properties, membrane characteristics, concentration gradient.
• Sink Conditions: Drug concentration in blood is substantially lower than in the GI fluids.

Active Transport

• Mechanism: Carrier-mediated, energy-dependent.
• Specificity: Requires specific chemical structures for molecule interaction.
• Saturability: Limited transport capacity—increasing drug concentration may not increase rate beyond saturated transporters.
• Relevance for Drug Absorption: Essential for certain nutrients and some drugs.

Facilitated Diffusion

• Energy Input: Does not require energy.
• Significance for Drug Absorption: Modest role in drug absorption—minor contribution.

Endocytosis

• Mechanism: Invagination of cell membrane → vesicle formation.
• Types: Pinocytosis, receptor-mediated endocytosis, phagocytosis.
• Significance for Drug Absorption: Important for macromolecule absorption.

Paracellular Pathway

• Suitable Drugs: Small, non-lipid-soluble drugs.
• Mechanism: Between cells in tight junctions.

Drug Efflux

• Main Protein: P-glycoprotein (P-gp).
• Impact on Bioavailability: Can limit drug absorption, particularly for P-gp substrates (e.g., digoxin).

Review Questions

• Small Intestine Transit: Dependent on the type and amount of material, dependent on gastric emptying rate.
• Food in GI Tract: May increase or decrease drug absorption.

Noyes-Whitney Equation & Factors

• Dissolution Rate: Affected by diffusion coefficient, surface area, saturation solubility, diffusion layer thickness, agitation, and volume (among other factors).
• Particle Size: Decreasing particle size generally enhances dissolution and can improve absorption, particularly if dissolution rate is the rate-limiting step.

Micronized Drug Use

• Not limited to oral preparations; beneficial for other dosage forms in enhancing dissolution and absorption.

Weak Electrolytes

• Solubility: Weak acids higher in small intestine; weak bases higher in stomach.
• Cimetidine (Acid Secretion Blocker): Reduces weak base absorption.

Salt Forms

• Dissolution Enhancement: Salts can increase drug dissolution rate via altered pH in solution surrounding drug particles.
• Naproxen/Naproxen Sodium: Naproxen sodium forms a finer precipitate in the stomach, thus improving solubility.

Acidic Salts for Weakly Basic Drugs

• Rationale: Enhanced dissolution in acidic environment.
• pH and Solubility: Creating a more acidic diffusion layer surrounding the drug particles that dissolve faster.

Factors Beyond Bioavailability

• Salts: Considerations include stability, hygroscopicity, manufacture, and crystallinity.
• Poorly Soluble Salts: Often helpful for extended-release formulations.
• pH Adjustment: Using excipients to change pH in solution surrounding drug particles.

Factors Affecting Drug Concentration

• Complexation: Interactions with components (e.g., food) may enhance or reduce absorption.
• Adsorption: Can reduce drug absorption if interaction with solids occurs.
• Chemical Stability: Important for maintaining effective levels of drug in solutions.
• Micellar Solubilization: Can improve solubility, dependent on drug lipophilicity.

Drug Complexation

• Absorption Effect: Can enhance or hinder drug absorption.
• Drug Examples: Cyclodextrins can complex with drugs, sometimes improving bioavailability.
• Complexes with Excipients: Some drug-excipient complexes increase solubility or bioavailability.

Drug-Adsorbent Interactions

• Can reduce drug absorption.
• Activated charcoal has therapeutic use.

Drug Instability

• Cause: Primarily chemical degradation.
• Stability Enhancement: Decreasing dissolution rate and use of excipients as stabilizers.
• Delaying Dissolution: Enteric coatings or salts that dissolve appropriately further down gastrointestinal tract.

Drug Handling in Dosage Production

• Often handled as powders during manufacture.
• Drug's solid-state form (polymorphism or crystal structure) impacts dosage stability and bioavailability.

Solid-State Forms

• Crystalline: Molecules arranged in a lattice pattern
• Amorphous: Random structure
• Semi-Crystalline: Combination of both

Amorphous Solids

• Production: Faster solidification from solution.
• Penetration: Solvents more readily penetrate amorphous structures.

Amorphous vs. Crystalline Forms

• Stability: Crystalline is more stable.
• Dissolution: Amorphous dissolves faster.
• Absorption: Amorphous is better for dissolution-limited absorption.

Polymorphism

• Definition: Multiple crystal structures for a compound.
• Chemical Differences: No chemical difference between different polymorphs of the same material.
• Effect on Bioavailability: Can affect the rate a drug dissolves and is absorbed, causing different outcomes based on the polymorph's characteristics.

Metastable Polymorphs

• Stability: Not as stable as stable polymorphs—may convert to stable form.
• Transitions: Can happen during the manufacturing process and in the body over time.

Polymorph Properties

• Solubility: Metastable forms can exhibit higher solubility.
• Suspensions: Stable polymorphs are more often preferred in suspensions due to greater consistency and stability.
• Permeation vs. Dissolution Limited Absorption: Difference more notable when absorption is dissolution-rate limited.

Hydrates, Solvates, and Pseudo Polymorphism

• Hydrates: Water molecules trapped in crystal lattice.
• Solvates: Other solvent molecules trapped in crystal lattice.
• Pseudo-polymorphism: Crystal form related to solvents or water.
• Dissolution Rates: Variations occur, often related to hydrogen bonding in the hydrate form.

pH-Partition Hypothesis

• Lipid Solubility: Lipid-soluble (non-ionized) drugs absorb more readily.
• Weak Electrolyte Form: Unionized forms penetrate better.
• Absorption: Determined primarily by the unionized drug proportion.

pH-Partition and Henderson-Hasselbalch

• Absorption Sites: Weak acids absorb better in acidic environments (stomach); weak bases in alkaline environments (intestine).

pH-Partition Hypothesis Limitations

• Additional Factors: Local pH at absorption site, instability in GI fluid, metabolism, and complexation with substances like mucin or bile salts.

Lipid Solubility

• Measurement: Not sufficient to use only a lipophilic solvent to estimate lipid solubility in consideration of drug absorption.

Partition Coefficient

• Definition: Solubility in lipid phase divided by solubility in aqueous phase.
• Poor Lipid Solubility (logP < 0) & Absorption: May still be absorbed, possibly via other mechanisms if low molecular weight.
• Lipid Soluble Drugs (logP > 0) & Oral Absorption: Generally exhibit good oral absorption.
• Homologous Series: Correlation between log P and extent of absorption is apparent in some drug groups like barbiturates and beta-blockers.

Overview of the GI tract including oral administration, GI epithelium mucus, the stomach, small intestine and colon. Focus on roles, volumes, pH, and secretions.