Blood Brain Barrier and Drug Delivery

Page 1: Defining the Blood Brain Barrier (BBB)

Overview of BBB

• The blood brain barrier is a selective barrier that protects the brain from circulating substances in the bloodstream.

• It regulates entry of molecules, including glucose, essential for brain function.

• Comprised mainly of endothelial cells with tight junctions that are more restrictive compared to other body areas.

Cellular Structure of BBB

• Endothelial cells: Form the capillary wall.

• Tight junctions: Ensure high restriction of molecules crossing the barrier.

• Supporting cells include astrocytes, microglia, and the basal lamina, which help maintain the integrity of the BBB.

• Endothelial cells help create a "wall" between blood and brain tissue, regulating molecular access.

Page 2: Pathological Conditions Affecting Drug Delivery

Impact of Disease

• Pathological conditions (e.g., Alzheimer’s, HIV) can disrupt BBB integrity.

• Such conditions may increase permeability, allowing both drugs and potentially harmful agents to enter the brain.

• Inflammation can significantly impact drug delivery efficacy as drugs may pass through more readily under compromised barrier conditions.

Importance of Crossing the BBB

• Targeting neurological diseases necessitates drug delivery across the BBB.

• Conditions such as Alzheimer's, migraines, epilepsy, and Parkinson's require effective therapeutic intervention via CNS medications.

Page 3: Pathways for Drug Delivery Across BBB

Non-Invasive Approaches

• Most drugs use existing pathways for transport across the BBB.

• Five primary pathways discussed:

  1. Paracellular Aqueous Pathway: Allows small, polar molecules to pass between cells.

  2. Transcellular Lipophilic Pathway: Drugs diffuse across lipid membranes; influenced by molecular weight and hydrogen bonding characteristics.

Considerations for Drug Properties

• Molecular weight: Ideally <500 Da for efficient transport.

• Hydrogen bond donors/acceptors: Lower counts lead to improved lipophilicity.

• Partition coefficient (Log P): Ideally 1.5 to 2.5 for optimal balance between water solubility and lipophilicity.

Page 4: Prodrugs and Drug Modification

Prodrugs Concept

• Prodrugs: Inactive derivatives converted to active forms upon reaching target sites, enhancing delivery across biological barriers.

• Lipidation: Modification of drugs to enhance lipophilicity for better membrane crossing, using esters of fatty acids or alcohols.

Examples

• Morphine vs. Heroin: Heroin's modifications increase BBB penetrability compared to morphine, illustrating the impact of chemical structure on drug efficacy.

Page 5: Transport Proteins and Receptor-Mediated Transcytosis

Carrier-Mediated Transport

• Endothelial cells utilize transport proteins to allow nutrient passage (e.g., glucose, amino acids).

• Key Transport Systems:

  • Glucose Transporters: High expression levels enabling glucose transport into the brain.

Challenges

• Size restriction limits effectiveness of pro-drug modifications for transport.

Page 6: Advanced Transport Mechanisms

Adsorptive Transcytosis Mechanism

• Involves non-specific binding of positively-charged molecules to anionic sites on cell membranes.

• May enhance drug delivery by utilizing electrostatic interactions to facilitate movement across the BBB.

Page 7: Innovations in Drug Delivery Systems

Emerging Techniques

• Cell-based Delivery Methods: Leverage immune cells or exosomes to transport drugs across the BBB.

• Focused Ultrasound: Enhances permeability of the BBB transiently to facilitate drug delivery.

• Intranasal Delivery: Bypasses BBB by delivering drugs through the olfactory epithelium directly to the brain.

Page 8: Invasive Approaches to BBB Disruption

Osmotic and Chemical Disruption

• Osmotic Disruption: Agents like mannitol induce temporary BBB disruption, enhancing drug delivery efficiency but risking brain edema.

• Chemical Disruption: Agents trigger inflammatory responses transiently improving accessibility but with potential long-term risks.

Page 9: Summary of Non-Invasive vs. Invasive Approaches

• The choice of drug delivery technique across the BBB depends on disease state, drug properties, and desired therapeutic outcomes.

Page 10: Ocular Drug Delivery Systems

Introduction to Ocular Pharmacology

• Discussed routes for delivering drugs to various ocular conditions through eye drops.

• Emphasized the unique challenges related to ocular bioavailability limits.

Page 11: Factors Affecting Ocular Drug Delivery

• Key factors include drug formulation, viscosity, solubility, and the methods of administration.

• Techniques to enhance bioavailability through formulation chemistry and physical adaptations suggested.

Page 12: Summary of Ocular Drug Delivery Methods

• Stressed the complexity of achieving effective ocular drug delivery due to anatomical features and physiological dynamics affecting absorption.

Additional Concepts Covered

• Further research on enhancing drug bioavailability in various delivery systems, including new formulations and design strategies.