Strategies for drug delivery through the blood-brain barrier通过血脑屏障的药物递送策略.ppt

Introduction to CNS pharmacology Anne McKinney Microanatomy Neurons Non-neuronal -Microglia -Microglial related macrophages -Cells of the cerebral vasculation -Meninges c) Blood brain barrier Blood brain barrier (BBB) Cortical microvasculature The BBB has several functions Protects the brain from “foreign substances” in the blood that my injure the brain Protects the brain from hormones and neurotransmitters in the rest of the body Maintains a constant environment for the brain General properties Large molecules do not pass through the BBB easily Low lipid (fat) soluble molecules do not penetrate into the brain. However lipid soluble molecules e.g. barbiturate drugs rapidly cross through the brain Molecules that have a high electrical charge are slowed Transport of substances into the brain are dependent on: Conc between compartments Size of molecule (MW) Flexibility and conformation of molecules Amino acid composition Lipophilicity Cellular enzymatic stability Cellular sequestration Affinity for efflux mechanisms Hydrogen bonding potentials (charge) Affinity for carrier mechanisms Effects of existing pathological conditions Penetration of drugs across BBB Factors determining the ability of a drug to cross the blood-brain barrier 1. Lipid solubility 2. Ionization 3. Plasma protein binding Molecular mass Transporter Diffusion of substances in the brain Paracellular (between cells) (not occur to great extent at the BBB due to tight junctions) - Transcellular (across cells) The higher the lipohilicity of a substance the greater the diffusion in the brain Transport at the BBB 4 basic mechanisms: Simple diffusion (low to high conc) Facilitated diffusion: a carrier mediated endocytosis( solute molecules bind to specific membrane protein carrier low to high conc Simple diffusion through an aqueous channel formed within membrane Active transport through a protein carrier: specific binding site that undergoes a change in affinity. Active transport requi