L11- Getting Medicines Into The CNS Flashcards
What is the BBB
A permeability barrier which separates circulating blood from the brains extracellular fluid
3 lines of defence of BBB
- Anatomic barrier of endothelial cells of the brain capillaries with tight junctions,basement membrane and surrounding astrocytes
2.enzymatic barrier of degrading enzymes localised in endothelial cells
- Transport systems actively transporting substances from the brain back to blood
Purpose of BBB
Provide essential nutrient supply to brain and ensure a constant internal environment within the CNS
(Gate keeper to CNS)
Problems with CNS
Limits drug delivery to brain
What drugs can pass BBB
lipid soluble <400 Da
Paracellular aqueous pathway
Water soluble agents pass through bbb through tight junctions
Transcellular lipophilic pathway
Lipid soluble agents diffuse through
Transport proteins
Glucose,amino acids, neucleosides bind to transport proteins and passed through bbb
Receptor mediated transcytosis
Allows insulin and transferrin to pass through bbb
Assertive transcytosis
Albumin and other plasma proteins taken up by adsorptive mediated endocytosis and transcytosis increased by cationization of poorly transported proteins
Ways to increase drug delivery to brain
1 chemical modification of a drug
2 Trojan horse
3 bbb disruption
4 nasal delivery
Chemical modification of a drug
Increase lipophilicity of drug
Trojan horse
Conjugation of the drug to a molecule which is able to cross bbb( by carrier/ receptor mediated endocytosis )
Encapsulate drug in a delivery system able to cross the bbb( miscelle, liposome or nanoparticle) which protects drug from degredation
Bbb distribution
Opening bbb by administering pharmacological agents or osmotic opening
should be reversible and short lasting as risk of neurological damage
Trojan hourse
Conjugation of the drug to a molecule which is able to cross bbb( by carrier/ receptor mediated endocytosis )
Encapsulate drug in a delivery system able to cross the bbb( miscelle, liposome or nanoparticle) which protects drug from degradation
Pharmacological agents
Angiotensin 2 and bradykinins
Osmotic opening
Intracarotid injection of hypertonic solutions of mannitol or urea by shrinking endothelial cells or opening tight junctions
Nasal delivery
Lack of efficacy under 0.1% actually reaches Brain
