drug delivery: brain, kidney, and liver

what is the blood-brain barrier?

• tight construction of the vessels in the head guards against brain entry

• protective layer of endothelial cells that strictly controls what substances can enter the brain

what are the functions of the BBB?

• protects the brain for foreign substances in the blood that may injure the brain
• protects the brain from hormones and neurotransmitters in the rest of the body
• maintains a constant environment for the brain

what are the general properties of the BBB?

• hydrophilic molecules do not penetrate easily in the absence of specific mechanisms (e.g. membrane transporters, endocytosis)
• large molecules do not pass easily
• molecules that have a high electrical charge are slowed

how is the BBB equipped for the efficient supply of hydrophilic nutrients?

with membrane transport systems and some of those transporter proteins have been shown to accept drug molecules and transport them into the brain

what is systemic drug delivery to the brain?

• making highly lipophilic drugs (e.g. nevirapine viramune)
• increasing the passive entry of "restricted" drugs into the central nervous system
• targeting drugs to the brain by redox chemical delivery systems
• conjugating drugs to molecules actively transported through the BBB
• "mask" drugs (nanoparticles, liposomes, etc)

what can the BBB be broken down by?

• hypertension
• hyperosmolarity
• radiation exposure
• infection
• trauma, ischemia, inflammation, pressure
• injection of irritating substances into the carotid artery

what % of drugs are too water-soluble or have too large MWs to cross the BBB?

95%

what are the limitations of systemic delivery?

• enzymatic degradation in the GI tract and liver after oral administration
• short half-life and degradation of drugs in the bloodstream
• low penetration of drugs into the brain
• low efficacy of treatment
• possible adverse side effects on other organs and tissues

what are gliadel wafers?

• dosage form of treatment for brain tumors: implanted into the tumor site at the time of surgery that slowly releases a chemotherapeutic drug
• designed to deliver a drug directly to the area of the brain tumor, bypassing the BBB
• implanted into the cavity formed by the removal of tumor at the time of the surgery, and left in
• the dissolved by themselves and don't have to be removed

what is the olfactory region?

primary site for nose-to-brain delivery, where drugs can cross the olfactory epithelium and enter the brain through the olfactory nerve

what is alzheimer's disease?

• progressive, neurodegenerative disorder that primarily affects memory, thinking, and behavior
• accumulation of beta-amyloid plaques and neurofibrillary tangles
• APOE ε4 mutation: genetic variant of apolipoprotein E (APOE) gene, strongly associated with an increased risk of AD

what is cirrhosis?

• scarring occurs when the EM of the liver is damaged by repeated/severe injury
• bile ducts then proliferate, regenerative nodules form, and collagenous scars become evident

what is mucosal and parenteral drug delivery?

• delivery directly into the bloodstream or via the absorptive mucosa in various easily accessible body cavities (e.g. ocular, nasal, buccal, rectal, vaginal mucosae)
• has the advantage of bypassing the hepatogastrointestinal first-pass elimination associated with oral administration

what is drug detoxification by the liver?

• after oral drug delivery, drugs are absorbed inZ GI tract and through the portal circulation enter liver where they are destroyed by first-pass metabolism
• even if drugs are delivered locally to target organs or systemically to the circulation, they enter liver by second pass metabolism and are subjected to detoxification

what is liver-targeted drug delivery?

• uses strategies like passive and active targeting to deliver drugs directly to the liver and its specific cells
• achieved by the coupling of drugs to (neo)glycoproteins that are specifically taken up by various target cells in the liver
• drugs can be coupled directly to HSA to obtain liver-specific delivery
• e.g. dexamethasone (anti-inflammatory) to Kupffer and endothelial cells when coupled to HSA

what happens with high blood supply in liver, kidney, and drug delivery?

• (+) easy drug delivery to the liver and kidney
• (-) detoxification of drugs targeted to other organs