Brain drug passage into

Drug distribution in such sites or compartments is a complex process that depends on the systemic circulation concentration and subsequent passage across single cell endothelial or epithelial membranes with specialized physical and molecular barrier functionality. For certain orally administered AIDS medications (e.g., zidovudine and didanosine), oral absorption is limited because of poor absorption from the G1 tract, enzymatic biotransformation in the intestinal epithelium, or first-pass effects (Sinko et al., 1995, 1997). For other AIDS drugs (e.g., protease inhibitors), oral absorption may be complete however, drug distribution into the brain is limited by drug efflux proteins, which promiscuously interact and translocate lipophilic substrates back into blood as they diffuse into the BBB endothelium (Edwards et al., 2005 Kim et al., 1998). 

The blood-brain boundary is defined physically by small openings in capillaries and the astrocyte cell membranes that prevent passage of large polar molecules. The barrier keeps large toxic polar molecules from passing into the brain. Drugs must be soluble in blood and soluble in the lipid layer of the membrane in order to reach the brain. 

Quantitative measurement of diffusional uptake and carrier-mediated transport of nutrients and drugs in experimental animals was greatly facilitated with the introduction of Olden dorfs brain uptake index (BUI) [42].Test and reference tracers are injected as an intraarterial bolus into the carotid artery of the anaesthetized animal. After 5 s the animal is killed and the brain is removed for radioactivity counting. This method measures the ratio of the unidirectional brain extraction, E, of the test substance and of the reference ([ H]-water, [ " C]-butanol), which are labelled with different isotopes, during a single passage through the brain capillary bed ... 

An ability to penetrate lipid bilayers is a prerequisite for the absorption of drugs, their entry into cells or cellular organelles, and passage across the blood-brain barrier. Due to their amphiphilic nature, phospholipids form bilayers possessing a hydrophilic surface and a hydrophobic interior (p. 20). Substances may traverse this membrane in three different ways. 

AU of the following statements concerning the blood-brain barrier and the passage of drugs from the systemic circulation into the cerebrospinal fluid are TRUE EXCEPT ... 

Not all substances in the bloodstream can readily gain entry into the brain. This apparent barrier to drugs and other chemicals is relative rather than absolute, and in fact there are several barriers to substances entering the brain from the systemic circulation. The term blood-brain barrier is usually applied to the lack of passage of certain drugs or other exogenously administered chemicals into the brain. 

Cocaine dissolves in the mucous lining of the nasal passages and quickly passes into the bloodstream, where it is carried to the brain. The user experiences the effects of the drug in a few minutes. [Jon Schulte/iStockphoto]... 

Figure 11.1 The blood-brain barrier prevents the passage of large molecules, such as proteins, into the brain. Small molecules, such as glucose and molecules found in drugs of abuse, are able to pass through the barrier.

The olfactory region located in the poorly accessible recessed roof of the nasal passages offers the potential for certain compounds to circumvent the blood-brain barrier and enter into the brain [48]. The olfactory sensory cells are in contact with both the nasal cavity and the CNS and this neuronal connection constitutes a direct pathway to the brain. By utilizing this pathway drugs would not only circumvent the blood-brain barrier, but also avoid any hepatic first-pass effect and degradation in the blood compartment, a particularly important issue in the case of peptide drugs. 

Blood-brain barrier The specialized anatomic arrangement of cerebral capillary walls that serves to restrict the passage of some drugs into the brain. 

Q10 An excessive amount of ADH may be produced by some brain tumours, certain drugs and some lung cancers. Since this causes a reduced water excretion, an excess of ADH leads to water retention and hyponatraemia. As hyponatraemia in the ECF causes passage of water into the body cells, there may be brain swelling, raised intracranial pressure and neurological symptoms, such as headache, muscle weakness, lethargy, nausea and vomiting, irritability, confusion and coma. 

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