Blood-brain barrier, cerebrospinal fluid

Specific barriers may serve to limit dmg distribution. The placental barrier is of obvious importance to dmg action in the fetus. Dmg transfers across the placenta primarily by Hpid solubiHty. Hence, this barrier is not particularly restrictive. Similarly, the Hpid solubiHty of a dmg is a primary deterrninant in access to the brain and cerebrospinal fluid. Generally, hydrophilic or charged dmgs can also penetrate to these latter areas, but the result is slow and incomplete. The blood brain barrier is composed of cells having tight junctions which are much less permeable to solutes than are the endotheHal cells of other tissues. 

The area postrema is a circumventricular brain region positioned on the dorsal surface of the medulla on the floor of the fourth ventricle. The blood-brain barrier and the cerebrospinal fluid-brain barrier are absent in this region and consequently many substances that do not pass across capillaries in other regions of the brain can do so in the area postrema. The chemoreceptor trigger zone (CTZ), located in the lateral area postrema is sensitive to blood-borne emetogens. Nerves from the CTZ connect with the vomiting centre. 

The CTZ, located outside the blood-brain barrier (BBB), is exposed to cerebrospinal fluid and blood.2,3 Therefore it is easily stimulated by uremia, acidosis, and the circulation of toxins such as chemotherapeutic agents. The CTZ has many serotonin type 3 (5-HT3), neurokinin-1 (NKj), and dopamine (D2) receptors.2 Visceral vagal nerve fibers are rich in 5-HT3 receptors. They respond to gastrointestinal distention, mucosal irritation, and infection. 

Embedded within the brain are four ventricles or chambers that form a continuous fluid-filled system. In the roof of each of these ventricles is a network of capillaries referred to as the choroid plexus. It is from the choroid plexuses of the two lateral ventricles (one in each cerebral hemisphere) that cerebrospinal fluid (CSF) is primarily derived. Due to the presence of the blood-brain barrier, the selective transport processes of the choroid plexus determine the composition of the CSF. Therefore, the composition of the CSF is markedly different from the composition of the plasma. However, the CSF is in equilibrium with the interstitial fluid of the brain and contributes to the maintenance of a consistent chemical environment for neurons, which serves to optimize their function. 

The exit of drugs from the CNS can involve (1) diffusion across the blood-brain barrier in the reverse direction at rates determined by the lipid solubility and degree of ionization of the drug, (2) drainage from the cerebrospinal fluid (CSP) into the dural blood sinuses by flowing through the wide channels of the arachnoid villi, and (2) active transport of certain organic anions and cations from the CSF to blood across the choroid plexuses... 

Variable penetration into cerebrospinal fluid (CSF) has been observed. Disease-related defects in the blood-brain barrier may be responsible for the variations seen. 

The steady-state volume of distribution following IV administration of a 1.5 mg dose averaged 0.534 L/kg. Cerebrospinal fluid obtained from 9 patients at 2 to 3.5 hours following 0.06 or 0.09 mg/kg IV infusion showed measurable concentrations of zalcitabine. The CSFiplasma concentration ratio ranged from 9% to 37% (mean, 20%), demonstrating drug penetration through the blood-brain barrier. 

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 ... 

Lithium is readily absorbed from the gastrointestinal tract, reaching a peak plasma level in 2 to 4 hours. Distribution occurs throughout the extracellular fluid with no evidence of protein binding. Passage through the blood-brain barrier is limited, so that cerebrospinal fluid levels are 50% of plasma levels at steady state. 

Pharmacokinetics Rapid, complete absorption after IM administration. Protein binding less than 30%. Widely distributed (doesn t cross the blood-brain barrier low concentrations in cerebrospinal fluid (CSF). Excreted unchanged in urine. Removed by hemodialysis. Half-life 2-4 hr (increased in impaired renal function and neonates decreased in cystic fibrosis and febrile or burn patients). 

Pharmacokinetics Rapidly and completely absorbed from the GI tract. Protein binding 25%-38%. Undergoes first-pass metabolism in the liver. Crosses the blood-brain barrier and is widely distributed, including to cerebrospinal fluid (CSF). Primarily excreted in urine. Minimal removal by hemodialysis. Half-life 0.8-1.2 hr (increased in impaired renal function). 

The blood-brain barrier foils most efforts to use the blood to measure the brain s chemistry, but researchers can get aroimd this obstacle by sampling cerebrospinal fluid (CSF). CSF is the fluid that circulates in the meninges of the brain and spinal cord and keeps the delicate tissues from getting rattled around and damaged in their hard, bony container. The brain makes CSF from blood, and certain metabolites get mixed in. One of these metabolites is 5-hydroxyindole acetaldehyde (5-FIIAA), a major metabolite of serotonin. Researchers who carefully puncture the meninges and extract a sample are rewarded with information concerning serotonin levels in the person s brain, as described below. 

The "chemoreceptor trigger zone" or area postrema is located at the caudal end of the fourth ventricle. This is outside the blood-brain barrier but is accessible to emetogenic stimuli in the blood or cerebrospinal fluid. The chemoreceptor trigger zone is rich in dopamine D2 receptors and opioid receptors, and possibly serotonin5-HT3 receptors and NKi receptors. 

First, the protein itself can be infused directly into the cerebrospinal fluid or implanted in a biodegradable, slow-release preparation. Second, the active protein can travel across the blood-brain barrier by hiding inside a Trojan horse molecule... 

Tong et al. [65] studied the pharmacokinetics of vigabatrin in rat blood and cerebrospinal fluid (CSF), and the major findings of this study are that (i) the pharmacokinetics of vigabatrin in serum are linear and dose-dependent, while in CSF are dose-independent (ii) vigabatrin is not protein bound in serum (iii) the elimination of vigabatrin from serum is rapid and (vi) vigabatrin is rapidly penetrated the blood-brain barrier (BBB). 

The permanent positive charge of QTA influences distribution in vivo and prevents passage of blood-brain barrier and blood-cerebrospinal fluid barrier [30, 31]. Myolitic QTA are muscarinic receptor antagonists but allow a better therapeutic index as they are insoluble in lipids and thus poorly systemically absorbed (e.g. bioavailability of A-butyl-scopolamine after oral intake <1 % [30]). Therefore, spasmolytic activity in the GIT (by, e.g. cimetropium, butropium or /V-butyl-scopolamine, Fig. 1), respiratory tract (ipratropium, Fig. 1) and overactive bladder (trospium, Fig. 1) appears as the primary local effect whereas systemic side effects are markedly minimized or absent [32-34],... 

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