Entry into the Brain

Once in the blood, ample evidence now suggests that aluminum Ccm cross the blood-brain barrier to enter the brain. Liss, using newborn rabbits, found that aluminum chloride ingestion by the mother rabbit resulted in increased aluminum content in the mother s milk and in the brains of the suckling rabbits. It is impor-temt to remember, however, that the blood-brain barrier may not have been fully formed in the infant rabbits. DeBoni et al. subjected adult rabbits to repeated subcutaneous injections of aluminum. Atomic absorption spectroscopy showed that brain aluminum levels increased from 1.1 xg/g diy weight (controls) to 2.5-47.9 Xg/g in injected animals. Using the aluminum-sensitive Morin stain, th found that neutrophils and monocytes within vessels and capillary endothelial cells exhibited intensely fiuores-cent nuclei, whereas the nuclei of cells of the choroid plexus were 

Several studies have suggested that blood aluminum levels, similar to blood levels of other metals, can serve as an indicator only of circulating aluminum levels, and not total body store. Bowdler et al. found an inconsistent relationship between serum and brain aluminum concentrations though there was a correlation in some groups of rats exposed to aluminum chloride, there was no correlation in others. These authors point out that serum aluminum concentration is not necessarily a reliable indicator of 

The amount of aluminum absorbed from the gastrointestinal tract may be dependent on certain factors. For example. Mayor et ai 56,57 report that increased parathyroid hormone treatment causes increased intestinal aluminum absorption and higher brain aluminum concentrations in rats given oral aluminum. They also observed that parathyroid hormone withdrawal in rats resulted in a rapid decrease of brain aluminum concentration independent of dietary aluminum. Those authors suggest that reduced parathyroid hormone aids in reducing brain aluminum accumulation, and that both Alzheimers disease and dialysis encephalopa- 

It is now well-established that an increase in body aluminum occurs with renal failure. This appears to result in part from an inability to excrete the small amount of aluminum absorbed fixim the gastrointestinal tract. In normeil mammeds eduminum excretion increases during periods of increased aluminum uptake. As King et al. point out, there are no studies that clearly delineate the mechanism of renal excretion of aluminum. They suggest that in order to appear in the urine, eduminum may exist as part of a sufficiently small molecule to allow it to permeate the glomerular membrane. 

As pointed out earlier, aluminum appears to occur in both a protein-bound and unbound form in the plasma. The fact that a portion of the aluminum is bound to plasma protein appears to explain why aluminum is nondialyzable, and is also consistent with the evidence that the component of the plasma protein that 

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Toluene, volatile nitrites, and anesthetics, like other substances of abuse such as cocaine, nicotine, and heroin, are characterized by rapid absorption, rapid entry into the brain, high bioavailability, a short half-life, and a rapid rate of metabolism and clearance (Gerasimov et al. 2002 Pontieri et al. 1996, 1998). Because these pharmacokinetic parameters are associated with the ability of addictive substances to induce positive reinforcing effects, it appears that the pharmacokinetic features of inhalants contribute to their high abuse liability among susceptible individuals. 

Blocking the conversion to DA would appear stupid unless this could be restricted to the periphery. More dopa would then be preserved for entry into the brain, where it could be decarboxylated to DA as usual. Drugs like carbidopa and benserazide do precisely that and are used successfully with levodopa. They are known as extracerebral dopa decarboxylase inhibitors (ExCDDIs). Carbidopa (a-methyldopa hydrazine) is structurally similar to dopa but its hydrazine group (NHNH2) reduces lipid solubility and CNS penetration (Fig. 15.4). 

Q67 Diazepam may be used in status epilepticus. Diazepam has a long half-life and exhibits rapid entry into the brain. 

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. 

Two obstacles effectively prohibit this availability. Serotonin has a free hydroxy group (the 5-hydroxy which is the H of 5-HT). This is a big polar water-loving pimple which denies it any passage across the brain s defensive Maginot Line, the blood-brain barrier. And there is the second problem. There is a exposed amino group, the amine of T of 5-HT, the tryptamine, which is immediately removed by the body s monoamine oxidase enzyme. In short, it is blocked from entry into the brain because it is both too polar and too metabolically fragile. 

It is the drug s sudden entry into the brain that accounts for the initial surge of energy. The rush is thought to last as long as it takes the brain and body to break heroin down into morphine, which is then absorbed by the body s opioid receptors. This stage finds the user going on the nod, an alternatively wakeful and pleasurably drowsy state that lasts four to six hours. 

Dopamine is synthesized in the terminals of dopaminergic fibers originating with the amino acid tyrosine and, subsequently, L-dihydroxyphenylalanine (L-dopa or levodopa), the rate-limiting metabolic precursor of dopamine. Fortunately, L-dopa is significantly less polar than dopamine and can gain entry into the brain via an active process mediated by a carrier of aromatic amino acids. Although L-dopa is itself basically pharmacologically inert, therapeutic effects can be produced by its decarboxylation to dopamine within the CNS. 

Franke et al. (1999) have described an in vitro model for screening of drug entry into the brain using primary cultures of porcine brain capillary endothelial cells (PBCEC). By using serum-free culture conditions... 

This lesson might be eventually extended to other drugs of abuse known to depend upon a rapid entry into the brain compartment via smoking, such as nicotine and cannabis. 

Rapoport SI, Ohno K, Pettigrew KD. Drug entry into the brain. Brain Res 1979 172 354-9. 

Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA (2004) Toll-liker receptor 3 mediates West Nile virus entry into the brain causing lethal encephlaitis. Nat Med 10 1366-1373. 

Increased plasma free tryptophan leads to an increase in the plasma concentration ratio of free tryptophan to the branched-chain amino acids (BCAA), which compete with tryptophan for entry into the brain through the blood-brain barrier. Therefore, the plasma concentrations of these amino... 

U.S. are summarized in Table 16-2. Note that most benzodiazepines can be used interchangeably. Benzodiazepines used as anticonvulsants have a long tj j, and rapid entry into the brain is required for efficacy in treatment of status epilepticus. A short elimination tj is desirable for hypnotics. 

Barbiturates Thiopental, thiamylal, and methohexital have high lipid solubility, which promotes rapid entry into the brain and results in surgical anesthesia in one circula-... 

Interestingly, pyridoxine is known to antagonize levodopa , perhaps by promoting possible premature decarboxylation (as a coenzyme to dopa decarboxylase) before the drug has gained entry into the brain. It has been observed that carbidopa curtails antagonism by pyridoxine to a certain extent. 

In salicylate intoxication (see p 331), acidemia enhances salicylate entry Into the brain and must be prevented. Alkalinization of the urine promotes salicylate elimination. 

B. Pharmacokinetics. Lithium is completely absorbed within 6-8 hours of ingestion. The initial volume of distribution (Vd) is about 0.5 L/kg, with slow entry into tissues and a final Vd of 0.7-0.9 L/kg. Entry into the brain is slow, which explains the delay between peak blood levels and central nervous system (ONS) effects after an acute overdose. Elimination is virtually entirely by the kidney, with a half-life of 14-30 hours. 

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