Blood-brain barrier drug

Concerning the distribution of a drug, models have been published for log BB blood/brain partition coefficient) for CNS-active drugs (CNS, central nervous system) crossing the blood-brain barrier (BBB) [38-45] and binding to human serum albumin (HSA) [46]. 

Blood-brain barrier permeation of 7, among other drugs, was predicted from its three-dimensional molecular structure by a computational method (0OJMC2204). The combination of molecular topological methods using 137 quinolones, including 7 provided an excellent tool for the design of new... 

The sedation side effect commonly observed on administration of classical antihistaminic drugs has been attributed in part to the ease with which many of these compounds cross the blood brain barrier. There have been developed recently a series of agoits, for example, terfenadine (198), which cause reduced sedation by virtue of decreased penetration into the CNS. This is achieved by making them more hydrophilic. Synthesis of a related compound, ebastine (197),... 

Alternate ways to interfere with the orexin system may be via inhibition of dipeptidyl peptidases or proteolysis-resistant peptide analogs as shown for other peptides. This could prolong and boost orexinergic signaling. OX-A but not OX-B can enters the brain by simple diffusion via the blood-brain barrier. Abundance of orexins and their receptors in the olfactory bulb and throughout all parts of the central olfactory system may offer transnasal routes for drug application. 

The symptoms of parkinsonism are caused by a depletion of dopamine in the CNS. Dopamine, when given orally, does not cross the blood-brain barrier and therefore is ineffective The body s blood-brain barrier is a mesh-work of tightly packed cells in die walls of the brain s capillaries that screen out certain substances. This unique meshwork of cells in the CNS prohibits large and potentially harmful molecules from crossing into die brain. This ability to screen out certain substances lias important implications for drug dierapy because some drugs are able to pass through die blood-brain barrier more easily dian odiers. 

Levodopa is a chemical formulation found in plants and animals that is converted into dopamine by nerve cells in the brain. Levodopa does cross die blood-brain barrier, and a small amount is dien converted to dopamine. This allows the drug to have a pharmacologic effect in patients witii Parkinson s disease (Pig. 29-1). Combining levodopa witii another drug (carbidopa) causes more levodopa to reach die brain. When more levodopa is available, the dosage of levodopa may be reduced. Carbidopa has no effect when given alone. Sinemet is a combination of carbidopa and levodopa and is available in several combinations (eg, Sinemet 10/100 has 10 mg of carbidopa and 100 mg of levodopa Sinemet CR is a time-released version of die combined drugs). 

The COMT inhibitors are used as adjuncts to levodopa7 carbidopa in Fhrkinson s disease Tolcapone is a potent COMT inhibitor that easily crosses the blood-brain barrier. However, the drug is associated with liver damage... 

Liu X, Tu M, Kelly RS, Chen C and Smith BJ. Development of a computational approach to predict blood-brain barrier permeability. Drug Metab Dispos 2004 32 132-9. 

Figure 5,4 Pharmacokinetics. The absorption distribution and fate of drugs in the body. Routes of administration are shown on the left, excretion in the urine and faeces on the right. Drugs taken orally are absorbed from the stomach and intestine and must first pass through the portal circulation and liver where they may be metabolised. In the plasma much drug is bound to protein and only that which is free can pass through the capillaries and into tissue and organs. To cross the blood brain barrier, however, drugs have to be in an unionised lipid-soluble (lipophilic) form. This is also essential for the absorption of drugs from the intestine and their reabsorption in the kidney tubule. See text for further details...

There are two sites in the body where a drug is not able to pass freely into the tissue. One is the plaeenta and the other the brain where the blood-brain barrier (see Chapter 1) is a formidable hindrance. Without pores in the capillaries a drug can only enter the CNS (or cross the placenta) by virtue of lipid solubility, as in the gut. 

Few drugs, apart from nicotine itself, act specifically on nicotine receptors. One is methylcarbachol, which lacks the muscarinic effects of carbachol and another is dimethylphenylpiperazinium (DMPP), which appears to have some selectivity for the neuronal nicotinic receptor. Neither of them can cross the blood-brain barrier. 

In contrast to the nicotinic antagonists and indeed both nicotinic and muscarinic agonists, there are a number of muscarinic antagonists, like atropine, hyoscine (scopolamine) and benztropine, that readily cross the blood-brain barrier to produce central effects. Somewhat surprisingly, atropine is a central stimulant while hyoscine is sedative, as least in reasonable doses. This would be the expected effect of a drug that is blocking the excitatory effects of ACh on neurons but since the stimulant action of atropine can be reversed by an anticholinesterase it is still presumed to involve ACh in some way. Generally these compounds are effective in the control of motion but not other forms of sickness (especially hyoscine), tend to impair memory (Chapter 18) and reduce some of the symptoms of Parkinsonism (Chapter 15). 

In parallel with the identification of distinct transporters for GABA there has been continued interest in the development of selective blockers of these transporters and the therapeutic potential that could result from prolonging the action of synaptically released GABA. It has been known for a long time that certain pro-drugs of nipecotic add (e.g. nipecotic acid ethyl ester) are able to cross the blood-brain barrier and are effective anticonvulsants in experimental models of epilepsy. More recently, several different systemically active lipophillic compounds have been described that act selectively on GAT-1, GAT-2 or GAT-3 (Fig. 11.4). Of these, tiagabine (gabitiil), a derivative of nipecotic acid that acts preferentially on GAT -1, has proved clinically useful in cases of refractory epilepsy. 

Since there is no reduction in striatal postsynaptic DA receptors in PD then drugs acting directly on them should be effective and in theory present some advantages over levodopa. They do not have to be converted to DA, they can be designed to be long-acting, cross the blood-brain barrier and act on specific DA receptors. In practice they have been somewhat disappointing. 

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