Central nervous system specific agents

The present chapter will address the following issues (1) a very brief overview on the properties of the different types of Cl -channels in the various mammalian cells (2) a short summary on what is known of Cl channels on a molecular basis (3) a discussion of pharmacological agents blocking the various Cl -channels and (4) a specific section dealing with the regulation of epithelial and maybe other Cl -channels. This entire area has been reviewed rather extensively in the recent past. A large number of references will be provided in order to keep this text concise. The entire field of Cl -channels in the central nervous system will only be touched upon to compare these channels to the Cl -channels in apolar cells and epithelia. 

More specifically regarding petroleum and petroleum products, the alkanes in gasoline and some other petroleum products are central nervous system depressants. In fact, gasoline was once evaluated as an anesthetic agent. However,... 

Each neuron has specific synthetic machinery that enables it to both synthesize and eliminate a specific neurotransmitter. For example, neurons of the sympathetic nervous system employ norepinephrine and epinephrine as their transmitters. Other neurons, particularly in the central nervous system, employ dopamine as their transmitter. Dopamine is a particularly important transmitter for a variety of neuronal functions. Its loss is associated with Parkinson disease, and it is a critical agent in the mediation of pleasure and reward processes. Dopamine, due to its association with pleasurable sensations, is widely implicated in the actions of a number of drugs of abuse, including cocaine, opiates, and methamphetamines. 

CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at several sites within the central nervous system (CNS). Alprazolam like other benzodiazepines exerts its anxiolytic action by potentiating GABA activity. GABA is a neurotransmitter which inhibits the CNS activity. Alprazolam acts preferentially in midbrain, ascending reticular formation (which maintains wakefulness) and on limbic system (thought and mental functions). 

Most adverse effects of phenoxybenzamine derive from its -receptor-blocking action the most important are orthostatic hypotension and tachycardia. Nasal stuffiness and inhibition of ejaculation also occur. Since phenoxybenzamine enters the central nervous system, it may cause less specific effects, including fatigue, sedation, and nausea. Because phenoxybenzamine is an alkylating agent, it may have other adverse effects that have not yet been characterized. 

The acute toxic properties of all the organochlorine pesticides in humans are qualitatively similar. These agents interfere with inactivation of the sodium channel in excitable membranes and cause rapid repetitive firing in most neurons. Calcium ion transport is inhibited. These events affect repolarization and enhance the excitability of neurons. The major effect is central nervous system stimulation. With DDT, tremor may be the first manifestation, possibly continuing to convulsions, whereas with the other compounds convulsions often appear as the first sign of intoxication. There is no specific treatment for the acute intoxicated state, and management is symptomatic. 

Some new compounds having an effective and specific activity on the central nervous system have thus been found among silatranes. This suggests that new types of psychotropic agents may be found among the substances of this class. 

Tertiary-amine muscarinic receptor antagonists gain access to the central nervous system and are therefore the anticholinergic drugs used to treat parkinsonism and the extrapyramidal side effects of antipsychotic drugs. Specific agents used primarily for these conditions include benztropine mesylate (Cogentin) and trihexyphenidyl hydrochloride (Artane, others). 

These agents are of interest because of pharmacokinetic features (oral activity, distribution to the central nervous system) or because of relative selectivity for specific receptor subclasses. 

Ethambutol [e THAM byoo tole] is bacteriostatic and specific for most strains of M- tuberculosis and M- kansasii. Resistance is not a serious problem if the drug is employed with other antituberculous agents. Ethambutol can be used in combination with pyrazinamide, isoniazid, and rifampin to treat tuberculosis. Absorbed on oral administration, ethambutol is well distributed throughout the body. Penetration into the central nervous system (CNS) is therapeutically adequate in tuberculous meningitis. Both parent drug and metabolites are excreted by glomerular filtration and tubular secretion. The most important adverse effect is optic neuritis, which results in... 

Indeed, the blockers do seem to be plagued by significant cross-talk to receptors other than histamine receptors. This is not uncommon - many agents, particularly those that readily penetrate into the central nervous system, have incompletely defined receptor specificities, although they are usually given a label suggesting otherwise. They are... 

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