Steroid anesthetics

The GABA-gated chloride ion channel is modulated by several classes of drugs that bind to allosteric sites on the receptor complex the benzodiazepines, barbiturates and related intravenous general anesthetics such as etomidate and propofol, as well as anesthetic steroids and endogenous neurosteroids. It appears that some types of GABAa receptor are directly enhanced by ethanol and volatile general anesthetics (Fig. 16-2) [7,8,20]. 

Gases Low relative molecular mass (100-600) Polar materials (200-2000) Drugs and metabolites Peptides, proteins Carbon dioxide, anesthetics Steroids, fatty acids Sugars, nucleosides, small peptides Glucuronides, sulfates Endorphins, albumin, proteomics Gas analyzer Isotope ratio MS GC-MS, LC-MS LC-MS, FAB-MS LC-MS/MS, FAB-MS/MS Digest followed by LC-ESI-MS/MS, nanoflow-MS/MS, MALDI-ToF-MS... 

AHopregnanolone and similar A-ring-reduced pregnanes potentiate GABA effects at these receptors. These steroids mimic the effects of the benzodiazepines, changing chloride ion conductance and producing sedative and hypnotic behavioral effects (276,277). Neuroactive steroids can be therapeutically useful as anticonvulsants, anxiolytics, or anesthetics (qv) (see also Hypnotics, sedatives, anticonvulsants, and anxiolytics). 

With very few exceptions, the biological activities of synthetic steroids tend to parallel those of the naturally occurring hormones on which they are patterned. Compounds with distant pharmacological activity are, as a rule, quite rare. It is thus intriguing that inclusion of a tertiary amine at the 11 position of a pregnane leads to a compound with activity far removed from its close analogues. The agent in question, minaxalone (47), exhibits anesthetic activity. 

Glycine receptor function is modulated by alcohols and anesthetics [4]. Amino acid residue al(S267) is critical for alcohol potentiation, as mutation to small residues (Gly, Ala) enhance, and mutation to large residues (His, Cys, Tyr) diminish the ethanol effect. Glycine recqrtor modulation by Zn2+ involves structural determinants located within the large N-terminal domain. Additional glycinergic modulators include neuroactive steroids and the anthelmintic, ivermectin, which activates glycine receptors by a novel, strychnine-insensitive mechanism. 

Classical or conventional pharmaceutical agents in combination with lactide/glycolide polymers have been widely studied since about 1973. In general, these compounds are bioactive agents usually produced by synthetic chemistry, with molecular weights of less than a few hundred and relatively stable structures. Examples include steroid hormones, antibiotics, narcotic antagonists, anticancer agents, and anesthetics. 

STEROID (alphaxalone, allopregnanolone) VOLATILE ANESTHETIC (halothane)... 

There are now indications for the interaction of progesterone metabolites with the Cl channel of the GABAa receptor (Fig. 52-7). The A-ring-reduced steroids, especially those with the 5a,3a configuration, are particularly active on the GABAa receptor [ 12]. By facilitating chloride-channel opening, these steroids produce anesthetic, anxiolytic and sedative-hypnotic effects (see Ch. 16). 

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