Ionized barbiturates

Example. Phenobarbital [Gardinal ]. The following scheme vividly explains the base hydrolysis of phenobarbital wherein the cyclic ureide ring (in barbiturate) undergoes cessation. Besides, it may also be seen that the aforesaid cessation strategically takes place either between C-l/C-2 and/or C-l/C-6 locations in the structure of barbiturate. However, the cleavage between C-1 and C-6 is considered to be the most preferred pathway prevailing in the ionized barbiturates , such as aqueous solutions of sodium salts. 

Early investigators adduced various kinds of chemical evidence in support of a monohydroxy-dioxo structure for barbituric acid (112) (a) reaction with diazomethane afforded a mono-O-methyl deriva- iye,i59,i6o barbituric acid and its 5-alkyl derivatives are much stronger acids than the 5,5-dialkyl derivatives, and (c) the 5-bromo and 5,5-dibromo derivatives have different chemical properties. - The early physical evidence also appeared to substantiate the monoenol structure, this formulation having been suggested for barbituric acid in 1926 on the basis of its ultraviolet spectrum and again in 1934, In the 1940 s, ultraviolet spectroscopic studies led to the suggestion of other monohydroxy and dihydroxy structures for barbituric acid, whereas its monoanion was assigned structure 113 (a clear distinction between ionization and tautomerism was not made in these papers). 

Jones JJ, Kidwell H, Games DE. 2003. Application of atmospheric pressure chemical ionization mass spectrometry in the analysis of barbiturates by high-speed analytical countercurrent chromatography. Rapid Commun Mass Spec-trom 17 1565. 

Effects of pH on urinary drug elimination may have important applications in medical practice, especially in cases of overdose. For example, one can enhance the elimination of a barbiturate (a weak acid) by administering bicarbonate to the patient. This procedure alka-linizes the urine and thus promotes the excretion of the now more completely ionized drug. The excretion of bases can be increased by making the urine more acidic through the use of an acidifying salt, such as ammonium chloride. 

The four derivatives of barbituric acid clinically useful as antiseizure drugs are phenobarbital, mephobarbital, metharbital, and primidone. The first three are so similar that they are considered together. Metharbital is methylated barbital, and mephobarbital is methylated phenobarbital both are demethylated in vivo. The pKas of these three weak acid compounds range from 7.3 to 7.9. Slight changes in the normal acid-base balance, therefore, can cause significant fluctuation in the ratio of the ionized to the un-ionized species. This is particularly important for phenobarbital, the most commonly used barbiturate, whose pKa is similar to the plasma pH of 7.4. 

Phenobarbital poisoning is exacerbated by its ionized forms also. Its pKa is about 7.2. At a urine pH of 7.4 there will exist about a 50 50 mixture of lipophilic and lipophobic species. Once again the uncharged form will be reabsorbed and the remaining barbiturate molecules will redistribute themselves according to the equilibrium eventually leading to the reabsorption of the virtually all of the phenobarbital. 

Changes in plasma pH may also affect the distribution of toxic compounds by altering the proportion of the substance in the nonionized form, which will cause movement of the compound into or out of tissues. This may be of particular importance in the treatment of salicylate poisoning (see chap. 7) and barbiturate poisoning, for instance. Thus, the distribution of phenobarbital, a weak acid (pKa 7.2), shifts between the brain and other tissues and the plasma, with changes in plasma pH (Fig. 3.22). Consequently, the depth of anesthesia varies depending on the amount of phenobarbital in the brain. Alkalosis, which increases plasma pH, causes plasma phenobarbital to become more ionized, alters the equilibrium between plasma and brain, and causes phenobarbital to diffuse back into the plasma (Fig. 3.22). Acidosis will cause the opposite shift in distribution. Administration of bicarbonate is therefore used to treat overdoses of phenobarbital. This treatment will also cause alkaline diuresis and therefore facilitate excretion of phenobarbital into the urine (see below). 

Barbiturates such as phenobarbital are weak acids. The toxicity of the barbiturate is mainly the result of the effects on the central nervous system. Only the nonionized form of the drug will distribute into the central nervous system. The proportion ionized will depend on the pKa and the pH of the blood. By increasing the pH of the blood using sodium bicarbonate administration to the poisoned patient, ionization of the barbiturate will be increased and distribution to tissues such as the brain will be decreased. Urinary excretion of the barbiturate will also be increased because the urinary pH will be increased. 

M. Riedman, Specific gas chromatographic determination of phe-nothiazines and barbiturate tranquillizers with the nitrogen flame ionization detector, J. Chromatogr., 92 55 (1974). 

C. R. Clarke and J. L. Chan, Improved detectability of barbiturates in HPLC by post-column ionization, Anal. Chem., 50 635 (1978). 

The effect of urinary pH on drug ionization also has toxicological implications. For example, in cases of phenobarbital (a weak acid barbiturate) overdose the urine can be alkalinized (the pH elevated) by administering sodium bicarbonate to the patient. The resultant increase in pH shifts the dissociation equilibrium for this weak acid to the right, producing an increase in the proportion of the ionized form, less reabsorption in the kidneys, and more rapid elimination. Conversely, acidifying the urine with ammonium chloride will increase the excretion rate of drugs that are weak bases since they will be more protonated (ionized) and less reabsorbed (more polar, less lipophilic). 

Therefore the pH of the solution will affect the overall partition coefficient of an ionizable substance. The barbiturate example given above (Table 1.2) is a simplified case, in which all three compounds have... 

Plastic microdevices for high-throughput screening with MS detection were also prepared for detection of aflatoxins and barbiturates. These devices incorporated concentration techniques interfaced with electrospray ionization MS (ESI-MS) through capillaries [2], The microfluidic device for aflatoxin detection employed an affinity dialysis technique, in which a poly (vinylidene fluoride) (PVDF) membrane was incorporated in the microchip between two channels. Small molecules were dialyzed from the aflatoxin/antibody complexes, which were then analyzed by MS. A similar device was used for concentrating barbiturate/antibody complexes using an affinity ultrafiltration technique. A barbiturate solution was mixed with antibodies and then flowed into the device, where uncomplexed barbiturates were removed by filtration. The antibody complex was then dissociated and electrokinetically mobilized for MS analysis. In each case, the affinity preconcentration improved the sensitivity by at least one to two orders of magnitude over previously reported detection limits. 

Elisabeth, I. Rene, S. Dieter, J. Screening for drugs in clinical toxicology hy high-performance liquid chromatography Identification of barbiturates by post-column ionization and detection by a multiplex photodiode array spectrophotometer. J. Chromatogr. 1988, 428, 369. 

Rg = H or CH, Rg = Et, R4 = Ph), which have pifa in the range of 7-8 and are 40-60% dissociated, are capable of crossing the blood-brain barrier and exertingCNS effeets, including sedation. It was shown that the ionized form of barbiturates can permeate liposomal bilayers provided that 5-substituents impart sufficient lipophilicity (157). 

Much of the beneht in solubihty enhancement from salt formation is attributable to the change in solution pH caused by the presence of the counterion. This occurs because the ionization and solubility of acidic drugs (such as barbiturates and non-steroidal anti-inflammatory drugs) increases in basic conditions but decreases in acidic conditions. This behavior is exemplified by derivations of the Henderson-Hasselbalch equations (37.2) and (37.3). The opposite situation occurs for basic drugs such as chlorpromazine, morphine and codeine, which are more soluble in acidic conditions. 

Over the range of serum protein levels usually encountered, the absorption of a 1 1000 dilution obeys Beer s law both at 225 nm (Wl), and at 210 nm (T14). Neither NaCl nor ammonium sulfate interferes. Direct measurement at a single low wavelength (T14) seems to be a satisfactory procedure for determining either serum protein or separated albumin (T14, W8). The method is applicable to electrophoretically separated albumin and globulins (M31), and to albumin in acid-alcohol mixtures, when suitable blanks are included (W8). With appropriate blanks, concentrations of acetate, citrate, succinate, phthalate, and barbiturate up to 0.005 M can be tolerated. Absorption in the far-ultraviolet is unaffected by pH in the range pH 4-8. Outside this range, an altered state of ionization may result in a new molecular form of protein with different spectroscopic characteristics (see Rosenheck and Doty, R24). 

Near-UV absorption spectra of barbiturates depend on the type of substitution and the state of ionization of the molecule.52-54 Absorption bands at — 210 nm for undissociated compounds are shifted to 240-270 nm... 

The electronic structure of barbiturates has also been investigated by spectropolarimetric methods.73-77 Circular dichroism (CD) spectra of a series of (S)-5-alkyl-5-(2 -pentyl)barbituric acids show three Cotton effects centered around 212, 240, and 260 nm, and the short-wavelength band is positive and has an opposite sign in relation to the longer wavelengths. However, in the case of (S)-5-(2 -pentyl)barbituric acid, the signs of all three Cotton effects are opposite to those of all the other derivatives. The solvent studies indicate that the 212- and 260-nm bands arise from the n - n and n - n transitions, respectively, but the 240-nm band is due to n - a or the second n - n transitions.74 An influence of concentration and ionization mode has not been observed. Similar assignment of three Cotton effects has been reported for (S)-5-alkyl-5-(2 -pentyl)-2-thiobarbituric acids.75... 

El mass spectroscopy gives valuable information about the fragmentation of barbiturates, but the molecular ion is not usually observed. The presence of the molecular ion is very important for the identification of particular derivatives. Therefore, other methods of ionization of a molecule are also employed. 

In field desorption (FD) and positive-ion chemical ionization (PICI) mass spectrometry of barbiturates, the molecular ion M+ and/or quasimolecular ion [M + 1]+ (41) are always observed.142-144 Fales et al.142 show that the... 

The negative ion chemical ionization (NICI) of some barbiturates is also described.145-148 The molecular ion MT (42) is formed by electron capture, and this is followed by the elimination of the H atom or R radical, yielding stable anions 43-45 (Scheme 5). Anion 46, present in low abundance, may arise from a McLafferty rearrangement. Ring cleavage is manifested by the presence... 

Quantum mechanical calculations by MINDO/3 suggest that barbiturates with alkyl and/or alkenyl substituents at the 5-position show in solution the same favored conformations as in the solid state109,182,183 (Fig. 8). This conclusion is also confirmed by the results of conformational analyses using H- and 13C-NMR spectroscopy.109,183 Moreover, Andrews et al. conclude that these preferred conformations in solution are independent of the ionization state of the barbiturate ring.109... 

---