Quaternary ammonium compound absorption

Diquat and paraquat are quaternary ammonium compounds largely used as contact herbicides and crop desiccants. When systemic absorption occurs, paraquat and diquat are rapidly distributed into the body. Paraquat primarily accumulates in the lungs and kidneys, while the highest diquat concentrations have been found in the gastrointestinal tract, liver, and kidneys (WHO, 1984). Urine is the principal route of excretion for both diquat and paraquat, which are primarily eliminated as unmodified compounds. Occupationally exposed workers can be monitored by measuring paraquat and diquat concentrations in urine samples (Table 6). Blood concentrations are useful to monitor acute poisoning cases. 

Martin H) has written a perceptive analysis of the possible ways in which an ionized species may behave in various models and contribute to or be responsible for a given activity. QSAR studies that have dealt with ion-pair partitioning include a study of fibrinolytics ( ) and the effect of benzoic acids on the K ion flux in mollusk neurons ( ). Schaper (10) recently reanalyzed a large number of absorption studies to include terms for the absorption of ionized species. Because specific values were not available for log Pj, he let the relation between log Pi and log P be a parameter in a nonlinear regression analysis. In most cases he used the approximation that the difference between the two values is a constant in a given series. This same assumption was made in the earlier studies (, ) Our work suggests that the pKa of an acid can influence this differential (see below). The influence of structure on the log P of protonated bases or quaternary ammonium compounds is much more complex (11,12) and points out the desirability of being able to easily measure these values. 

Absorption of some highly ionized compounds (e.g., sulfonic acids and quaternary ammonium compounds) from the gastrointestinal tract cannot be explained in terms of the transport mechanisms discussed earUer. These compounds are known to penetrate the Upid membrane despite their low Upid-water partition coefficients. It is postulated that these highly lipophobic drugs combine reversibly with such endogenous compounds as mucin in the gastrointestinal lumen, forming neutral ion pair complexes it is this neutral complex that penetrates the Upid membrane by passive diffusion. 

Kimura, R., Miwa, M., Kato, Y., Sato, M., and Yamada, S. (1991), Relationship between nasal absorption and physicochemical properties of quaternary ammonium compounds, Arch. Int. Pharmacodyn. Ther., 310,13-21. 

The interaction of dmgs in the charged form with other ions to form absorbable species with a high lipid solubility is a possible explanation for the ability of molecules such as quaternary ammonium compounds, ionised under all pH conditions, to be usefully absorbed. The origin of the ions which pair with dmg ions is not clear, but there is evidence that ion-pair formation will aid absorption. 

Orally administered corticosteroids are effective in the treatment of chronic bronchial asthma. The inhalation route has been widely used in attempts to avoid systemic side-effects, such as adrenal suppression, but evidence suggests that inhaled steroids are absorbed systemically to a significant extent. The respiratory tract epithelium has permeability characteristics similar to those of the classical biological membrane, so lipid-soluble compounds are absorbed more rapidly than lipid-insoluble molecules. Cortisone, hydrocortisone and dexamethasone are absorbed rapidly by a nonsaturable diffusion process from the lung, the half-time of absorption being of the order of 1-1.7 min. Quaternary ammonium compounds, hippurates and mannitol have absorption half-times, in contrast, of between 45 and 70 min. 

In an attempt to reduce the occurrence of side effects associated with absorption into the systemic circulation, quaternary ammonium compounds have been developed as muscarinic cholinoceptor antagonists, for example, ipratropium bromide, glycopyrrolate methylbromide. As a result of their polar nature, these compounds are poorly absorbed across lipid membranes and, therefore, do not easily enter the systemic circulation or the central nervous system (to produce undesirable side effects), but they do induce bronchodilation of long duration [34,35]. The only significant side effect of the quaternary ammonium compounds is dry mouth, an effect perhaps to be expected for a muscarinic cholinoceptor antagonist administered as an aerosol via the mouth. 

Greving et al. analyzed some basic drugs and quaternary ammonium compounds by means of ion-pair chromatography in the straight-phase adsorption mode. Bromide or perchlorate were used as counter-ions in connection with microparticulate silica gel columns. Chloride and iodide were less suitable as counter-ions, because they caused, respectively, corrosion of the equipment or a too strong UV absorption background of the mobile phase. Methanol was used as mobile phase, containing 0.01-0.1 M of the counter-ion. 

For acids and bases only the non-ionized molecules can be absorbed. At all physiological pH values weak acids and bases exist mostly in the unionized form and can be absorbed as well from the stomach as from the intestine. In theory, weakly acidic drugs are better substrates for passive diffusion at the pH of the stomach than at that of the intestine. However, the limited residence time of the drug in the stomach and the relatively small surface area of the stomach more than balance the influence of pH in determining the optimal site of absorption. Strong bases such as the quaternary ammonium compounds are, to a large extent, ionized at all physiological pH s, and are hardly absorbed at all. 

Jane et al have recorded retention (125x5 (i.d.) mm Spherisorb S5W Silica column) and relative detector response data (EC (V25 grade GCE, -1-1.2 V V5 Ag/ AgCl) and UV absorption (254 nm)) for 462 basic drugs and quaternary ammonium compounds using methanolic ammonium perchlorate (10 mmol L pH 6.7) as... 

This preservative is comparatively new to ophthalmic preparations and is a polymeric quaternary ammonium germicide. Its advantage over other quaternary ammonium seems to be its inability to penetrate ocular tissues, especially the cornea. It has been used at concentrations of 0.001-0.01% in contact lens solutions as well as dry eye products. At clinically effective levels of preservative, POLYQUAD is approximately 10 times less toxic than benzalkonium chloride [87,137], Various in vitro tests and in vivo evaluations substantiate the safety of this compound [137,141,142], This preservative has been extremely useful for soft contact lens solutions because it has the least propensity to adsorb onto or absorb into these lenses, and it has a practically nonexistent potential for sensitization. Its ad-sorption/absorption with high water and high ionic lenses can be resolved by carefully balancing formulation components [143],... 

Manxine (l-azabicyclo[3.3.3]undecane 60) is an interesting compound which can be prepared in 60% yield by reduction of the quaternary ammonium salt (59) with sodium in liquid ammonia. It has a melting point of 150-152 °C and a remarkably long wavelength absorption [Amax 240 nm, e 2935 (ether)] for a saturated amine. Its pKa (9.9) is one unit... 

Alkyl Pb compounds, mainly tetramethyl and tetraethyl Pb, are added to gasoline as anti-knock agents. The amount added varies from country to country but is generally in the range 200—1500/igml-1 Pb and this may be present as one or both of the Pb alkyl species mentioned. Unfortunately, it has been found that the Pb response in atomic absorption spectroscopy is dependent on the particular alkyl with which it is associated. Thus, unless it is known that only one particular Pb alkyl is present in a gasoline sample, it is not possible to employ a simple dilution procedure. Since the exact nature of the Pb species is seldom known for sure, then a general analytical method must ensure that the response from the various Pb alkyls is equalised in some manner. This is achieved by stabilisation with iodine and a quaternary ammonium salt. 

The presence of carboxylate anions in the polymer was demonstrated by IR spectroscopy. The polymer and model compound HOCH2CH2COOeNa had identical absorptions at 6.3 fim, which disappeared on exposure to HCl-vapour, No evidence for the presence of quaternary ammonium ions can be gained from IR spectroscopy, but the presence of the only conceivable cations H and (CH3)3N -CH2COOH can be ruled out. Carboxylate anions could not exist in their presence. 

The belladonna alkaloids are absorbed rapidly from the gastrointestinal tract. They also enter the circulation when applied locally to mucosal surfaces. Only limited absorption occurs from the intact skin. Atropine disappears rapidly from the blood and is distributed throughout the entire body. Most is excreted in the urine within the first 12 h, in part unchanged. Only about 1% of an oral dose of scopolamine is eliminated as such in the urine. Traces of atropine are found in various secretions, including milk. The total absorption of quaternary ammonium derivatives of the alkaloids after an oral dose is only about 10-25 percent (10,11) nevertheless, some of these compounds can cause mydriasis and cycloplegla if applied to the eye. 

Fluorescence data have been reported for thirty-one corticosteroids in sulphuric acid, allowing identification of the structural features necessary for strong fluorescence. The u.v. absorption maxima of 4-en-3-ones are red-shifted by amino or quaternary ammonium functions in compounds such as (18) or (19). ... 

Ipratropium bromide is a nonselective muscarinic receptor blocker, and blockade of inhibitory muscarinic receptors theoretically could result in an increased release of acetylcholine and overcome the block on the smooth muscle receptors (M3). Oifly the quaternary ammonium derivatives such as ipratropium bromide should be used because they have the advantage of poor absorption across mucosae and the blood-brain barrier. This results in negligible systemic effects with a prolonged local effect (i.e., bronchodilation). In addition, the quaternary compounds do not appear to produce a decrease in mucocfliary clearance. Ipratropium bromide has a duration of action of 4 to 8 hours. Both intensity and duration of action are dose-dependent. Time to reach maximum bronchodilation is considerably slower than from aerosolized short-acting 82-agonists (2 hours versus 30 minutes). However, this is of little clinical consequence because some bronchodilation is seen within 30 seconds, 50% of maximum response occurs within 3 minutes, and 80% of maximum is reached within 30 minutes. Ipratropium bromide is oifly indicated as adjunctive therapy in severe acute asthma not completely responsive to 82-agonists alone because it does not improve outcomes in chronic asthma. ... 

Absorption of quaternary ammonium and sulfonium compounds from the GI tract is incomplete and unpredictable, due to the limited ability of these ionized substances to penetrate cell membranes and depression of propulsive movements of the small intestine and gastric emptying. 

---