Infection Ionisation

Ambient pH in the extracellular fluid (ECF) is approximately 7.4 but the value varies and this determines the proportions of ionised and unionised local anaesthetic drug. A decrease in ambient pH will increase the amount of ionised drug and reduce the unionised fraction available for transfer across the cell membrane. A common example of this is when infection or inflammation reduces the ambient pH. In the case of lidocaine (lignocaine), a fall in tissue pH from 7.4 to 7.0 will halve the amount of unionised drug. This has obvious implications for efficacy. Similar effects occur following repeated administrations of acidified local anaesthetic solutions. 

Sulphonamides have to he partially un-ionised to enable penetration of the cell membrane of the microbial cell. Thus the antimicrobial activity is increased with an increase in the pKa value of the dmg up to the point where the degree of penetration into the microbial cells is hindered by the extent of low ionisation of the dmg in physiological fluids. It was found that the ionised form of a sulphonamide has the antimicrobial activity because of its ability to accumulate inside the microbial cell and its close similarity to PABA (Fig. 4.18) which has an acidic pKa = 4.8 and is totally ionised at the physiological pH. In addition, low pKa sulphonamides (e.g. sulfisoxazole, pKa = 5.0, Fig. 4.19) are fully ionised at physiological pH and are consequently excreted rapidly in the urine. Thus these agents can be used for the urinary tract infections. 

The prototype sulphonamide, sulfanilamide has a pKa of 10.4. Substimtion of an electron withdrawing group at the R position increases the acidity (decreased pKa) of the sulphonamido N-H. Subsequently, compounds with a pKa of 6-7 will be ionised at physiological pH (7.4) and can be useful in the treatment of systemic infection with decreased risk of crystalluria. This principle has been applied in the design of sulfadimidine (pKa 7.4) and sulfadiazine (pKit 6.5) (Fig. 22.39) by the addition of the electron withdrawing 4,6,-dimethylpyrimidine and pyrimidine, respectively. 

A typical example is sulfacetamide (Fig. 22.40) which possesses a carbonyl substituent directly attached to the sulphonamido nitrogen. The reduced pKa (5.4) means it is 99.9% ionised at physiological pH. The potentially rapid excretion of sulfacetamide has limited its use to the treatment of ocular infections, such as conjunctivitis, caused by susceptible organisms. It is formulated as the sodium salt and used as a 10-30% w/v ophthalmic solution. 

The sulphonamides have been used in the treatment of intestinal infections. Substitution of the aniline N with a succinyl group produces an acidic compound which is fully ionised at intestinal pH and is therefore not appreciably absorbed into the bloodstream. Slow enzjmatic hydrolysis of the product in the intestine releases the free primary amine group which is essential for activity. This concept of prodmg design has been exploited in the sjmthesis of succinyl-sulfathiazole (p/Gt 4.5) from sulfathiazole (p/Gt 7.1) (Fig. 22.42). 

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