Physicochemical activity of solutions as an integral part of the mechanism of local drug action

Introduction. In recent years, there has been evidence that local post-injection tissue damage may be caused by injectable solutions themselves, since they are produced without monitoring for their local physicochemical aggressiveness for patient's tissues, particularly without controlling their local irritant effect. The current standards for injections do not include monitoring for changes in tissues at the sites of injection of drug solutions and in blood viscosity within the veins and intravascular catheters. Objective: to reveal the dependence of the local irritant effect of injectable solutions on their temperature, osmotic and acidic (alkaline) activities. Material and methods. Changes in the symptoms of tissue inflammation through the routes of drug administration were evaluated in 20 wakeful Landrace piglets. The test substances were injected into the conjunctival cavity and subcutaneously into the anterior abdominal wall. The osmotic activity of the solutions was determined by the cryoscopic method using an Osmomat-030 RS osmometer. The degree of ocular inflammation in the piglet was assessed according to changes in the symptoms of conjunctivitis. Skin inflammation at the injection site was assessed by changes in local hyperthermia, hyperemia, and swelling of drug-induced infiltration; the duration and completeness of its resorption and the appearance of post-injection necrosis were also analyzed. Local temperature changes were examined by infrared radiation using a Thermal Tracerth91xx imager. Venous blood, extremity veins, and their inserted intravascular catheters were studied in 200 patients. Blood viscosity was scrutinized using a Brookfield DV-II viscometer; blood coagulation was examined by the Lee-White method; vein lumen size and walls were assessed using a Logiq Book XP ultrasound apparatus. The skin, subcutaneous fat, and saphenous veins at the injection sites were additionally investigated by thermal infrared imaging; information was subsequently processed according to thermal explorer and image processor programs. The results were statistically processed using the Biostat program according to the generally accepted methods. Results. The physicochemical and local inflammatory activities of 40 quality solutions for injection were determined before and after their dilution with water. Subcutaneous injections of drug solutions at a more than 10% concentration of active ingredients gave rise to subcutaneous fat infiltrates that failed to resolve, but became inflamed, increasing in sizes and causing necrosis. Immediate chipping of the subcutaneous infiltrates with 5% sodium citrate or 5% ethylenediaminetetraacetic acid disodium salt solution prevented necrosis of the skin and subcutaneous fat. Zones of hyperthermia were found to emerge in the veins at the location of the pointed tips of vascular catheters. The temperature of the injected solutions affects that of the venous wall. The simultaneous administration of 4% sodium hydrogen carbonate solution with drugs prevented the formation of a focus of local hyperthermia. Conclusion. It has been experimentally shown that the physicochemical activity of injectable solutions may underlie their local action on subcutaneous fat and blood during subcutaneous and intravenous injections. Dilution of injectable drug solutions with water to the total concentration of ingredients being less than 2% eliminates the physicochemical aggressiveness of drugs and ensures their safety during their local application. The acidifying and heating effect of drugs can cause blood clots and occlusion of the lumen of veins and catheters.

injectable solutions, drug quality, drug safety, physicochemical pharmacology