Osmolality drugs

A series of calibration standards (CS) is made up that covers the concentration range from just above the limit of detection to beyond the highest concentration that must be expected (extrapolation is not accepted). The standards are made up to resemble the real samples as closely as possible (solvent, key components that modify viscosity, osmolality, etc.). A series of blinded standards is made up (usually low, medium, high the analyst and whoever evaluates the raw data should not know the concentration). Aliquots are frozen in sufficient numbers so that whenever the method is again used (later in time, on a different instrument or by another operator, in another laboratory, etc.), there is a measure of control over whether the method works as intended or not. These so-called QC-standards (QCS) must contain appropriate concentrations of all components that are to be quantified (main component, e.g., drug, and any impurities or metabolites). 

In situ perfusion studies assess absorption as lumenal clearance or membrane permeability and provide for isolation of solute transport at the level of the intestinal tissue. Controlled input of drug concentration, perfusion pH, osmolality, composition, and flow rate combined with intestinal region selection allow for separation of aqueous resistance and water transport effects on solute tissue permeation. This system provides for solute sampling from GI lumenal and plasma (mesenteric and systemic) compartments. A sensitive assay can separate metabolic from transport contributions. 

Hyponatmemia is common with the thiazides and to a lesser extent with the loop diuretics. It occurs when the osmolality of the urine persistently exceeds that of the fluid intake and is associated with the inability of the kidney to produce a dilute urine. It is not usually severe. The origin is multifactorial and involves unrestricted fluid intake and increased ADH activity due to volume depletion. Co-administration of dipsogenic drugs, such as the tricyclic antidepressants, or those with ADH-like effects, such as chlorpropamide, can exacerbate the problem. There are rare occasions when hyponatraemia (Nan- concentration less than 100 mmol-L-l) can be of sufficient severity to be life threatening. 

Urea concentration in the medulla plays an important role maintaining the high osmolarity of the medulla and in the concentration of urine. ADH secretion is regulated by serum osmolality and by volume status. A new class of drugs, the vaptans (see under Agents That Alter Water Excretion), are ADH antagonists. 

For an aqueous solution depot in Figure 1, the drug concentration gradient can also be affected by using excipients to modify the osmolality of the depot. This in turn affects movement of water into or out of the depot with respect to the surrounding... 

Safety is a prime concern in the development of pharmaceutical products. A drug that has an excellent therapeutic effect cannot be released to the market if it has serious adverse effects. Extensive pharmacologic studies and strict evaluations of CAs are required before gaining approval from the Food and Drug Administration (FDA). Factors assessed include the formulation, hemodynamic effect, toxicity, adverse effects, viscosity, osmolality, and immunogenicity of the agent [86]. 

To work around this concentration limitation, formulation scientists often use a solid-state formulation as a means to achieving a higher protein concentration for the final drug product. By reconstituting the solid formulation with less water than was used to initially formulate the drug, one gets an increased protein concentration in the reconstituted product, as depicted in Fig. 1. It is important for the formulation scientist to remember that, in addition to the protein, the excipients in the formulation are also increased in concentration when the solid formulation is reconstituted to a lower final volume. Care should be taken to maintain a suitable final product osmolality for injection. 

Fig. 19 (A) Cross-sectional view of the Alzet osmotic pump, an osmotic pressure-activated drug-delivery system. (B) The effect of 7 days of subcutaneous delivery of antidiuretic hormone (vasopressin) on the daily volume of urinary excretion and urine osmolality in the Brattleboro rats with diabetes insipidus.

Drug absorption may be dependent on concentration, but available data do not allow us to determine whether an increased or decreased drug concentration results in better absorption. An increase in the osmolality of a pharmaceutical preparation secondary to the addition of another substance such as an excipient may decrease or slow down i.m. adsorption. Absorption occurs more rapidly when diffusion involves a large area of muscle or the drug spreads over a large muscle mass. The massaging of an injection site after i.m. administration increases the rate of absorption. ... 

Characteristics of the drug and the fluid such as drug volume, osmolality, pH, and density may affect i.v. drug delivery. The frequency and duration of drug administration is also important as is the need for the infusion system to handle multiple drugs. This may lead... 

In addition, one must remember that for infants the amount of fluid required for drug administration may take away from the amount of fluid available for nutrition. Thus, with medication administration, the fluid volume must be as restrictive as possible so that the bulk of the daily fluid intake can be saved for nutrition. Health care providers must closely monitor daily fluid intake from all sources to prevent fluid overload and must also watch the osmolality of medications with diluents. 

Bloss, C.S. Sybert, K. Osmolality of Commercially Available Oral Liquid Drug Preparations, In ASHP Annual Meeting June 1991 48P-35 Abstract. 

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