Homeostatic compensatory mechanisms

Furosemide is a widely used loop diuretic indicated for the treatment of different pathological conditions such as congestive heart failure, hepatic cirrhosis, and chronic renal failure. It has a narrow absorption window and mainly absorbed from the stomach and the upper part of the small intestine. Following administration of furosemide, the natriuretic effect rapidly disperses and is concealed before the next administration. This problematic aspect in furosemide therapy is mostly attributed to the natural homeostatic compensatory mechanisms. Lately, it has been demonstrated that the diuretic and natriuretic effects of furosemide can be significantly improved, following a continuous input (intravenous infusion) compared to immediate release DFs. Beside the narrow absorption window, this pharmacodynamic feature of the drug provides another rationale for the development of a GRDF for furosemide. 

Because the no-effect level can often be only statistically proven to the level of the background noise (recall our discussion in Chapter 1 about spontaneous disease level), it is impossible to statistically prove a zero- or no-effect dose. In fact, as will be touched on later, subtoxic chemical exposure may be beneficial for many chemicals as homeostatic compensatory mechanisms are induced which have a beneficial, not adverse, biological effect. 

Homeostatic reflex A neuronal compensatory mechanism for maintaining a body function at a predetermined level, eg, the baroreceptor reflex for blood pressure... 

Any sudden alteration in the mean arterial blood pressure tends to produce compensatory reflex changes in heart rate, contractility, and vascular tone, which will oppose the initial pressure change and restore the homeostatic balance. The primary sensory mechanisms that detect changes in the mean arterial blood pressure are stretch receptors (baroreceptors) in the carotid sinus and aortic arch. 

Strategies underlying drug Rx include reduction in blood volume, reduction in sympathetic one, reduction in vagal tone, and relaxation of vascular smooth muscle. Note that depending on the anti-HTN drug used, homeostatic mechanisms may lead to compensatory responses of salt and water retention and/or reflex tachycardia. 

Treatments for HTN aim to reduce sympathetic tone and blood volume and/or relax vascular smooth muscle. However, homeostatic mechanisms may lead to compensatory increases in heart rate and/or salt and water retention. 

At present, the approach of preference appears to be the search for qualitative differences, such as the appearance of an enzyme band in an electropherogram where none was present before, rather than a quantitative difference in a substance which is always present. For normal blood or urine constituents, normal values vary over a considerable range, and the values seen in a subpopulation known to have a given genetic disease may overlap it. This is especially true for metabolites, where alternate biochemical pathways and compensatory changes due to either homeostatic mechanisms or therapy may exist. Hence our initial emphasis is on the detection of qualitative changes in substances which are direct gene products. 

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