17.1. THE PATHOLOGY, THE HEPATORENAL SYNDROME
Patients that die of hepatic liver disease die in renal failure (see Chapter 13). Chronic liver disease is associated with massive accumulation of circulating blood volume and formation of ascitic fluid that can reach volumes of 20 liters in the abdomen of a victim of chronic cirrhosis. The debate as to the mechanism and the therapeutic approach to treat the hepatorenal syndrome has resulted in numerous symposia and contrasting controversial approaches. When searching for a new paradigm to explain a significant pathology or observation, it is important to identify the anomalies in the current accepted or alternate paradigms. It was generally accepted that the renal dysfunction in liver disease was not secondary to a renal dysfunction, per se, but that it was some regulator of renal function that was dysfunctional. Denervation of the liver or kidneys resulted in reduction of the renal fluid retention. The general consensus was that hepatic baroreceptors were responding to hepatic or portal venous hypertension and stimulating reflex sympathetic nerves to the kidney, resulting in renal fluid retention. However, the logic of that explanation implied a physiological positive feedback system whereby an increase in portal blood flow, for instance, which would result in an increase in intrahepatic pressure, would result in activation of sympathetic nerves to the kidneys and fluid retention, which would result in increased circulating blood volume and increased cardiac output and increased portal blood flow, with further elevation in the pressure that was proposed as the afferent limb in this hepatorenal reflex. A positive feedback physiological homeostatic mechanism appeared highly unlikely; therefore, we suggested the unlikely possibility that what was being sensed by the hepatic nerves was blood flow rather than blood pressure. By this model, any disease process that resulted in a reduced portal blood flow into the liver would result in stimulation of the afferent nerves and activation of the hepatorenal reflex. For this hypothesis to be considered viable, it was necessary to propose a specific physiological mechanism by which changes in blood flow could be detected by afferent nerves. Based on our studies related to the hepatic arterial buffer response, we knew that a reduction in portal blood flow would result in an elevation of adenosine in the space of Mall in exactly the region where hepatic sensory nerves have been shown to arise. Because adenosine had been shown to activate sensory nerves in the heart and carotid artery, it seemed feasible that adenosine could also activate sensory nerves in the liver. To test this hypothesis, we administered adenosine into the portal vein in rats and measured renal fluid and electrolyte output. Adenosine administration was intended to mimic the effect of reduced portal blood flow and did result in a decrease in renal fluid and electrolyte output that could be blocked by denervation of the liver, or of the kidney, or by administration of a nonselective adenosine receptor antagonist to the liver. The physiological regulation therefore seemed to be feasible. Additional studies showed that reductions in portal blood flow also produced renal retention that could be blocked by hepatic denervation or adenosine receptor blockade. Thus, a normal physiological process was reasonably well defined and pharmacological tools were developed.
Pathophysiology and pathopharmacology often overlap. A chronic liver disease model was created using the hepatotoxin thioacetamide and demonstrated to show the anticipated decrease in renal function. However, to have an acute index of renal function, we used an intravenous saline volume stimulus to activate renal fluid and solute excretion. This method proved an extremely valuable tool. The renal dysfunction produced by the chronic liver disease model was similar to that seen with either intraportal adenosine administration or by shunting portal blood around the liver. The pharmacology predicted that the disease state involved adenosine stimulation of hepatic sensory nerves and therefore could be corrected by administration of an adenosine receptor antagonist. The logic was that the chronically damaged liver had elevated intrahepatic adenosine levels due to either or both mechanisms. Chronic liver disease results in increased intrahepatic portal venous resistance and portal hypertension with resultant portacaval shunt formation. According to the hepatic arterial buffer response mechanism, shunting of portal blood to the inferior vena cava results in reduced portal inflow to the liver, which results in increased adenosine concentration in the space of Mall. The elevation in adenosine levels in the space of Mall activates afferent nerves arising in that space, thus activating the hepatorenal reflex. However, another potential source of adenosine could arise from the inflammatory or hypoxic response to the liver, whereby ATP breaks down progressively to ADP, AMP, and finally to adenosine. Inflammatory conditions are often associated with increased production of cyclic AMP, which breaks down to adenosine. Application of the adenosine receptor antagonist corrected the baseline fluid retention and restored the ability to respond to an acute saline overload.
You are viewing: What Is Pathopharmacology
The pathopharmacological phase of the investigation included using selective adenosine receptor antagonists to determine which adenosine receptor subtype was involved. From our previous work with adenosine, we knew that the A2 receptor was primarily involved with vasodilation and was therefore unlikely to be the relevant receptor. In contrast, the A1 receptor is known to be the mechanism of stimulation of the central nervous system. An A1 receptor antagonist restored salt and water excretion and the ability to respond to a saline load, whereas A2 receptor antagonism was without effect.
Read more : What Are Back Tab Curtains
Drug repurposing then became a consideration. The question became what was the most suitable adenosine A1 receptor antagonist that was already on the market and had a solid track record of effects and toxicities. Because of our previous studies, we knew that caffeine had virtually no A2 receptor antagonist effects in the circulation of either the liver or intestine (Chapter 10), and the literature clearly indicated that caffeine had A1 antagonistic activity. We therefore tested caffeine as a potential as a repurposed pharmaceutical and demonstrated a very clear therapeutic potential. The disadvantage with the caffeine approach was that the kinetics of absorption and elimination were too rapid to be applied as a useful diuretic. However, modifying the kinetics of caffeine by using a slow-release capsule formulation offers a viable, testable, and patentable drug repurposing that would allow for direct entrance into phase 2 clinical trials.
The pathopharmacology approach to directing a research program is demonstrated by this one example. A similar approach has led to successful drug repurposing for diabetes therapy that is an entirely different story [233].
Source: https://t-tees.com
Category: WHAT
