Organ directed toxicity

Organ directed toxicity

Whether cell death results in organ failure depends primarily on the regenerative capacity of the organ. The liver has a relatively high capacity for regeneration. Three kinds of liver damage exist: hepatic necrosis (e.g. from paracetamol), inflammation due to autoimmune reactions (e.g. from halothane), and cholestasis (accumulation of bile due to e.g. steroids, OACs). When these kinds of injury occur chronically or often, the repair mechanisms cause fibrosis. Liver cirrhosis occurs after chronic hepatotoxicity, e.g. as with alcohol abuse. The kidneys are specifically susceptible to toxicity because they are the principal organ for drug excretion. Toxic agents (drugs or metabolites) can accumulate and concentrate in the renal tubules. Different mechanisms underly nephrotoxicity: changes in renal haemodynamics, glomerular nephropathy, interstitial nephritis, and tubular destruction.

Renal function is mainly dependent on the filtration capacity of the glomeruli. Thus, loss of functional glomeruli leads to renal failure. The kidneys are able to compensate for the loss of glomerular function, but this ultimately worsens the situation and progressive renal failure is inevitable. Examples of nephrotoxic drugs are antibiotics, NSAIDs, and ACE inhibitors. Heavy metals are also nephrotoxic because they accumulate in the kidney. Platinum-containing oncolytic drugs such as cisplatinum are notorious examples. Neuronal tissue (not shown in the figure) is not capable of regeneration. Thus, damage from neurotoxicity is permanent and means loss of neurological function. Fortunately, the brain is protected by the blood-brain-barrier and prevents the entry of many toxic drugs into the brain. The peripheral nervous system has some regenerative capacity.