In addition, due to the high risk of serious hepatotoxicity, flutamide should not be used in the absence of a serious indication.The mechanism of action of flutamide-induced hepatotoxicity is thought to be due to mitochondrial toxicity. Specifically, flutamide and particularly its major metabolite hydroxyflutamide inhibit enzymes in the mitochondrial electron transport chain in hepatocytes, including respiratory complexes I (NADH ubiquinone oxidoreductase), II (succinate dehydrogenase), and V (ATP synthase), and thereby reduce cellular respiration via ATP depletion and hence decrease cell survival. Inhibition of taurocholate (a bile acid) efflux has also been implicated in flutamide-induced hepatotoxicity. In contrast to flutamide and hydroxyflutamide, which severely compromise hepatocyte cellular respiration in vitro, bicalutamide does not significantly do so at the same concentrations and is regarded as non-mitotoxic. It is thought that the nitroaromatic group of flutamide and hydroxyflutamide enhance their mitochondrial toxicity; bicalutamide, in contrast, possesses a cyano group in place of the nitro moiety, greatly reducing the potential for such toxicity.The hepatotoxicity of flutamide appears to depend on hydrolysis of flutamide catalyzed by an arylacetamide deacetalyse enzyme. This is analogous to the hepatotoxicity that occurs with the withdrawn paracetamol (acetominophen)-related medication phenacetin. In accordance, the combination of paracetamol (acetaminophen) and flutamide appears to result in additive to synergistic hepatotoxicity, indicating a potential drug interaction. Others
Flutamide has also been associated with interstitial pneumonitis (which can progress to pulmonary fibrosis). The incidence of interstitial pneumonitis with flutamide was found to be 0.04% (4 per 10,000) in a large clinical cohort of 41,700 prostate cancer patients.
Metamorphopsia is a type of distorted vision in which a grid of straight lines appears wavy and parts of the grid may appear blank. People can first notice they suffer with the condition when looking at mini-blinds in their home. For example, straight lines might be wavy or bendy. Things may appear closer or further than they are. Initially characterized in the 1800s, metamorphopsia was described as one of the primary and most notable indications of myopic and senile maculopathies. Metamorphopsia can present itself as unbalanced vision, resulting from small unintentional movements of the eye as it tries to stabilize the field of vision. Metamorphopsia can also lead to the misrepresentation of an object’s size or shape.It is mainly associated with macular degeneration, particularly age-related macular degeneration with choroidal neovascularization. Other conditions that can present with complaints of metamorphopsia include: pathological myopia, presumed ocular histoplasmosis syndrome, choroidal rupture and multifocal choroiditis. Pathology
The mechanisms that result in the development of metamorphopsia involve structural changes in the retina of the eye (retinal mechanism) as well as processing changes in the cerebral cortex of the brain (cortical mechanism). The retinal mechanism involves the displacement of retinal layers which results in the mislocation of light on the retina. The cortical mechanism, which was discovered after the retinal mechanism, is affected by perceptual “filling-in” and visual crowding effects. The cortical mechanism was found to work in combination with the retinal mechanism to contribute to metamorphopsia in long-standing maculopathy or after the treatment of macular disorders.