pt 3: target organ toxicity Flashcards
The fact that hepatic lesions are often centrilobular has been attributed to the HIGHER concentration of (1)——- there. In addition, the relatively LOWER concentration of (2)——– there, compared to that in other parts of the liver
(1) cytochrome P-450
(2) glutathione
carbon tetrachloride leads to which toxic subcellular effects on organelles in liver cells?
- enzyme leakage from plasma membrane
and
-mitochondria swelling
enzyme leakage from plasma membrane of liver cells is caused by which toxicants
acetaminophen, carbon tetrachloride, phalloidin
nucleus neoplasia of liver cells is caused by which toxicants
aflatoxin, tannic acid,…
mitochondria swelling of liver cells is caused by which toxicants
carbon tetrachloride, cycasin, phosphorus.
-1- what agents produce acute hepatic lesions?
-2- what agents produce both acute and chronic lesions?
-1- ethionine, phosphorus, or tetracycline
-2- Ethanol and methotrexate
what is the most common mechanism of lipid accumulation in the liver
the impairment of the release of hepatic triglyceride to the plasma.
carbon tetrachloride exerts toxicity via its metabolite trichloromethyl through several MOAs leading to liver necrosis, which include:
-lipid peroxidation
-disturbances of Ca2+ homeostasis
-depletion of adenosine triphosphate (ATP),
-shifts of the Na+ and K+ balance between hepatocytes and blood,
-depletion of glutathione,
-damage to cytochrome P-450, and
-loss of NAD and NADP
Reduction of biliary excretory activity of the canalicular membrane appears to be the predominant mechanism for ——-
cholestasis
——- seem to impair the permeability of the biliary tract, thus reducing bile salt–independent bile flow
Ethinyl estradiol and chlorpromazine
The pathogenesis of cirrhosis in a majority of cases seems to originate from single-cell —– associated with a deficiency in the repair mechanism.
necrosis
-This condition then leads to fibroblastic activity and scar formation
The most important cause of human cirrhosis is chronic ingestion of alcoholic beverages.
—- may damage mitochondria and increase local production of reactive oxygen species. These may lead to steatosis, necrosis, and cirrhosis
Ethanol
what are characteristics of drugs that cause viral-like hepatitis
- such liver injuries are not demonstrable in animals
- the effects in humans do not seem to be related to the dose
- the latent period varies greatly
- the toxicity is manifest in only a few susceptible individuals
- the histologic picture is more variable
- the patients usually show other signs of hypersensitivity and sometimes respond to a challenge dose
- fever, rash, and eosinophilia are present in many cases.
—– induces hepatocarcinogenesis via a nongenotoxic mechanism only in the mouse and not in the rat
Dieldrin
—— in addition to producing hepatotoxicity also induces hepatocellular adenoma and carcinoma
Fumonisin B
steatosis, necrosis, and cirrhosis can result from exposure to —–
- CCl4 (and related chemicals such as chloroform),
- aflatoxins, and
- phosphorus.
——– was shown to produce liver cell death by depletion of glutathione and an oxidative phase characterized by mitochondrial permeability transition and protein nitration
chloroform
The serum level of alanine aminotransferase (ALT) is increased in reliable correlation with the severity of hepatic ——-. It is therefore the choice test in this liver injury.
necrosis
-OCT and SDH are more sensitive but less specific, so they’re used in addition to ALT
Measurements of barbiturate-induced sleeping time and the duration of zoxazolamine-induced paralysis have been used as indications of ——- effects
hepatic
what tests are used to detect liver function
ALT / OCT / SDH / bilirubin LS / BSP excretion MS / prolongation of prothrombin time (after vitamin K excretion) / drugs like BARBs-induced sleeping time and zoxazolamine-induced paralysis.
acetaminophen, aflatoxin, allyl alcohol, ethanol, ethionine, fumonisin B
the following are toxic to what type of injury
necrosis and fatty liver
p-aminosalicylic acid, amitriptyline, carbamazapine
M
the following are toxicants of what type of injury
cholestasis (drug induced)
imipramine
cholchicine
halothene
the following are toxicants of what type of injury
viral-like hepatitis (drug induced)
-acetylaminofluorene
-aflatoxin B1
-Cycasin
the following are toxicants of what type of injury
carconogenesis in experimental animals
what are the most sensitive and consistent indicators of nephrotoxicity
In vitro accumulation of organic ions,
urinary concentrating ability, and
kidney weight
what is the most sensitive indicator of the nephrotoxicity of a platinum complex
urine osmolarity
what halogenated hydrocarbons are nephrotoxicants, and what is the site of toxicity
bromobenzene, chloroform, carbon tetrachloride
site: proximal tubule
what heavy metals are nephrotoxicants, and what is the site of toxicity
- cadmium and chromium are toxic at the proximal tubules
- Gold is toxic at the Glomeruli
what antibiotics are nephrotoxicants, and what is the site of toxicity
-Aminoglycoside: at glomeruli and proximal tubules
-Amphotericin B: glomeruli and blood vessels and distal tubules
- Cephaloridine: proximal tubules
what analgesics are nephrotoxicants, and what is the site of toxicity
-Acetaminophen: various parts of the nephron and blood vessels
-Methoxyflurane: various parts of the nephron
what patient groups are more susceptible to chemical-induced nephrotoxicity.
geriatric males
what are MOAs of NEPHROTOXICANTS
- interaction with receptors,
- inhibition of oxidative phosphorylation
-disturbance of Ca2+ homeostasis
-adverse effects in plasma and subcellular membranes
—— induce a nephropathy with functionally a decease in renal volume, but histologically there is thickening of the basement membrane of the LOOP OF HENLE, isolated necrosis of interstitial and papillary tubular cells followed by fibrosis and cortical interstitial nephritis
Analgesics
which antibiotic is not secreted from the proximal tubules but is accumulated in these cells, thereby producing damage.
cephaloridine
The antibiotic ——– can increase the permeability of the glomerulus to proteins such as ALBUMIN. This has been attributed to an alteration in the electrical charge of glomerular basement membrane
puromycin
Certain toxicants, for example, ——, may induce membranous glomerulonephritis by the deposition of ANTIGEN-ANTIBODY conjugates in the glomerular basement membrane.
gold, mercury, and penicillamine
—— produces acute thrombotic microangiopathy and chronic nephropathy with interstitial fibrosis
Cyclosporin
——-, produce chronic renal failure, with adverse effects located predominantly in the medulla, that is, loop of Henle, vasa recta, interstitial cells, and collecting tubules.
Analgesic mixtures containing aspirin and phenacetin, a derivative of acetaminophen
- due to vasoconstriction of the vasa recta
—— were reported to produce inflammatory interstitial nephritis in humans.
Penicillins and sulfonamides
