Liver failure protein metabolism

Disorder of protein metabolism could be noticed in 13% decrease of total protein content in blood serum. The observed hypoproteinemia was stipulated by 25% decrease of albumin fraction. The index showing correlation between the level of middle molecules and total protein was 65% higher in Group 2 indicating prevalence of protein degradation processes over their synthesis. The revealed disorders indicated the development of liver failure syndrome. Profound disorders were also registered in lipid metabolism. We determined the intensification of lipolysis by increase in the concentration of the main lipid fractions in blood serum. The level... 

Serious liver disease can affect the 12 main metabolic functions of the liver, with their 60 - 70 even more important partial functions, to widely differing degrees, (s. tab. 3.1) The result is either global insufficiency or partial insufficiency, each with very varied clinical and biochemical symptoms. The failure of certain metabolic functions is responsible to a greater or lesser extent for the development and intensity of liver insufficiency. Impairments in the functions of detoxification and protein metabolism are particularly significant in this respect. 

The indication for administering BCAA in patients with hepatic encephalopathy to compensate amino-acid imbalance was proposed by J.E. Fischer et al. in 1974, and implemented parenterally. However, oral application of BCAA for an adequate treatment period also has beneficial effects on cirrhosis and HE (7.) improvement in protein tolerance and the nutritional condition, (2.) improvement in cerebral functions (II8, 122), probably due to an amelioration of liver function, (2.) stimulation of ammonia detoxification with a positive nitrogen balance (118), (4.) reduction in or normalization of AAA levels, and (5.) promotion of glutamine synthesis with a favourable effect on the cells of the immune system and on renal function. By means of BCAA, it was possible to prolong the survival time and delay the occurrence of liver failure in rats with CC -induced cirrhosis. (123, 126) However, there are diverging results, which need further clarification. In principle, the use of BCAA is considered to be a necessary form of supplementary treatment for catabolic metabolism in cirrhosis (124,125, 127, 128, 130-132), in (also latent) HE and after curative resection of hepatocellular carcinoma. (I2l) (s. p. 280)... 

After a valproate overdose a 27-year-old man developed seizures, hypernatremia, respiratory failure, metabolic acidosis, liver failure, and bone marrow depression (125). His plasma valproic acid concentration was 1414 pg/ml. Treatment with hemodialysis was effective in enhancing valproic acid clearance, while hemoperfu-sion was relatively less effective, because of saturation of the column. Overall, the half-Ufe of the drug was reduced from over 20 hours before treatment to less than 3 hours during hemodialysis/hemoperfusion drug removal was probably favored by saturation of drug binding to plasma proteins, which resulted in a low unbound fraction (32% at the start of treatment). He was comatose for 5 days but recovered fully thereafter. 

Protein metabolism depends on both kidney and liver function therefore, protein requirements will be altered with decreased kidney or liver function (see Chap. 139). Critical illness (e.g., sepsis, burns, or trauma) will result in a hypercatabohc state in which there is increased protein synthesis and degradation. Consequently, protein requirements wiU be increased to 1.5 to 2 g/kg per day. In burn patients, protein requirements may be as high as 2.5 to 3 g/kg per day. Liver failure typically results in the need for protein restriction (0.5 g/kg per day) except if a hypercatabohc state is also present, in which case the requirement may be increased to 1.5 g/kg per day. Protein needs in renal failure are variable and affected by the various renal replacement therapies available. The apphcation of these guidelines requires both chnical judgment and frequent monitoring of renal and liver function, serum chemistries, chiucal condition, and nutrition outcomes (see Chap. 139). 

Use cimetidine with caution in >50 year olds w/kidney or liver failure Little plasma protein binding, little metabolism. Cimetidine T levels of many drugs (see notes ) by inhibiting liver P450 enzymes. Oral anticoagulants, theophylline, caffeine, phenytoin, phenobarbital, benzodiazepines, propranolol. 

Hepatic coma—In this condition the brain is intoxicated by an excess of ammonia which accumulates in the blood during liver failure. Normally, the liver converts the ammonia formed in protein metabolism to urea which may be excreted safely in the urine... 

Sotalol is rapidly and almost completely (>90%) absorbed. Bioavahabhity of absorbed dmg is 89—100%. Peak plasma levels are achieved in 2—4 h. Sotalol is 50% bound to plasma proteins. Plasma half-life of the compound is about 5.2 h. No metabolites of sotalol have been identified indicating littie metabolism. The dmg is excreted mainly by the kidneys (80—90%) and about 10% is eliminated in the feces. The plasma half-life is prolonged in patients having renal failure. Kinetics of the compound are not affected by changes in liver function (1,2). Sotalol has ah the adverse effects of -adrenoceptor blockers including myocardial depression, bradycardia, transient hypotension, and proarrhythmic effects (1,2). 

Diazoxide lowers blood pressure within 3 to 5 minutes after rapid intravenous injection, and its duration of action may be 4 to 12 hours. Interestingly, if diazoxide is either injected slowly or infused its hypotensive action is quite modest. This is believed to be due to a rapid and extensive binding of the drug to plasma proteins. Both the liver and kidney contribute to its metabolism and excretion. The plasma half-life is therefore prolonged in patients with chronic renal failure. 

Sotalol is well absorbed orally with bioavailability of approximately 100%. It is not metabolized in the liver and is not bound to plasma proteins. Excretion is predominantly by the kidneys in the unchanged form with a half-life of approximately 12 hours. Because of its relatively simple pharmacokinetics, solatol exhibits few direct drug interactions. Its most significant cardiac adverse effect is an extension of its pharmacologic action a dose-related incidence of torsade de pointes that approaches 6% at the highest recommended daily dose. Patients with overt heart failure may experience further depression of left ventricular function during treatment with sotalol. 

Paracetamol is a widely used analgesic, which causes liver necrosis and sometimes renal failure after overdoses in many species. The half-life is increased after overdoses because of impaired conjugation of the drug. Toxicity is due to metabolic activation and is increased in patients or animals exposed to microsomal enzyme inducers. The reactive metabolite (NAPQI) reacts with GSH, but depletes it after an excessive dose and then binds to liver protein. Cellular target proteins for the reactive metabolite of paracetamol have been detected, some of which are enzymes that are inhibited. Therefore, a number of events occur during which ATP is depleted, Ca levels are deranged, and massive chemical stress switches on the stress response. 

Pharmacokinetics Itraconazole is well-absorbed orally and food increases its bioavailability. It is extensively bound to plasma proteins and distributes well throughout most tissues, including bone, sputum and adipose tissues. However, therapeutic concentrations are not attained in the CSF. Like ketoconazole it is extensively metabolized in the liver but does not inhibit androgen synthesis. Little of the parent drug appears in the urine and thus doses do not have to be reduced in renal failure. 

Emetine [EM e teen] and dehydroemetine [de hye dro EM e teen] are alternate agents for the treatment of amebiasis. They inhibit protein synthesis by blocking chain elongation1. Intramuscular injection is the preferred route. Emetine is concentrated in the liver where it persists for a month after a single dose. It is slowly metabolized and excreted and can accumulate. Its ty2 is 5 days. The use of these ipecac alkaloids is limited by their toxicities. Dehydroemetine is probably less toxic than emetine. Close clinical observation is necessary when these drugs are used. Among the untoward effects are pain at the site of injection, transient nausea, cardiotoxicity (e.g., arrhythmias, congestive heart failure), neuromuscular weakness, dizziness, and rashes. 

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