Hepatic disease altered drug metabolism

The liver is the principal metabolic organ, and hepatic disease or dysfunction may impair drug elimination. Any alteration in the serum albumin or bilirubin levels and in the prothrombin time indicates impaired liver function. Similarly, skin bruising and bleeding tendency indicate decreased production of clotting factors by the liver. 

Disorders of lipoprotein metabolism involve perturbations which cause elevation of triglycerides and/or cholesterol, reduction of HDL-C, or alteration of properties of lipoproteins, such as their size or composition. These perturbations can be genetic (primary) or occur as a result of other diseases, conditions, or drugs (secondary). Some of the most important secondary disorders include hypothyroidism, diabetes mellitus, renal disease, and alcohol use. Hypothyroidism causes elevated LDL-C levels due primarily to downregulation of the LDL receptor. Insulin-resistance and type 2 diabetes mellitus result in impaired capacity to catabolize chylomicrons and VLDL, as well as excess hepatic triglyceride and VLDL production. Chronic kidney disease, including but not limited to end-stage... 

Hepatic function impairment Administer with caution to patients with diseases that may alter the absorption, metabolism, or excretion of drugs. The bioavailability may be markedly increased in patients with liver disease. No dosage adjustment is necessary when frovatriptan or eletriptan is given to patients with mild to moderate hepatic impairment. Do not use eletriptan in severe hepatic impairment. 

Some chemical exposures may be hepatic enzyme inducers/inhibitors, altering the effects of drugs like warfarin. Some foods such as mono-amines, will cause reactions in patients given MAOIs grapefruit juice may interact with terfenadine and some other drugs. New diseases may cause problems heart failure causing reduced liver blood flow can reduce the metabolism of drugs like warfarin. 

Orally active agents used in the treatment of ED are more affected by aging and disease processes than are those injected intracavernosally. In addition, alterations in hepatic metabolism and/or renal clearance in the elderly man (see Chapter 6) influence the frequency of appearance of adverse reactions between several coadministered drugs in the treatment of ED. For example, the concomitant use of sildenafil and nitroglycerin is contraindicated by cardiovascular complications. Also, the use of testosterone in the presence of androgen-dependent tumors may promote tumor growth. 

When drugs are administered orally, they typically are absorbed in the small bowel, enter the portal circulation, and pass through the liver. Both CYP enzymes in the bowel wall and in the hepatocytes can metabolize a fraction of the drug before it reaches the systematic circulation (i.e., first-pass metabolism or first-pass effect). The extent of this effect can be broadly altered by diseases (e.g., cirrhosis, portacaval shunting, persistent hepatitis, congestive heart failure), and by some drugs (e.g., alcohol, ketaconazole, fluoxetine) influencing the peak concentrations achieved and the ratio of the parent compound to metabolites ( 11, 19, 20). 

The plasma clearance of theophylline varies widely. Theophylline is metabolized by the liver, so typical doses may lead to toxic concentrations of the drug in patients with liver disease. Conversely, clearance may be increased through the induction of hepatic enzymes by cigarette smoking or by changes in diet. In normal adults, the mean plasma clearance is 0.69 mL/kg/min. Children clear theophylline faster than adults (1-1.5 mL/kg/min). Neonates and young infants have the slowest clearance (see Chapter 59). Even when maintenance doses are altered to correct for the above factors, plasma concentrations vary widely. 

Diseases such as hepatic or renal diseases can influence the incidence of ADRs by altering the pharmacokinetics of drugs, such as absorption, distribution, metabolism, or excretion. 

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