Blood flow drug clearance affected

An implication of the high degree of hepatic extraction is that clearance of nicotine should be dependent on liver blood flow. Thus, physiological events, such as meals, posture, exercise, or drugs perturbing hepatic blood flow, are predicted to affect the rate of nicotine metabolism. Meals consumed during a steady state infusion of nicotine result in a consistent decline in nicotine concentrations, the maximal effect seen 30-60 min after the end of a meal (Gries et al. 1996 Lee et al. 1989). Hepatic blood flow increases about 30% and nicotine clearance increases about 40% after a meal. 

Some drugs are metabolized so readily that even marked reduction in liver function does not significantly prolong their action. However, cardiac disease, by limiting blood flow to the liver, may impair disposition of those drugs whose metabolism is flow-limited (Table 4-7). These drugs are so readily metabolized by the liver that hepatic clearance is essentially equal to liver blood flow. Pulmonary disease may also affect drug metabolism, as indicated by the impaired... 

In the clinic, esmolol s distribution half-life is 2 min and its elimination half-life is 9 min. Esmolol hydrochloride is rapidly metabolized by hydrolysis of the ester linkage, chiefly by esterases in the cytosol of red blood cells and not by plasma cholinesterases or red cell membrane acetylcholinesterase [22]. Its volume of distribution is 3.4 L kg-1, and its total clearance is 285 mL kg-1 min-1, "... which is greater than cardiac output thus the metabolism ofesmolol is not limited by the rate of blood flow to metabolizing tissues such as the liver or affected by hepatic or renal blood flout [22]. As expected from such a "... high rate of blood-based metabolism, less than 2% of the drug is excreted unchanged in the wind [22]. Within 24 h after infusion, approximately... 

However, in severe hepatic disease, not only is hepatic blood flow reduced but the degree of liver damage may influence intrinsic clearance to the extent that it also affects total drug clearance. Consequently, patients with hepatic disease are at particular risk of developing adverse effects to high extraction ratio drugs. 

The factors that affect hepatic clearance include blood flow to the liver (Q), the fraction of drug not bound to plasma proteins (fu), and intrinsic clearance (CGjjf) (1, 2). Intrinsic clearance is simply the hepatic clearance that would be observed in the absence of blood flow and protein binding restrictions. As discussed in Chapter 2, hepatic clearance usually can be considered to be a first-order process. In those cases, intrinsic clearance represents the ratio of Vmax l m, and this relationship has been used as the basis for correlating in vitro studies of drug metabolism with in vivo results (3). However, for phenytoin and several other drugs, the Michaelis-Menten equation is needed to characterize intrinsic clearance. 

Beta-blockers can also affect the clearance of high clearance drugs by altering hepatic blood flow. This occurs when propranolol is co-administered with lido-caine (400), but it appears that this interaction is due more to inhibition of enzyme activity than to a reduction in hepatic blood flow (401). Atenolol inhibits the clearance of disopyramide, but the mechanism is unknown... 

Variables in addition to liver blood flow that may influence the capacity of the liver to extract a drug from the blood for elimination by hepatic processes (biotransformation and/or biliary excretion of unchanged drug) are the unbound fraction in blood and the hepatic intrinsic clearance, which is a measure of the maximal ability of the liver to eliminate the drug. The hepatic clearance (with respect to blood concentrations) is determined by the following relationship between the variables which affect drug elimination by the liver ... 

The hepatic clearance of drugs with an intermediate extraction ratio (Eh, 0.3-0.6) is affected by all three physiological variables blood flow to the liver, the unbound fraction in blood and the activity of hepatic drug-metabolizing enzymes. Disease-induced changes in the disposition of these drugs is least predictable. 

---