Propranolol renal clearance

Cimetidine not only reduces the metabolism of beta-blockers such as propranolol, it is also known to act as an inhibitor of tubular secretion of a number of organic cations. Therefore it is not surprising to see that the renal clearance of pindolol is substantially and stereoselectively reduced by coadministration of this drug [59]. The administration of 400 mg cimetidine twice a day for 2 days before and 2 days after pindolol administration resulted in 26% and 34% reductions in the renal clearances of S(—)- and R(-t-)-pindolol, respectively. Therefore the plasma concentrations of the R(-l-) enantiomer increased more drastically (47%) than those of the S(—) enantiomer (38%) in the presence of cimetidine [59]. Because renal clearance accounts for only 50% of pindolol elimination, the significant increases in the plasma concentrations of pindolol enantiomers as a result of cimetidine coadministration cannot be explained from the inhibition of its renal clearance only. Apparently, cimetidine also reduces the metabolism of pindolol. 

In patients with heart failure, lidocaine s volume of distribution and total body clearance may both be decreased. Thus, both loading and maintenance doses should be decreased. Since these effects counterbalance each other, the half-life may not be increased as much as predicted from clearance changes alone. In patients with liver disease, plasma clearance is markedly reduced and the volume of distribution is often increased the elimination half-life in such cases may be increased threefold or more. In liver disease, the maintenance dose should be decreased, but usual loading doses can be given. Elimination half-life determines the time to steady state. Thus, although steady-state concentrations may be achieved in 8-10 hours in normal patients and patients with heart failure, 24-36 hours may be required in those with liver disease. Drugs that decrease liver blood flow (eg, propranolol, cimetidine) reduce lidocaine clearance and so increase the risk of toxicity unless infusion rates are decreased. With infusions lasting more than 24 hours, clearance falls and plasma concentrations rise. Renal disease has no major effect on lidocaine disposition. 

The paucity of QSAR studies in whole animals is understandable in terms of the costs, the heterogeneity of the biological data, and the complexity of the results. Nevertheless, in the few studies that have been done, excellent QSAR have been obtained, despite the small number of subjects in the data set (164). One particular example is insightful. The renal and nonrenal clearance rates of a series of 11 jS-blockers, including bufuralol, tolamolol, propranolol, alprenolol, oxprenolol, acebutol, timolol, metoprolol, prindolol, atenolol, and nadolol were measured (230). The following QSAR were formulated using those data (164). 

Another physicochemical parameter with some clinical correlation is the relative lipophilicity of different agents. Propranolol is by far the most lipophilic of the available P-blockers, and it enters the CNS far better than the less lipophilic agents, such as atenolol or nadolol. Lipophilicity as measured by octanol-water partitioning also correlates with the primary site of clearance, as seen in Table 13.8. The more lipophilic drugs are primarily cleared by the liver, whereas the more hydrophilic agents are cleared by the kidney. This could influence the choice of agents in cases of renal failure or liver disease. Several of the p-blockers must be dose adjusted in patients with impaired renal function, as indicated in Table 13.7. 

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