Drug distribution , volume renal disease

Methods for calculating volume of distribution (VD) can be influenced by renal disease. Of the commonly used terms (i.e., volumes of central compartment, terminal phase, and distribution at steady state [ Vss]), Vss is the most appropriate for comparing patients with renal insufficiency versus those with normal renal function because Vss is independent of drug elimination. 

Distribution - Valproic acid is rapidly distributed. Volume of distribution of total or free valproic acid is 11 or 92 L/1.73 m, respectively. Valproic acid has been detected in CSF (approximately 10% of total concentrations) and milk (about 1% to 10% of serum concentrations). Therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate. The plasma protein binding of valproate is concentration-dependent. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (eg, aspirin). Conversely, valproate may displace certain protein-bound drugs (eg, phenytoin, carbamazepine, warfarin, tolbutamide). 

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. 

As previously discussed in the context of renal disease (Chapter 5), reduced protein binding will increase the distribution volume referenced to total drug concentrations and this will tend to increase elimination-phase half-life (26). 

Renal disease (uraemia) may increase the volume of distribution of acidic drugs that extensively bind to plasma albumin (e.g., phenytoin, valproic acid, naproxen, phenylbutazone, furosemide). As decreased protein binding would increase the unbound (free) fraction in the plasma, the therapeutic concentration range (based on total drug concentration) would be lower than the usual... 

Question Drug C has a total clearance of 7 L/hour, a volume of distribution of 420 L, and a rate of excretion unchanged of 80%. Will drug levels of this drug be affected by induction and/or inhibition of lever metabolism, compromised liver blood flow due to cardiovascular disease, or the presence of liver disease Would renal disease affect levels of drug C ... 

Altered tissue binding may also affect the apparent volume of distribution of a drug. For example, the distribution volume of digoxin has been reported to be reduced by 30% to 50% from normal values in patients with renal disease. It has been postulated that this reduction in the distribution volume is secondary to a decrease in tissue... 

Fluoxetine is rapidly and completely absorbed orally, reaching a peak in 6-8 h. Food does not affect absorption. Fluoxetine is N-demethylated in the liver to an active metabolite, norfluoxetine, and many other minor inactive metabolites. Both fluoxetine and norfluoxetine are then conjugated prior to excretion. Protein binding is 94%. The volume of distribution is estimated to be 11-88.41 kg Approximately 2.5% of the drug is renally excreted unchanged and 10% as the norfluoxetine metabolite. A total of 65% of radiolabeled fluoxetine is recovered in the urine after 35 days and 15% is recovered in the feces. The elimination half-life of fluoxetine is 48-72 h, averaging almost 70 h. The half-life of norfluoxetine is 7-9 days. The elimination half-lives for both are prolonged in patients with hepatic disease. 

Theophylline is a classic example. Its bronchodi-lator effects are related to plasma concentrations in the range of 5-20 mg l-1, while higher concentrations are associated with tachyarrythmias and other serious adverse effects. This is a drug with a narrow therapeutic window . Elderly patients commonly have several risk factors that can lead to unexpectedly high serum concentrations after administration of standard doses reductions in renal clearance, reduced volume of distribution and an increased probability of concomitant disease and other therapies (Ohnishi et al., 2003). Monitoring plasma levels is thus helpful in avoiding the adverse effects of theophylline. 

All three barbiturates are primarily eliminated by hepatic metabolism and renal excretion of inactive metabolites a small fraction of thiopental undergoes desulfuration to the longer-acting hypnotic pentobarbital. Each drug is highly protein bound (Table 13-2). Hepatic disease or other conditions that reduce serum protein concentration will decrease the volume of distribution and thereby increase the initial free concentration and hypnotic effect of an induction dose. 

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