Page 1760 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 125: Critical Care Pharmacology 1229

in this decision include drug characteristics (half-life and therapeutic What are the predominant routes of elimination of the parent drug
index), patient characteristics, the desired pharmacologic effect, and and its metabolites (particularly those that are pharmacologically
cost/staffing considerations. When drugs with a low therapeutic index active or toxic)?
are dosed intermittently, the fluctuations (peak-to-trough) of plasma Renal insufficiency (Table 125-3), hepatic disease (Table 125-4), or
concentration may require formal monitoring of plasma concentrations circulatory dysfunction (Table 125-5) may affect clearance of parent
and PK parameter estimates to ensure adequate therapy without toxicity. drug or metabolites. There are several well-known examples of drugs
Administration by infusion eliminates the peak-to-trough plasma with metabolites that are pharmacologically active or even toxic.
concentration fluctuations associated with intermittent parenteral Accumulation of active or toxic metabolites in the presence of renal
boluses, which may be accompanied not only by failure to achieve failure is probably the most common clinical scenario in which this fea-
continuous therapeutic effect, but also by activation of rebound counter- ture of drug disposition is important (Table 125-6). Nonrenal (usually
regulatory effects during trough periods (negating prior and subsequent hepatic) elimination of parent drug or metabolites has been increas-
drug action). Continuous intravenous infusion may thus improve thera- ingly documented to be quantitatively important in subjects with renal
peutic efficacy of some agents. Loop diuretic agent infusions have been impairment (as discussed below). Likewise, renal drug or metabolite
reported to augment sodium excretion compared to equivalent inter- elimination assumes an increased role in subjects with liver disease.
mittent dosing, probably because of a combination of effects: increased
cumulative renal tubular diuretic agent exposure (the product of time Is a dose reduction or escalation required, owing to impaired (renal,
and concentration) and avoidance of periods of physiologic rebound hepatic, or circulatory dysfunction) or augmented (induction of
salt conservation. 22,23 Since diuretic effect onset is delayed when using metabolism or extracorporeal drug removal) clearance of the drug
only continuous intravenous infusion (until drug accumulates; see or its metabolites?
Fig. 125-2), the ideal regimen to maximize natriuresis may include an As outlined below, glomerular filtration rate (GFR) may be estimated
initial bolus dose to achieve the required luminal threshold drug con- routinely to a reasonable approximation, and the effects of renal
centration and induce immediate natriuresis. dysfunction on drug clearance may be estimated with some degree
Continuous infusion of short-acting agents may also be desirable to of precision (see Table 125-3). The effects of varying levels and
allow titration of effect; nitrovasodilators, esmolol, propofol, and atra- etiologies of hepatic and circulatory dysfunction (see Tables 125-4
curium may be used for optimal control of vasodilation, β-blockade, and 125-5) on drug disposition are far more difficult to predict.
sedation, or neuromuscular paralysis, respectively. It is widely assumed Estimation of renal and hepatic clearance functions and factors that
that continuous infusion of agents that have a short elimination half- alter drug metabolism and excretion will be further discussed below.
life guarantees rapid reversal of drug effect following cessation of Biliary, pulmonary, cutaneous, and extracorporeal elimination may
the infusion, but various factors may retard offset of effect, as is the be important for clearance of some specific agents and will not be
case for reversal of sedation using agents administered by continuous discussed in detail here. For further information regarding drug
infusion. 24,25 Potential explanations for such alterations in drug disposi-
tion or response during continuous infusion compared to intermittent
bolus therapy include compartmentalized tissue distribution, accumu- TABLE 125-3 Effects of Renal Failure on Drug Disposition and Effect
lation of active metabolites, or saturation of clearance mechanisms. Bioavailability
Intermittent bolus administration titrated to specific sedation parameters
is less likely than continuous infusion to result in undetected drug or Absorption of specific drugs may be impaired by increased gastric pH (because of gastric
metabolite accumulation if excretory mechanisms deteriorate or become urease–produced ammonia), chelation by orally administered phosphate-binding agents,
saturated, unless a routine assessment of time to awakening is performed or by bowel wall edema. Conversely, bioavailability may be increased by uremia-induced
daily in patients receiving continuous infusion. Clinically, it has been impairment of first-pass metabolism. Uremic effects on intestinal motility (ileus) affect the
shown that daily interruption of sedation of mechanically ventilated rate, rather than the extent, of drug absorption, unless emesis result in loss of ingested drug.
patients results in decreased duration of ventilation, likely due to the Protein binding
minimization of drug accumulation. Conversely, tolerance to the effects Binding of acidic drugs to albumin is decreased, because of competition with accumulated
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of several drugs (a pharmacodynamic phenomenon) occurs if a drug- organic acids, and because of uremia-induced structural changes in albumin, which decrease
free interval cannot be included in the administration regimen, requiring drug-binding affinity (eg, barbiturates, cephalosporins,. penicillins, phenytoin, salicylate,
escalating dosages of agents such as nitroglycerin, dobutamine, and opi- sulfonamides, valproate, warfarin).
ate analgesics to maintain a therapeutic effect. Finally, the convenience Volume of distribution
for nursing staff of administering agents by continuous infusion rather Vd may be altered in the presence of renal failure. Drugs that are acidic, are highly protein
than intermittent bolus translates into decreased staffing expenditures. bound, and have a small volume of distribution are likely to be significantly affected. Other
Clearance: Clearance includes all processes that eliminate the drug from drugs may also be affected (eg, aminoglycosides [volume status effects]), digoxin
the body—both excretion and biotransformation. Because the total body (displacement from tissue sites by [“uremic substances”]).
clearance of a drug involves the actions of multiple organ systems, the Biotransformation
estimation of the predominant rate of elimination and route of elimina- Nonrenal (ie, hepatic ) clearance may be impaired. This phenomenon is best characterized
tion is often complicated, and warrants further discussion. in chronic renal insufficiency (rather than acute renal failure), affecting oxidative metabo-
lism (phase I enzymes). Conversely, phenytoin clearance is augmented.
What is the predicted elimination rate of the drug? Excretion
The predicted elimination of the drug usually corresponds to the drug Drugs that are more than 30% eliminated unchanged in the urine are likely to have signifi-
administration regimen that elicits an optimal therapeutic response in cantly diminished CL in the presence of renal insufficiency. This results in a prolonged half-life
most subjects. Agents with a low therapeutic index may be subjected for elimination of drugs such as digoxin, aminoglycosides, insulin, and others. The renal excre-
to therapeutic drug monitoring, aiming for a maintenance dose equal- tory route may assume increased importance in clearance of some drugs in the presence of
ing the product of CL × Cp . The desired Cp is selected based on hepatic impairment. Other drugs have toxic or active metabolites requiring renal elimination
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the therapeutic response required (eg, target plasma lidocaine level (Table 125-6). If dialysis or hemofiltration is required, drug removal may be significant.
for suppression of ventricular arrhythmias) and the clearance rate Pharmacodynamic effects
is estimated based on published data (usually obtained from healthy
patients). At steady state, the rate of administration (Ra) equals the Some drugs, such as sedative agents, may have enhanced effect in combination with the
rate of excretion (Re). Ra is dose (mg) divided by interval (minutes), uremic milieu. Electrolyte abnormalities and acidosis may alter effects of drugs such as
and Re is CL (mL/min) × Cp (mg/mL). antiarrhythmic agents.
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