Page 1768 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 125: Critical Care Pharmacology 1237

(see the section “General Drug Information References” below). For patient with hepatic dysfunction which serves as the cornerstone for
example, since both cyclosporine and tacrolimus are metabolized by dosage adjustment, in analogy to the creatinine clearance test used
CYP3A4, biotransformation of both agents is predictably affected for drug dosage adjustment in renal patients. So far, the usefulness of
by known inhibitors and inducers of this enzyme (see Table 125-9). various dynamic liver function tests is rather limited and clinicians
Ketoconazole is a particularly potent inhibitor of CYP3A4 and has rely more on the Child-Pugh score, which may not be better but is
been used to deliberately lower cyclosporine dosage requirements as readily available for liver patients. Activity of particular cytochrome
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a cost-saving measure. 80,81 By contrast, phenobarbital induces cyclo- P450 isozymes or conjugating enzymes may be decreased, preserved,
sporine metabolism to such an extent that concomitant use of these or even increased in the presence of different liver diseases at vari-
agents is not advisable; likewise, therapeutic cyclosporine levels are ous stages of severity. 21,84,86 Most data suggest that cirrhosis variably
difficult to maintain during rifampin therapy. Inducers and inhibi- affects the hepatic content and activity of particular cytochrome 450
tors of phase II enzymes have been less extensively characterized, isozymes; contents of CYP3A are not demonstrably changed, CYP1A2
but some clinical applications of this information have emerged; for and CYP2E1 activities are decreased, and CYP2C activity may even
example, phenobarbital is used to induce glucuronyl transferase activ- be increased (as is tolbutamide clearance in cirrhosis). In addition,
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ity in icteric neonates, and both phenobarbital and valproate have the presence of gastrointestinal hypomotility, hypoalbuminemia,
been used to modulate the chemotherapeutic agent glucuronidation increased or decreased plasma glycoprotein levels, ascites/edema, and
and toxicity. 82 altered hepatic blood flow may all alter drug absorption, distribution,
elimination, and effects unpredictably (see Table 125-4). Gastric hypo-
Effects of Disease States: Critical illness routinely alters all the physi- motility does not alter bioavailability; rather it delays absorption and
ologic processes involved in drug disposition. It would be surprising reduces the peak plasma level. Altered levels of the major drug-binding
if drug disposition and/or response were not significantly altered in plasma proteins in cirrhosis or other forms of liver dysfunction have
such patients. Unfortunately, most data regarding drug disposition complex secondary effects. The frequent presence of hypoalbumin-
in critically ill patients must be extrapolated from other populations; emia decreases binding of acidic drugs, such as phenytoin. Production
clearly, such information must be interpreted with extreme caution. of α -acid glycoprotein, which binds many basic drugs (eg, lidocaine
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Effects of Circulatory Dysfunction: The effects of congestive heart failure and quinidine), is impaired by severe cirrhosis but increased by
(CHF) on drug disposition are the best-studied examples of altera- inflammatory states (it is an acute-phase reactant). The importance of
tions of drug absorption, distribution, and elimination associated decreased plasma protein binding (caused by decreased binding pro-
with circulatory insufficiency (see Table 125-5). Secondary decre- tein levels or by displacement by a competing substance) is determined
ments in hepatic and renal blood flow result in impaired clearance by the hepatic extraction ratio of the drug, and the presence or absence
of some drugs excreted by these routes. Reduced renal perfusion due of concomitant impairment of hepatic biotransformation capac-
to physiological changes in CHF can lead to acute cardiorenal syn- ity (caused by disease or by competition with an interacting agent).
drome which predisposes to AKI and acute tubular injury. Drugs with Changes in protein binding do not alter clearance of high-extraction
nephrotoxic potential are more likely to cause AKI in this setting. (flow-limited) drugs, but if hepatic metabolism of a low-extraction
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Clearance of hepatically eliminated drugs is more likely to be (capacity-limited) drug is impaired and protein binding of the drug
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impaired by CHF if their metabolism is flow limited (ie, characterized is also decreased, then the plasma-free drug level will increase.
by a high extraction ratio, such as lidocaine). It is doubtful that most Renal elimination of drugs or metabolites (inactive, active, or toxic) is
such information, even from populations with decompensated CHF, also commonly impaired in patients with cirrhosis by the associated
is applicable to the setting of cardiogenic shock. decrement in glomerular filtration rate, which is often unappreciated
because of the poor correlation between plasma creatinine values and
Effects of Multiorgan Dysfunction: Critically ill patients frequently GFR in cirrhotic subjects. The serum cystatin C level, another endog-
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develop AKI, multiorgan dysfunction syndrome (MODS), or multi- enous marker for renal function, may reflect glomerular filtration
system organ failure (MSOF). Although most cases occur secondary more accurately in cirrhotic patients. Finally, liver disease patients
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to shock, sepsis, and severe trauma, a multiplicity of other risk factors appear to have increased sensitivity to many drugs or their metabo-
have been identified. Unfortunately, there are large gaps in knowl- lites; some of this phenomenon is attributable to synergistic sedation
edge of drug metabolism and disposition in patients with MSOF/ (a PD phenomenon), although many such instances are probably
MODS as well as AKI, and thus patients may be at significant risk of caused by unrecognized accumulation of active or toxic metabolites
underdosing as well as overdosing. It is suspected that there is erratic or abnormally increased CNS distribution (eg, increased blood-brain
gastrointestinal absorption as well as variations in extracellular fluid barrier permeability to cimetidine in cirrhosis). 89
volume and altered drug metabolism due to the systemic inflam- In practice, the presence of hepatic dysfunction should prompt
matory response or liver and/or kidney dysfunction component of a thorough drug regimen reevaluation to examine all disposition
MODS. Drug transporters such as p-glycoprotein and organic anion parameters. 21,83,85,90 Useful data may be available regarding the effects
transporter may be affected by critical illness states, such as inflam- of cirrhosis on clearance of the agent, permitting an appropriate dose
mation, sepsis, CKD/AKI acute or chronic liver disease, hypoten- reduction. More commonly, the only information available details the
sion, burns and trauma which predominantly leads to a reduction predominant route of drug elimination. In either case, careful dose titra-
in cytochrome P450 enzyme activity. Prospective measurement of tion upward from a dose lower than normal is obviously the prudent
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serum drug concentration and the subsequent use of sound PK/PD approach; however, such a cautious approach may not be consistent with
therapeutic drug-monitoring approaches should be used whenever the rapid therapeutic effect desired in critically ill patients. Dose reduc-
possible, especially for the drugs with a narrow therapeutic range. tion is most likely to be necessary when a drug that usually undergoes
When this is not a possibility because of the unavailability of rapid extensive first-pass metabolism is enterally administered in the presence
specific analytical methods for the determination of serum drug of liver disease severe enough to impair hepatic clearance of the agent; in
concentrations, the development of excessive pharmacologic effect or such a situation, both increased oral bioavailability and decreased clear-
toxicity may be the primary indicator of a need for dosage adjustment. ance tend to increase plasma drug levels:
Effects of Liver Disease: The effects of hepatic disease on PK and PD Cp = (Bioavailability × MaintenanceDose)/
parameters of drug disposition are much more difficult to predict ss (DosingInterval × Clearance)
than the consequences of renal disease, based on data available for
most agents. 83,84 The challenge is to develop a dynamic liver function Careful therapeutic monitoring of agents that have a low therapeu-
test that measures the residual elimination capacity of the liver in a tic index (see Table 125-8), using plasma levels if these are clinically

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