Page 1769 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

1238 PART 11: Special Problems in Critical Care

available, represents the optimal approach in cases in which impaired physicochemical complexing (eg, tetracycline and milk products);
clearance is suspected. Otherwise, monitoring of physiologic parameters gastric pH changes (eg, failure to absorb ketoconazole when gastric
during graded upward dose titration may be the best available option. It pH is made alkaline by coadministration of antisecretory agents);
is important to remember that because of impaired elimination and the alterations in gastrointestinal motility; effects on gastrointestinal
resultant prolongation of half-life, achievement of steady-state plasma mucosa or flora (eg, increased digoxin levels after antibiotic therapy;
drug levels and corresponding maximal effect will be correspondingly see Chap. 124); changes in mesenteric blood flow; and finally changes
delayed. Failure to wait for achievement of steady-state conditions in first-pass metabolism (eg, cyclosporine with ketoconazole 80,81,93 ).
prior to dose escalation may result in drug accumulation to toxic levels. Distribution: Altered drug binding because of displacement by another
Important drug interactions are also more likely to occur in the pres- agent is of far lesser importance as a source of drug interaction than is
ence of impaired drug elimination “reserve,” so that increased vigilance generally appreciated. In fact, drug displacement from binding sites sim-
regarding potential protein-binding or hepatic biotransformation inter- ply makes more free drug available for excretion or biotransformation.
92
actions is warranted in the presence of liver disease (see below). The net effect on plasma levels of active drug is thus usually
■ HALF-LIFE negligible, unless clearance of the displaced drug is also impaired

When clearance is diminished, elimination half-life increases propor- because of organ dysfunction or the inhibition of drug metabolism or
excretion by the displacing agent itself.
94
tionately, as does the time required to achieve steady-state plasma levels Hepatic Metabolism: Inducers and inhibitors of hepatic biotransforma-
(three to five half-lives). The appropriate time for assessment of full tion are important causes of drug interactions. This is well illustrated
pharmacologic effect and measurement of levels may thus be markedly by considering common interactions with the enzyme predominantly
delayed. For example, the elimination half-life of digoxin is normally responsible for cyclosporine metabolism, underlining the impor-
20 hours, but increases to 1 week with end-stage renal disease (ESRD); tance of considering drug interactions when adding new agents to a
an ESRD patient discharged from the hospital with a plasma level within patient’s drug regimen. Cyclosporine, a potent immunosuppressive
the therapeutic range 1 week after starting maintenance therapy with drug used in the prevention of allograft rejection, is metabolized by
0.25 mg per day of digoxin will probably subsequently develop digi- the CYP3A4 enzyme in both the liver and small intestine. Modulation
talis toxicity. of the pharmacokinetics of cyclosporine has been reported with a
■ CONSIDERATION OF POTENTIAL DRUG-DRUG INTERACTIONS large number of drugs. For example, ketoconazole is known to be a

Drug-drug interactions may occur owing to alterations in drug dispo- potent inhibitor of CYP3A4, and therefore both increases oral bio-
availability and reduces the rate of elimination of the drug, increasing
sition (PK interactions), or drug effect (PD interactions). 4,91,92 PK blood cyclosporine levels. This predictable interaction can be used
interactions occur through effects on four drug disposition mechanisms: favorably to minimize the cost of therapy by decreasing the necessary
(1) gastrointestinal absorption, (2) drug distribution, (3) hepatic metab- dose of cyclosporine by coadministration with the cheaper drug,
olism, and (4) renal excretion. These categories will be further discussed ketoconazole. More commonly, drug interactions result in unfavor-
below. PD interactions occur by three basic mechanisms: (1) pharmaco- able outcomes. Inadvertent coadministration of cyclosporine with
logic interactions, usually based on binding of an antagonist to the target a CYP3A4 inducer, such as troglitazone (now removed from the
receptor mediating drug effect (eg, use of a nonselective β-blocker such market) or rifampin, can result in rapid drug elimination (a state
as propranolol in a patient requiring inhaled nebulized β-agonist ther- similar to the previously described “ultrarapid metabolizer” phe-
apy for bronchospasm); (2) physiologic interactions, such as the additive notype) and subtherapeutic cyclosporine levels, with subsequent
effects of multiple sedatives or vasodilators, or the opposing effects of potential rejection of the transplanted organ. 95
warfarin and vitamin K on coagulation factor synthesis; and (3) drug- There are numerous clinically important examples of such interac-
induced changes in the intracellular milieu resulting in altered effects tions involving the other P450 isozymes also. Theophylline is metabo-
of other agents (the best such example is the precipitation of digitalis lized by CYP1A2; theophylline toxicity may be precipitated by addition
toxicity by loop diuretic–induced hypokalemia and hypomagnesemia). of the quinolone antibiotic ciprofloxacin (an inhibitor of CYP1A2) or
It is worth emphasizing the fact that individual sensitivity to drug effect by smoking cessation (because of withdrawal of the CYP1A2-inducing
(eg, sedative effects in the elderly) may predispose particular patients effect of cigarette smoking), unless theophylline dosage is reduced
to suffer the consequences of PD drug interactions more readily than appropriately. Only one dose of quinidine (a CYP3A4 substrate) is
others. Prevention of PD drug interactions is best accomplished through required to convert a normal, extensive metabolizer of CYP2D6 sub-
a basic understanding of the mechanism of action, common side effects, strates (including numerous β-blockers, antidepressants, and antipsy-
and population-specific issues (if any) pertinent to any drug prescribed. chotic agents) into a poor metabolizer of these agents. Inhibition of
PK interactions are the subject of many exhaustive compendia, but drug biotransformation activity by a drug which is not a substrate of the
a few general principles are required to interpret such information. In impaired enzyme is not uncommon: Quinidine is a powerful CYP2D6
order for a reported PK drug interaction to be of clinical significance, inhibitor and CYP3A4 substrate; fluconazole is also a CYP3A4 substrate
three criteria should be fulfilled. First, one of the drugs involved but impairs phenytoin and warfarin metabolism by CYP2C enzymes,
5,41
must have a low therapeutic index, so that an alteration in its disposi- in addition to competitive inhibition of metabolism of other CYP3A
tion results in either toxic or subtherapeutic effect (there are impor- substrates. Such instances reinforce the need to examine both the known
tant exceptions to this rule). Second, the drug disposition parameter and potential interactions of each additional agent with those in the
alteration should be on the order of 30% or more, because changes of patient’s current regimen.
lesser magnitude are unlikely to be of clinical importance. Finally, only For certain statins metabolized by CYP3A4 (simvastatin and
reports in humans should be considered definite, since animal studies lovastatin, atorvastatin), an increase in susceptibility to myopathy is
of drug disposition do not always accurately reflect human processes. substantially greater in patients receiving concurrent therapy with
Conversely, the absence of reported data from animal studies does not a number of drugs, particularly those that inhibit CYP3A4 such as the
preclude drug interactions in humans, particularly with respect to newer macrolides and cyclosporine. 96
agents undergoing wide use for the first time. Finally, agents that diminish hepatic blood flow (vasopressors and
Absorption: Most such interactions affect the rate rather than the cimetidine) may impair clearance of high-extraction drugs such as lido-
extent of absorption, so that the magnitude and timing of peak caine and propranolol.
plasma drug level is altered, but the fraction absorbed (and thus Renal Excretion: Drug interactions can affect glomerular filtration,
bioavailability) is unchanged. Interaction mechanisms include tubular secretion, or tubular reabsorption (active or passive). It is

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