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CHAPTER 125: Critical Care Pharmacology 1239

obvious that agents that impair or augment glomerular filtration tend and pharmacist for potential errors including patient identity, known
to cause a corresponding change in excretion of drugs eliminated by patient allergies, correct dosing, and potential drug-drug interac-
this route, such as aminoglycosides. Active tubular drug secretion is tions. Most preventable ADRs involve (1) prescribing a drug despite a
performed primarily by two groups of proximal tubular pumps: an documented allergy to the medication ordered or to a cross-reactive
anion pump (which secretes organic acids) and a cation pump (which agent; (2) the use of anticoagulants or thrombolytic agents; (3) failure
secretes organic bases). Competitive inhibition of the anion pump to appropriately monitor and adjust low-therapeutic-index drug admin-
by probenecid impairs elimination of penicillin, thus prolonging the istration using plasma drug concentration analysis; and (4) failure to
half-life of this organic acid. Methotrexate is another anion secreted adjust the regimen for administration of renally eliminated drugs in the
by this pump, and subject to the same interaction. Cimetidine and presence of renal dysfunction. Accordingly, we advocate a daily review
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trimethoprim inhibit cationic pump secretion of procainamide and of all medications given to each ICU patient, focusing on the following
some other cationic drugs. Digoxin undergoes distal tubular secre- issues: (1) drug-patient interactions, including known drug allergies;
tion by a third pump system, which is inhibited by multiple drugs, (2) drug-disease interactions, including presence and severity of organ
including quinidine, amiodarone, spironolactone, and several calcium dysfunction, and appropriate dosing adjustments; (3) potential drug-
channel blockers; this is the mechanism partly responsible for the drug interactions; (4) the possibility of an ADR causing any new cor-
elevation of serum digoxin levels routinely encountered following poreal dysfunction; and (5) discontinuation of all unnecessary drugs, in
combination of these agents with digitalis therapy. Finally, as dis- an ongoing attempt to simplify and rationalize therapy. The importance
cussed in Chap. 124, alterations in urinary pH alter passive distal of minimizing the number of drugs prescribed is demonstrated by the
tubular reabsorption of weak acids and bases, including drugs such as fact that there is a 40% probability of developing an ADR when more
salicylic acid and phenobarbital (a basic drug). than 15 drugs are given to a hospitalized patient, compared to a 5%
■ THERAPEUTIC DRUG MONITORING ADR probability when receiving fewer than 6 medications. A recent
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study showed that patients with AKI receiving angiotensin-converting
Most drugs are dosed according to population-based PK/PD data. In enzyme inhibitors, angiotensin receptor blockers, antithrombotics, and
most cases, critical care therapy is initiated in this fashion, but may antibiotics are at highest risk of an ADR and should receive more inten-
be monitored and titrated using readily available pharmacodynamic sive monitoring. 100
parameters (sedation, analgesia, paralysis, hemodynamic data, cardiac Adverse drug reactions may be classified as type A (an exaggerated
rhythm, and electroencephalography). Selected agents, usually those pharmacologic effect related to high drug concentration), or type B (an
with a low therapeutic index, are additionally monitored and dose idiosyncratic reaction). Increasingly, reactions formerly classified as
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adjusted using plasma drug levels and calculations of individual drug idiosyncratic (type B) have been shown to be type A reactions based on
disposition parameters. Whether monitored using pharmacodynamic polymorphic expression of metabolizing enzyme activity and impaired
indexes alone, or more precisely with the addition of PK data, ongoing drug metabolism and target effect. Individuals deficient in activity of the
attempts to optimize therapeutics should minimize the occurrence of necessary metabolizing enzyme develop ADRs caused by accumulation
inadequate therapy or adverse drug reactions (ADR). of previously undocumented toxic metabolites; for example, sulfon-
Appropriate direct therapeutic drug monitoring involves consider- amide hypersensitivity has been linked to an increase in prevalence of
ation of many variables. The form of drug measured is important, espe- the “slow acetylator” phenotype, and defective detoxification of hydrox-
cially in drugs with high plasma-protein binding. Because only the free ylamine metabolites. 101,102 Other idiosyncratic phenomena, such as
fraction of the drug is clinically active, the useful plasma test is one that halothane hepatitis and carbamazepine reactions, may also be caused by
accurately reflects the free fraction. For example, phenytoin is highly defective metabolism. There has been a reported association of human
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albumin bound. In the setting of critical illness, hypoalbuminemia, leukocyte antigen (HLA)-B*1502 with carbamazepine-induced Stevens-
malnutrition, or cirrhosis, total phenytoin levels may be low, while free Johnson syndrome/toxic epidermal necrolysis in a meta-analysis involv-
phenytoin levels are likely to be in the therapeutic range. The timing of ing Asians. Furthermore, HLA-A*3101 was observed to be associated
plasma drug testing is also important. In drugs such as aminoglycosides, with carbamazepine-induced hypersensitivity in a pooled population of
peak and trough levels need to be monitored, since peak levels reflect Asian and Caucasian patients. 103
therapeutic efficacy and trough levels are monitored to ensure adequate The diagnosis of an ADR requires a high index of suspicion that signs
drug clearance and to avoid drug accumulation. or symptoms may be drug related. Distinguishing between an ADR
Drug regimen adjustment may be precipitated by multiple intercur- and manifestations of other diseases can be challenging, particularly in
rent factors, including changes in volume status; alterations (worsening critically ill patients with a myriad of problems. Serotonin syndrome is
or improvement) in gastrointestinal tract or circulatory, renal, or liver a potentially life-threatening adverse drug reaction that is not an idio-
function; the application of extracorporeal therapies which impact drug pathic drug reaction but a predictable consequence of excess serotoner-
disposition; and potential drug interactions or other ADRs associated gic agonism of central nervous system (CNS) receptors and peripheral
with addition of new agents. Finally, any change in patient status should serotonergic receptors. The difficulty for clinicians is that mild symp-
be considered a potential ADR, and this possible diagnosis assessed toms may be easily overlooked, and an inadvertent increase in the dose
using available resources. If an ADR is strongly suspected, this should of the causative agent or the addition of a drug with proserotonergic
be reported to the appropriate institutional and extramural authorities, effects may provoke a dramatic clinical deterioration. A striking number
and management altered accordingly. of drug and drug combinations have been associated with serotonin syn-
■ ADVERSE DRUG REACTIONS drome but some of the most commonly encountered in an ICU setting
include linezolid, tramadol, and fentanyl in combination with an SSRI.
Drug prescribing intended to achieve beneficial therapeutic effects is However, a single therapeutic dose of an SSRI has caused the serotonin
necessarily accompanied by the possibility of eliciting an unintended syndrome but also the addition of drugs that inhibit cytochrome iso-
adverse drug reaction (ADR). ADRs are common in the ICU, where forms CYP2D6 and CYP3A4 to therapeutic SSRI regimens have also
multiple drugs are administered to unstable patients who commonly been associated with the condition. 104
are unable to give a complete medical history and manifest altered drug Identification of a temporal relationship between drug initiation
disposition parameters (including metabolism and excretion). ADRs and onset of signs or symptoms is useful, but not always possible. For
present diagnostic and therapeutic problems that complicate ICU example, supraventricular tachycardia after initiation of theophylline,
admission, increasing morbidity, mortality, and length of stay. 97 wheezing after β-blocker administration, or seizures during meperi-
To minimize ADRs, all drugs prescribed by a critical care physician dine therapy may each be caused by, aggravated by, or unrelated to
should be reviewed (prior to administration) by the critical care nurse drug effects. Furthermore, patients may develop a type A adverse drug

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