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1232 PART 11: Special Problems in Critical Care

values closer to those of subjects with CKD (10 mL/min) after 1 week TABLE 125-7 Selected Cytochrome P450 Inhibitors and Inducers
of AKI. This phenomenon requires an appropriate dosage adjustment,
46
which is facilitated in this case by the routine availability of plasma-level Inhibitors Inducers
monitoring. Conversely, nonrenal clearance of imipenem in acute renal Amiodarone Anticonvulsants
failure is nearly double that found in chronic renal insufficiency (95
vs 51 mL/min), approaching that found in patients with normal renal Celecoxib Carbamazepine
function (130 mL/min; comprising over half of normal total clearance Cimetidine Phenobarbital
of approximately 230 mL/min). As a result, the total clearance of imipe- Erythromycin Phenytoin
nem in anuric AKI patients is 108 mL/min, compared with 64 mL/min Ethanol (acute intoxication) Cigarette smoking
in CRI, and 230 mL/min in normal subjects. Therefore, the daily dose
requirement is appropriately reduced from 2000 to 4000 mg/d in normal Fluconazole Corticosteroids
subjects to 1847 mg/d in AKI patients—a near doubling of the dose that Fluoxetine Prednisone
would be administered based on CKD data (1111 mg/d). In this case, Isoniazid Dexamethasone
47
the risk of seizure because of impaired clearance and imipenem accumu- Itraconazole Ethanol (chronic use)
lation is balanced against the risk of undertreatment, but accurate dosing
would not be achieved based solely on clearance data from CRI patients, Ketoconazole Grape fruit juice
and plasma drug levels are not routinely available for clinical use in most Neuroleptics Omeprazole
institutions. Definitive conclusions on the pharmacokinetics of metabo- Oral contraceptives Pioglitazone
lized medications in AKI remain hampered by the clinical complexity Psoralen dermatologics Rifampin
and potential confounders in the critically ill patients. AKI data should
19
be used whenever possible; in the absence of this information, CKD data Quinidine
must be used, but with an appropriate cautionary approach. Quinolone antibiotics
■ HEPATIC BIOTRANSFORMATION Selective serotonin reuptake

Most drugs are lipophilic, so that they tend to be reabsorbed across inhibitors
Ticlopidine
renal tubular or intestinal membranes following glomerular filtration
or biliary excretion, respectively. These drugs must therefore undergo Tricyclic antidepressants
biotransformation to more polar/hydrophilic compounds to allow
urinary or biliary excretion. Drug biotransformation reactions are clas- metabolize a particular drug, but metabolism of many drugs is depen-
sified as phase I (functionalization reactions, exposing or introducing a dent on a single enzyme. Since the CYP450 nomenclature is based on
functional group) or phase II (biosynthetic) reactions. Phase I reactions structural criteria, rather than biotransformation function, isozymes of
are predominantly oxidations, reductions, and hydrolysis reactions, and a particular class often lack any common substrates.
are usually catalyzed by enzymes of the cytochrome P450 (CYP450)
system, located in the endoplasmic reticulum (Tables 125-7 to 125-9).
Phase II reactions are conjugations, catalyzed by a variety of (mainly TABLE 125-8 Low Therapeutic Index Drugs Cleared by Cytochrome P450 Oxidation
cytosolic) enzymes, which covalently link the parent drug or metabolite
to a variety of compounds. Biliary excretion of a conjugated compound Anesthetic agents Enflurane
may result in enterohepatic recirculation of the parent compound if Halothane
intestinal flora cleave the conjugate bond. Both phase I and II reactions Isoflurane
generally result in a loss of pharmacologic activity, although more active Methoxyflurane
metabolites are less commonly produced. Hepatic drug metabolism is
functionally characterized by two patterns of clearance, which may be Sevoflurane
flow limited or capacity limited. The hepatic extraction ratio (ER) is Antiarrhythmic drugs Amiodarone
derived as follows: ER = (C – C )/C , where C and C are the drug Flecainide
V
A
V
A
A
concentration in hepatic arterial (or portal venous) and hepatic venous
blood, respectively. The hepatic ER is low for capacity-limited drugs Lidocaine
(which have saturable biotransformation pathways) and high for flow- Mexiletine
limited drugs (the liver essentially metabolizes any drug delivered, a Propafenone
process limited only by drug-delivering blood flow). Quinidine
The bulk of drug biotransformation is performed by hepatic enzymes,
and the remainder by renal tubular, intestinal, cutaneous, and pulmo- Anticonvulsants Carbamazepine
nary enzymes. The CYP450 system, comprising of over 50 proteins Phenobarbital
organized into 18 families and 43 subfamilies (in humans) of heme- Phenytoin
containing endoplasmic reticulum enzymes, is the major catalyst of β-Adrenergic receptor blockers Carvedilol
hepatic drug biotransformation reactions (see Table 125-9). 5,48-53 Three
families (CYP1, CYP2, and CYP3) are responsible for essentially all Metoprolol
drug biotransformations, through phase I (primarily oxidative) reac- Timolol
tions. Cytochrome P450 nomenclature is based on amino acid sequence Immunosuppressive/antineoplastic drugs Cyclophosphamide
homology. Families (designated by numbers, such as CYP3) contain at Cyclosporine
least 40% homology; subfamilies (designated by capital letters, such as
CYP3A) are over 55% homologous; individual P450 enzymes are again Etoposide (VP16)
designated by Arabic numerals (for example, CYP3A4). The CYP3A Ifosfamide
subfamily accounts for over 50% of phase I drug metabolism, predomi- Tacrolimus (FK506)
nantly by the CYP3A4 subtype. Most other drug biotransformations Oral anticoagulant Warfarin
are performed (in decreasing order of frequency) by CYP2D6, CYP2C,
CYP2E1, and CYP1A2 (Fig. 125-6). More than one enzyme may Bronchodilator Theophylline
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