Page 1766 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 125: Critical Care Pharmacology 1235

CYP2E1 TABLE 125-10 Phase II Drug Metabolizing Enzymes: Substrates and Polymorphisms
CYP1A2 Polymorphism Examples
“Slow” acetylation N-acetylation polymorphism. Slow acetylators have deficient
N-acetyltransferase activity (NAT-2).
Incidence of slow acetylators: 50%-60% (Caucasian and African
CYP2C
Americans; southern Indians); 5%-20% (Chinese, Japanese, Eskimos)
Incidence increased in HIV patients (thus sulfa reactions are more
CYP3A
common)
CYP2D6 Slow acetylators have increased risk of (1) isoniazid-induced
peripheral neuropathy, and possibly hepatotoxicity; (2) drug-
induced lupus: hydralazine, procainamide; (3) sulfonamide
hypersensitivity: deficient hydroxylamine metabolite detoxification;
(4) sulfasalazine-induced hemolysis
FIGURE 125-6. The proportion of drugs metabolized by the major cytochrome P450 enzymes. Dihydropyrimidine Dihydropyrimidine dehydrogenase polymorphism. 3%-4% taking
(Reproduced with permission from Benet LZ, Kroetz DL, Sheiner LB. Pharmacokinetics: the dynamics of dehydrogenase 5-fluorouracil (5-FU) have deficient metabolism, and develop
drug absorption, distribution, and elimination. In: Hardman JG, Gilman AG, Limbird LI, eds. Goodman & deficiency severe toxicity (myelosuppression, etc).
Gilman’s The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996.) Glucuronidation UDP-glucuronyltransferase polymorphism. Deficiency of hepatic
deficiency UDP-glucuronyltransferase activity manifests as two syndromes of
being recognized. These differences can sometimes have major clinical impaired bilirubin conjugation: Gilbert’s (2%-12% of population)
impact, or be as subtle as gender-related differences in metabolism of and Crigler-Najjar (<1%) syndromes.
specific stereoisomers of a particular drug formulation. Differences
in rate of absorption and extent of first-pass metabolism have been Potential but undocumented effects on metabolism of heavily
reported for some drugs, including ondansetron and zolmitriptan, glucuronidated drugs (acetaminophen; HIV drugs; oncologic agents).
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but these generally lack major clinical significance. Gender differences Glucose-6- G-6-PD deficiency. Occurs in approximately 20% of African-American
in volume of distribution, after adjustment for weight effects, have also phosphate- males; less frequent in females. Since erythrocytes from these patients
been identified for a number of drugs. Theophylline exhibits a smaller dehydrogenase are susceptible to oxidative stress, they are prone to develop hemolytic
volume of distribution in females compared to males, as do the fluo- deficiency anemia induced by antimalarials (chloroquine, mefloquine, primaquine),
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roquinolones. Possible explanations include differences in body com- probenecid, nitrofurantoin, sulfa drugs (sulfamethoxazole, dapsone),
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position between men and women, physiologic changes associated with sulfonylurea hypoglycemic agents (chlorpropamide, tolbutamide)
menstrual cycles, and differences in plasma protein binding secondary Glutathione transfer- Glutathione-s-transferase polymorphism. Absent activity of GSTM1 (50%
to hormonal characteristics. Gender differences in drug elimination ase deficiency Caucasians, 30% African-Americans) and/or GSTT1 (15% Caucasians,
have been studied in hepatic and renal processes. Clinically significant 24% African-Americans) impairs clearance of electrophilic toxins.
differences were predominantly linked to gender-specific expression of Increased vulnerability to acetaminophen, metronidazole, and
metabolic enzymes (eg, CYP3A4 and CYP1A2); gender differences in
renal handling of drugs tend to be clinically silent. Pharmacodynamic nitrofurantoin toxicity, because of depletion of mitochondrial
glutathione stores.
variability in humans is more difficult to measure, because the mea-
sured parameters can often be subjective, such as pain or depression. Atypical pseudocho- Pseudocholinesterase polymorphism. Subjects have impaired
Nonetheless, relevant gender differences have been identified. Women linesterase hydrolysis of succinylcholine, resulting in prolonged paralysis
treated with thrombolytics after a myocardial infarction are more likely following use of this agent; incidence is 1 in 2500 people.
to experience intracranial hemorrhage. Other examples include drugs Thiopurine methyla- Thiopurine methyltransferase polymorphism. Deficient (heterozygotes:
involved in glucose management and arrhythmia treatment. 65 tion deficiency 11%) or absent (homozygotes: 1 in 300) s-methylation of thiopurine
Pharmacogenetics: Many adverse drug reactions that were formerly termed drugs: azathioprine and 6-mercaptopurine, resulting in development
idiosyncratic are now recognized to be caused by genetic polymorphisms of profound leukopenia with standard doses.
of expression (through autosomal recessive traits) of genes involved in drug Atypical alcohol and Alcohol dehydrogenase activity. Five- to sixfold more rapid alcohol
disposition and effects, including the hepatic drug metabolizing enzymes aldehyde dehydro- dehydrogenase activity is found in the majority of Japanese subjects
(phase I or phase II) in particular individuals and racial groups, which genase activities (compared to Caucasians), resulting in acute symptoms following con-
have been most well studied 16,66-69 (Tables 125-9 to 125-11). The identified sumption of low doses of ethanol, because of rapid aldehyde production.
polymorphisms of these metabolic enzymes differ in their rate of metabo-
lism: “Extensive metabolizers” are the common wild-type phenotype, [SSRIs], and antipsychotics, including haloperidol ); other substrates
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“poor metabolizers” exhibit a decreased rate of substrate metabolism, and include β-blockers (all except atenolol and sotalol, which are renally
the rare “ultra-rapid metabolizers” display an increased rate of substrate excreted, not metabolized), other antiarrhythmic drugs, and codeine.
metabolism. The incidence of expression of the different phenotypes varies Approximately 7% to 10% of the Caucasian population, 2% to 5% of
by race and ethnic group. The effect of racial origin on drug metabolism Africans, but only rare Asian subjects lack expression of this enzyme and
is receiving increasing attention in the drug development process, 13,70-72 are poor metabolizers of CYP2D6 substrates. Such patients are prone
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although it must be remembered that pharmacogenetic factors controlling to develop profound bradycardia during standard β-blocker therapy or
drug disposition and response vary not only according to race and gender, severe drowsiness when receiving psychoactive drug therapy; in each
but also between individuals of the same race and gender. case the adverse event is caused by accumulation of the parent drug.
CYP2D6 Polymorphism The most common P450 polymorphism in Caucasians Conversely, these individuals derive little analgesic effect from codeine,
is of CYP2D6 expression. CYP2D6 is highly polymorphic, with over which must be metabolized by CYP2D6 to its more potent metabolite
90 known allelic variants. CYP2D6 is responsible for metabolism morphine to achieve therapeutic efficacy. Quinidine, fluoxetine, and
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of approximately 30 to 40 commonly used drugs, about half of amiodarone are potent inhibitors of CYP2D6 activity, and convert
which are psychoactive agents (antidepressants, including all tricyclic genetically extensive metabolizers into phenotypically poor metabolizers
antidepressants [TCAs] and selective serotonin reuptake inhibitors of CYP2D6 substrates.

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