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LIPOSUCTION TEXTBOOK
The Tumescent Technique By Jeffrey A. Klein MD

lipo-class

LIPOSUCTION TEXTBOOK

Chapter 18:

Cytochrome P450 3A4 and Lidocaine Metabolism

Lidocaine toxicity can occur as a result of adverse drug interactions between lidocaine and agents that inhibit the hepatic enzymes cytochrome P450 1A2 (CYP1A2) and cytochrome P450 3A4 (CYP3A4), which metabolize lidocaine. One patient had a reduced rate of lidocaine metabolism after tumescent liposuction as a result of CYP3A4 inhibition by sertraline (Zoloft) and flurazepam (Dalmane).1

When two or three drugs are substrates for the same enzyme, an adverse drug reaction is possible when they are used simultaneously. Lidocaine is rapidly eliminated by hepatic CYP3A4. The newer antidepressant selective serotonin reuptake inhibitors (SSRIs), such as sertraline, are metabolized by the hepatic enzymes CYP3A4 and CYP2D6. The benzodiazepines, such as midazolam (Versed) and diazepam (Valium), are also metabolized by the CYP3A4 isoenzymes. The specific cytochrome P450 enzyme responsible for the metabolism of flurazepam has not been identified.

Since 1994, information has expanded rapidly about the specificity of hepatic microsomal enzymes of the cytochrome P450 family for the metabolism of different drugs. This new information permits a knowledgeable clinician to anticipate adverse drug interactions.

For several years, 60-mg/kg doses of lidocaine for tumescent liposuction had been widely regarded as the maximum dose. After my experience with lidocaine toxicity following a tumescent lidocaine dosage of 60 mg/kg, the maximum dose that I will use in any patient is now 50 to 55 mg/kg. When the need for a larger dose is anticipated, the surgical plan is reevaluated and the surgery divided into sequential procedures separated by at least 4 days. The two procedures are typically performed one month apart to allow the resolution of most of the postoperative effects from the initial procedure before subjecting the patient to additional surgical trauma.

The safety of tumescent lidocaine at a dose of 55 mg/kg has yet to be well documented by rigorous pharmacologic studies involving a large number of patients. Before Case Reports 18-1 and 18-2, we had performed tumescent liposuction on more than 400 patients using lidocaine doses in the range of 50 to 60 mg/kg without evidence of significant lidocaine toxicity.

Cytochrome P450 System

The cytochrome P450 (CYP450) family of enzymes is essential for most drugs eliminated by hepatic metabolism.2 These enzymes have 450 nm as the wavelength of maximum absorption in the reduced state when carbon monoxide is present; thus the “P450” designation. Based on the homology of amino acid sequences, the CYP450 enzymes have been categorized into families, subfamilies, and individual enzymes.3

Microsomes are the microvesicles formed from fragments of endoplasmic reticulum after liver tissue has been homogenized and centrifuged. The enzymes located in the endoplasmic reticulum are referred to as microsomal enzymes. Until recently, hepatic metabolism of drugs and metabolic drug interactions were usually studied in vitro using liver tissue.

Cytochrome P450 evolved as an important means of converting potentially harmful concentrations of lipid-soluble nutrients and environmental substances into water-soluble compounds that are more easily eliminated. In humans there are 12 known families of CYP450 isoenzymes, of which five are important in drug metabolism: 3A4, 1A2, 2C9, 2C19, and 2D6.

When two drugs, both requiring the same enzyme for metabolism, are given concurrently, one drug may inhibit or induce metabolism of the other, and thus an adverse drug interaction may occur. Many factors determine the relative effects of one drug on the metabolism of another drug. Drug concentration and relative enzyme affinity determine metabolic drug interactions.

Significant interpatient variability exists with respect to the enzymatic activity of the CYP450 isoenzymes. This makes it difficult to predict the probability of any specific drug interaction.4

Hepatic Metabolism of Lidocaine

Lidocaine is rapidly eliminated by hepatic metabolism.5 The liver metabolizes 70% of the lidocaine that enters the hepatic circulation at any given moment. When 1 L of blood passes through the hepatic circulation of a healthy volunteer, more than 700 ml of the blood is completely cleared of its lidocaine content.6

With a high hepatic extraction ratio of 0.7, lidocaine metabolism is said to be “flow rate limited.” In other words, the rate of lidocaine metabolism usually depends on the rate of blood flow to the liver.

At typical, therapeutic plasma concentrations of lidocaine, metabolism of lidocaine is so efficient that it does not seem to cause any substrate inhibition of the enzymes CYP1A2 and CYP3A4. Lidocaine clearance can be reduced by any drug that inhibits CYP3A4 enzymes, such as erythromycin or ketoconazole (see Boxes 18-1 to 18-3). Similarly, any condition that reduces hepatic blood flow, such as shock or decreased cardiac output associated with congestive heart failure, will decrease lidocaine clearance. The beta-blockers, such as propranolol, decrease lidocaine metabolism and elimination by decreasing cardiac output and therefore hepatic blood flow.7 Cimetidine inhibits CYP3A4 and decreases hepatic blood flow.8 Patients with cirrhosis of the liver have a reduced lidocaine clearance; in renal insufficiency, however, lidocaine clearance is normal.

Lidocaine Metabolites. The hepatic CYP1A2 and CYP3A4 microsomal isoenzymes alter lidocaine by a sequential process of oxidative N-dealkylation. First, oxidative deethylation of the amino nitrogen occurs, yielding monoethyl glycine xylidide (MEGX). Next, an additional oxidative reaction removes the residual ethyl group from MEGX, yielding glycine xylidine (GX).9

Both of these metabolites, MEGX and GX, have some local anesthetic effect and antidysrhythmic effect.10 After 10 to 24 hours of lidocaine infusion, the ratio of total serum concentrations of MEGX to lidocaine ranges from 0.11 to 0.36 in cardiac patients without cardiac failure.11 MEGX and GX are much less lipophilic than lidocaine, having octanol/buffer (pH 7.4) partition coefficients of 6:1 and 2:1, respectively. The lidocaine partition coefficient for octanol/water is 43:1. After prolonged intravenous (IV) infusion, less than 5% of lidocaine appears in the urine,12 whereas most of MEGX is excreted by the kidneys. After an oral dose, only 2% of lidocaine is excreted intact in the urine.13 Ultimately, 73% of the dose appears in the urine as xylidine (Figure 18-1).

With prolonged systemic delivery, the rate of lidocaine metabolism and clearance decreases, possibly because of competition between lidocaine and its metabolites for the binding sites of hepatic enzymes. Lidocaine metabolism is a sensitive means for evaluating liver CYP450 function in a bioartificial liver.14 Determining the amount of MEGX produced by a patient’s liver has been used to measure the degree of liver dysfunction and to predict survival in critically ill patients.15

Drug Metabolism

The most abundant of all human cytochrome P450 enzymes, the isoenzyme CYP3A4, is responsible for the metabolism of more drugs and a broader range of drugs than any other hepatic enzyme. CYP3A4 metabolizes such drugs as lidocaine, antidepressants, carbamazepine16 (Tegretol), nifedipine17 (Procardia), methadone (Dolophine), and alfentanil.18,19

Drugs that inhibit CYP3A4 or CYP1A2 are avoided or discontinued, if possible, before tumescent liposuction (Boxes 18-1 to 18-3). If these inhibitors cannot be discontinued, the total dosage of lidocaine should be reduced to 35 mg/kg or less.

Many substrate drugs are metabolized by CYP3A4 and CYP1A2 but do not significantly inhibit enzymatic function of these cytochromes. Under certain conditions, substrate drugs may adversely affect lidocaine metabolism. If multiple substrate drugs are used simultaneously, they have an additive effect, producing competitive inhibition of lidocaine metabolism. In addition to the inhibitor drugs, it is helpful to know which drugs are substrates for CYP3A4 and CYP1A2 (Boxes 18-4 and 18-5).

Certain drugs augment the enzymatic activity of CYP3A4. Rifampin (Rifampicin) induces CYP3A4 and augments the metabolism of lidocaine20 and triazolam (Halcion).21 An infusion of heme arginate induces CYP3A4 and augments lidocaine metabolism in patients with variegate porphyria.22

Whereas CYP3A4 is inducible by some drugs, CYP2D6 is not inducible but can be inhibited by certain drugs.23 Potent in vitro inhibitors of both CYP3A4 and CYP2D6 include sertraline (Zoloft), fluoxetine (Prozac), fluvoxamine (Luvox), and paroxetine (Paxil), all of which are selective serotonin reuptake inhibitors (SSRIs).24 Almost all the available newer antidepressants, including the SSRIs, as well as nefazodone (Serzone), an antidepressant unrelated to SSRIs, inhibit CYP3A4 and are associated with clinically significant drug interactions.

SSRIs are being used with increasing frequency. Antidepressants also are widely prescribed for nonpsychiatric conditions and may be taken by prospective liposuction patients; for example, fluoxetine (20 mg/day) is used in the treatment of premenstrual dysphoria.25 Similarly, alprazolam (Xanax) has a role in the treatment of severe premenstrual syndrome (PMS).26 Potential tumescent liposuction patients might be taking a combination of fluoxetine and alprazolam. The combination of an SSRI and a benzodiazepine might inhibit lidocaine metabolism in a way analogous to Case Report 18-1.

The metabolism of alfentanil, which is dependent on CYP3A4, is no different on menstrual cycle days 3 (menstruating phase), 13 (estrogen peak), and 21 (progesterone peak). This strongly suggests that a woman’s menstrual phase does not affect the activity of CYP3A4.27

Drug Interactions

Examples of drug interactions mediated by inhibition or induction of CYP3A4 are increasing. When two drugs require the same enzyme for metabolism, one drug may decrease the rate of metabolism of the others. For most cases, when a drug is metabolized by CYP3A4, it is not known how a drug and lidocaine might interact. Therefore, until a specific evaluation has been completed, one must assume that the drug will reduce the rate of lidocaine metabolism.

Rifampin induces and increases the metabolic activity of CYP3A4, whereas troleandomycin inhibits CYP3A4 activity. In human volunteers, alfentanil has clearance and elimination half-life of 5.3 ml · kg–1 · min–1 and 58 minutes, respectively. When alfentanil is administered with rifampin, CYP450 activity is increased, and alfentanil clearance and elimination half-life are 14.6 ml · kg–1 · min–1 and 35 minutes, respectively. When troleandomycin is given concomitantly, alfentanil clearance and elimination half-life are 1.1 ml · kg–1 · min–1 and 630 minutes, respectively.28 Thus, in human volunteers, drugs that affect CYP3A4 activity can produce significant alterations in the systemic clearance of alfentanil. Similar interactions can also affect lidocaine clearance.

Drug interactions mediated by CYP3A4 can have devastating consequences. For example, the nonsedating antihistamines terfenadine (Seldane) and astemizole29 (Hismanal), as well as cisapride (Propulsid), used to treat nocturnal heartburn caused by gastroesophageal reflux disease, are metabolized by CYP3A4. Ketoconazole (Nizoral), itraconazole (Sporanox), erythromycin, and clarithromycin (Biaxin), however, are potent inhibitors of 3A4 and block the metabolism of terfenadine, astemizole, and cisapride. The resulting elevated plasma levels can cause fatal QT prolongation and torsades de pointestype ventricular tachycardias.

Erythromycin inhibits the ability of CYP3A4 to metabolize midazolam. This interaction can result in a prolonged coma.30

Not all macrolide antibiotics inhibit CYP3A4. Azithromycin (Zithromax) and dirithromycin (Dynabac) are eliminated by a combination of hepatic metabolism and bilary excretion. There are no reports of the effects of azithromycin or dirithromycin inhibiting CYP3A4, but clinical pharmacologic studies have shown that these drugs do not cause elevated terfenadine blood levels.

Methadone is extensively metabolized by CYP3A4. Fluvoxamine, a newer SSRI antidepressant, is a potent mixed-type inhibitor of methadone metabolism. Conversely, the metabolism of nifedipine by CYP3A4 is potently inhibited by methadone.

The apparent decrease of CYP3A4 enzymatic activity with advancing age might be secondary to changes in liver blood flow, size, or drug binding and distribution with age.31,32

Dietary factors, such as grapefruit juice, can inhibit CYP3A4 found in intestinal mucosa. Grapefruit juice inhibits CYP3A4 located in intestinal wall tissue (but not hepatic CYP3A4), which decreases the rate of metabolism of substrate drugs in the gastrointestinal tract and augments the drugs’ systemic absorption and bioavailability. For example, grapefruit juice increases the maximum plasma concentration of diazepam by a factor of 1.5. Grapefruit juice also appears to increase the bioavailability of oral doses of triazolam, midazolam, cyclosporine, and several dihydropyridine calcium channel blockers, such as felodipine, nifedipine, nitrendipine, and nisoldipine. The effects of grapefruit juice on intestinal CYP3A4 persist for about 3 days.

Fluoxetine, through its metabolite norfluoxetine, inhibits CYP3A4 and impairs the metabolism of warfarin (Coumadin).

In addition to diverse drugs inhibiting lidocaine metabolism, lidocaine may inhibit the metabolism of other drugs. For example, given intramuscularly for minor gynecologic surgery, lidocaine enhances the hypnotic effect of thiopental when it is given intravenously as an induction agent for general anesthesia.

Sertraline and Other SSRIs

The majority of the newer SSRI antidepressants, including sertraline (Zoloft), are associated with clinically significant drug interactions mediated by the inhibition of cytochrome P450 enzymes.33 Sertraline can inhibit both CYP2D6 and CYP3A4.

The usual oral dose of sertraline ranges from 50 to 200 mg once daily. Based on an elimination half-life of 26 hours, steady-state plasma sertraline levels are achieved after 7 days of once-daily dosing in patients with healthy hepatic metabolism. Conversely, in patients who have a healthy liver, 1 week is required for the body’s content of sertraline to be 98% eliminated after discontinuing the drug. In patients with mild cirrhosis, more than 2 to 3 weeks is required for sertraline to be eliminated.

In vitro studies show that sertraline inhibits CYP3A4. However, sertraline does not necessarily affect the metabolism of all drugs metabolized by CYP3A4. In vivo, sertraline does not seem to affect the metabolism of diazepam.34

Sertraline is tightly bound to plasma proteins. It may competitively displace other protein-bound drugs, such as lidocaine, increasing the amount of free (unbound) drug and the potential for toxic reactions.

After discontinuing sertraline, the physician should wait 7 to 14 days before prescribing any drug known to have potential adverse CYP450 (metabolic pathway) interactions. SSRIs are known to interact with monoamine oxidase inhibitors (MAOIs) to produce fatal reactions. Fatal drug interactions have even occurred in patients who have discontinued an SSRI and were immediately started on an MAOI.

Benzodiazepines

The benzodiazepines are often used for anxiolysis and sedation in conjunction with lidocaine for tumescent local anesthesia. Thus it is important to understand the effects of CYP3A4 inhibitors on benzodiazepines.

Benzodiazepines are metabolized by several different microsomal enzymes. Approximately 75% of the available benzodiazepines are significantly metabolized by CYP3A4, including alprazolam36 (Xanax), triazolam37 (Halcion), diazepam38,39 (Valium), and midazolam40 (Versed). Plasma concentrations of these benzodiazepines increase when they are administered with drugs that inhibit CYP3A4, including most newer SSRI antidepressants. The rate of metabolism of midazolam and triazolam varies considerably among healthy volunteers.

The specific CYP450 isoenzyme responsible for the metabolism of flurazepam (Dalmane) has not been identified.35 The half-life of flurazepam in plasma is 2 to 3 hours, but its major active metabolite (N-desalkylflurazepam) has a half-life of 47 to 100 hours.

The antipsychotic clozapine (Clozaril) and the antifungal ketoconazole (Nizoral) noncompetitively inhibit midazolam metabolism through the inhibition of CYP3A4. The metabolism of midazolam is also decreased by itraconazole (Sporanox) and fluconazole (Diflucan).41 The antipsychotic olanzapine (Zyprexa), however, has little effect on midazolam metabolism.42 Fluoxetine appears to impair the metabolism of alprazolam but not clonazepam (Klonopin).43

Nefazodone (Serzone), an antidepressant, is a competitive inhibitor of CYP3A4 in the metabolism of alprazolam and triazolam. In contrast, the metabolic clearance of lorazepam (Ativan) depends on conjugation rather than hydroxylation, and thus it is not inhibited by nefazodone. Although fluoxetine (Prozac) may impair the metabolism of both diazepam and warfarin, it does not impair lorazepam or oxazepam (Serax).44 Fluoxetine does not affect the metabolism of triazolam,45 but the combination of the tricyclic antidepressant amitriptyline and triazolam has been associated with a fatality.46

I recommend lorazepam as the benzodiazepine of choice for tumescent liposuction. Lorazepam is the only benzodiazepine that is not metabolized by CYP450 enzymes and therefore is less susceptible to adverse drug interactions. In its initial metabolic reaction, lorazepam is conjugated to lorazepam-glucuronide, which has no central nervous system activity, and is excreted in the urine. Available in 0.5-mg, 1-mg, and 2-mg tablets, lorazepam at 2 mg is equivalent in peak effectiveness to 10 mg of diazepam. Lorazepam, 1 mg orally, is given the night before and the day of surgery to minimize anxiety before liposuction. Larger doses are not necessary and may cause nausea in some patients.

A 2-mg to 4-mg oral dose of lorazepam produces more consistent and longer-lasting anxiolysis, sedation, and anterograde amnesia, comparable to 10 to 20 mg of diazepam.47,48 Lorazepam appears to increase respiratory drive and attenuate the respiratory depression associated with meperidine (Demerol).49

Lidocaine

Lidocaine is principally metabolized by CYP3A4, which oxidizes a diversity of substrates, including drugs, carcinogens, and steroids (see earlier discussion).50,51

By competitive inhibition or by enzyme induction, drugs can either inhibit or accelerate lidocaine metabolism. As noted, sertraline (Zoloft) has been shown to inhibit CYP3A4 in vitro, but the clinical significance of this has not been established. Lidocaine and the antidysrhythmic amiodarone (Cordarone) are both metabolized by CYP3A4, and each drug inhibits the metabolism of the other.52 The combination of lidocaine and amiodarone is associated with bradycardia and seizures.53

Antiepileptic drugs appear to compete with lidocaine for CYP3A4 and slow lidocaine metabolism.54 Although the clinical significance is not clear, lidocaine and propranolol exhibit mutual metabolic inhibition in rat liver microsomes.55

Drugs that inhibit enzymatic activity of CYP3A4 have the potential for elevating the plasma concentrations of lidocaine. With tumescent liposuction, in which patients’ lidocaine blood levels are typically in the low therapeutic range of 1 to 3.5 mg/L, anything that causes a diminution of lidocaine metabolism can result in lidocaine levels above the 6-mg/L threshold for potential toxicity.

Drugs that interfere with lidocaine metabolism should be discontinued at least 1 or 2 weeks before using the tumescent technique when high doses of lidocaine are anticipated. If a drug that might interfere with lidocaine metabolism cannot be discontinued, the surgery should be limited and smaller total doses of lidocaine used.

See Chapters 16 and 21 for recommended maximum safe doses of tumescent lidocaine.

Protease Inhibitors

Antiretroviral medications are now widely used to treat patients with human immunodeficiency virus (HIV) and include indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir), and saquinavir (Invirase). CYP3A4 is responsible for up to 90% of the metabolism of protease inhibitors. The protease inhibitors also inhibit CYP3A4.

With other drugs that interact with CYP3A4, the patient can be asked to discontinue the medicine a week or two before surgery. Asking a patient to discontinue an antiretroviral medication (e.g., protease inhibitor) for cosmetic surgery, however, may not be an appropriate solution.

Protease inhibitors can increase the metabolism and thus decrease the plasma concentration of estradiol and theophylline. By increasing the metabolism of estradiol, protease inhibitors may impair the efficacy of oral contraceptives. Similarly, plasma levels of theophylline in asthma patients may be decreased.

Protease inhibitors appear to decrease the metabolism of lidocaine by approximately 50%, but the exact effect has not been adequately studied. Therefore, until more is known about the effects of protease inhibitors on tumescent lidocaine metabolism, tumescent liposuction is contraindicated in patients taking protease inhibitors.

Michaelis-Menten Enzyme Kinetics

In healthy patients the hepatic enzymes that metabolize lidocaine are so efficient that they do not become saturated at clinically relevant plasma lidocaine concentrations. The rate of hepatic lidocaine metabolism is perfusion rate limited, with a 70% extraction ratio. Thus, within the physiologic ranges of hepatic blood flow, the liver extracts lidocaine so quickly that for every liter of blood that flows through the liver, 700 ml of blood is completely cleared of all lidocaine. In other words, the hepatic enzymes CYP3A4 and CYP1A2 remove lidocaine as fast as lidocaine is presented to the liver. In vitro, enzymes extracted from human liver might demonstrate enzyme saturation when exposed to high concentrations of lidocaine. In vivo, however, no clinical evidence indicates that CYP3A4 or CYP1A2 become saturated.

Most mammalian enzymes that metabolize drugs can accommodate greater drug (substrate) concentrations than are ever achieved, even after an overdosage. Typically the rate at which an enzyme metabolizes a drug is linearly related to the drug’s concentration. That is, the rate of enzymatic drug metabolism is proportional to the first power of the drug’s concentration, which is known as a first-order kinetic process.

An occasional enzyme has only limited ability to process a substrate, and the enzyme’s maximum capacity is readily exceeded. An enzyme is said to be saturated and shows zeroorder kinetics when an increase in the substrate drug concentration does not change the rate of drug metabolism. A classic example of a saturated enzyme is alcohol dehydrogenase, which becomes saturated at very low concentrations of ethanol in the blood. At very low ethanol concentrations, alcohol dehydrogenase shows first-order kinetics. At relatively low but increasing blood ethanol levels, the rate of ethanol metabolism gradually changes, to the point where an increasing concentration of ethanol no longer increases the rate of metabolism. Saturable enzymes are said to show Michaelis-Menten kinetics.

At toxic concentrations of lidocaine, the enzymes that metabolize lidocaine are not saturated. The rate of lidocaine metabolism continues to increase with increasing plasma concentration.

Most of the drug metabolism mediated by CYP450 microsomal enzymes follow simple Michaelis-Menten kinetics; within certain limits of substrate concentration, a linear relationship exists between the concentration of the substrate and the initial velocity of the reaction. The enzyme kinetics of CYP3A4, however, often exhibits nonlinear or allosteric (sigmoidal) characteristics, which imply that each CYP3A4 molecule has more than one substrate binding site. In fact, CYP3A4 apparently has two active binding sites. Furthermore, access and binding affinity of the first substrate molecule of lidocaine to either site in an active pocket of CYP3A4 enhance the binding affinity and reaction rate of the vacant site for the second molecule of lidocaine.56,57

Lidocaine has such a high hepatic extraction ratio (0.7) that its elimination is limited by the rate of hepatic perfusion. The rate of lidocaine clearance is limited by the rate of blood flow to the liver, not by the rate of lidocaine metabolism by hepatic enzymes.

There is little risk of CYP3A4 becoming saturated at plasma lidocaine concentrations within the therapeutic range of less than 6 μg/ml.

Recent Technical Advances

Until recently, measuring the in vitro effects of CYP3A4 on drugs required a tedious process of obtaining fresh human liver tissue, extracting endoplasmic reticulum, assaying the CYP enzymatic activity on a control substance, then testing the enzymatic inhibition caused by an individual drug. Technical advances published in 1998 and 1999 promise to provide fully automated techniques for screening many drugs in clinical use and potential drug candidates.

Molecular biologic techniques now provide a means for rapid screening of multiple possible CYP-drug interactions. Recombinant human CYP450 enzymes expressed in Escherichia coli have been shown to be reliable surrogates for the native human liver enzymes, and such technology appears to be suitable for automated drug metabolism and CYP-drug interactions in humans.58

Hybridoma technology has been used successfully to produce monoclonal antibodies to human CYP1A2 and CYP3A4. This has been accomplished, for example, by infecting insect cells with recombinant baculoviruses encoded with human CYP3A4 complementary (copy) deoxyribonucleic acid (cDNA). When microsomal proteins derived from these cells are injected into mice, monoclonal antibody [mAb(3A4a)] specific to human CYP3A4 is produced. Monoclonal antibodies to human CYP3A4 promise to provide a precise tool for identifying the role of CYP3A4 in the metabolism of any drug.59,60

Fluorometric and radiometric analytic techniques using human liver microsomes allow rapid determination of inhibitory effects of any drug on CYP1A2, CYP3A4, CYP2C9, and CYP2D6.61 A 1999 in vitro study suggests that CYP1A2 may be more important in the hepatic metabolism of lidocaine than CYP3A4.62 Within a few years, new technology and studies should provide a more accurate perspective of the drug interactions that affect lidocaine metabolism.

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Figure 18-1 Lidocaine metabolism. (Modified from de Jong RH: Local anesthetics, St Louis, 1994, Mosby.)

CASE REPORT 18-1 Sertraline and Lidocaine Toxicity
A 39-year-old female weighing 80 kg (176 pounds) underwent tumescent liposuction surgeries. Five years earlier, her breast cancer was treated by chemotherapy, radiation, and bone marrow transplantation. She had a long history of treatment with sertraline (Zoloft, 200 mg daily) for anxiety disorder, panic attacks, and mild depression. Sertraline was not discontinued before either surgery.
The first surgery, liposuction of the hips and outer thighs, was uneventful. Perioperative sedation consisted of 10 mg of oral zolpidem (Ambien). The dose of tumescent lidocaine totaled 59 mg/kg (lidocaine 800 mg/L, epinephrine 0.65 mg/L, sodium bicarbonate 10 mEq/L) in 0.9% NaCl at 37° C (98.6° F). Liposuction produced 2700 ml of supranatant fat and 250 ml of blood-tinged infranatant anesthetic solution.
One month later the patient returned for liposuction of the inner thighs, inner knees, and buttocks. Perioperative sedation on this occasion was 30 mg of oral flurazepam (Dalmane). Between 11:20 AM and 1 pm she received 58 mg/kg of tumescent lidocaine (lidocaine 900 mg/L, epinephrine 0.65 mg/L, bicarbonate 10 mEq/L) in 0.9% NaCl at 37° C. The liposuction was uneventful, yielding 1800 ml of supranatant fat and and 650 ml of blood-tinged infranatant anesthetic solution. The patient was discharged at 7:20 pm, alert and fully ambulatory.
Ten hours after completion of the tumescent infiltration of lidocaine, the patient experienced nausea, vomiting, unsteady gait, mild confusion, and dysarthria. Physical examination in a local emergency room revealed anxiety, short-term memory impairment, and slight pallor; otherwise the neurologic and cardiovascular findings, electrocardiogram, and routine laboratory studies were unremarkable. Blood drawn at 11:48 pm had a plasma lidocaine concentration of 6.3 mg/L by immunoassay (IA) and confirmed by gas chromatography (GC) as 6.1 mg/L. Lidocaine plasma levels greater than 6 mg/L are associated with an increased risk of toxicity. Admitted to hospital for overnight observation, she was discharged the next morning, with a 6:45 AM lidocaine level of 2.9 mg/L by IA and confirmed at 3.0 mg/L by GC.
Discussion. our knowledge, this is the first documented case of tumescent liposuction totally by local anesthesia in which a standard dose of lidocaine, widely recognized as safe, has led to potentially toxic plasma lidocaine concentrations. It demonstrates the possibility of serious interactions between tumescent lidocaine and commonly used oral medications. Both sertraline and flurazepam have the potential for significantly reducing lidocaine clearance through inhibition of CYP3A4, thereby increasing plasma lidocaine concentrations above the threshold for toxicity. Whether the patient’s prior treatment for breast cancer affected her ability to metabolize lidocaine is unclear.
Sertraline and flurazepam may have had an additive effect on reducing the rate of lidocaine metabolism. During the first surgery, when sertraline but not flurazepam was administered, the patient had no symptoms of lidocaine toxicity. Lidocaine plasma concentrations were possibly elevated asymptomatically.

 

CASE REPORT 18-2 Clarithromycin and Lidocaine Toxicity
After our report of the CYP3A4-mediated sertraline-lidocaine drug interaction case was published, a physician told me about another case of a CYP3A4-mediated toxic drug interaction. This patient developed nausea, vomiting, confusion, and disorientation after receiving 60 mg/kg of tumescent lidocaine.
Eleven days before the scheduled liposuction the patient started taking clarithromycin for an upper respiratory infection and discontinued it the day before surgery. At surgery the patient was not taking any drugs. Because of the long half-life of clarithromycin, however, lidocaine metabolism was sufficiently impaired to account for the toxic events.

 

BOX 18-1 Cytochrome P450 3A4 Inhibitors Affecting Lidocaine Metabolism
Alprazolam (Xanax)
Amiodarone (Cordarone)
Anastrozole (Arimidex)
Cannabinoids
Cimetidine (Tagamet)
Clarithromycin (Biaxin)
Cyclosporine (Neoral)
Danazol (Danocrine)
Diazepam (Valium)
Diltiazem (Cardizem)
Erythromycin
Felodipine (Plendil)
Fluconazole (Diflucan)
Fluoxetine (Prozac)
Fluvoxamine (Luvox)
Indinavir (Crixivan)
Isoniazid
Itraconazole (Sporanox)
Ketoconazole (Nizoral)
Metronidazole (Flagyl)
Mibefradil (Posicor)
Miconazole (Monistat)
Midazolam (Versed)
Naringenin (grapefruit juice)
Nefazodone (Serzone)
Nelfinavir (Viracept)
Nevirapine (Viramune)
Nicardipine (Cardene)
Nifedipine (Procardia)
Norfloxacin (Noroxin)
Norfluoxetine
Omeprazole (Prilosec)
Paroxetine (Paxil)
Quinidine (Quinaglute)
Remacemide
Ritonavir (Norvir)
Saquinavir (Invirase)
Sertinadole
Sertraline (Zoloft)
Stiripentol
Terfenadine (Seldane)
Triazolam (Halcion)
Troglitazone (Rezulin)
Troleandomycin (TAO)
Verapamil (Calan)
Zafirlukast (Accolate)
Zileuton (Zyflo)
Data from Park GR: Br J Anaesth 77:32-49, 1996.

 

BOX 18-2 Categories of Cytochrome P450 3A4 Inhibitors Acetazolamide
Antifungal Medications
Fluconazole
Itraconazole
Ketoconazole
Miconazole
Benzodiazepines
Alprazolam
Diazepam
Flurazepam
Midazolam
Triazolam
Calcium Channel Blockers
Amiodarone
Diltiazem
Felodipine
Nicardipine
Nifedipine
Verapamil
Macrolide Antibiotics
Clarithromycin
Erythromycin
Troleandomycin
Protease Inhibitors
Indinavir
Nelfinavir
Ritonavir
Saquinavir
Selective Serotonin Reuptake Inhibitor(SSRI)
Antidepressants
Fluoxetine
Fluvoxamine
Nefazodone
Paroxetine
Sertraline

 

BOX 18-3 Cytochrome P450 1A2 Inhibitors
Anastrozole (Arimidex)
Caffeine
Cimetidine (Tagamet)
Ciprofloxacin (Cipro)
Clarithromycin (Biaxin)
Diethyldithiocarbamate
Diltiazem (Cardizem)
Enoxacin (Penetrex)
Erythromycin
Fluvoxamine (Luvox)
Isoniazid
Ketoconazole (Nizoral)
Mexiletine (Mexitil)
Mibefradil (Posicor)
Naringenin (grapefruit juice)
Norfloxacin (Noroxin)
Omeprazole (Prilosec)
Paroxetine (Paxil)
Ritonavir (Norvir)
Tacrine (Cognex)
Zileuton (Zyflo)

 

BOX 18-4 Cytochrome P450 3A4 Metabolic Substrates
Alfentanil (Alfenta)
Alprazolam (Xanax)
Amitriptyline (Elavil)
Amlodipine (Norvasc)
Astemizole (Hismanal)
Atorvastatin (Lipitor)
Carbamazepine (Tegretol)
Cerivastatin (Baycol)
Chloramphenicol (Chloromycetin)
Cisapride (Propulsid)
Clomipramine (Anafranil)
Clozapine (Clozaril)
Cyclosporine (Neoral)
Dexamethasone (Decadron)
Dextromethorphan
Donepezil (Aricept)
Erythromycin
Estrogens
Felodipine (Plendil)
Fentanyl
Flurazepam (Dalmane)
Fluvastatin (Lescol)
Imipramine (Tofranil)
Isradipine (DynaCirc)
Losartan (Cozaar)
Lovastatin (Mevacor)
Methadone
Methylprednisolone
Midazolam (Versed)
Nicardipine (Cardene)
Nimodipine (Nimotop)
Nisoldipine (Sular)
Pentoxifylline (Trental)
Pravastatin (Pravachol)
Prednisone
Progestins
Propafenone (Rythmol)
Rifabutin (Mycobutin)
Rifampin (Rifampicin)
Sildenafil (Viagra)
Simvastatin (Zocor)
Tacrolimus (Prograf)
Tamoxifen (Nolvadex)
Terfenadine (Seldane)
Testosterone
Tetracycline
Theophylline
Thyroxine
Valproic acid (Depakene)
Warfarin (Coumadin)
Zileuton (Zyflo)
Zonisamide

 

BOX 18-5 Cytochrome P450 1A2 Metabolic Substrates
Chlordiazepoxide (Librium)
Clomipramine (Anafranil)
Clozapine (Clozaril)
Cyclobenzaprine (Flexeril)
Desipramine (Norpramin)
Diazepam (Valium)
Haloperidol (Haldol)
Imipramine (Tofranil)
Riluzole (Rilutek)
Theophylline
Warfarin (Coumadin)
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