Libby Zion's Lesson: Adverse Drug Reactions and Interactions

July 2, 2009

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By Laurence Kinsella, MD, FAAN, Saint Louis University, Saint Louis, MO

In 1984, an 18-year-old college freshman died in New York Hospital. Few events have had as great an impact on the training of medical residents. Libby Zion was admitted for agitation, confusion, and muscular twitching. She had a history of depression and was taking phenelzine, an MAO inhibitor. The house officers assigned to her care sedated her with meperidine and haloperidol and placed restraints to prevent self-harm. By the following morning, she had a fever of 107 and died from cardiac arrest. Her father, Sidney Zion, a prominent journalist for the New York Daily Post, brought charges against the hospital and the physicians, indicting the medical training system for excessive work hours and poor supervision that, he argued, contributed to poor judgment and medical negligence.1

In 1995, the jury in the Zion v. New York Hospital trialreturned a mixed verdict, finding that the doctors were partially responsible for Libby's death, but that Libby was also responsible based on autopsy samples positive for cocaine metabolites.2

As a result of Libby's death—and her father's considerable influence—the Bell Commission was convened in New York to address the issue of residency work hours.3 In 2003, the Accreditation Council for Graduate Medical Education (ACGME) adopted most of the Bell Commission's recommendations, restricting residency work hours at all US training programs to their current levels of 80 hours per week.4

But would the current work hour restrictions have saved Libby Zion? Would a well-rested, post-Bell Commission resident have recognized the signs and symptoms of serotonin syndrome that Libby Zion exhibited on admission, namely confusion, agitation, and muscular hyperactivity? Would s/he have known that meperidine is associated with significant drug interactions that might worsen serotonin syndrome?

The lesson to be learned from Libby Zion's death is that drug-drug interactions (DDI) and adverse drug events (ADE) are under-recognized, and many are unaware of the potential for harm in many commonly prescribed medications.

Serotonin Syndrome and Other Adverse Drug Events

A number of clinical syndromes relevant to neurologic practice result from drug toxicity (Table 1). Several are associated with acute confusional states, a common reason for neurologic consultation.

Table 1—Selected Clinical Syndromes Related to Medication Toxicity

Syndrome  Medication Examples
Serotonin Syndrome SSRI, meperidine, MAOI 
Neuroleptic Malignant Syndrome haloperidol, chlorpromazine
Akinetic-Rigid Syndromes metoclopramide, neuroleptics
Acute Confusional States baclofen, topiramate, many others
Anticholinergic Syndrome TCA, trihexiphenidyl
Orthostatic Myoclonus/Asterixis gabapentin           
Stevens Johnson Syndrome carbamazepine, lamotrigine          
Drug-Induced Seizure buproprion, theophylline, TCA

The term "serotonin syndrome" was coined by Sternbach in 1991.5 It is an increasingly common complication of serotonergic drugs, especially when used in combination.6 The incidence is unclear, since most cases are probably unrecognized. Over 200 cases have been published, most since Sternbach's review.7 Toxicity occurs in 27% and deaths in 0.3% of patients overdosing on SSRIs.8 For nefazadone alone, the incidence is 0.4 cases per 1,000 patient-months.9  Patients present with a clinical triad of mental status changes, autonomic instability, and motor hyperexcitability, usually within 24 hours of a change in medication.10 Most patients recover within one to two days after drug withdrawal; however, some may develop respiratory failure, seizures, rhabdomyolysis, and cardiac arrest. Most of the deaths reported due to serotonin syndrome occurred in patients taking an MAO inhibitor.11

Adverse Drug Events and Drug-Drug Interactions: Magnitude of the Problem

Adverse drug events (ADEs) are common. Nearly seven percent of all hospitalized patients experience ADEs, with a fatality rate of 0.32%.12 Drug-drug interactions (DDIs) account for a quarter of all adverse drug events. Some suggest that ADEs are the fifth  leading cause of death in hospitalized patients.17

Risk factors for ADEs and DDIs include: age greater than 65, multiple medications and over-the-counter medications (OTCs), genetic variability in drug metabolism, and medical comorbidity. Sixty-four percent of outpatient visits result in a prescription.13 In 2000, there were 2.8 billion prescriptions written, 10 for every person in the US. ADEs rise with number of prescribed medications, exceeding 50% likelihood over four medications.

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Mechanism of DDIs

The P450 enzyme system is an important determinant of drug interactions. Formerly, protein binding was considered an important cause, yet it is rarely clinically relevant.14 Even highly protein-bound drugs such as phenytoin and warfarin quickly alter binding ratios when co-administered and achieve a new steady state. Less well appreciated by practicing physicians is the importance of the few P450 enzymes that metabolize 90% of all medications, and that many medications may either inhibit or induce the metabolism of other drugs. Further, these enzymes are subject to genetic variation, making some patients susceptible to toxicity at low doses.15,16

Drugs undergo phase 1 and phase 2 metabolism. Phase 1 is carried out by the P450 system, primarily in the liver, and includes oxidation, hydroxylation, and methylation. Monamine oxidation, also phase 1, is not part of the P450 system.

Phase 2 prepares the drug for elimination. Glucuronidation makes the drug water soluble for elimination in the urine or stool. Further discussion of phase 2 metabolism may be found in Sirot et al.17

P450 Enzyme System

These enzymes are located primarily in the liver, kidney, intestine, lungs, and brain. Six enzymes metabolize over 95% of all medications.16,17 They are CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A4. CYP2D6, 2C19, and 2C9 are especially prone to genetic variability. Depending upon the number of copies of a particular allele, patients may be poor metabolizers (no functioning alleles), intermediate metabolizers (one copy), extensive metabolizers (two copies—the wild type), or ultra-metabolizers (three to thirteen copies).

Table 2—Genetic Polymorphisms and Clinical Relevance16

Polymorphism

Frequency

Interacting Drugs

CYP2C9 poor metabolizer

1–10% of Caucasians
1–4% of Africans

Phenytoin, warfarin, glipizide

CYP2C19 poor metabolizer

13–23% of Asians

Barbiturates, benzodiazepines

CYP2D6 poor metabolizer

5–7% of Caucasians
2–4% of Africans

Amiodarone, TCA, neuroleptics

CYP2D6 ultra-metabolizer

5–20% of Turks, Southern Europeans, Saudi Arabians, Ethiopians

Opioid intoxication with codeine

Pharmacogenomics is the study of the marked variability in drug metabolism in individuals. Screening tests are available from a number of laboratories to assess the likelihood of genetic susceptibility to a drug interaction (cf. Genelex and others). Phillips reviewed 18 studies of ADEs related to genetic variations of CYP enzymes. Of 27 drugs identified, 59% were metabolized by a polymorphic enzyme, including cardiac, psychiatric, antibiotic, and analgesic classes.18

Although 2D6 polymorphisms are present in 7% of the population, 14% of hospitalized psychiatric patients have 2D6 variants, suggesting a far greater risk of adverse drug events requiring hospitalization.19

  • CYP1A2 metabolizes 15% of all drugs, including caffeine, benzodiazepines, SSRIs, and clozapine.20 Activity of metabolism is accelerated by tobacco,21 and is inhibited by fluvoxamine, quinolones, and cimetidine. There is mild genetic variability.
  • CYP2C9 metabolizes 20% of the most commonly prescribed drugs, most importantly warfarin. Other "substrates" include phenytoin, tolbutamide, glipizide, losartan, fluvastatin, and NSAIDs. It is inhibited by fluconazole, and induced by phenobarbital and rifampin. Up to 10% of Caucasians may be 2C9-deficient, and may develop bleeding on usual doses of warfarin due to an inability to metabolize the drug. A recent FDA alert encourages physicians to consider genetic screening in patients whose anticoagulation is difficult to manage.22
  • CYP2C19 metabolizes citalopram, diazepam, and omeprazol. It is inhibited by fluoxetine, fluvoxamine, omeprazole, and certain HIV drugs. It is induced by phenobarbital and rifampin. Up to 20% of Asians may be 2C19 poor metabolizers, and are susceptible to toxicity on standard doses of diazepam.15,23
  • CYP2D6 is responsible for 25% of all drug metabolism, particularly the SSRIs, TCAs, phenothiazines, risperidone, and codeine. It is inhibited by amiodarone, fluoxetine, paroxetine, cimetidine, and quinidine. It is induced by dexamethasone. 2D6 has significant polymorphisms. One in ten-to-fourteen Caucasians, and four percent of African-Americans, are poor metabolizers. Because codeine must be converted to morphine to have an analgesic effect, these patients experience no analgesia with codeine. They develop toxicity on standard doses of substrates. A small percentage are ultra-metabolizers (one to seven  percent of Caucasians, 25% of Ethiopians), leading to narcosis on standard doses of codeine.14
  • CYP3A4 metabolizes sixty percent of currently available medications, including calcium channel blockers, HIV drugs, statins, cyclosporin, antihistamines, and cisapride. It is present in the intestinal mucosa and liver, and accounts for the majority of first-pass metabolism. It is strongly inhibited by grapefruit juice. The furanocoumarins in the fruit inactivate the enzyme in the gut, reducing first-pass metabolism, and allowing for higher concentrations of drug, leading to toxicity. Other inhibitors include ketoconazole, metronidazole, AZT, omeprazole, erythromycin, and verapamil. The enzyme is induced by hypericum (St John's Wort), carbamazepine, phenobarbital, and phenytoin.24

Table 3—A Stepwise Approach to Drug-Drug Interactions

1. Take a medication history (mnemonic—AVOID Mistakes)
                  Allergies?
                  Vitamins and dietary supplements
                  Old drugs and OTC?
                  Interactions risk?
                  Dependence?
                  Mendel: any family history of drug sensitivity?
2. Identify high risk patients
                  > 3 medications
                  red-flag drugs—anticonvulsants, antibiotics, digoxin,
                  warfarin, amiodarone
3. Check pocket reference card
4. Consult pharmacist/ drug specialist
5. Check computer programs
                  Epocrates  
                  Medical letter drug interaction program

Source: Preventable Adverse Drug Reactions: A Focus on Drug Interactions

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References

  1. Maganti R, White BD. Resident Work Hours, Fatigue, and Impairment.
  2. Hoffman, Jan. Judge Sets Aside Use of Cocaine as Part of Verdict in Zion Case. New York Times, May 2, 1995.
  3. Asch DA, Parker RM. The Libby Zion Case. NEJM 1988;318:771-775.
  4. Report of the ACGME Work Group on Resident Duty Hours. Chicago: Accreditation Council for Graduate Medical Education, June 11, 2002.
  5. Sternbach H. The Serotonin syndrome. Am J Psychiatry 1991;148:705-713.
  6. Boyer EW, Shannon M. The Serotonin syndrome. NEJM 2005;352:1112-1120.
  7. Keck PE, Jr., Arnold LM. Serotonin Syndrome. Psychiatric Annals 2000;30:333-343.
  8. Watson WA, Litovitz TL, Rodgers GC, et al. 2002 Annual report of the American association of poison control center toxic exposure surveillance system. Am J Emerg Med 2003;21:353-421.
  9. Mackay FJ, Dunn NR, Mann RD. Antidepressants and the serotonin syndrome in clinical practice. B J Gen Pract 1999;49:871-874.
  10. Keck PE, Jr. "Serotonin Syndrome." Neuroleptic Malignant Syndrome website.
  11. Lazarou J, Pomeranz B, Corey PN. Incidence of adverse drug reactions in hospital patients; a meta-analysis. JAMA 1998; 279:1200-1205.
  12. Jacubeit T, Drisch D, Weber E. Risk factors as reflected by an intensive drug monitoring system. Agents Actions 1990;29:117.
  13. FDA Center for Drug Evaluation and Research. Preventable Adverse Drug Reactions: A Focus on Drug Interactions 2002.
  14. Gasche Y, Daali Y, Fathi M et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. NEJM 2004;351:2827-2831.
  15. Ghoneim MM, Korttila K, Chiang CK, Jacobs L, Schoenwald RD, Mewaldt SP, et al. Diazepam effects and kinetics in Caucasians and Orientals. Clin Pharmacol Ther 1981;29(6):749–756.
  16. Sirot EJ, Van der Velden JW, Rentsch K, et al. Therapeutic Drug Monitoring and Pharmacogenetic Tests as Tools in Pharmacovigilance Drug Safety 2006; 29 (9): 735-768.
  17. Flockhart DA. Cytochrome P450 Drug Interaction Table 2005.
  18. Phillips KA, Veenstra DL, Oren E, et al. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA 2001;286:2270-2279.
  19. deLeon J, Susce MT, Pan RM, et al. The CYP2D6 poor metabolizer phenotype may be associated with risperdone adverse drug reactions and discontinuation. J Clin Psychiatry 2005;66:15-27.
  20. Raaska K, Neuvonen PJ. Ciprofloxacin increases serum clozapine and N-desogymethylclozapine: a study in patients with schizophrenia. Eur J Clin Pharmacol 2000;56(8):585–589.
  21. Zevin S, Benowitz NL. Drug interactions with tobacco smoking. An update. Clin Pharmacokinet 1999;36(6):425–438.
  22. FDA Alert. (August 16, 2007) Warfarin (marketed as Coumadin).
  23. Rosenblat R, Tang SW. Do Oriental psychiatric patients receive different dosages of psychotropic medication when compared with Occidentals? Can J Psychiatry 1987;32(4):270–274.
  24. Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: a systematic review Database of Abstracts of Reviews of Effects. Drugs, 2001;61(15): 2163-75.

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Author Disclosure

Within the past 24 months, Dr Kinsella has received honoraria for speaking for American Medical Seminars, Medical Education Resources, and CME LLC. He has also received honoraria for consultation with Cross Country Education and Therapath Laboratories. Additionally, he held stock in Passnet Air Ambulance, serving Native American communities in South Dakota. Dr Kinsella has also received personal compensation for case reviews and serving as an expert witness.