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An unexpected adverse drug effect
CLINICAL ROUNDS An Unexpected Adverse Drug Effect Cara J. Krulewitch, CNM, PhD Adverse drug-drug interactions can occur between active and/or inactive ingredients in different formulations. The occurrence of a disulfiram reaction that developed postpartum following a 7-day course of metronidazole is presented. The case is presented, followed by a discussion of the mechanism of action and treatment. Recommendations for prevention of adverse drug effects are reviewed. J Midwifery Womens Health 2003;48:67– 68 © 2003 by the American College of Nurse-Midwives. keywords: drug-drug interactions, disulfiram reaction, metronidazole, clindamycin
CASE PRESENTATION
DISCUSSION
A 26-year-old G4 P1021 at 40 4/7 weeks presented to Labor and Delivery for induction of labor secondary to decreased amniotic fluid. She was 2 cm dilated during an office prenatal examination earlier in the day. Her prenatal course is significant for a cholecystectomy at 28 weeks and diagnosis of bacterial vaginosis diagnosed at 39 5/7 weeks that was treated with a 7-day course of metronidazole (Flagyl). She took her last dose in the morning of the day she was admitted. She is allergic to penicillin (develops hives and shortness of breath) and is group beta strep (GBS) positive. Her plan for pain relief was epidural anesthesia; however, the only option available at the hospital where she received care was intrathecal anesthesia. She was accompanied by her husband, mother, and 4-year-old child who has been prepared to be present at the birth. Her intrapartum course was uneventful. She rested overnight and Pitocin induction began the next morning at 5 AM along with clindamycin 800 mg IV for GBS prophylaxis. At 7 AM, she was 6 cm dilated and requested pain relief. She received an intrathecal anesthetic. The anesthetic provided minimal relief and the anesthesiologist administered an additional dose. She had a normal spontaneous vaginal delivery of a female infant at 9:40 AM. Apgar scores were 9 at 1 minute and 9 at 5 minutes. During the first half hour post partum she developed severe nausea and vomiting. She received a series of medications (following anesthesia protocol) including prochlorperazine (Compazine), diphenhydramine (Benadryl), metoclopramide (Reglan), and ondansetron (Zofran) to relieve her nausea, vomiting, and pruritus. None of the antiemetics administered were effective, and the nausea and vomiting continued for the next 20 hours. The symptoms abated 24 hours after the birth, and she was released the next afternoon at her request with no further complaints and in stable condition.
Intrathecal anesthesia is commonly associated with nausea post delivery;1–3 however, the extent and duration of the nausea is usually short-lived and can be successfully treated with antiemetic drugs.4 Therefore, what was the cause of this woman’s intractable and prolonged nausea? In this case, the cause may be in the patient’s use of medication prior to labor. Metronidazole (Flagyl) is a common and effective treatment for bacterial vaginosis. A known adverse effect of metronidazole (Flagyl) is a drug-drug reaction that occurs when metronidazole and alcohol are taken together.5 Symptoms of this disulfiram-like reaction include severe nausea and vomiting. In this case, the exposure may have occurred in the hospital. Benzyl alcohol is a common preservative for medications and provides a stable base for administration of many intravenous drugs including clindamycin.6 Edwards et al.6 described a case study in which a person was given both clindamycin and metronidazole at staggered times during the same day. The patient developed intractable nausea and vomiting, similar to our laboring woman. The disulfiram reaction was first noted by two Danish physicians who, studying the potential of disulfiram as a treatment for helmintic infections, became violently ill after exposure to disulfiram followed by alcohol consumed at a cocktail party.7 Disulfiram (Antabuse) prevents breakdown of acetaldehyde, which is one of the metabolic intermediaries created during metabolism of alcohol. Acetaldehyde is normally oxidized rapidly and, therefore, does not accumulate in tissue. In the presence of disulfiram (Antabuse) or metronidazole (Flagyl), acetaldehyde accumulates and causes the typical severe nausea and vomiting that was noted in this woman. The antiemetics were not effective because they did not eliminate the acetaldehyde. Metabolism of acetaldehyde occurs over several hours and, therefore, the adverse reaction is self-limited, albeit very uncomfortable. The treatment for “acetaldehyde syndrome,” which is also called “disulfiram reaction,” is supportive therapy and fluid replacement.
Address correspondence to Cara Krulewitch, CNM, PhD, 655 W. Lombard St., Suite 575A, Baltimore, MD 21201.
Journal of Midwifery & Women’s Health • www.jmwh.org © 2003 by the American College of Nurse-Midwives Issued by Elsevier
67 1526-9523/03/$30.00 • doi:10.1016/S1526-9523(02)00361-6
Because both metronidazole and clindamycin are drugs commonly given to women during pregnancy and birth, it seems prudent to consider this example when prescribing metronidazole (Flagyl) in the third trimester. Preservatives or other additives to intravenous, intramuscular, and topical medications may cause adverse reactions, including apparent allergic reactions. Persons prescribed metronidazole (Flagyl) should be counseled to avoid alcohol in any form, including mouthwash. A thorough history of prior drug reactions should be taken before prescribing metronidazole (Flagyl). A working knowledge of both active and inert ingredients in all products used regularly will allow practitioners to prescribe carefully and effectively and help clients develop awareness of unidentified sensitivities for their future protection.
REFERENCES 1. Fontaine P, Adam P. Intrathecal narcotics are associated with prolonged second-stage labor and increased oxytocin use. J Fam Pract 2000;49:515–20. 2. Richardson MG, Thakur R, Abramowicz JS, Wissler RN. Maternal posture influences the extent of sensory block produced by intrathecal dextrose-free bupivacaine with fentanyl for labor analgesia. Anesth Analg 1996;83:1229 –33. 3. Manullang TR, Viscomi CM, Pace NL. Intrathecal fentanyl is superior to intravenous ondansetron for the prevention of perioperative nausea during cesarean delivery with spinal anesthesia. Anesth Analg 2000;90:1162–6. 4. Riley ET, Ratner EF, Cohen SE. Intrathecal sufentanil for labor analgesia: do sensory changes predict better analgesia and greater hypotension? . Anesth Analg 1997;84:346 –51. 5. Williams CS, Woodcock KR. Do ethanol and metronidazole interact to produce a disulfiram-like reaction? Ann Pharmacol. 2000; 34:255–7. 6. Edwards DL, Fink PC, Van Dyke PO. Disulfiram-like reaction associated with intravenous trimethoprim-sulfamethoxazole and metronidazole. Clin Pharmacy 1986;999 –1000.
Cara Krulewitch, CNM, PhD, is assistant professor in the Department of Child, Women’s, and Family Health at the School of Nursing, University of Maryland at Baltimore, Baltimore, Maryland.
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7. Hardman JG, Limbrid LE, editors. Goodman & Gilman’s: the pharmacological basis of therapeutics, 9th ed. New York: McGraw Hill, 1996.
Volume 48, No. 1, January/February 2003
CASE PRESENTATION
DISCUSSION
A 26-year-old G4 P1021 at 40 4/7 weeks presented to Labor and Delivery for induction of labor secondary to decreased amniotic fluid. She was 2 cm dilated during an office prenatal examination earlier in the day. Her prenatal course is significant for a cholecystectomy at 28 weeks and diagnosis of bacterial vaginosis diagnosed at 39 5/7 weeks that was treated with a 7-day course of metronidazole (Flagyl). She took her last dose in the morning of the day she was admitted. She is allergic to penicillin (develops hives and shortness of breath) and is group beta strep (GBS) positive. Her plan for pain relief was epidural anesthesia; however, the only option available at the hospital where she received care was intrathecal anesthesia. She was accompanied by her husband, mother, and 4-year-old child who has been prepared to be present at the birth. Her intrapartum course was uneventful. She rested overnight and Pitocin induction began the next morning at 5 AM along with clindamycin 800 mg IV for GBS prophylaxis. At 7 AM, she was 6 cm dilated and requested pain relief. She received an intrathecal anesthetic. The anesthetic provided minimal relief and the anesthesiologist administered an additional dose. She had a normal spontaneous vaginal delivery of a female infant at 9:40 AM. Apgar scores were 9 at 1 minute and 9 at 5 minutes. During the first half hour post partum she developed severe nausea and vomiting. She received a series of medications (following anesthesia protocol) including prochlorperazine (Compazine), diphenhydramine (Benadryl), metoclopramide (Reglan), and ondansetron (Zofran) to relieve her nausea, vomiting, and pruritus. None of the antiemetics administered were effective, and the nausea and vomiting continued for the next 20 hours. The symptoms abated 24 hours after the birth, and she was released the next afternoon at her request with no further complaints and in stable condition.
Intrathecal anesthesia is commonly associated with nausea post delivery;1–3 however, the extent and duration of the nausea is usually short-lived and can be successfully treated with antiemetic drugs.4 Therefore, what was the cause of this woman’s intractable and prolonged nausea? In this case, the cause may be in the patient’s use of medication prior to labor. Metronidazole (Flagyl) is a common and effective treatment for bacterial vaginosis. A known adverse effect of metronidazole (Flagyl) is a drug-drug reaction that occurs when metronidazole and alcohol are taken together.5 Symptoms of this disulfiram-like reaction include severe nausea and vomiting. In this case, the exposure may have occurred in the hospital. Benzyl alcohol is a common preservative for medications and provides a stable base for administration of many intravenous drugs including clindamycin.6 Edwards et al.6 described a case study in which a person was given both clindamycin and metronidazole at staggered times during the same day. The patient developed intractable nausea and vomiting, similar to our laboring woman. The disulfiram reaction was first noted by two Danish physicians who, studying the potential of disulfiram as a treatment for helmintic infections, became violently ill after exposure to disulfiram followed by alcohol consumed at a cocktail party.7 Disulfiram (Antabuse) prevents breakdown of acetaldehyde, which is one of the metabolic intermediaries created during metabolism of alcohol. Acetaldehyde is normally oxidized rapidly and, therefore, does not accumulate in tissue. In the presence of disulfiram (Antabuse) or metronidazole (Flagyl), acetaldehyde accumulates and causes the typical severe nausea and vomiting that was noted in this woman. The antiemetics were not effective because they did not eliminate the acetaldehyde. Metabolism of acetaldehyde occurs over several hours and, therefore, the adverse reaction is self-limited, albeit very uncomfortable. The treatment for “acetaldehyde syndrome,” which is also called “disulfiram reaction,” is supportive therapy and fluid replacement.
Address correspondence to Cara Krulewitch, CNM, PhD, 655 W. Lombard St., Suite 575A, Baltimore, MD 21201.
Journal of Midwifery & Women’s Health • www.jmwh.org © 2003 by the American College of Nurse-Midwives Issued by Elsevier
67 1526-9523/03/$30.00 • doi:10.1016/S1526-9523(02)00361-6
Because both metronidazole and clindamycin are drugs commonly given to women during pregnancy and birth, it seems prudent to consider this example when prescribing metronidazole (Flagyl) in the third trimester. Preservatives or other additives to intravenous, intramuscular, and topical medications may cause adverse reactions, including apparent allergic reactions. Persons prescribed metronidazole (Flagyl) should be counseled to avoid alcohol in any form, including mouthwash. A thorough history of prior drug reactions should be taken before prescribing metronidazole (Flagyl). A working knowledge of both active and inert ingredients in all products used regularly will allow practitioners to prescribe carefully and effectively and help clients develop awareness of unidentified sensitivities for their future protection.
REFERENCES 1. Fontaine P, Adam P. Intrathecal narcotics are associated with prolonged second-stage labor and increased oxytocin use. J Fam Pract 2000;49:515–20. 2. Richardson MG, Thakur R, Abramowicz JS, Wissler RN. Maternal posture influences the extent of sensory block produced by intrathecal dextrose-free bupivacaine with fentanyl for labor analgesia. Anesth Analg 1996;83:1229 –33. 3. Manullang TR, Viscomi CM, Pace NL. Intrathecal fentanyl is superior to intravenous ondansetron for the prevention of perioperative nausea during cesarean delivery with spinal anesthesia. Anesth Analg 2000;90:1162–6. 4. Riley ET, Ratner EF, Cohen SE. Intrathecal sufentanil for labor analgesia: do sensory changes predict better analgesia and greater hypotension? . Anesth Analg 1997;84:346 –51. 5. Williams CS, Woodcock KR. Do ethanol and metronidazole interact to produce a disulfiram-like reaction? Ann Pharmacol. 2000; 34:255–7. 6. Edwards DL, Fink PC, Van Dyke PO. Disulfiram-like reaction associated with intravenous trimethoprim-sulfamethoxazole and metronidazole. Clin Pharmacy 1986;999 –1000.
Cara Krulewitch, CNM, PhD, is assistant professor in the Department of Child, Women’s, and Family Health at the School of Nursing, University of Maryland at Baltimore, Baltimore, Maryland.
68
7. Hardman JG, Limbrid LE, editors. Goodman & Gilman’s: the pharmacological basis of therapeutics, 9th ed. New York: McGraw Hill, 1996.
Volume 48, No. 1, January/February 2003