使用 verapamil, diltiazem, nifedipine, amlodipine, or felodipine 等降血壓劑者，再使用 erythromycin 或 clarithromycin 治療感染時很容易休克，住院!!
January 27, 2011 — Physicians need to be careful when prescribing macrolide antibiotics to patients on calcium-channel blockers (CCBs) because of an underappreciated drug-drug interaction that can lead to hypotension and shock, new research shows [1]. The findings are important because millions of people take CCBs and many are prescribed antibiotics every year, say Dr Alissa J Wright (University of Toronto, ON) and colleagues in a study published online January 17, 2011 in CMAJ.
This paper attaches a risk estimate to how dangerous this drug combination is.
Although the interaction "is perfectly predictable based upon the pharmacology of the drugs, it has been previously documented in only about five case reports," senior author Dr David Juurlink (University of Toronto, ON) explained to heartwire . He says that this study is the first rigorous attempt to describe the clinical consequences of this interaction: "In a sense, this paper attaches a risk estimate to how dangerous this drug combination is."
It's not wrong to use a macrolide, but it's probably more sensible if you are going to use one to use azithromycin.
The research also shows that there is a safe choice if doctors do need to use a macrolidelike antibiotic, he adds. The study found that macrolides such as erythromycin or clarithromycin increase the risk of hypotension if used in combination with a CCB, but a related antibiotic, azithromycin, does not.
Juurlink observes that "it's not wrong to use a macrolide [in a patient taking a CCB], but it's probably more sensible if you are going to use one to use azithromycin. If, for some reason, you had to use clarithromycin or erythromycin, it might be reasonable just to edge back a little bit on the dose of the CCB."
Biggest Risk With Erythromycin
In their population-based, nested, case-crossover study, Wright and colleagues analyzed the healthcare records of around a million individuals over the age of 65 who were receiving a single CCB between 1994 and 2009. Of these patients, 7100 were admitted to hospital for hypotension or shock, and 176 had received a macrolide antibiotic (36 received erythromycin, 100 received clarithromycin, and 40 received azithromycin) in a seven-day interval immediately before admission to the hospital or in a seven-day control interval one month earlier. For each antibiotic, the researchers estimated the risk of hypotension or shock associated with the use of a CCB.
They found a strong association between erythromycin use and hospital admission for hypotension, with an almost sixfold increased risk
of low BP (odds ratio 5.8), and a lower but still significant risk associated with the use of clarithromycin (OR 3.7). In contrast, there was no such link with azithromycin use (OR 1.5).
Juurlink explains that, pharmacologically, macrolide antibiotics inhibit a cytochrome P450 enzyme, which metabolizes all CCBs, so their use can lead to the accumulation of the CCB and potential toxicity. But azithromycin does not inhibit this cytochrome P450 enzyme. The use of combination CCBs and macrolide antibiotics "isn't exactly uncommon, but no one has actually ever attached a measure of how dangerous the combination is, and that's what this study does," he notes.
The findings, says Juurlink, apply to all CCBs, because they are all metabolized by the same pathway, although it may be a bigger problem with some than others, he says, adding that his team could not examine the risks for separate CCBs because of a lack of statistical power.
Nevertheless, the results "have considerable clinical relevance, highlighting the consequences of an underappreciated yet avoidable drug interaction involving medications used by millions of people every year. Clinicians should be aware of the potential interaction between these drugs," he and his colleagues state.
Juurlink adds that although the use of erythromycin is declining, clarithromycin is still used frequently. "But I don't think clarithromycin and azithromycin are that different in price, quite frankly, so the latter represents a good choice if macrolide antibiotic therapy is required."
Juurlink declares no conflicts. Disclosures for the coauthors are listed in the paper.
References
1. Wright AJ, Gomes T, Mamdani MM, et al. The risk of hypotension following co-prescription of macrolide antibiotics and calcium-channel blockers. CMAJ 2011; DOI:10.1503/cmaj.100702. Available at www.cmaj.ca.
Clinical Context
Macrolides are the most commonly prescribed antibiotics, according to IMS Health. In the October 2000 issue of the British Journal of Clinical Pharmacology, Westphal reported that cytochrome P450 isoenzyme 3A4 is inhibited by clarithromycin and erythromycin, but not azithromycin. CCBs are substrates for cytochrome P450 3A4, as noted by Dorne and colleagues in the February 2003 issue of Food and Chemical Toxicology, and, therefore, might be potentiated by the use of macrolide antibiotics.
This population-based, nested, case-crossover study assesses the risk for hospitalization because of hypotension or shock in older patients who use CCBs and macrolide antibiotics.
Study Highlights
- 999,234 adults 66 years or older (median age, 71 years) taking a single CCB during a 5-year period were identified.
- Exclusion criteria were first year of eligibility for coverage of prescription medication and prescriptions for more than 1 macrolide in the 30 days before hospitalization.
- 7100 patients were admitted to the hospital for treatment of hypotension.
- Hospitalized patients had a median age of 77 years, and 47.2% were men.
- Types of CCBs used were diltiazem in 40%, amlodipine in 29.6%, nifedipine in 19.4%, verapamil in 8%, and felodipine in 3%.
- Prescription drug data were obtained from the Ontario Drug Benefit Claims Database.
- Demographic records were obtained from the Registered Persons Database.
- CCBs included verapamil, diltiazem, nifedipine, amlodipine, or felodipine.
- Continuous use of CCBs was defined as refill within 180 days of the date of the previous prescription.
- The endpoint was admission to the hospital for treatment of hypotension or shock, death, discontinuation of treatment, or switch to a different CCB.
- Exposure to each macrolide in a 7-day risk period immediately before hospitalization was compared vs a 7-day control period 1 month prior.
- 176 patients received a macrolide during the risk or control periods.
- Erythromycin use had the strongest association with an increased risk for hospitalization for hypotension (OR, 5.8; 95% confidence interval [CI], 2.3 - 15.0; P < .001).
- Clarithromycin use was also associated with an increased risk for hospitalization (OR, 3.7; 95% CI, 2.3 - 6.1; P < .001).
- However, azithromycin use was not associated with an increased risk for hospitalization (OR, 1.5; 95% CI, 0.8 - 2.8; P = .21).
- Results were similar for patients taking a dihydropyridine CCB (nifedipine, amlodipine, or felodipine).
- Study limitations were inability to quantify medication adherence, type and severity of infection, and accuracy of diagnostic codes for hypotension; insufficient power to assess bradycardia; and inability to assess the magnitude of interaction for each CCB.
Clinical Implications
- In adults taking CCBs, erythromycin, followed by clarithromycin, is related to an increased risk for hospitalization for hypotension or shock.
- In adults taking CCBs, azithromycin use is not related to an increased risk for hospitalization for hypotension or shock
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