Neil B. Sandson

Perioperative Statin Therapy May Be Implicated in a Wide Array of Drug-Drug Interactions

To the Editor:—We read with interest and appreciation the excellent article by Le Manach et al. in the June 2008 issue of ANESTHESIOLOGY entitled “Statin Therapy within the Perioperative Period: Clinical Concepts and Commentary.” However, there is an important area, namely drug-drug interactions involving statins, which merits more attention than the brief treatment in that review. We would like to make readers aware that a wide array of interactions can occur in the perioperative period and have been responsible for considerable morbidities. The authors are certainly correct that the risk of statin-induced rhabdomyolysis is associated with coadministration of such drugs as “cyclosporin, antifungal agents, calcium-channel blockers, and amiodarone.” However, there is a much broader array of medications that is likely to inhibit the metabolism or otherwise raise blood levels of statins to increase the risk of rhabdomyolysis. Atorvastatin, lovastatin, and simvastatin are primarily metabolized by the enzyme cytochrome P450 3A4 (CYP3A4). Coadministration of any of the many inhibitors on CYP3A4 (including cyclosporin, etc.) will raise blood levels of these specific statins. In addition, fluvastatin is metabolized by CYP2C9, and inhibitors of that enzyme’s function will raise fluvastatin levels as well. Pravastatin’s metabolism is primarily through phase II, or conjugative, metabolism, which is more difficult to inhibit to a clinically significant degree, so it is much less susceptible to these metabolic drug interactions. Rosuvastatin undergoes* very little hepatic metabolism and it is generally excreted unchanged. However, through nonmetabolic mechanisms (probably inhibition of various transmembrane transporters), coadministration of either cyclosporin or gemfibrozil will significantly raise both pravastatin and rosuvastatin blood levels. There is an entire other dimension to drug-drug interactions involving statins that was not mentioned at all in the article: Coadministration of statins with enzymatic inducers. These drugs will, over the course of days to weeks, increase the quantity of enzymes available for metabolism of these statins. The addition of enzymatic inducers such as phenytoin, carbamazepine, and rifampin are likely to significantly decrease the concentrations of various statins. This is a particularly important interaction, especially in view of the ramifications for cardiac morbidity, as discussed in the authors’ section on the risks of statin discontinuation in the perioperative period. In summary, this subject is clearly quite detailed and complex. A thorough treatment of this topic was published by Bellosta et al.

The “Fatal Forty”

This chapter discusses the “Fatal Forty.” These forty drugs or drug classes are involved in drug–drug interactions that are the basis for this book and are “must know” for the perioperative clinician.

The Six Patterns of Pharmacokinetic Drug–Drug Interactions

This chapter discusses the six patterns of cytochrome P450-mediated drug–drug interactions.

The Funeral Is on Monday

This case discusses a complex pharmacokinetic interaction between phenytoin and valproic acid involving both metabolism and distribution.

Uridine 5′-diphospho-glucuronoslytransferases (UGTs): Conjugating Cousins

This chapter discusses the chemical pathways, metabolic actions, substrates, inducers, and inhibitors of the uridine 5′-diphosphate glucuronosyltransferases, also known as UGTs.

Clopidogrel (II): Conferring over the Kung Pao

This case further discusses the aggregation of risk factors for significant drug–drug interactions involving clopidogrel, proton pump inhibitors, and calcium channel blockers.

You Can’t Trick Us!

This case discusses two pharmacokinetic interactions between ibuprofen and phenytoin, resulting in phenytoin toxicity.

The Ultimate Ultram Primer II: I “Haight” Narcotics, but I Hate Seizures More

This case discusses the synergistic pharmacodynamic interaction between tramadol and bupropion resulting in new-onset seizures. A possible pharmacokinetic interaction is also discussed.

Check Check and Double Check

This case discusses the pharmacokinetic interaction between diazepam and fluvoxamine resulting in excessive sedation. Diazepam is a cytochrome P450 3A4 and 2C19 substrate and fluvoxamine is a cytochrome P450 3A4 and 2C19 inhibitor.

You Do Not Look Well Today, Mon Ami

This case discusses pharmacokinetic and pharmacodynamic interactions between amitriptyline and amiodarone, resulting in QRS widening.