Adverse Drug Interactions
Allan P. Klock Jr.
CASE SUMMARY
A 67-year-old man weighing 84 kg, with a history of urinary incontinence following a radical prostatectomy, is scheduled for insertion of a urethral sphincter under general anesthesia. His hypertension is well controlled with isradipine 5 mg twice daily. Concerned about the potential for infection of the implanted device, the urologist orders the intravenous administration of 1 g of vancomycin and 120 mg of gentamicin immediately before surgery. General anesthesia is induced with 1 mg midazolam, 150 µg fentanyl, 160 mg propofol, and 9 mg vecuronium. Maintenance of the general anesthetic with inhaled desflurane is uneventful. Two hours and twenty minutes after the first and only dose of neuromuscular blocker, the patient has no twitches when a train-of-four stimulus is applied to the right ulnar nerve. One small twitch is noted after a tetanic stimulus. The patient is given 1 g of calcium chloride intravenously >3 minutes to counteract the synergistic effect of gentamicin and vecuronium on the neuromuscular junction. Following the administration of calcium, two twitches are noted on train-of-four stimulus. At the end of the procedure, he is given 5 mg neostigmine and 1 mg glycopyrrolate. When the patient emerges from general anesthesia and his trachea is extubated, he is carefully monitored for signs of recurarization in the postanesthesia care unit, where recovery is uneventful.
Why Is It Important to Understand the Mechanisms of Drug Interactions?
Drug interactions are important to anesthesiologists for several reasons. Patients who undergo surgical procedures often take many medications regularly, whether prescribed or over-the-counter. These medications may interact with drugs and agents given preoperatively, intraoperatively, or postoperatively. Drug interactions can prolong the duration, or enhance the effects, of sedative agents and neuromuscular blockers. They can account for many clinical situations in which an administered drug does not work as well as expected. On rare occasions, drug interactions can even lead to serious, life-threatening complications. The prevalence, impact, and mechanisms of perioperative drug interactions are discussed.
▪ POLYPHARMACY
A prospective study of surgical patients admitted to a university hospital in New Zealand found that 49% of patients were taking medications unrelated to the condition requiring surgery. There were 286 different medications administered to this cohort, and the average number of medications administered per admission was 9.38 (patients individually were given anywhere from 1 to 47 different ones.) The potential for drug interactions is high when such a large number of agents are administered.1 At an ambulatory surgical center, 12% of patients interviewed before admission were identified with the potential for drug interaction by the ePocrates computing program.2
▪ RESEARCHING THE MECHANISMS OF DRUG INTERACTIONS
When constructing a mental model for dealing with a problem, a physician may try to memorize every potential problem or construct a cognitive framework that explains how and why problems happen. With the issue of drug interactions, there are two reasons why it is better to understand the mechanisms and develop a mental list of medications that are potentially problematic, rather than try to memorize every potential drug interaction that may affect a patient.
The first reason is that, as the number of drugs given to a patient increases, the number of possible drug interactions increases in a quadratic nature. For example,
if a patient is taking two drugs—drug A and drug B—only one interaction is possible between drug A and drug B (AB interaction). If the patient is taking three drugs—drugs A, B, and C—three interactions are possible (AB, BC, and AC). If the patient is taking four drugs, six interactions are possible (AB, BC, CD, AD, AC, and BD). This progression increases in a manner such that the number of potential interactions amongst n medications is n (n – 1)/2.
if a patient is taking two drugs—drug A and drug B—only one interaction is possible between drug A and drug B (AB interaction). If the patient is taking three drugs—drugs A, B, and C—three interactions are possible (AB, BC, and AC). If the patient is taking four drugs, six interactions are possible (AB, BC, CD, AD, AC, and BD). This progression increases in a manner such that the number of potential interactions amongst n medications is n (n – 1)/2.
Mathematicians call these “triangular numbers.” For example, if one visualizes bowling pins set up in the standard triangular arrangement, the relation between the number of medications and number of drug interactions is revealed. The number of rows of bowling pins correlates with the number of medications exceeding the first medication, whereas the total number of pins in the triangle correlates with the number of potential interactions (see Table 64.1).
The result of such a progression is that it becomes increasingly complicated to mentally consider every potential interaction as the number of medications increases. As an example, a patient taking nine medications will have 36 potential drug interactions to consider.
The second reason why it is important to understand the mechanisms of drug interactions is that the volume of reported literature on the subject is overwhelming. A search in the PubMed (www.pubmed.com) database from 1970 to 2006 using the phrase “drug interactions” revealed more than 61,000 references (representing an increase of 3,500 citations during the preceding year). When this search was limited to “drug interactions and anesthesia,” 2,109 references were produced. Mentally cataloging these interactions is impossible, so a framework for understanding them must be constructed. If an anesthesiologist understands the mechanisms of these interactions, he or she will be equipped to predict and remember the vast majority of clinically significant interactions.
How Are Drug Interactions Classified?
Drug interactions can be classified as pharmacodynamic, pharmacokinetic, or pharmaceutical. In a pharmacodynamic drug interaction, the effects of medications given decrease or increase in an additive (linear) or synergistic (nonlinear) manner. In a pharmacokinetic interaction, one drug affects the absorption, distribution, metabolism, or elimination of another. In a pharmaceutical interaction, drugs react chemically with each other before or during their administration, or with the vessel in which they are stored or administered. Finally, as in the case of giving meperidine to a patient taking a monoamine oxidase inhibitor (MAOI), drug combinations can lead to difficult-to-predict but devastating interactions. Fortunately, these types of interactions are the exception rather than the rule.
TABLE 64.1 Polypharmacy and Potential Drug Interactions | ||||||||||||||||||||
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▪ PHARMACODYNAMIC
Pharmacodynamic interactions can be additive or supraadditive (i.e., synergistic). In additive interactions, two drugs of the same class act on the same receptor or have the same mechanism of action. Combining two volatile anesthetics or two benzodiazepines produces an additive interaction. Combining propofol and thiopental has an additive interaction.3 In synergistic interactions, two drugs produce the same effect through different mechanisms of action or through different receptors. An example of a synergistic interaction is the hypnosis produced with a combination of a small dose of midazolam and thiopental.4
Antagonistic interactions are regularly utilized by anesthesiologists to reverse neuromuscular blockers, opiates, or benzodiazepines. Unintended antagonistic interactions that are not due to changes in kinetics are relatively rare.5
▪ PHARMACOKINETIC
Because anesthesiologists administer most medications parenterally, they usually do not consider pharmacokinetic drug interactions that affect drug absorption. However, they frequently administer agents that alter gastric emptying. Opiates and anticholinergics delay gastric emptying, whereas metoclopramide speeds up the transit of gastric contents into the small intestine. As little as 0.05 mg per kg of morphine will significantly delay gastric emptying.6 This delay may be relevant if a patient is given oral medications that are absorbed in the small bowel (such as acetaminophen, antibiotics, or benzodiazepines) in conjunction with a drug that affects gastric emptying.
Nearly all medications administered by anesthesiologists are ultimately eliminated by the kidney or lung. Toxicologists will raise or lower urine pH in attempts to enhance the renal elimination of toxic substances that are weak acids (e.g., aspirin) or weak bases (e.g., amphetamines or phencyclidine [PCP or “angel dust”]), respectively. Activated charcoal and cholestyramine resins bind drugs in the intestine and reduce reabsorption of drugs that are eliminated in bile salts.
▪ PHARMACEUTICAL
Some pharmaceutical interactions are visible to the naked eye. When the very alkaline drug, thiopental, is mixed with an acidic solution such as that formed by many muscle relaxants when they are dissolved, a visible inactive precipitate is formed. However, many pharmaceutical interactions are not visible and therefore are potentially more hazardous. For example, penicillin inactivates aminoglycoside antibiotics.7 Insulin and nitroglycerin bind to the polyvinyl chloride in standard intravenous tubing, so that less drug than intended is delivered. An example of a pharmaceutical interaction inside the body is the formation of inactive chemical complexes when the polycationic drug, protamine, is given to a patient with circulating heparin. The formation of protamineheparin complexes allows the patient to resume normal coagulation long before heparin is inactivated by the normal pathways of N-demethylation and uptake by the reticuloendothelial system.
What Is the Influence of Drug Interactions on Biotransformation or Elimination?
Most drugs undergo metabolism in the liver. They can be biotransformed to smaller molecules through oxidation, reduction, or hydrolysis in processes known as phase 1 reactions. Phase 2 reactions involve conjugation of a hydrophobic drug with a water-soluble ligand such as glucuronic acid, glycine, or sulfate. Phase 2, and usually phase 1, reactions form hydrophilic compounds that are more easily eliminated in the urine or bile.
The oxidative and reductive phase 1 reactions are catalyzed by cytochrome P-450 enzymes. Over 150 P-450 enzymes have been characterized in animals. Drugs may be characterized as cytochrome P-450 inhibitors, inducers, or substrates. Many drugs and agents induce or inhibit the activity of P-450 enzymes (see Table 64.2). Enzyme inducers usually are lipophilic drugs that increase the activity of the enzyme(s) responsible for their biotransformation. Inhibition of P-450 enzymes is usually reversible and competitive, although some inhibitors cause an irreversible inactivation of the enzyme. An excellent review of the anesthetic implications of liver enzyme induction and inhibition has been recently published.8
According to the nomenclature for P-450 enzymes, each enzyme is assigned a unique name. First, the enzymes are divided into three families: CYP 1, 2, and 3. The families are further divided into subfamilies designated by a capital letter. The CYP 3A family metabolizes large planar molecules such as lidocaine and midazolam. Finally, each enzyme is assigned a unique number. For example, the CYP 3A4 enzyme accounts for 40% to 60% of the P-450 enzyme activity in humans.
The liver is the primary site of drug metabolism for most P-450 enzymes, but CYP3A4 is also active in the enterocytes of the small intestine. Grapefruit juice contains flavonoids and other compounds that inhibit CYP3A4 activity in the gut wall but not in the liver.9 This is important for anesthesiologists to recognize because grapefruit juice will only cause problems with orally administered medications. Intravenous medications should not be subject to pharmacokinetic interactions in patients who have ingested grapefruit juice.
CYP2D6 accounts for only 2% to 5% of total hepatic P-450 isoenzymes but accounts for 25% of drugs metabolized, including many opiates, antiarrhythmics, β-blockers, and antihypertensive medications. CYP2D6 is easily saturated, leading to nonlinear kinetics. It is inhibited by a large number of drugs, including ketoconazole, many selective serotonin reuptake inhibitors (SSRIs), diphenhydramine, and haloperidol. In contrast to CYP3A4, CYP2D6 activity is not induced by medications.10
Enzyme induction can have significant effects on the kinetics and metabolism of anesthetic agents. Enzyme induction with rifampin has been implicated in a nearfatal case of halothane hepatotoxicity.11 Chronic isoniazid therapy induces enflurane and isoflurane metabolism, markedly increasing peak fluoride concentrations.12,13 Rifampin can lead to increased methadone metabolism, reducing plasma concentrations by up to 68%.14 Oral midazolam, which is used for preoperative sedation in children and as a sleep aid in Europe, normally undergoes significant first-pass metabolism in the liver, rendering an oral availability of 30% to 70%. A 5-day course of rifampin given to healthy volunteers reduced the area under the concentration-time curve (AUC) for subsequent doses of oral midazolam by 96%.15 Rifampin can have a significant effect on the bioavailability and AUC of a large number of drugs, particularly those that undergo extensive first-pass metabolism.
What Are Some of the Important Interactions between Anesthetic and Nonanesthetic Agents?
Anesthesiologists rely on their knowledge of drug interactions in their daily practice. For example, using midazolam, which synergistically reduces the amount of intravenous induction agents (propofol or thiopental) needed to achieve unconsciousness, minimizes the undesirable cardiovascular side effects of the induction agent. In fact, the concept of the “balanced anesthetic” is based on the premise that the undesirable side effects of one medication are minimized by taking advantage of the interaction between several drugs.
Important interactions within the category of nonanesthetic agents and between the category of nonanesthetic and anesthetic agents follow.
TABLE 64.2 P-450 Enzyme Substrates, Inhibitors, and Inducers | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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