BAD CHEMISTRY

JEFF SCHEIN, M.S., M.P.H.

A 9-year-old boy from Tennessee was taking theophylline for his asthma. On numerous occasions he received erythromycin without any ill effects. Then his theophylline dose was increased and he received erythromycin. This time he lapsed into a coma.

In a Maryland case, a young man was taking Tegretol and theophylline. After the pediatric neurologist noted that the man had not had any seizures for some time, he discontinued the Tegretol. The man developed nausea, vomiting and seizures (all symptoms of theophylline toxicity). He is now in a vegetative state.

An 18-year-old woman was taking an MAO inhibitor antidepressant. She received a prescription for Demerol. Unfortunately, this drug interaction proved fatal.

Drug interactions do happen. "The sad thing is that in nearly every case, they are preventable," states Philip Hansten, Pharm. D., professor of clinical pharmacy at the University of Washington in Seattle.

The human mind cannot possibly remember every interaction. One possible solution is to think of categories. Pharmacists today also have tools well suited to the task of pinpointing and tracking drug interactions: computers, or more specifically, software programs.

As evidenced in the theophylline interactions mentioned above, drugs that act as enzyme inhibitors tend to cause theophylline toxicity. Erythromycin and ciprofloxacin are enzyme inhibitors -- and both can lead to theophylline toxicity. It very well may be that erythromycin's ability to inhibit the metabolism of another drug -- terfenadine (Seldane) -- can lead to high plasma levels of terfenadine and toxicity (including arrhythmias).

Other enzyme inhibitors include cimetidine, diltiazem, enoxacin, isoniazid, omeprazole, quinidine and verapamil.

Enzyme inducers are another category of agents that can slow the metabolism of other drugs and thereby lead to decreased plasma levels and reduced efficacy.

Rifampin, for example, can induce the metabolism of oral contraceptives, possibly leading to unwanted pregnancy. Drugs that induce the metabolism of other medications include barbiturates, carbemazepine and phenytoin. Cigarette smoking is an enzyme inducer; heavy smokers taking theophylline may require up to twice the dose of their counterpart nonsmoker.

Following is a summary of significant drug interactions, based on those medications most commonly dispensed in supermarket pharmacies for five major disease states: hypertension, heart disease, infection, ulcer and pain. The list of medications is from a survey conducted by Supermarket Pharmacy earlier this year.

Hypertension

The most commonly dispensed drugs were Vasotec, Procardia, Tenormin, Cardizem, Capoten, and Dyazide.

Diltiazem (Cardizem) interacts with lithium (Cibalith-S, Eskalith, Lithane, Lithobid and others). This interaction could lead to neurotoxicity. Possible symptoms include nausea, vomiting, muscular incoordination and ringing in the ears.

Nifedipine (Adalat, Procardia XL) and diltiazem (Cardizem CD) interact with cimetidine (Tagamet). The combination of cimetidine with either nifedipine or diltiazem may increase the amount of nifedipine or diltiazem in the blood, thereby increasing the antihypertensive effect. Possible toxicity -- evidenced by symptoms such as dizziness, flushing, and headache -- may occur.

Nifedipine interacts with barbiturates. A significant decrease in the amount of nifedipine available in the body can result, possibly leading to a decreased effect of the nifedipine. Much of the evidence for this interaction comes from studies of phenobarbital, but other barbiturates can be expected to interact similarly.

Heart Disease

The most common drugs were Lanoxin, Cardizem, Procardia and Calan.

Digoxin (Lanoxin) interacts with cyclosporine (Sandimmune). Cyclosporine may result in an increased amount of digoxin in the body, possibly leading to digoxin toxicity (symptoms include nausea, poor appetite, weakness, lethargy and visual abnormalities).

Digoxin interacts with diuretics (potassium-losing). As the amount of potassium in the body decreases, the likelihood of digoxin toxicity increases. Symptoms of digoxin toxicity include nausea, poor appetite, weakness, lethargy and visual abnormalities. Pharmacists should determine whether the patient's potassium levels are being monitored by the physician, and whether the patient is eating potassium-rich foods.

Digoxin interacts with sulfasalazine (Azulfidine). Sulfasalazine taken together with digoxin may decrease the absorption and effectiveness of digoxin. Pharmacists should determine whether digoxin levels are being monitored.

Mexiletine (Mexitil) interacts with theophylline. The combination can elevate the amount of theophylline in the blood, possibly leading to theophylline toxicity. Signs of toxicity include nausea, vomiting, diarrhea, headache, irritability, rapid heart rate, insomnia, tremor and seizure.

Infection

The most commonly dispensed drugs were amoxicillin, cephalexin, penicillin, Ceclor and erythromycin.

Amoxicillin (Amoxil, Larotid, others); penicillin V (Ledercillin VK, Pen-Vee K, V-Cillin K, Veetids) can interact with estrogen-containing oral contraceptives.

Although aminopenicillins

(such as amoxicillin) may reduce the efficacy of oral contraceptives, this result is probably rare. Menstrual irregularities, such as spotting or breakthrough bleeding, may be a sign that this interaction is occurring. Other types of penicillins and other oral antibiotics may produce similar effects. Recommendation: Women wishing to avoid pregnancy would be prudent to use another form of contraception -- in addition to use of their oral contraceptive -- while taking amoxicillin or other penicillins in this class.

Ciprofloxacin (Cipro) interacts with dairy products, multivitamin supplements and antacids (containing aluminum or magnesium), resulting in greatly diminished absorption of ciprofloxacin. Cations (calcium, magnesium, iron, aluminum, etc.) bind with ciprofloxacin and markedly reduce its absorption, possibly leading to decreased antibiotic effect. Ciprofloxacin should not be taken simultaneously with cations (iron-containing vitamin supplements, dairy products, antacids, etc.). Ciprofloxacin should be taken at least two hours before or six hours after to minimize the occurrence of this interaction.

Erythomycin interacts with cyclosporine (Sandimmune). Erythromycin markedly increases the amount of cyclosporine in the blood, and may increase the risk of cyclosporine-induced kidney damage. Recommendation: Erythromycin should be avoided if possible in patients taking cyclosporine. If the combination is given, it may be necessary to monitor cyclosporine blood concentrations during and after treatment with erythromycin.

Erythromycin interacts with terfenadine (Seldane) and astemizole (Hismanal). Erythromycin may cause increased plasma levels of Seldane or Hismanal, which could lead to cardiac arrhythmias. Changes in the EKG -- namely prolonged QT interval -- have been observed in patients combining erythromycin with these allergy medications. This interaction is serious. How often this interaction occurs is unknown, but caution is certainly warranted.

Erythromycin interacts with theophylline (Primatene tablets, Slo-Bid, Theo-Dur, Theo-24, Uniphyl and others). Erythromycin may increase the amount of theophylline in the blood. Although most people do not seem to have much trouble with this interaction, some develop theophylline toxicity. Symptoms of toxicity include nausea, vomiting, diarrhea, headache, irritability, nervousness, rapid heartbeat, insomnia and tremor. In serious cases, seizure can occur. The effect is usually delayed so that theophylline concentrations start to rise after five to seven days of treatment with erythromycin. Further, theophylline may cause reduced blood levels of erythromycin, possibly leading to diminished effect of erythromycin.

Erythromycin interacts with triazolam (Halcion). This combination can lead to a substantial increase in the concentration of triazolam in the blood, possibly increasing its sedative effect, which could lead to drowsiness, impaired ability to concentrate, and forgetfulness. Recommendation: If signs of triazolam toxicity are present, the pharmacist may wish to discuss this with the patient's physician; dosage reduction may be necessary.

Tetracycline interacts with calcium (milk, dairy products, calcium supplements, calcium-containing multivitamins). Calcium supplements and foods containing calcium may substantially reduce the absorption of tetracycline, thereby diminishing its effect. The absorption of related compounds (for example, doxycycline, minocycline) when taken with calcium is also reduced, but to a lesser extent than with tetracycline. Foods with moderate to high amounts of calcium include milk, yogurt, cheese, sardines, salmon, soybeans, tofu, broccoli and turnip greens.

Recommendation: Patients should not take tetracycline and calcium products simultaneously. Indeed, patients must avoid taking any cations (including iron, magnesium, zinc, aluminum) with tetracycline. They should take tetracyclines at least two hours before or at least four hours after eating dairy products or calcium-containing vitamins.

Ulcer

The most commonly dispensed drugs were Zantac, Tagamet, Pepcid, Axid, Prilosec and Carafate.

Theophylline interacts with smoking. Smoking leads to a decrease in the amount of theophylline in the blood, possibly leading to a decreased effect. The mechanism involves cigarette smoke inducing a specific hepatic enzyme (CYP1A2), which enhances the metabolism of theophylline. Some smokers require twice the dosage of their nonsmoking counterparts.

Cimetidine (Tagamet) interacts with alprazolam (Xanax). Cimetidine may increase the plasma concentration of alprazolam, which could lead to an increased effect as evidenced by decreased alertness, an impaired ability to concentrate, dizziness, incoordination, forgetfulness and drowsiness. The physician may need to monitor your patient's response to the anti-anxiety medication more carefully than usual. Two anti-anxiety benzodiazepines that do not appear to be affected by cimetidine are lorazepam (Ativan) and oxazepam (Serax). Another way to reduce the risk of interaction is to use ranitidine (Zantac) or famotidine (Pepcid) rather than cimetidine.

Cimetidine interacts with anticoagulants (Coumadin, Panwarfin). Increased anticoagulant effect can result and some patients may develop bleeding. Pharmacists should discuss with the physician whether the patient can take ranitidine, famotidine or nizatidine (Axid).

Cimetidine interacts with carbamazepine (Tegretol). Patients receiving carbamazepine who then begin taking cimetidine may experience higher concentrations of carbamazepine for about one week, which could lead to an increased effect. High concentrations of carbamazepine can lead to symptoms of dizziness, drowsiness, nausea, vomiting, twitching and blurred vision. These symptoms may occur after the first few days of taking cimetidine if the patient is already taking carbamazepine.

Cimetidine interacts with ketoconazole (Nizoral). Since cimetidine reduces the secretion of stomach acid -- which is needed for the proper absorption of oral ketoconazole -- cimetidine tends to reduce the absorption of ketoconazole.

Cimetidine interacts with meperidine (Demerol, Mepergan). Cimetidine may increase the effect of meperidine, possibly leading to increased sedation and impaired breathing. Ranitidine and probably famotidine and nizatidine appear less likely to interact with narcotic analgesics.

Cimetidine interacts with phenytoin (Dilantin). Cimetidine increases the amount of phenytoin in the blood, possibly leading to phenytoin toxicity. Symptoms of phenytoin toxicity include rapid involuntary eye movements, muscular incoordination, slurred speech and confusion. Phenytoin blood levels will probably need to be monitored when cimetidine therapy is initiated. In people who are stabilized on phenytoin and cimetidine, discontinuation of cimetidine may cause inappropriately low levels of phenytoin, resulting in a decreased effect. Ranitidine and famotidine appear less likely to interact with phenytoin in this way.

Cimetidine interacts with theophylline. Increased levels of theophylline in the blood when cimetidine also is taken can result in symptoms of theophylline toxicity. Symptoms of theophylline toxicity include nausea, vomiting, diarrhea, headache, irritability, restlessness, nervousness, rapid heartbeat, insomnia, tremor and seizure. Pharmacists may wish to investigate whether ranitidine or famotidine, which are less likely to interact with theophylline, are more appropriate choices.

Sucralfate (Carafate) interacts with ciprofloxacin (Cipro) and norfloxacin (Noroxin). Sucralfate may reduce the absorption of ciprofloxacin and also norfloxacin. As a result, these antibiotics may not work as effectively. Pharmacists should recommend that patients not take ciprofloxacin or norfloxacin simultaneously with sucralfate. They also should advise patients to take ciprofloxacin at least two hours before or six hours after taking sucralfate.

Pain

The most common drugs prescribed were Tylenol with codeine, Vicodin, Darvocet and acetaminophen with codeine.

Meperidine (Demerol, Mepergan) interacts with the following monoamine oxidase inhibitors: isocarboxazid (Marplan), phenelzine (Nardil) and tranylcypromine (Parnate). This interaction can lead to severe side effects. Some individuals receiving meperidine and a monoamine oxidase inhibitor may develop severe alterations in blood pressure (either excessively high or low blood pressure), impaired breathing, rigidity, convulsions, coma and death. Less severe side effects include excitation and sweating.

Propoxyphene (Darvocet-N, Darvon, Darvon with ASA, Dolene and Wygesic) interacts with carbamazepine (Tegretol). Propoxyphene has consistently been shown to increase the amount of carbamazepine in the blood. This effect may lead to carbamazepine toxicity, with symptoms such as drowsiness, dizziness, nausea, vomiting, incoordination, headache, involuntary rapid eye movement and blurred vision. It's also important to be alert for a reduced effect of the carbamazepine (as shown by reduced control of seizures) if propoxyphene is suddenly discontinued or reduced in dosage.

Propoxyphene interacts with doxepin (Adapin, Sinequan). Increased blood concentration of doxepin (and possibly other tricyclic antidepressants) can lead to an enhanced effect of the doxepin. Possible symptoms of excessive doxepine effect include lethargy, dry mouth, blurred vision and constipation.

Additional Reading

"Drug Interactions" (Applied Therapeutics Inc., Vancouver, Wash.), by Philip D. Hansten, Pharm. D. and John Horn, Pharm. D. Written for the pharmacist and physician, this text describes clinically significant interactions, identifies the mechanism of action, and provides useful patient-management tips.

"Drug Interaction Facts" (J.B. Lippincott Co.), edited by David Tatro, Pharm. D. Also written for pharmacists.

"The Consumer's Guide to Drug Interactions" (Collier Books), by Jeffrey Schein, M.S., and Philip Hansten, Pharm. D. Jeff Schein, M.S., M.P.H., is a doctoral candidate in public health at the University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway.