FROM THE AMERICAN COLLEGE OF PHYSICIANS

Douglas S. Paauw, MD, FACP

SAN DIEGO—Did you know that a lack of acid in the stomach significantly affects the body's ability to absorb thyroid hormone? Or that concomitant use of prednisone and warfarin increases the international normalized ratio (INR)? Or that antibiotics and niacin increase statin toxicity, and the use of a proton-pump inhibitor (PPI) reduces calcium absorption?

These are just some of the common, but often surprising, drug interaction challenges that internists face on a daily basis, according to Douglas S. Paauw, MD, FACP, professor of medicine and medicine clerkship director at the University of Washington School of Medicine in Seattle, who discussed how to avoid top medication errors at Internal Medicine 2007, the annual meeting of the American College of Physicians.

Absorption Issues: TSH, PPIs, Calcium, H₂ Blockers

Two common drugs that are greatly affected by absorption issues are thyroid hormone and quinolones, Dr Paauw points out. These drugs are easily bound by:

• Iron
• Antacids, especially those containing aluminum/magnesium
• Calcium
• Cholestyramine (Questran)
• Sucralfate (Carafate).

If you have a patient who had a stable thyroid-stimulating hormone (TSH) while using thyroxin, and now her TSH is rising, look at her medication list, and ask about over-the-counter drugs, Dr Paauw stresses.

Ask these 6 questions:

1. Is the patient compliant?
2. Is the patient taking ferrous sulfate?
3. Is the patient taking calcium carbonate?
4. Is the patient taking sucralfate/ cholestyramine?
5. Is the patient taking a PPI or a H₂ blocker?
6. Could the patient have achlorhydria?
7. Could the patient have sprue?

"Calcium is more problematic in some ways than iron, because many patients take iron once a day, whereas they're taking calcium multiple times a day [with food], and it's harder for them to come up with a schedule where they're not taking it together," Dr Paauw says. "And sprue malabsorbs thyroxine as well, so there are a number of things for us to think about other than just increasing the dose of thyroxine when our patients' TSH goes up."

The antifungals ketoconazole (Nizoral) and itraconazole (Sporanox) also greatly depend on acid for absorption. Itraconazole may be the most clinically important, because it is used frequently for the treatment of fungal nail disease, Dr Paauw notes.

Issues related to PPI use include:

• Decreased thyroid absorption
• Decreased ketaconazole/itraconazole absorption
• Decreased calcium absorption
• Increased risk of Clostridium difficile.

Many physicians are not aware that patients "cannot be taking a PPI with itraconazole, if you want it to be absorbed. The same goes for ketoconazole. H₂ blockers will also have an effect; it's not quite as total an effect as a PPI," he says.

So, what do you do with your patients who have severe reflux disease who are taking itraconazole? "During their week on itraconazole, have them try antacids or something that doesn't block acid suppression for 12 or 24 hours, and then have them separate their itraconazole dose away from when they're taking antacids," Dr Paauw suggests.

Another issue is the effect of PPIs on calcium absorption, Dr Paauw points out. This subject received a lot of attention with the recent publication of an article (JAMA. 2006;296:2947-2953) that looked at hip fracture rates in PPI users and nonusers (patient age, >50 years). The adjusted odds ratio was 1.44 for <1 year of PPI use, 1.54 for >3 years of PPI use, and 1.55 for >4 years.

"So what do we do with this, since all our patients are on PPIs, and we're very worried about osteoporosis? I'm not sure we have an answer," Dr Paauw says. "I do think it's important that all those patients are on significant calcium supplementation...because we know that with the PPI they're going to absorb less."

And a new side effect of PPI use that has come up in the past 18 months is "an increased risk for C difficile infection," he says.

"So there are a number of things that your patients who are on PPIs may be at risk for. Again, these probably are not going to change what we do, but if we know that this risk is a little bit higher, we might be thinking more about it when they come in with diarrhea than we would be if we were unaware of that."

Deadly Warfarin Interactions

"Warfarin interactions are among the most deadly drug interactions that we have in patients," Dr Paauw stresses. "The group that probably gets into the most trouble are the people that have mechanical valves, where we generally push the INRs higher. We want them at 2.5 to 3.5, so we have less [of a] safety net if we have drug interactions."

Important interactions with warfarin that decrease metabolism are:

Most severe interactions

• TMP/SMX (trimethoprim and sulfamethoxazole [eg, Bactrim, Septra])
• Erythromycin (Ery-Tab)
• Amiodarone (Pacerone)
• Propafenone (Rythmol)
• Ketoconazole/fluconazole (Diflucan)
• Itraconazole
• Metronidazole (Flagyl)

Possible interactions

• Quinolones (eg, cinoxacin, ciprofloxacin [Cipro])
• Omeprazole (Prilosec)
• Clarithromycin (Biaxin)
• Azithromycin (Zithromax)
• Prednisone
• Acetaminophen

TMP/SMX. Of these interactions, Dr Paauw says, the interaction with TMP/SMX is the "most severe" because of its short half-life, and because it displaces binding of warfarin from albumin and decreases the metabolism of warfarin.

Erythromycin also has a short half-life, he notes. "The shorter the half-life, the quicker the problem comes to light. Drugs with long half-lives—they can bump the INR quite high, but it takes longer to get to that steady state, and usually you can pick this up before it gets too out of hand."

Quinolones also can have a significant impact on the INR, but the effect is more variable, Dr Paauw says. "There are patients who will have zero effect from a quinolone, and there are patients who will have doubling or tripling of their INR with a quinolone."

Omeprazole. The fact that omeprazole has an effect on warfarin "kind of scared me when I learned that, because I thought I was protecting them," Dr Paauw admits. "I thought, okay, they're on warfarin, I'll put them on omeprazole so they don't get gastrointestinal bleeding [but] potentially it can bump the INR."

Prednisone. Another frequently used drug that can adversely interact with warfarin is the corticosteroid prednisone, which may come as a surprise to some physicians and even caught Dr Paauw off-guard. "We've been using predinsone forever, and we use it in our medically complicated patients—a lot are on Coumadin. This was relatively new to me."

He points to a recent article (Ann Pharmacother. 2006;40:2101-2106) that reported a 62% increase in target INR levels in patients taking warfarin who received oral corticosteroids. Although Dr Paauw notes that this is not a huge interaction, he stresses that physicians need to be on the lookout for increased INR levels in patients who are using corticosteroids. "I worry that they might get their warfarin dose decreased, and then the steroid treatment ends, and the next time they are underanticoagulated."

Acetaminophen. Yet another surprising drug that physicians think of as a "safe drug," but one that can interact with warfarin, is acetaminophen. "We don't want to put them on aspirin or an NSAID [nonsteroidal antiinflammatory drug] if we can help it when they're on warfarin, so we encourage them to take acetaminophen-which I still think in most cases is the right and safest option," he says; however, there are data showing an increased risk of an elevated INR in patients taking it on a daily basis.

"If a patient is going to take acetaminophen around the clock for pain relief, it's probably reasonable to check their INR in about a week or two. You just need to warn them that if they bag the acetaminophen they're probably going to be on less warfarin than they need, and they'll need to go back to get their INRs rechecked," he says.

And naturally, the older the patient and the more drugs he or she is taking, the greater the likelihood that these effects are going to occur, "because there are a lot of drugs that have small effects, not large enough to measure, but when you start to add up 8 to 10 drugs, and you measure metabolism because the patient is over 60, we see a lot more trouble," Dr Paauw stresses.

Problems with Statins

Several drugs increase the risk of statin toxicity, according to Dr Paauw:

• Fibrates
• Azole antifungals
• Niacin
• Erythromycin/clarithromycin
• Protease inhibitors
• Verapamil (Calan)/diltiazem (Cardizem).

In addition, hypothyroidism can (1) decrease the metabolism of statins, and (2) increase the likelihood of a statin causing muscle pain or mimicking the pain associated with statins. "If you have someone with statin-related muscle problems, it's probably reasonable to check the TSH and make sure hypothyroidism isn't part of the problem," Dr Paauw says.

He mentions several things physicians can do to ensure that patients can continue to take statins:

• Use the lowest possible statin dose
• Have the patient discontinue use and report any sudden onset of symptoms
• Have the patient take a holiday off statins before major excursion/ surgery
• If myalgias are severe, stop the drug, let the symptoms resolve, and then start a different statin.

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Additional Interactions to Consider

• TMP/SMX is an important cause for hyperkalemia in elderly patients, especially if the patient has renal insufficiency and is taking other drugs that may affect potassium excretion
• All selective serotonin reuptake inhibitors (SSRIs) increase the likelihood of gastrointestinal bleeding. This risk is greatly increased in patients who are also taking NSAIDs; SSRIs are often an overlooked cause of hyponatremia; and they are known to cause sexual dysfunction
• NSAIDs can worsen heart failure. Remember to look at the medication list of patients who have heart failur exacerbation, or ask them if they are taking OTC NSAIDs
• NSAIDs can also block the effect of angiotensin-converting-enzyme inhibitors and diuretics.