Drug interactions - Deadly cocktails

Dispensing a cocktail of drugs is now every doctor's stock in trade. But new evidence shows that many drugs interact with food and other drugs, and the risk of side effects skyrockets, the more drugs you take.

You have a mild heart condition, joint pains and a cough a not unlikely trio of complaints. But go to your doctor and you could easily find yourself on the receiving end of 16 different drugs two for your heart (perhaps aspirin and digitalis), a third one for arthritis, and a fourth to counter the side effects of the third; you then pop along to the chemist for a cough remedy which itself might contain a dozen different compounds. You're now deep in drug interaction territory, a no man's land of medical Russian roulette.

Because so much of modern conventional medicine is based on drugs, and doctors (and some patients) have been led to believe that there's a pill for every ill, it's hardly surprising that more and more people are taking more than one medication at a time.

Multi drug taking, or polypharmacy as it's known in the trade, is obviously not discouraged by the pharmaceutical industry, but there is growing concern within some of the more enlightened parts of the medical profession of the potential for hazardous interactions between drugs.

A recent American report showed that the side effects and misprescribing of medications result in "drug induced disorders" of epidemic proportions, costing the US economy a staggering $136 billion a year quite apart from the toll in human suffering and even death. The authors point out that "many adverse drug events occur as a result of drug drug. . . or drug food interactions, and therefore, are preventable" (see box, p 3) (Am Fam Physician, 1998; 57: 2615-6).

Detailed studies have revealed the potential scale of the interaction problem. Researchers at the University of Southern California Medical Center showed that the risk of an adverse drug interaction rises from 13 per cent for patients taking two medications at the same time to 82 per cent for patients taking seven or more (Am J Emerg Med, 1996; 14: 447-50).

Quite how many people experience drug interactions is not known. Figures vary widely, but a review of the records of over 370,000 patients showed that up to 70 per cent may have been affected by adverse drug drug effects (DICP, 1990; 24: 982-9).

That drug companies should wish to develop drugs that require long term use makes commercial sense, and they are constantly on the look out for new chronic conditions to treat. Drugs have even been developed for people who aren't ill and have true symptoms, such as for high blood pressure or high cholesterol "patients".

Often the side effects of drugs don't become apparent for years but when they do, doctors are not discouraged from continuing the drugs, often prescribing yet more drugs (dubbed "chasers" by some industry insiders) to counteract the side effects of the first. This polypharmacy is, of course, highly profitable. Sometimes, however, doctors won't even be aware they're prescribing a chaser drug.

"There is no doubt that the unwanted effects of a drug are not recognised as drug side effects, and therefore a new diagnosis is entered into and a new drug prescribed," admits clinical pharmacologist Prof Patrick Vallance of University College, London.

However, polypharmacy is routinely used for many chronic conditions, such as heart disease and arthritis.

Medications for heart disease and high blood pressure abound there are ACE inhibitors, calcium antagonists, anticoagulants, antiarrythmia drugs, alpha blockers, beta blockers, stimulants and diuretics and cardiologists claim that combining them can often produce a beneficial additive effect. But, with the co-administration of so many drugs, there is a danger of overloading the body's ability to metabolise them and causing kidney failure, particularly in the susceptible patient (Drug Saf, 1995; 12: 334-47).

Interactions are particularly a problem when one of the drugs has a critical dosage, such as the heart drug digoxin too little won't work, too much may be toxic. If other drugs interfere with the absorption and metabolism of digoxin, the side effects may poison the patient.

In the welter of heart drugs, cardiologists themselves have questioned what is "rational" polypharmacy and what is not (J Hum Hyperten, 1991; 5: 9-14). To add to the confusion, chaser drugs have now been developed to counter the side effects of digoxin.

But it's in arthritis therapy that chaser drugs have reached their apogee.

The major treatments used in arthritis are the so called non steroidal anti inflammatory drugs (NSAIDs). Most of the major drug companies have products in this area: brand names include Advil, Aleve, Anaprox, Ansaid, Clinoril, Feldene, Lodine, Motrin, Naprosyn, Nuprin, Relafen and Voltarol. Many of these are related to aspirin, but are chemically different enough to allow them to be patented and so be sold at a high price. However, despite their apparent sophistication, NSAIDs exact an equally high price on the patient, for they often cause serious stomach ulceration. In fact, a recent study by Prof Michael Langman of the University of Birmingham has shown that NSAIDs are responsible for up to a quarter of all cases and a quarter of all deaths from peptic ulcer bleeding (Ital J Gastroenterol Hepatol, 1999; 31: S2-5). In the US, an estimated 70,000 people are hospitalised annually because of the ulcers caused by NSAIDs (J Muscul-skeletal Med, 1991; 8: 21-8).

To counter the side effects of NSAIDs, at first doctors used cheap, non prescription ant acids, but the drug companies soon weighed in with two patented anti ulcer "improvements" Zantac (ranitidine) and Tagamet (cimetidine); sales rocketed and these two drugs are now among the most successful in the history of the pharmaceutical industry.

However, doctors have been faced with another potential problem the interaction of the NSAIDs and the anti ulcer drugs. The drug marketers had assured them there would be no problem, but within a few years it became apparent this claim was, at best, naive. Cimetidine was found to "inhibit the oxidative metabolism of many. . . NSAIDs" (Clin Pharmacokinet, 1990; 19: 44-66), so increasing their effect and potential

toxicity.

To add to the vicious circle of interactivity, up to 30 other major drugs have been shown to become toxic or fail to work due to cimetidine. Because cimetidine affects a key enzyme in the liver, its widespread use has resulted in "numerous case reports of therapeutic failure primarily from drug toxicity" (J Clin Gastroenterol, 1983; 5 : 95-113).

Recognition of the whole drug interaction problem is seriously deficient according to many industry watchers, among them Prof Vallance of UCL. Take the regulatory process: in theory, drugs are only allowed on the market after the manufacturers have demonstrated that serious interactions with other drugs are likely to be minimal. However, as recently as last year, a major new heart drug called mibefradil, marketed by Roche as Posicor, was withdrawn worldwide because of toxic interactions with other heart drugs-but only after it had caused serious cardiogenic shock and death (JAMA, 1998; 280: 157-8).

But as a recent UK National Health Service document admits, "drug interactions are not always easy to predict" (Medicines Resource Centre Bulletin, June 1999). And in any case, it would be impossible for drug companies to test every possible interaction. Ultimately, therefore, it is the patients who are the unknowing guinea pigs for both the drug companies and the regulatory authorities.

In Britain, GPs are meant to be on the look out for adverse drug reactions, including interactions, and report back to the Medicines Control Agency via the so called Yellow Card system. But with fewer than 10 per cent of GPs ever filling in a yellow card in the whole of their career, the system is obviously seriously flawed. In the US, there is no organised reporting system at all (Arch Dermatol, 1995; 131: 468-73).

Sometimes years can pass and many patients can suffer and even die before a drug interaction is recognised. For example, it took 60 years for doctors to recognise that the heart stimulant digoxin was seriously life threatening when given with another heart drug quinidine.

Similarly, by the time physicians realised that the powerful antidepressant drugs called monoamine oxidase inhibitors reacted with certain foods (see box, above), scores of people had experienced strokes and at least 15 people had died (A Gilman, et al, eds, The Pharmacological Basis of Therapeutics, Pergamon, 1990: 417).

Much the same story occurred in 1985, when the new antihistamine drug terfenadine (Seldane) was brought out. The manufacturers Merrell-Dow trumpeted it as "a major advance", claiming it had minimal side effects. Within five years, Seldane had become the world's best selling allergy medicine, with US physicians alone writing 16 million prescriptions a year. It was so popular, and apparently so safe, that Merrell-Dow lobbied for it to be available as a non prescription medicine, like aspirin. As a result, Seldane became an over the counter medicine (OTC) but only briefly.

Allergy patients soon began developing mysterious symptoms. One case concerned a 39 year old woman who developed "light headedness and fainting" after only 10 days on Seldane. Her heart was checked and the electrocardiogram (ECG) showed a dangerous irregularity called torsade de pointes (a twisting together of the ECG trace). Besides Seldane, she was also taking an antifungal drug, Nizoral, for a simple vaginal yeast infection.

More reports came in about Seldane some were of fatalities. One 29 year old woman had a cardiac arrest; she too had been on Seldane at the same time as ketoconazole, another antifungal drug. By the time the authorities had alerted doctors to its deadly interaction with other drugs, at least 25 people had been hospitalised and two had died (JAMA, 1993; 269: 1532-6). Seldane has now been withdrawn from the OTC market but is still available on prescription.

But in the Russian roulette of interactions, it is the elderly who most often have the gun put to their head.

Because the old tend to have multiple medical problems at the same time, the "pill for every ill" philosophy often dictates that separate drugs are prescribed for each condition.

Survey after survey reveals that modern medical treatment of the elderly has become polypharmacy on a grand scale. While the average elderly person used less than three drugs in 1978 (J Clin Epidemiol, 1991; 44: 1353-9), by the 1990s, that figure had risen dramatically, so that today people over 65 are taking up to nine medications at once (Drugs Aging, 1994; 4: 449-61).

Even doctors themselves are becoming concerned at the trend; it is becoming clear that these medical cocktails are often prescribed ad hoc and, far from helping the elderly, are frequently making them worse. As one report baldly observed: "A significant proportion of their disease states is related to adverse reactions to prescribed drugs" (Am J Cardiol, 1986; 57: 59C-62C). In fact, a recent survey discovered that drug related illness is responsible for nearly a quarter of all hospital admissions, many of which are due to drug interactions from polypharmacy (Therapie, 1996; 51: 269-82).

It is only now being appreciated that the elderly are particularly susceptible to drug side effects and therefore adverse interactions. The major reason appears to be that the old have a "diminution in the function of organs which play a role in drug distribution and elimination" (Med Clin North Am, 1983; 67: 315-31). However, old people with impaired metabolism are not chosen for research into drug interactions what few clinical studies there are always use healthy young volunteers.

Geriatricians have recently begun to document the size of the problem. A 1992 study in the US uncovered "poor prescribing practices by physicians" both in and out of hospital, and highly prevalent polypharmacy and drug misuse in long term care facilities (Clin Geriatr Med, 1992; 8: 143-58). A similar study in old people's homes in the UK showed that over 85 per cent of the residents were taking an average of three medications some were on 13 drugs a day (DICP, 1990; 24: 533-6). Outside the nursing home, polypharmacy is also rife and it's not always the GP's fault. The problem may be due to the overspecialisation of medicine. Because old people tend to be polysymptomatic, they will be sent to a variety of specialists. Scandalously, however, it has been found that each specialist often thoughtlessly adds a new drug prescription without reference to the others (Therapie, 1995; 50: 247-52).

That study also showed that many of the major classes of drugs were responsible for most of the interactions a long litany of drugs including NSAIDs, diuretics, benzodiazepines (tranquillisers), heart drugs (antiarrhythmics, diuretics and blood pressure drugs), oral antidiabetics and antihistamines.

Although deaths have sometimes occurred from these interactions, most of the time they result in a constellation of debilitating conditions, many of which mimic the symptoms of old age. A recent German investigation part of the Berlin Study of Aging was one of the first to document in detail what drug interactions can do to the old. The researchers found that they resulted in postural hypotension (low blood pressure causing dizziness and fainting when standing up), toxicity from digitalis type heart drugs (leading to confusion, depression and loss of appetite), toxic central nervous system effects, and low potassium levels causing breathlessness, muscle cramps and weakness (Z Gerontol Geriatr, 1995; 28: 420-8).

These findings were confirmed in Britain by pharmacologists at the University of Wales, who cautioned doctors to take a closer look at an elderly patient's drug list when confronted with nonspecific complaints such as confusion, lethargy, weakness, dizziness, incontinence, depression, and falling (Drugs Aging, 1998; 12: 485-94).

It's hardly surprising, therefore, that there's a growing chorus of concern about how the old are being increasingly poisoned by modern drug based medicine. Indeed, one obviously despairing British geriatric hospital department recently came up with a radical solution that must have rather stuck in the craw. Perhaps, they suggested, doctors should try "alternative medicine first in non acute conditions" (Drug Saf, 1990; 5: 421-35).

!ATony Edwards