Drugs and Porphyria

Issues concerning drugs in acute porphyrias

Doctors with experience in treating porphyria are often asked to provide lists of safe and unsafe drugs or to give an opinion about the safety of a particular drug. This document discusses why it is sometimes difficult to decide whether or not a drug should be used in a patient with porphyria.

Attacks of acute porphyria were much more common 20-30 years ago than they are now. Phenobarbital and other barbiturates were usually implicated. At that time, these drugs were commonly used as tranquilizers and sleeping pills. Many attacks of porphyria were not recognized until they were very advanced and barbiturates had been given for many days or weeks. Therefore, those who had porphyria and were not yet diagnosed were at considerable risk from what was then common medical practice. Severe attacks of porphyria are now less frequent, partly because barbiturates are seldom prescribed. Thus, the decline in use of barbiturates has contributed greatly to improving the prognosis for patients with acute porphyrias. Barbiturates have been largely replaced by benzodiazepines, which are much less hazardous in porphyria. Commonly used benzodiazepines include chlordiazepoxide (Librium), diazepam (Valium), triazolam (Halcion) and oxazepam (Serax). It may be that benzodiazepines are harmful in porphyria if large doses are taken, however, small or occasional doses seem to pose little risk in most patients.

Other drugs are still important causes of porphyria attacks. The major ones are listed in the Drug Table. After a diagnosis of acute porphyria is established, patients generally do well, at least in part, because they avoid harmful drugs.

Many drugs that make porphyria worse do so by increasing the synthesis of heme and its precursors in the liver. When the liver in a patient with acute porphyria is induced to make more heme, the genetic block in the pathway (the heme biosynthetic pathway) becomes exaggerated and heme precursors accumulate. Heme made in the liver is used mostly to make certain enzymes found in the cytochrome P450 (a metabolic pathway). Therefore, when a drug causes the liver to make more cytochrome P450 enzymes, it induces the liver to make more heme precursors, and then an exacerbation of a genetic porphyria can follow.

An increase in cytochrome P450 can also have unfavorable consequences in people who do not have porphyria. Cytochrome P450 enzymes assist in removing many drugs from the blood stream. When these enzymes are increased, the clearance of such drugs from the blood is also increased. Therefore, a drug that increases cytochrome P450 enzymes can shorten the effects of other drugs that a patient is taking at the same time. This makes the other drugs less effective. It is well known, for example, that barbiturates increase the amounts of cytochrome P450 enzymes in the liver and alter the effects of other drugs.

Fortunately, many drugs do not increase the synthesis of cytochrome P450 enzymes and are, therefore, likely to be safe in porphyria. However, a drug that does not induce cytochrome P450 enzymes and heme synthesis in the liver may worsen porphyria through other mechanisms. Unfortunately, these other mechanisms have been studied very little and are not well understood. For example, sulfonamide antibiotics are harmful in porphyria but apparently do not cause an increase in heme synthesis in the liver. Sulfanomides may have a harmful effect by inhibiting porphobilinogen deaminase (the enzyme that is genetically deficient in acute intermittent porphyria), but this important possibility has not been studied in great detail. Because this and other mechanisms have not been adequately researched, we cannot assume, at present, that all drugs that do not induce the liver to make more heme and cytochrome P450 enzymes are safe to use in porphyria. However, it does seem that most drugs that are harmful in acute porphyrias are capable of increasing heme and cytochrome P450 synthesis in the liver.

Laboratory studies can help determine which drugs cause increases in synthesis of heme and cytochrome P450 enzymes in the liver. Chicken embryos have been especially useful for looking for drugs that may be harmful in porphyria. Their livers are very responsive to the inducing effects of drugs. However, it cannot always be assumed that the responses of the chicken embryo are equivalent to what would occur in people. Moreover, the doses used in such studies are sometimes much higher (on a body weight basis) than in people, so that any effects seen may not be completely relevant. This problem can be overcome by detailed analysis of the effects of varying doses and by comparing the responses to known harmful drugs, such as barbiturates. Our laboratory, for example, recently found that felbamate, a new anti-seizure drug, had effects in the chicken embryo liver that predict that it would be harmful in porphyria. This may not be surprising because felbamate is closely related chemically to other harmful drugs. Thus, there is a strong and specific indication that this drug should be considered contraindicated in the acute porphyrias.

Reports of porphyria attacks occurring after exposure to the use of safe drugs in porphyria patients are also of value. The fact that a drug is causing an exacerbation of porphyria may be hard to recognize, because the symptoms may be delayed and develop slowly. Also, the patient may be taking two or more medications, making it difficult to appreciate the effects of any one of them. There are other reasons why we cannot rely completely on reported experiences with drugs in porphyria patients.

Sometimes, when a patient with well-documented porphyria takes a harmful drug, an attack does not follow. This is understandable because attacks of porphyria are often due to a combination of factors including hormonal changes and nutrition, and a harmful drug may not always be sufficient. Individuals with "latent" porphyria who have never had attacks may be less likely to have attacks due to drugs than patients who have had frequent attacks. Therefore. the fact that some patients with porphyria have tolerated a drug safely does not always mean that the drug will not induce attacks in others.

On the other hand, an attack that develops in a patient who is taking a certain drug does not necessarily mean that the attack was due to that drug. As already noted, drugs are not the only precipitants of acute attacks. Therefore, a safe drug can be an "innocent bystander" and be falsely blamed as the cause of an attack.

Porphyria is often misdiagnosed. Therefore, one cannot assume that reports about experiences with drug use in patients is valid, unless detailed documentation of the diagnosis is also provided. Unfortunately, this is often not the case even for cases described in the medical literature.

The major drugs known to be harmful or safe in the acute porphyrias are listed in the drug table. Most are drugs that are widely accepted as safe or unsafe. All drugs that are on the market are not included because, unfortunately, for most drugs, there is insufficient information to allow them to be classified as definitely harmful or safe. The Table also lists those drugs that are indicated in U.S. "product labeling" to be harmful in acute porphyrias. "Product labeling" refers to the "package insert" that can be obtained from a pharmacy when a drug is purchased. The same information is included in the Physicians' Desk Reference (PDR), a reference book commonly found in physicians' offices or hospitals. It is also available to the public. "Product labeling" is written by the manufacturer and then reviewed and approved by the U.S. Food and Drug Administration. Therefore, it may be considered "official", at least, in the U.S. However, the PDR is not necessarily a good source for information about drug use in porphyria. The information in the Table regarding product labeling was gleaned by obtaining the CD-ROM version of the PDR and doing a search using the word "porphyria". More importantly, there are some harmful drugs that are not acknowledged by the manufacturer as contraindicated. Other drugs may have been labeled as harmful based on too little evidence. This may be the case for ranitidine (Zantac), one of the most widely sold drugs in the world. The FDA has not provided any uniformity with regard to information about porphyria in product labeling. The best way to obtain information about drugs in porphyria is to refer to the general list published in the American Porphyria Foundation brochures, or to have your physician call a center with experience in porphyria. Lists may also be obtained from pharmacies that have access to on-line services. A problem with longer lists is that some listings may be based on only a little information or on conflicting data.

When a patient with porphyria develops another medical problem, it is important to treat it in the best way possible. When a particular drug treatment is contemplated, because it is particularly effective for the other medical problem, the lack of information as to whether that drug is safe in porphyria can interfere with the patient getting the best treatment. In this situation a discussion of the treatment options with a center that specializes in porphyria may be more helpful than simply referring to a drug list.