Drug Interactions Casebook: The Cytochrome P450 System and Beyond

The development of psychoactive drugs in the 1950s gave psychiatry a new way to treat many of its most challenging patients. Although the new medications were initially rejected by the then regnant Freudians, devotees of the new generation of drugs considered them so benign as to be almost “miraculous.” The enthusiastic and sometimes irresponsible application of these new compounds generated an unanticipated epidemic of neurological disorders and other serious side effects. For psychiatrists these ill effects brought new ethical and legal considerations and a focus on the precept of “risk-benefit ratio,” not formerly promulgated widely for any psychiatric treatment.

The newly dominant role of pharmacotherapy brought psychiatry back into the mainstream of medicine from which the Freudians had alienated it, but it also reminded psychiatrists that they would have to learn some of the old-time principles of doctoring from which they had excused themselves for about 40 years. Learning how and why drugs are absorbed, metabolized, and excreted; how they interact with food and with other drugs; how they activate, suppress, enhance, and antagonize endogenous agents; and how they open or close channels to therapeutic work became the responsibility of the people whose job it was to prescribe them. T.M. Luhrmann’s seminal but unflattering study of the profession’s mastery of the tools of its trade (1) exposed the poor quality of therapeutics practiced by (and presumably being taught to) some of the psychiatric house staff she studied as recently as the turn of the millennium.

Dr. Sandson, Director of Education and Training at Sheppard Pratt Hospital, has centered his book on the cytochrome P450 system and other enzymes found primarily in the liver, with small concentrations in the intestinal wall and other tissues. Their important role is to help rid the body of toxins, including the medications we psychiatrists go to so much trouble to introduce. Through a process of oxidative metabolism and conjugation, these enzymes render lipid-soluble drugs water soluble so that they can be excreted through the kidneys. Not all of the P450 enzymes act on all drugs, but each acts on many. When one enzyme is acting on two or more concomitantly prescribed medications at the same time, conditions are ripe for an unanticipated drug interaction. These interactions can include one drug’s slowing another’s excretion, causing it to accumulate until it reaches the clinical equivalent of an overdose, or the first drug can expedite excretion of another, reducing its therapeutic action.

There are many more mechanisms of interference, some less important, some very important. Dr. Sandson has chosen to expound on them at book length because, although many psychiatrists prescribe multiple drugs simultaneously, not many have enough basic clinical pharmacology at their fingertips to predict and work around the interactions they create.

Dr. Sandson opens with a section titled Core Concepts, an array of brief but pertinent explications of ground-level pharmacology in drug-drug interactions. Read it; it will help you to understand and appreciate the rest of the book. Seven chapters explain specifics of phase I (primarily the cytochrome P450 subgroups) and phase II (mainly glucuronidation) drug metabolism. The case reports are cleverly titled to help take some of the weight off. A lot of the featured interactions can be mid-therapy surprises, when a drug added or subtracted for fine-tuning of a nicely progressing case causes changes in medication blood levels to which a patient has become well accommodated. Interactions like this can seem threatening and mysterious, precisely because they are unanticipated, hard to recognize, and tough to treat. They can also be discouraging to fragile patients and hazardous to a critical therapeutic relationship.

“Cranky and Crampy” is about how an additional drug slowed metabolism of an acetylcholinesterase inhibitor, causing higher blood levels and the miserable abdominal cramping side effects common to these drugs at high doses; naturally, the physician who was prescribing the medication at a standard dose couldn’t understand where things had gone wrong. “Nauseated Nanny” is about how an angiotensin-converting enzyme inhibitor slowed renal excretion of lithium and raised the ion’s blood level to toxicity. There is also a case of a drug interactively decreasing another’s blood level, with attendant sacrifice of therapeutic effect.

Another case illustrates caffeine’s combination with a prescribed medication and is intended to alert us to the potential dangers of interactions between drugs that we do not necessarily think of as drugs. For example, when cigarettes, potent P450 inducers, are withdrawn, an index drug’s blood value can rise to toxic levels. You might well encounter this kind of problem (so-called reversal of induction) when you’ve admitted a patient maintained on clozapine to the hospital, where smoking is not permitted. Even though the patient may be in acute exacerbation of psychotic symptoms and your natural predilection would be to increase the antipsychotic dose, the smoking cessation retards the patient’s P450 production and clozapine is being excreted more slowly. Thus, the patient is accumulating higher blood levels. If you raise the dose you could very well precipitate a toxic overload.

Dr. Sandson and his colleagues have included three useful appendixes, and I would recommend that you take a good look at each so you will know where to return when you have a sick patient and have to look up a specific interaction. The appendix titled “P450 Tables” groups the drugs that induce and inhibit these enzymes; those titled “Phase II Glucuronidation Tables” and “P-Glycoprotein Table” contain extensive listings of relevant psychotropic and medical pharmaceuticals regularly encountered in clinical practice.

This is an attractive and genuinely useful reference book. Certainly not the first to be published on drug interactions, it is nevertheless among the more readable and entertaining, with the feel of a classic English who-done-it in the mystery enfolding nearly every case. I highly recommend it as a much-needed contribution that is likely to improve the medication management skills of everyone who reads it.