Why specifically, will combining Zoloft, Lexapro and Methadone kill you? What happens?

[astro]

Per the story the article doesn’t really say. What happens in the body that combining these will kill you?

Toxicology tests showed Daniel Smith had methadone, Zoloft and Lexapro in his system when he died Sept. 10 in a hospital room in the Bahamas where his former Playboy playmate mother was recuperating from giving birth to a daughter, according to Cyril Wecht.

“The fact that we have these drugs and the levels of the drugs overwhelmingly and most logically point to this being a tragic, accidental, drug-related death,” Wecht told The Associated Press from his home in the Pittsburgh area.

Wecht, who performed the autopsy in the Bahamas, said Smith apparently died from a “classical” combination of the drugs which had a lethal “cumulative effect on the central nervous system.”

Smith had been reported to be suffering from depression in the weeks before he went to the Bahamas to visit his reality TV star mom and his newborn half-sister. Zoloft and Lexapro are antidepressants commonly prescribed for patients with anxiety and panic disorders.

Methadone, a pain-reliever, is also commonly used by people recovering from drug addictions

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[KarlGauss]

It’s an interesting, if not tragic, question and answer.

I wonder whether he, upon arrival in Florida, began to dink grapefruit juice. As we’ve discussed here before, grapefruit can inhibit the breakdown of certain medicines (such as methadone, and, to a degree, sertraline) such that blood levels of those medicines rise to toxic levels. Here’s a reference.

In addition, sertraline inhibits an enzyme that breaks down methadone. Here’s a (not very sophisticated) reference.

So, a double whammy.

When methadone levels rise, the heart rhythm can be affected. In particular, a fatal rhythm ("torsades de pointes") can develop.

This is all my guess. There may be more of which I’m unaware. Moreover, I am not a clinical pharmacologist.

[KarlGauss]

sertraline = Zoloft

[KarlGauss]

Here is a more readable link regarding grapefruit-drug interactions.

And here is an old thread with some more links on the subject.

Again, I am speculating that he was drinking grapefruit juice. It struck me as ironic and suspicious, though, that his fatal drug reaction (or interaction) happened shortly after arrival to Florida (a “grapefruit state”).

[simster]

except that the report says that none of the medicines were at toxic levels in his bloodstream (individually).

[astro]

@simster

except that the report says that none of the medicines were at toxic levels in his bloodstream (individually).

If the breakdown process were munged up would the individual drugs even have to be at a toxic level?
Grapefruit juice

Grapefruit juice, a beverage consumed in large quantities by the general population, is an inhibitor of the intestinal cytochrome P-450 3A4 system, which is responsible for the first-pass metabolism of many medications. Through the inhibition of this enzyme system, grapefruit juice interacts with a variety of medications, leading to elevation of their serum concentrations. Most notable are its effects on cyclosporine, some 1,4-dihydropyridine calcium antagonists, and some 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. In the case of some drugs, these increased drug concentrations have been associated with an increased frequency of dose-dependent adverse effects. The P-glycoprotein pump, located in the brush border of the intestinal wall, also transports many cytochrome P-450 3A4 substrates, and this transporter also may be affected by grapefruit juice. This review discusses the proposed mechanisms of action and the medications involved in drug–grapefruit juice interactions and addresses the clinical implications of these interactions.

[Bippy_the_Beardless]

@KarlGauss

I
In addition, sertraline inhibits an enzyme that breaks down methadone. Here’s a (not very sophisticated) reference.

Do you know if this effect is common with other opiates, or is it specific to methadone?

[KarlGauss]

To a large extent, the interactions between and among grapefruit juice, antidepressants, and narcotics are not terribly significant. Indeed, in most cases, the potential for drug interactions is based exclusively on theoretical considerations. But what really counts is whether the predicted, or theoretical, interactions are actually a problem in the real world. For a sertraline and methadone interaction, the phenomenon is real. For other narcotics, it’s just theoretical (and, the fact that case reports detailing or describing such interactions have not been published by now, suggests the interaction is not even relevant in the real world).

With that as background, you may want to look at this chart. The chart lists a number of things about a group of enzymes called called, collectively, cytochrome P450. The cytochrome P450 series of enzymes plays a critical role in the body’s breaking down or metabolism of many drugs.

Cytochrome P450 is often abbreviated as CYP.

In fact, there are a number of subtypes, or variations, of CYP. These are called isoforms of CYP. Examples of CYP isoforms include 3A4 and 2C9. There are many others. Usually, the isoforms are written as CYP3A4 and CYP2C9, or sometimes just as 3A4 or 2C9.

Although it is often the case that drugs are broken down or metabolized by enzymes of the CYP system, it is also the case that a number of drugs can inhibit the CYP enzymes, as well. This means that drugs that inhibit a particular CYP enzyme(s) can prevent the body’s breaking down of other drugs (i.e. drugs which are normally broken down by that same enzyme).

Now look at the chart again. At the top it says “Substrates” and lists across the top a number of the most important CYP isoforms (e.g. 1A2, 2b6, etc.). What this is referring to are drugs which are broken down, or metabolized, by those various CYP isoforms, i.e. drugs that are “subsrates” for those isoforms.

As you scroll down the chart, you see the word, “Inhibitors”. Listed across are, once more, some important CYP isoforms. What this is showing are drugs which inhibit those isoforms.

Now, look again at the “Substrates” section at the top. Under the isoform column ‘2D6’, you can find both codeine and oxycodone (Percocet, Oxycontin, etc.). This means that both codeine and oxycodone are broken down by the CYP2D6 enzyme.

Now, look once more at the “Inhibitors” section, under the column ‘2D6’. This is the list of drugs which inhibit the CYP2D6 enzyme. You’ll see that sertraline (Zoloft) is there. This means that, in theory, the use of sertraline, by virtue of its ability to inhibit CYP2D6, may prevent the body from breaking down codeine and oxycodone. If so, and if someone is taking both oxycodone and sertraline simultaneously, the person may not be able to break down the oxycodone normally. High blood levels of oxycodone could result.

As another example, look at the far right hand side of the “Inhibitors” section. You’ll find the column labeled 3A4, 5, and 7. In other words, drugs and other substances listed in that column inhibit CYP3A4, CYP3A5, and CYP3A7. Notice that grapefruit juice is listed. In other words, there is something in grapefruit juice that inhibits those three CYP isoforms. Now, look at the far right hand column under the “Substrates” section. These are drugs which are normally broken down by CYP3A4, 5, or 7. So, grapefruit juice which inhibits those very same enzymes will prevent the body from breaking down drugs on that list. As an example, a person drinking grapefruit juice won’t be able to break down drugs such as clarithromycin (Biaxin) and alprazolam (Xanax).

For reasons that I can’t understand, methadone isn’t listed in the chart. Regardless, for an example, look here. Basically, what it says is that for the same dose of methadone, the simultaneous use of sertraline (Zoloft) leads to an increase in blood methadone concentrations. During the first six weeks or so of such dual ingestion, the level of methadone can double.

Finally, just to repeat but with less extraneous material, sertraline use can clearly lead to elevation in blood methadone levels (by virtue of sertraline inhibiting the CYP enzymes that your body normally uses to break down methadone). And, with reference to the table of CYP450 enzymes and their substrates and inhibitors, the use of sertraline simultaneously with either codeine or oxycodone could lead to elevations in the latter, since sertraline inhibits CYP2D6, yet it is CYP2D6 that’s normally responsible for breaking down codeine and oxycodone. That being said, there does not seem to many, if even any, reports of such a phenomenon occurring in the real world with real people. On the other hand, it is a genuine concern for sertraline used with methadone.