What is the difference between an additive Vs. synergistic drug interaction?

Question

Additive: effects from two separate drugs increase the efficacy or adverse effects of one or both of the drugs and it is more predictable and sometimes useful. 1+1 = 2

Example: If Tylenol decreases pain by 20%, and ibuprofen decreases pain by 40%, taking both drugs concurrently should give you a 60% reduction in pain.

Synergistic: the effects (adverse or positive) of one drug are increased by the presence of another drug. These interactions are typically dangerous and unpredictable. 1+1 = anything greater than or equal to 2

Examples:

The stomach acid reducer cimetidine, an H2 (Histamine type 2) receptor antagonist (antihistamine) inhibits CYP450 which is a system of enzymes responsible for breaking down the vast majority of drugs and other substances. If CYP450 is inhibited then drugs broken down by it will not be eliminated, allowing them to reach higher and often toxic concentrations in the body.

Answer 1

Hello Asked,

This is a great question, and this concept can be confusing!

Let's start with the CYP 450 system: these are enzymes that help metabolize medications. After this process the medications turn into another chemical, which can either be an inactive medication (see EX1) or an active medication (see EX2). Now let's say, the CYP 450 enzyme system does not work. This can be from a genetic factor, a medication or a disease state. If the CYP 450 enzyme breaks down the medication to an inactive form, then the drug will accumulate in the body (see EX3). If the CYP 450 breaks down the medication to an active form, then you will have less in the body (see EX4).

EX1: Medication A is a blood thinner that is broken down by CYP450 enzymes to make chemical A. Chemical A is an inactive chemical, that leaves the body without issue.

EX2: Medication B is a blood thinner broken down by CYP450 enzymes to make chemical B. Chemical B is an active chemical that acts as a blood thinner, causing an additive effect.

EX3: Medication A (from above) is not able to get broken down by CYP450 enzymes. This means you will have more of the medication, causing a synergistic effect.

EX4: Medication B (from above) is not able to get broken down into an active form. Therefore, giving more medication will lead less of the active chemical B.

If you add a medication that blocks the activity of a CYP450 enzyme, it will make the activity of that CYP 450 enzyme less effective (see EX5). Let's say you add a medication that makes your CYP450 enzymes more active, that will lead to the CYP450 enzyme to be more effective (see EX6).

EX5: Medication C blocks the CYP450 enzymes that break down medication A. Medication C can be any medication, but prevents medication A from being broken down. This means it causes a synergistic effect of medication A.

EX6: Medication D, makes the CYP450 enzymes that work on medication B more effective. This means that there will be more of the active chemical B (the chemical made after Medication B is processed through CYP450 enzymes), leading to a synergistic effect.

Now, lets pretend that we add a medication that does the same thing as the other medications, but does not effect the CYP450 enzymes. That is considered an additive effect (see EX7).

EX7: Medication A is added to medication B. Neither medication A or B affect the CYP450 enzymes, and both are blood thinners. Medication A only adds its effect to the effect of Medication B. It does not do anything the the affect the metabolism of the other drugs. This is additive.

Hope this makes sense!

Answer 2

Hi Asked,

The passages are pretty clear. Additive, means you can add the individual results (although, perhaps multiplicative would also fall into this; thus (1-0.2)*(1-0.4) = 0.48 or 52% reduction, for the first example) and predict the effect of both combined.

But synergistic implies interactive by more than that amount. This is what is typically referred to as drug interactions. So in the second example, although the antihistamine doesn't necessarily have an effect on proton secretion by itself, it certainly kicks the effect of the cimetidine up. There are many many drugs (as well as foods!) which have drug potentiations via interactions with CYP450 oxidases, like this.

If the second drug reduces the effect of the first, you generally call that interference or antagonism.

Similar terminology applies to ecology -- species interactions are termed inhibitory (or even predatory!), commensal, or synergistic depending on effect on targeted species population.

-- Cheers, -- Mr. d.