Dear Mostafa

You do not mention a drug class so it is difficult to give a straight answer.

Also the website dose probably gives the dose as a per day dosage for a patient without taking body mass into consideration.

There are several pathologies that a patient may have that could influence the ease at which they could "overdose" such as hepatic or renal damage, the extent of dehydration, cardiac output, if the patient is ambulatory or bed ridden, the presence of other drugs or certain foods, whether the patient is taking herbal or traditional medication in addition to that being prescribed.

Most dosage data is collected during clinical trials where relatively well defined populations and ages of the participants are treated, so not all possible conditions are tested before the doses are determined.

There are also pharmacogenetic differences between people, with some people being unable to metabolize the drug while others metabolize the drug so fast that there is limited therapeutic effect.

Also some drugs accumulate relatively fast in certain tissue or organs and can later reach saturation so that further doses increase the plasma concentration unexpectedly quickly.

As you can see it is easy to overdose even at the recommended dosages and the safety of the drug and the possibility of a narrow therapeutic window must be taken into account and the patient monitored. A good understanding of the pharmacokinetics of the drug is important.

So Dr.Duncan, it is better to asses this using the concentration instead of the dose? So minimum effective concentration and maximum tolerated concentration? And any factor affecting the concentration will raise the probability of overdose?

Hi Mostafa

Determining the concentration is not always that easy but it would be a good measure of the extent to which the patient is above the safe limit.

Usually the term overdose is applied when there is some measurable clinical effect that does not fit the expected therapeutic effect we wish to achieve, and could be a minor effect, a serious effect or even life threatening.

For many drugs with narrow therapeutic index there are therapeutic drug monitoring methods available to be sure that the patient is not compromised but there are many drugs for which this is not feasible due to cost, to lack of good analytical methods that can be performed in the limited time required for testing of overdosing.

There are many factors that can cause overdosing at apparently safe doses, but the most important concern is the patient safety and this can be monitored directly and clinically with some effective ways to reduce the plasma concentration rapidly if needed.

So Dr.Duncan, when we read someone overdosed a specific medication like acetaminophen, they aren't referring to exceeding the maximum dosage like the attached image? Or when can you say someone overdosed acetaminophen?

Here it is attached

The overdose is the supra-therapeutic dose i.e., the dose above the maximum tolerated dose in the therapeutic window. And this dose is likely to cause toxic effect.

Thank you Dr.Anroop!

Acetaminophen toxicity is related to the toxic metabolite that forms when the conjugation enzyme systems in the liver become saturated and N-Acetyl imidoquinone (NAPQI) is formed from the excess drug by the CYP3A4 and CYP2E1 enzymes.

This compound will bind to any available protein and thereby cause serious long term liver damage.

Glutathione can preferentially bind NAPQI if it is available, thereby reducing the levels sufficiently to avoid fulminant liver failure later. To increase the levels of reduced glutathione the patient can be treated with NAC which can also act as a NAPQI scavenger.

Acetaminophen is the most common drug reported for overdosing as it is easily available and also present in many formulations where its presence is not always known.

There are good reviews on acetaminophen toxicity, just search for them on the web.

Thanks Dr.Duncan!

Hi Mostafa,

As Dr Cromarty has said without knowing a specific drug class as to which you are looking at this is a difficult question to answer.

Most drugs will list a maximum dose that can be given but in some circumstances those doses may be maximum starting doses, for instance opiates. In the literature there is, provided, a safe starting dose however in chronic or palliative pain these doses are slowly or rapidly titrated upwards as the patient develops tolerance or the analgesic effects diminish. In many cases dosing can be many times over the stated initial maximum dose. In this case we are dosing to effect whilst observing toxicity, but despite going over a stated maximum dose we would not call this an overdose, unless someone accidentally gave a dose like this to an opiate naive patient.

Another example maybe with anti-biotics such as vancomycin or aminoglycosides most reference sources will state a maximum dose for these, however in clinical practise we measure plasma levels to guide whether we are acheiving a therapeutic level or not and where levels are low we may advocate increasing the dose above a stated maximum to obtain a desired MIC.

There are numerous examples of these types of drugs. However there are also many examples of drugs with definite maximum doses. Paracetamol as you have highlighted would constitute one of these where exceeding beyond the stated maximum causes saturation of clearance mechanisms causing significant morbidity, toxicity and potential death.

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