Therapeutic and fatal doses of drugs

Below is one of the many countless student discussions posted by this author as a current student in Forensic Toxicology in during the 3^rd week into the course at the University of Cambridge

Q. What is a toxin?

A. A toxin is a poison of biological origin, normally a protein expressed by the organism

For instance, botulinum toxin is a neurotoxic protein produced by the bacterium Clostridium botulinum.

 Another example, is tetanus toxin, an extremely potent neurotoxin produced by Clostridium tetani  in anaerobic conditions and this toxin causes tetanus (lock jaw in humans)

Other examples are mycotoxins, for instance aflatoxin B and G expressed by the microfungi , Aspergillus flavus, that in small doses over long exposure can cause liver cancer, and in large doses in one sitting causes acute liver failure

Others are the different types of neurotoxins and haematoxins expressed by vipers and cobras. The list goes on and on.

 

Q. What are the therapeutic and fatal doses of the various poisons and drugs given in the list 

A. As far as the therapeutic and lethal doses of other poisons and drugs are concerned here are just two examples

Poison                                 Therapeutic dose                                                                             Lethal dose

Arsenic                                 Arsenic trioxide 0.15 mg/kg IV                                                    70 to 200 mg mg/kg/day

Paracetmaol                       1-2 tablets bd – tds (twice or three times a day                  10–15 g (20–30 tab)

For arsenic this is found in a few medicinal preparations

For instance, Salvarsan, an organic arsenical, was introduced in 1910 by Nobel laureate, physician and founder of chemotherapy, Paul Ehrlich. His compound, which was one of 500 organic arsenic compounds, cured syphilis.

Today, arsenic compound is still used in the treatment of trypanosomiasis. Therapeutic doses of these compounds depends on the formulation and preparation

For instances for acute promyelocytic leukemia (APL), arsenic trioxide at a dose of 0.15 mg/kg body weight is given IV until bone marrow remission; not to exceed 60 days.

Other formulation such as Tretinoin is given at 22.5 mg/m²

Arsenic exerts its toxicity by inactivating up to 200 enzymes, especially those involved in cellular energy pathways and DNA synthesis and repair.

But what is more important is the long term exposure to arsenic in the soil and drinking water

WHO estimated through drinking water, more than 200 million people globally are exposed to higher than safe levels of arsenic (1). The areas most affected are Bangladesh and West Bengal (1). Exposure is also more common in people of low income and minorities (2).

 Acute poisoning is uncommon (1). The toxicity of arsenic has been described as far back as 1500 BC in the Ebers papyrus (3).

The acute minimal lethal dose of arsenic in adults is estimated to be 70 to 200 mg or 1 mg/kg/day (4)

As far as paracetamol is concerned, the therapeutic dose as an analgesic is normally 1 -2 tablets x tds. But this depends on age

An overdose of 10–15 g (20–30 tablets) of paracetamol can result in fatal hepatotoxicity (5, 6).

Patients who are malnourished, have been fasting, take enzyme inducing drugs, or regularly drink alcohol to excess are at higher risk of liver damage.

Again the fatal dose depends on a person's body weight, age and other drug interaction. For instance if a person takes 5 g of paracetamol together with alcohol, that dose probably would be the lethal dose for him, especially if he / she is a small child.

Similarly, if he already has a liver disorder, and his kidneys are already compromised with low GFR, low creatinine and urea clearance,  the lethal dose for paracetamol can be would be much lower than 20 -30 tablets in one dose.  It all depends on the patho-physiology state of an individual

The same can be said for strychnine.   A few minutes after ingestion, strychnine is excreted unchanged in the urine, and accounts for about 5% of a sublethal dose given over 6 hours (Boyd et al., (1983)

Higher doses over a longer period are fatal. Again this depends on the body weight

I think it is very difficult to give any strict and specific values for all these drugs / poisons especially the lethal doses because it is not possible for us to carry studies on lethal doses using human subjects.

Most of toxicological studies are done using animal models, and their lethal dosage per kg of body weight are then extrapolated into humans

Then again, the biochemistry and genetic make-up of animal models may not necessary be the same for humans. But that is the best we can do. We can’t carry out toxicological trails on humans

There are many other methods used for evaluating toxicity. One common method is to determine the LD 50 (lethal dosage of a substance that kills 50 % of a population in experimental animals),

Toxicologists can also use cell cultures and cell lines studies  in vivo exposure, skin sensitization tests, Draize test, open epicutaneous test, optimization test, split adjuvant test, guinea pig maximization test (GPMT), Buehler test, and murine local lymph node assay (LLNA)…etc. etc.

Normally we would use some of these studies such as developmental toxicology in embryotoxicity studies, genetic toxicity testing, neuro-toxicological evaluation,  two-generation reproduction toxicity studies, carcinogenicity testing, subchronic oral toxicity testing to better understand their toxico dynamics and toxicokinetics (how they act on the body). The list goes on.

Most of these we would focus on the various experimental animal models and methods used for toxicity testing. It depends what we want to evaluate

These pre-clinical toxicity testing helps the toxicologist to calculate out “No Observed Adverse Effect Level” which is needed to initiate the clinical evaluation of  products under investigation such as a novel drug to be marketed much later after 10 - 15 years from cell-lines studies on toxicity, clinical efficacy, to various phrases of clinical trials. It takes a very long time at high cost in R & D before approval by FDA can be obtained

On the issue of adverse drug reaction and toxicity, post marketing pharmaco vigilance is still observed and in place

So I cannot tell you exactly what each dose, therapeutic, fatal or otherwise would be for the various poisons and drugs given in the list because of so many confronting factors 

Some poisons like arsenic, lead and mercury are accumulative at very low doses over many years, or they can also be acute at high doses if administered in a single dose

I would like to leave this very complicated and very lengthy subject here as this is a very complicated and controversial issue

There are already too many studies and published literature on this with some studies contradicting each other.

            

References:

1. Naujokas, Marisa F.; Anderson, Beth; Ahsan, Habibul; Aposhian, H. Vasken; Graziano, Joseph H.; Thompson, Claudia; Suk, William A. (3 January 2013). "The Broad Scope of Health Effects from Chronic Arsenic Exposure: Update on a Worldwide Public Health Problem". Environmental Health Perspectives. 121 (3): 295–302.

2.  Joca, L; Sacks, JD; Moore, D; Lee, JS; Sams R, 2nd; Cowden, J (2016). "Systematic review of differential inorganic arsenic exposure in minority, low-income, and indigenous populations in the United States". Environment International. 92-93: 707–15.

3.  Howie, Frank (2013). Care and Conservation of Geological Material. Routledge. p. 135. ISBN 9781135385217. Archived from the original on 2017-09-10.

4. https://pmj.bmj.com/content/79/933/391.full

5.            Prescott LF. Paracetamol overdosage: pharmacological considerations and clinical management, Drugs, 1983, vol. 25 (pg. 290-314)

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6              BMJ Group, British National Formulary 59 March 2010, 2010LondonBMJ Group; Pharmaceutical Press

7.  Boyd RE, Brennan PT, Deng JF, Rochester DF & Spyker DA (1983). Strychnine poisoning.  Am. J. Med., 74: 507-512.