Drugs and Poisons in the Body

"Only remember one thing—a small dose is a remedy, a large one is poison. One drop will restore life, as you have seen; five or six will inevitably kill, and in a way the more terrible inasmuch as, poured into a glass of wine, it would not in the slightest degree affect its flavor."

—The Count in The Count of Monte Cristo

What is a drug, what is a poison, and how are they differentiated? Often it is not the substance itself that makes something a drug or a poison but rather the amount of it that is ingested. The source of the substance does not matter; hemlock extracted from a plant is a deadly poison even though it could be regarded as an herbal tea. Many drugs are obtained from plants directly or were synthesized. Heavy-metal poisons such as lead can come from soil, batteries, or pollution. But no matter where a substance comes from, it is the dose that makes it a poison. Even common materials and pharmaceuticals can be poisons if too much is ingested.

The chemical structure of aspirin (acetylsalicylic acid)

A drug is a substance or compound that is used to treat or prevent a disease or to treat symptoms of a disease or injury. Aspirin (acetylsali-cylic acid) is a drug that can be used to help prevent heart attacks or to treat the pain and swelling that results from an injury such as a twisted ankle. Strictly speaking, a drug is a single compound, while a mixture of compounds is defined as a medicine. Over-the-counter (OTC) cold medicines contain many substances, such as aspirin, decongestants, and antihistamines. Many people, however, use the terms drug and medicine interchangeably.

A drug acts to change the chemistry and conditions of the body; this is called the mechanism of action (MOA). Aspirin works by inhibiting the action of a class of compounds called prostaglandins, which promote many functions in the body. This explains in part why aspirin can be used to treat such variety of symptoms and conditions.

The history of aspirin as a drug is typical of many other substances, starting with folk knowledge. As early as 400 b.c.e. the Greek physician Hippocrates recommended that his patients chew on willow bark when they had a fever or pain. (Willow bark, as it turns out, contains compounds related to aspirin.) It is likely that the use of aspirin-based folk remedies predates this, perhaps by centuries, yet it took nearly 2,000 years for chemists to synthesize the active ingredient of aspirin. By the 1800s salicylic acid, which is closely related to acetylsalicylic acid and also found in willow bark, was available, but it produced stomach pain, a side effect still associated with aspirin. A German chemist, Felix Hoffman, is generally credited with the first synthesis of acetylsalicylic acid. Hoffman performed his work at a company with a familiar name, Bayer. Interestingly, Bayer, a company that has become nearly synonymous with aspirin, was not active in pharmaceuticals until the 1890s. Many of their

The chemical structure of aspirin (acetylsalicylic acid)

52 drugs, poisons, and chemistry early drugs were actually by-products of making dyes, a fairly complex chemical process and not as far removed from drug synthesis as it might seem. Aspirin hit the market in 1899 and soared in popularity. By 1915 it was available OTC so that anyone could purchase and use it. Still, it was not until the 1970s that scientists had unraveled the mechanism of the drug. Although aspirin was originally released as an analgesic (a drug meant to alleviate pain), many people who now take aspirin do so to prevent heart attack or for related reasons.

As useful as it has proven to be, aspirin is not without dangers and side effects. Some people are allergic to aspirin, and taking it can cause a deadly episode of anaphylactic shock (a severe immune response). Buffering aspirin can reduce stomach pain, but for many people stomach discomfort is part of taking an aspirin. An aspirin overdose can cause injury and death. Although aspirin is a drug, it is also a poison, which brings us back to the idea that "the dose makes the poison."

How then do a drug and a poison differ? A poison is a substance that is capable of causing harm to an organism, whether it is an illness, injury, or death. The modern definition of the term poison is essentially the same as that of a toxic substance. The more toxic or poisonous a substance is, the more harm a small amount of it can cause. Looking at it this way, everything is poisonous; it is the amount and time over which the substance is administered that determines how harmful it will be.

MEASURING TOXICITY

Although there are many measures of toxicity, one that is commonly used is the LD50 value, or lethal dose 50 percent. This is the dose that will result in the death of half of a test population that is exposed to this level of the substance in a single dose. A test population would be something such as a group of laboratory mice used in the experiment. A corollary to the LD50 is the ED50, or effective dose 50 percent, which reflects the dose of a drug or medicine that shows a therapeutic effect in 50 percent of the tested patients. There are two graphical ways to interpret LD50 and ED50. In both approaches the X axis is the dose, increasing from left to right. In the first approach (top frame of the figure), as the dose increases, it reaches a threshold at which some individuals taking that amount die.

Graphical presentation of lethal and effective doses. In the top frame, the Y axis is the percentage of the population that dies at a given dose. At low doses only susceptible members of the population will die. Similarly, even at high doses, some will survive and are labeled as tolerant. The dose at which half of the population is affected is the 50th percentile. At the LD50 dose half of the test population dies. The bottom frame shows the same thing in a different way; the number of deaths peaks at the LD50 The same methods can be used to evaluate effective dose.

These people (or test animals) are labeled "sensitive" or "susceptible," since they are affected at a lower dose than most. As the dose increases, the percentage of the test population that dies increases. A dose that kills 50 percent of the population is the LD50 value. There will be some individuals who are resistant or tolerant of that dose, and they will die only when ingesting more than the LD50. A second graphical approach (bottom frame of the figure) shows what fraction of the population dies at a given dose, with the largest percentage dying at doses at or near the LD50. For ED50 the graphs would be identical except that the effect noted would not be death but rather a therapeutic response to the drug. Some people would need smaller doses (susceptible) while others would need a larger dose (tolerant) to achieve the desired effect.

To find the LD50 toxicologists often turn to a document called the materials safety data sheet (MSDS) or other toxicity indexes found in books or online. An MSDS contains a wealth of information in addition to toxicity data, including how materials should be safely handled, stored,

Dose LD50

Dose LD50

High

Susceptible

Tolerant

High

Susceptible

Tolerant

G Infobase Publishing

High

G Infobase Publishing

High and disposed of. The following table shows a sampling of the toxicity data taken from the MSDS forms for two common household substances.

Which is more toxic? Acetylsalicylic acid (aspirin) can cause harm, at least in rats, at a lower dose than sodium chloride (table salt) can, but the data is incomplete. LD50 data will only be available if a substantially sized population is exposed to a substance. The data for rats is obtained from laboratory studies, but any human data has to come from accidental exposures. Children are much more likely to take a large dose of aspirin accidentally than are adults, and therefore, there is enough clinical data from such incidents to report a reliable LD50 value. The same is not true of table salt, for which rat data alone is presented. If the response of rats can be applied to humans, aspirin is more toxic than table salt.

For the sake of an example, assume that the LD50 for aspirin for an adult is 200 mg/kg, which refers to the amount of material in milligrams (mg) that is ingested per kilogram (kg) of body weight. A kilogram is the equivalent of 2.2 pounds, so a person's weight in kilograms will always be less than when the weight is expressed in pounds. To determine the LD50 value for a typical woman weighing 130 pounds the necessary calculations are

1. Convert her weight to kilograms.

1. Multiply her weight in kilograms by the LD50 value.

LETHAL DosEs of common MATERiALs TAKEN BY mouth (orally)

LD50 (mg/kg) acetylsalicylic acid sodium chloride

(aspirin) (table salt)

oral child oral rat

104 200

not available 3,000

For this 130-pound woman the LD50 value is almost 12 grams (g), nearly half of an ounce. A typical aspirin tablet contains 325 mg (1 milligram = 1/1000 of a gram) of aspirin, so this lethal dose translates to about 37 aspirin tablets. Does this mean that any woman weighing 130 pounds

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