POPULATION RESPONSE CURVES

If you put a person under gen. anesthesia, calling the response CNS depression, there is a whole spectrum of effects that occur ranging from no effect, to losing consciousness, to death. We call this a graded scale; it’s a continuum of effects. With respect to general anesthesia, the responses are called “Guedel signs”.

Now, lets look at loss of consciousness specifically ( Brody fig. 3-3a). What dose of drug is required for loss of consciousness for individual patients? Some people pass out at higher or lower doses with respect to others. A given patient either does, or does not lose consciousness from a certain dose, this is a ‘quantal’ response. What we’re plotting is the number of patients who are knocked out at a specific amount of anesthetic. Some patients are more susceptible or resistant than average. Each dot represents the number of patients who pass out at a certain drug dose. Usually you’ll get a bell-shaped (or Gaussian) curve. Since we’re plotting log does, this is called a log normal distribution of drug sensitivities. This is how a population largely responds.

The dose at which most patients lose consciousness is where the graph peaks, called the median dose. In a population, half the pop. will fall below and half above the peak. That particular dose is called ED₅₀ (***usually when we refer to ED₅₀ it is in this context, NOT in the context discussed above in which it is equal to Kd for the dose-response curves). ED₅₀ is the median effective dose to produce the response for 50% of the population.

Usually we’re interested in the Therapeutic Response, so ED₅₀ is called the median effective therapeutic dose. We could talk about ED₅₀ with respect to anything… it’s the dose of drug that will produce the response in 50% of the population.

We can also talk about the effective dose for 10% or 90% of the population (ED₁₀ or ED₉₀, respectively).Lets now think of 2 curves with the same ED₅₀, but have different values of ED₁₀ and ED₉₀… The closer the ED₁₀ and ED₉₀ are to ED₅₀, the narrower the curve. This means that the drug will have a more predictable response.

Another important quantal response is DEATH!!! If too much of the drug is given you get into toxicity and can kill the patient. You then get a different type of curve, similar to the ED₅₀ curve we’ve been talking about . This is called the LD₅₀, or the dose of drug required to kill half the population. Obviously, LD₅₀ will be a bigger number than ED₅₀. The LD₅₀ curve will also have a bell shape, although it can have a different overall curve than the ED₅₀. We can also define LD₁₀, LD₅₀, etc. Drug safety is parameterized by the ration LD₅₀/ED₅₀. This is called the therapeutic index.

We want the therapeutic index to be high, in order to be safe. A good index is 10 or larger. Some drugs are less safe than this, general anesthetics can have therapeutic indices of 1.5 or 2… you’ve got to deal with patients in hospitals to administer these types of drugs. You’re literally bringing the patient to death’s door.

There is often an overlap between the ED and LD curves. This is a very dangerous region. If, for example, ED₉₀ coincides with LD₁, that means that if you gave the average patient enough drug to lose consciousness in 90% of patients, one out of one-hundred patients will die. The Certain Safety Factor (CSF) gives us information about this overlap.

CSF is defined by the ration LD₁/ED₉₉. What we want is this ratio to be greater than one. If CSF>1, this means that LD₁>ED₉₉, so the curves are pretty much separated. Unfortunately, CSF is not as commonly used as Therapeutic Index. CSF is a more certain parameter for drug safety.

Looking at Brody fig. 3-3b , we’ve plotted an analogous curve to the previous one. Here we’re plotting the number of patients that achieve a given response at or below each dose. For example if we’re talking about loss of consciousness, we can look at the total % of subjects achieving the end-point at or below the indicated dose. This is an integral of the previous curves… it’s a percentage of the area that happens to be unconscious at each dose. There’s no new information in this new curve, it has the same information as the curve . You’ll see both types of representations, don’t be confused between the two.

These two types of curves are TOTALLY DIFFERENT, you mustn’t confuse them!!! .

Category: Pharmacology Notes