PHARMACOKINETICS AND BIOPHARMACEUTICS (46:138)

LECTURE TUTORIAL

DETERMINANTS OF PHARMACOLOGIC EFFECT

 

Key Terms:

 

Determinant: A factor that influences. When used in the context of this lecture, we are referring to those factors that influence the measured pharmacologic effect.

 

Disposition: The distribution, metabolism and elimination of xenobiotics in the body. In essence, the disposition of a compound describes its fate once it has entered the body. Thus, disposition considers those events that occur after absorption (if the route of administration necessitates absorption prior to drug entry into the body).

 

Xenobiotic: A compound to which the body is exposed that is foreign to the body. Compounds referred to as xenobiotics include, medicinal agents (drugs), industrial chemicals, and environmental chemicals. This term is used to emphasize the fact that the principles that govern the disposition of drugs in the body are identical to those that determine the disposition of industrial or environmental chemicals.

 

Onset: The time required for a xenobiotic to exhibit its pharmacologic or toxicologic effect. It is measured as the time from administration to the first measurable response to the agent. A measurable response will not be observed until the drug exceeds the minimal concentration necessary to provoke the observed response. A drug that is absorbed quickly will reach that minimum concentration more rapidly than a drug that is slowly absorbed. Students often get confused when comparing the onset of drugs. Remember that a drug with a quicker onset will require less time before exerting a pharmacologic effect. Increasing the onset means more time is required before the effect is observed.

 

Duration: The length of time a drug exhibits a pharmacologic effect after administration. This is determined by the amount of time drug concentration is at or above the minimum effective concentration. The duration of drug in the body is not equivalent to the duration of effect. A drug may be in the body for a period of time that is much longer than the duration of action, if the concentration remains below the minimum effective concentration. In fact, some drugs that are slowly absorbed may never exert a pharmacologic effect, even though they are in the body for a prolonged period of time. This occurs when the drug is absorbed so slowly that it never reaches concentrations that meet or exceed the minimum effective concentration.

 

Intensity: A quantitative measure of the magnitude of pharmacologic/toxicologic effect. Examples would include the percentage reduction in heart rate, the millimeters the pupil diameter is reduced, or the amount of increase in urine production. Intensity is generally related to the peak concentration. The higher the peak concentration - the greater the intensity of effect.

 

Potency: Generally a comparison measure of the relative concentration of drug required to achieve a given magnitude of response. This comparison is often made by determining the concentration necessary to produce 50% of the maximal effect (EC50) for both compounds. The compound with the lower EC50 is the more potent compound. When the concentration response curve for a drug shifts to the right, it is an indication that the potency has decreased. This can happen in disease states where the target organ becomes less responsive to the drug, such that more drug is needed to achieve a given response.

 

Therapeutic Index: When administering drugs, we must be aware that they produce both desired and undesired (often called adverse) effects. The ratio of the minimum concentration of drug that produces toxic effects (MTC minimum toxic concentration) and the minimum concentration that produces the desired effect (MEC minimum effective concentration) is used to determine the therapeutic index. The term therapeutic window is often used to refer to the span of concentration between the MEC and MTC. The larger the therapeutic window for a drug, the easier it is to use that drug without causing unwanted toxicity in patients.

 

Pharmacokinetics: The study of the absorption, distribution, metabolism, and elimination of xenobiotics. This is often referred to in pharmaceutical industry as determining the ADME profile for a compound. In essence, pharmacokinetics describes the fate of a compound in the body.

 

Pharmacodynamics: The study of the biochemical and physiological effects of xenobiotics and their mechanisms of action. Pharmacodynamics is concerned with what effect the drug has on the body.

 

 

Key Principles:

 

Concentration-Effect Relationship: Studies in vitro and in vivo have demonstrated that, for most drugs, there is a relationship between the concentration of a drug at the site of action and the effect that is observed. For most drugs, it is not possible to measure the concentration of drug at the site of action. Thus, as an alternative, the concentration of drug in a fluid that is in equilibrium with the site of action is measured. Assessment of the concentration-effect relationship reveals that most drugs exhibit a graded response. A graded response is one wherein the magnitude of effect increases with increasing concentrations, eventually reaching some maximal effect.

 

Variability: As you begin to consider drug use in man, one of the most important facts to keep in mind is the variability in response that is observed. The same dose of drug administered by the same route to different subjects will produce a varied response. This creates a serious challenge in using drugs to treat and prevent disease. How can we use drugs rationally if we cant tell the magnitude of effect that will be observed in a given patient if we administer a set dose to that patient? Based on our knowledge of concentration-effect relationships, we might initially conclude that all we need to do is identify the effective concentration for a drug in a sample group of subjects, then make sure we give all patients enough drug to achieve that concentration. However, the same concentration of drug in a group of patients may not produce the same magnitude of effect in all patients. This was exemplified in Figure 9-5 in the lecture handout (and reproduced below), which shows the frequency of cardioversion as a function of concentration in patients with atrial fibrillation. The objective in administering quinidine to these subjects is to convert their heart rhythm from atrial fibrillation back to normal sinus rhythm (hence the term, cardioversion). This would be an example of an all-or-none response (also referred to as a quantal response); which means there is no degree of measured response you either achieve the desired end (in this, normal sinus rhythm) or you do not. At a concentration of 4 mg/L, less than 20% of the subjects returned to normal sinus rhythm. However, once a concentration of 10 mg/L was achieved, greater than 90% of subjects achieved normal sinus rhythm.

 

 

This example illustrates the fact that in a population of subjects, a concentration-response relationship represents a probability curve, such that as the concentration of drug is increased the probability that a given patient will respond with the desired effect is increased. Again, this may lead one to conclude that we should simply give a large enough dose of the drug to make sure 90% or more of the subjects will achieve the desired effects. A problem in achieving this goal is the variability in concentration obtained after a standard dose in a group of subjects.

 

The variability in concentration needed to achieve the desired effect is most commonly secondary to differences in the pharmacodynamics of the drug between patients. This may reflect differences in receptor affinity for the drug, differences in the number of receptors, or a variety of other factors. In contrast, the largest cause of variability in the dose needed to achieve a given effect is due to differences in the pharmacokinetics of the drug, which will cause variations in the concentration achieved after a given dose.

 

Practice Problems:

 

1.      Dipyridamole is marketed in a tablet that exhibits an absorption pattern rate-limited by disintegration (i.e., disintegration is the slowest step). Draw the concentration versus time profile for dipyridamole when a tablet is swallowed whole and the expected curve if the tablet was chewed before swallowing. Describe what would happen to the onset, intensity and duration when a tablet is chewed before swallowing versus swallowing the tablet intact. Answer

 

2.      Draw the expected concentration versus time curve for pentobarbital administered as an aqueous solution, an aqueous suspension, or a tablet. Which dosage form would provide the shortest onset? Which dosage form would provide the greatest intensity of effect? Answer

 

3.     The therapeutic window for phenytoin is 10 to 20 mg/L. This means that a patient in whom a concentration of 8 mg/L is achieved will not clinically benefit from the drug. True or False? Explain the reason for your answer. Answer

 

 

 

 

 

Last revised 06/02/04

 

2004 - Craig K. Svensson, Pharm.D., Ph.D.

 

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