Chapter 38
Introduction to Pharmacokinetics

What is Pharmacokinetics?

When we speak about a drug's action on the body, we are speaking of pharmacology and toxicology. When we speak of the body's action on the drug, we are speaking of pharmacokinetics.

Pharmacokinetics is an extremely complicated subject which isn't possible to cover completely in a course like this, but that isn't our purpose anyway. What we will do in this chapter is introduce you to the theory and definitions of pharmacokinetics and give you an understanding of the processes involved.

Pharmacokinetics consists of the properties of absorption, distribution, metabolism, and elimination of a drug. A drug's "kinetic profile" is a compilation of all of these properties.

As we have talked about in a previous chapter, the ideal drug would be available directly to its site of action, with no other areas affected. This is almost never the case. Instead, most drugs need to be administered by a route of administration which makes the drug wind its way though the body until it finally reaches its target area. (ie, orally or intravenously)

Absorption

The process of a drug being moved from its site of administration into the bloodstream is called absorption. Most commonly, you would think of absorption taking place with tablets or capsules taken orally and then being taken from within the GI system into the bloodstream. That is a great example of absorption, but by no means the only one. Drugs are also absorbed through the tissues after an IM or SQ injection. They are also absorbed through the skin, as in transdermal nitroglycerin. They are also absorbed through the tissue of the lungs, as in anesthetic gases. The list is long. The key being, once the drug is deposited at its site of administration, the process of absorption takes it from there and moves it to the bloodstream.

The rate at which this process occurs is called the drug's rate of absorption. How completely this movement occurs is called the drug's extent of absorption. The greater the rate and extent of absorption, the greater the amount of the drug which will reach the bloodstream, and the higher the initial blood level will be.

Distribution

Once a drug reaches the bloodstream, it must be moved throughout the body to the intended site of action. If a drug is absorbed, but doesn't reach its target area, it would be useless. The process of moving the drug throughout the body is known as the drug's distribution. Different drugs may vary according to how they are distributed. Many drugs are fat soluble, and will be taken up into the fat tissues of the body. Others are not, and they will not permeate the fat cells. Our body has a protective mechanism to effectively screen chemicals from crossing into the blood stream into the central nervous system (ie, the brain). Some drugs readily cross the blood/brain barrier and are distributed to the nervous system tissues. Others are not. A drug meant to treat a CNS disease state, like Parkinsonism, would be ineffective if it can not cross the blood/brain barrier. Areas in which a drug travels once inside the bloodstream are reflected in the property of distribution. The greater the distribution of a drug, the greater the value of its "volume of distribution" value.

Metabolism and Elimination

Even as a drug is being absorbed and distributed, the body becomes busy trying to remove it. This speed at which this of removal occurs is called a drug's elimination rate. Drugs may be eliminated in a number of ways. The primary method you can think of occurs via the kidneys through urine. You may think of the kidneys as being the primary organ involved in drug elimination from the body. This is not the only way elimination occurs. Elimination also takes place through feces, and even much less commonly through exhalation (ie, anesthetic gases)!

In order to more effectively remove drug products from the body, the body also has chemical processes to breakdown or physically change a drug's structure. These changes may:

• make an active drug inactive
• make an inactive drug active
• change an active drug into another active drug which may be more or less effective than the original
• attach a chemical "handle" which makes it easier for the kidney to "grab onto" the compound

The primary organ involved in the metabolism of drugs is the liver. The liver contains many enzyme systems which attack drug compounds.

With the way in which the GI system is organized, any product which is taken into the GI tract and absorbed into the blood stream must first pass through the liver before the drug gets distributed through the body. This is called the first pass effect. It means that before a drug is available at the intended target area, the liver has already had a shot at breaking it down! This first pass effect must be taken into account during dosage calculations, and the dose the patient receives must be increased accordingly.

The first pass effect does not apply to administration routes other than enteral administration. You would not have to worry about first pass on a drug administered parenterally.

Also, keep in mind that not all drugs are metabolized. Some are eliminated unchanged.

Factors Which Affect a Drug's Kinetics

Many things can alter a drugs pharmacokinetic profile. Factors such as age, race, alcohol consumption, food, cigarette smoking, and other drugs commonly alter a drugs kinetics.

Food may often enhance or retard absorption. In the case of metoprolol, when taken with food, the drug will have a greater extent of absorption than when it is taken without food. However, the other side also exists. The drug ampicillin is a penicillin antibiotic which is broken down by stomach acid. When ampicillin is taken with food, the food stimulates acid release in the stomach, and less of the ampicillin is available for absorption. Another example is the drug tetracycline which readily binds with calcium. Therefore, tetracycline should never be taken with the calcium containing dairy products.

Age often changes a drug's kinetic profile. Every factor of kinetics may be affected. The rate and extent of absorption may change. The volume of distribution may change. Metabolism and elimination may become prolonged due to the aging process. Adjustments in dosing are often required.

Prolonged excessive alcohol consumption can damage the liver permanently. It is common for this damage to result in a lowered ability to metabolize many drugs. Some drugs, when combined with an already damaged liver, may make matters even worse. A prime example of this is the drug acetaminophen.

When a drug's kinetic profile is altered by another drug being taken is known as a drug/drug interaction. These influences may be direct or indirect. A drug, such as cimetidine, can stimulate enzymes in the liver which cause a faster breakdown of other medicines that are taken concurrently. Or the effect may be more direct, such as when iron is taken with ciprofloxacin. When these two are taken together, the iron binds to the ciprofloxacin molecule and inactivates it.

Importance of Pharmacokinetics

So we see that pharmacokinetics depends on the factors of absorption, distribution, metabolism and elimination. So why is it important? As we've seen in the pharmacology chapter, a guiding premise states that the effectiveness, and the toxicity, of a drug depends on the concentration of the drug at the target site. Too little, and the drug is ineffective. Too much, and harm may result.

By knowing factors such as the rate and extent of absorption, the extent of distribution, and the rate of metabolism and elimination, you can predict how a particular patient will fare with a particular drug dose. You can also determine whether or not a patient should take the drug at all. Take, for instance, the drug digoxin. Digoxin is eliminated by the kidney. Using the rules of pharmacokinetics, we can understand that any disease or condition affecting the kidney can have an effect on digoxin elimination from the body. What would the result be? Correct. If normal digoxin dosing is used, the drug can quickly accumulate to toxic levels within the body. If the kidney impairment is minor, dosing adjustments could be made to allow for the slowed elimination. If the damage was major, the drug should not be used. Another drug, which is not eliminated by the kidney, could be used.

An example of metabolism changing the dosing of a drug exists with theophylline. Theophylline is used to keep the breathing passages open in patients with a compromised respiratory system. Problems with dosing occur in patients who are cigarette smokers. In these patients, metabolism of theophylline is increased over nonsmokers, and the same dose given in smokers vs nonsmokers will result in a lower blood level present in smokers. In order to compensate for this fact, an increase in the number of doses given per day in smokers is necessary. Pharmacokinetics tells us how much of the drug needs to be given and how often.

First Order Kinetics

An important parameter of kinetics is half-life. Half-life is a function of metabolism and elimination. It is a measure of the time required for the blood level of a drug to reduce by one-half its previous value. This means if we have a drug with a half-life of 2 hours, the blood levels will fall in this manner:

You see that for every half-life period, the amount of drug present decreases by 50% from the value at the start of the period. Drugs which follow this pattern of elimination are said to follow first order kinetics. The more drug that is there, the more drug that is metabolized per time.

Following first order kinetics, it takes 4 & 1/2 half-lives for a drug to be effectively "eliminated" from the body. Even though, theoretically, a minute part of drug could be present to infinity.

It is important to realize that when elimination is slowed by disease, or increased by some condition (ie, the smoker), the half-life of the drug will change as well.

Zero Order Kinetics

Not all drugs follow first order kinetics. Some drugs have a metabolic pathway which can become saturated. That means elimination will proceed at a relatively first order manner until the threshold is met. From that point on, the metabolism occurs at a set constant rate. Any more drug added after the point simply accumulates until the level dips under the threshold, once again. These drugs are said to follow zero order kinetics. An excellent example of zero order is the drug, ethanol. So when you are out celebrating after you receive notice of your passing the tech exam, remember the drinks you put down at the pub will follow zero order kinetics. (Make sure someone else drives, so you won't have to explain this to a member of the law enforcement community!)

Let me try to give you an example to be sure the difference between first order and zero order kinetics is clear. Let's imagine we have an empty 55 gallon drum. Coming out of this drum from the bottom is a 6 inch pipe. When we add water to the drum, the water is allowed to flow freely out of the pipe.

In either first or zero order kinetics, as long as we are adding water to the drum so that the depth doesn't exceed the 6 inches of pipe height, both types will allow the same amount of water to leave the drum.

Let's imagine now, that instead of adding water slowly, we dump the full 55 gallons of water into the drum all at once. With zero order kinetics, the emptying of the drum will still be restricted be the 6 inch diameter of the pipe exiting the drum. The diameter, and hence the rate of exit, can not change in zero order. The rate of removal does not change once the threshold (in this case 6 inches of depth) has been exceeded.

In first order kinetics, the diameter of the pipe leaving the drum will increase in diameter proportional to the amount of water we place in the drum, and the rate of water leaving will also increase proportionally. The rule of first order is, the more we put in, the faster it can be removed.

Repeated Dosing of Medications

We have seen what happens following a single dose of medicine. What happens when we repeatedly administer a drug? If we know the target level for a drug, we can calculate the dose, and dosing schedule, required to obtain and maintain that level. To do this, we must know the rate of elimination for the drug. Eventually, as we approach the target concentration, we want the amount of drug being cleared from the body to equal the amount entering the body. This is called steady state.

For ease of explanation, we will confine our discussion to a drug which follows first order kinetics. If you remember, that means "the more that goes in, the faster it comes out".

When a dose is first taken and absorption occurs, the blood level of the drug increases. Eventually this level will stop rising once the entire dose has been absorbed. This point is called the peak of drug concentration.

As elimination takes over and absorption ceases, the blood level begins to fall. Since we know therapeutic activity is dependent on the drug staying within its therapeutic range, we do not want to let the level fall too far. Consequently, the next dose is administered before the first dose is completely cleared from the body. The point right before the next dose begins to be absorbed is the lowest drug level in the blood, and that is called the trough of drug concentration. Multiple dosing is a repeat of these peaks and troughs.

Since the first dose was not completely cleared from the body when we added the second dose of medicine, we would rightly expect the second peak to be higher than the first. As more doses are given, this peak will continue to get higher until 4 & 1/2 of the drugs half lives have elapsed. At this point, if no change in drug dose or schedule has been made, steady state shall have been achieved. An equalization of drug coming in and the bodies ability to clear it has occurred.

Many drugs have a very narrow therapeutic index. The ability to predict and control the peak and trough allows us to minimize the potential for harm while keeping the concentration within the therapeutic range.

Chapter 38 Quiz