Welcome to the first part of your journey!
I know you probably have your calculators out and are ready to do some practice problems, but first, we need to review some essential key terms to ensure your success in this course. Take a look at the words below. Do they ring any bells? If it does, it is because you have probably come across many of these words in various pharmacokinetic lessons. Let’s take a moment and review them!
NOTE: If you feel comfortable with these terms, feel free to scroll down to the end and complete the quiz to move on to the next lesson.
|Peak||Highest serum concentration of a drug achieved in the bloodstream collected 1-2 hours after the completion of infusion|
|Trough||Lowest serum concentration of a drug in the bloodstream collected prior to the administration of the next dose|
|Half-life (t ½)||The time required for serum concentrations of the drug to decrease by 50%|
|Steady State||When serum drug concentrations in the body remain constant. For most drugs this is around 4-5 half-lives.|
|Volume of distribution||Value of the physiologic volume of blood and tissues that the drug binds or distributes into (e.g. higher Vd, the more the drug distributes into tissues and the lower the Vd the more the drug stays in the blood)|
|Creatinine Clearance||Value that determines how well the blood plasma is cleared of creatinine per unit of time by the kidneys. It is a measurement of renal function and correlates with how well drugs will be eliminated from the kidneys.|
Absorption is the amount of drug that is absorbed at the site of administration (e.g., gut, lungs, intramuscular, rectal, topical,etc.) and enters the blood circulation. Intravenous drugs are not absorbed since they are injected directly into the bloodstream and, therefore, are considered 100% bioavailable.
How drugs cross membranes:
Unless administered intravenously, all drugs have to cross a membrane to be absorbed and reach the site of action. There are two main ways most drugs achieve this, passive or active diffusion.
Passive diffusion is the passage of drugs across the cell membrane (e.g., from gut to the bloodstream) from a higher concentration gradient to a lower concentration gradient. The vast majority of drugs utilize this type of absorption.
Certain characteristics allow drugs to diffuse easier across membranes:
- Smaller in size
- Uncharged or unionized
- Lipid soluble
- Weak acids and bases
‘Essentially, the smaller, weaker, uninteresting, and slippery (lipids) a drug is, the easier it passes through membranes and gets absorbed into the circulation!’
Active transportation is the passage of drugs across the cell membrane using energy in the form of ATP, hence the name active. This type of absorption is usually limited to drugs that are structurally similar to other substances in the body (e.g., ions, vitamins, proteins, amino acids).
Why is absorption important?
How well a drug is absorbed is linked to the drug’s bioavailability. The higher the amount of drug that is absorbed, the higher blood concentrations will be leading to increased bioavailability. If a drug’s oral dose is the same as it’s IV dose (such as levofloxacin), then it has a bioavailability of 100%, or 1. A drug’s bioavailability is particularly important when deciding which medication to give in serious infections (e.g., bacteremia) where higher drug concentrations are desired.
Once a drug is absorbed, it distributes throughout the body via the bloodstream. The bloodstream acts as an internal highway transporting drug molecules to target organs where it intends to work as well as other tissues, where unwanted side effects or adverse reactions can occur. This process is described as distribution, by which drug molecules move from the bloodstream to various tissues and organs of the body.
How widespread a drug distributes in the body depends on the drug molecule’s characteristics.
• Lipophilic drugs tend to distribute into fat tissues
• Highly protein-bound drugs can accumulate in certain organs
• Small, lipophilic drugs can cross the blood-brain barrier into the central nervous system
Do these characteristics sound familiar to you? If so, good. They are the same characteristics that make a drug molecule more easily absorbed from its site of administration. Our body is made of the same cellular membranes, so having the same features can help facilitate distribution.
To relate distribution to the pharmacokinetics of drugs, we use the term volume of distribution (Vd). The volume of distribution estimates the apparent volume that the drug dissolves in. This volume is a representation of the different fluid and tissue compartments in our bodies.
Suppose you dissolve 100 mg of sugar in a container of unknown size. You take a sample of the dissolved mixture and find that the concentration is 1 mg/mL (don’t ask me how you were able to find this concentration – maybe you have a special lab in your basement). Utilizing the simple equation below, you can figure out what volume of liquid the container holds.
Let’s try our example now in the human body.
You give your friend 500 mg of a drug to test your experiment. They were kind enough to provide you with a sample of blood, and utilizing the special lab you have in your basement, you obtain a plasma concentration of 0.01 mg/mL. You then perform the fancy equation you learned and find the following result.
Volume of distribution = 500 mg drug/0.01 mg/mL = 50,000 mL or 50 L
To put it into perspective, 50 L is the amount of water the standard-size tub can hold. Aside from assuming your friend is a giant water balloon, it is crucial to understand that this is a hypothetical volume. The concentration in the blood measured low (0.01 mg/mL), but you are sure you saw your friend swallow the whole pill. Where could the rest of the drug have gone? This example illustrates that the drug is widely distributed in the body elsewhere besides the bloodstream, such as the tissues, fat, bound to protein, etc.
From the example above, you can see that the volume of distribution is not an actual volume. It just gives you an IDEA of how well the drug has distributed into all the different fluid compartments, tissues, and organs of the body. The higher the volume of distribution, the more extensive drugs distribute throughout the body into tissues and organs. The lower the volume of distribution, the higher concentration of drug remains in the bloodstream.
Metabolism is a process by which your body converts food into energy, eliminates waste, and transforms drug molecules for easier facilitation of excretion. Drugs administered orally will need to pass through the liver to be metabolized before entering the blood circulation. This process is called the first-pass metabolism.
IMPORTANT TO NOTE:
First-pass metabolism only applies to drugs administered orally. Alternative routes of administration such as intravenous, sublingual, intramuscular, etc. all BYPASS first-pass metabolism since they are absorbed directly into the systemic circulation.
Metabolism of drugs in the liver turns it into a new molecule (often called metabolites) that is easier for the kidneys to excrete. Some drug formulations depend on liver metabolism to activate the drug (called prodrugs).
The liver is the body’s metabolic factory, hosting a series of enzymes called cytochrome P-450. These enzymes can be inhibited or induced by drugs. If a drug inhibits one of these enzymes, it can prevent another drug that is dependent on the same metabolic pathway from being broken down, increasing drug concentrations, and leading to toxicity. On the flip side, if a drug induces (ramps up) these enzymes, it will increase the rate of metabolism, reducing the effectiveness of some medicines.
Let’s take a look at an example.
Drug A inhibits CYP3A4
Drug B is metabolized by CYP3A4
The inhibition of CYP3A4 will lead to higher plasma concentrations of Drug B.
Metabolism plays a direct role in how much drug reaches blood circulation, affecting therapeutic outcomes and toxicity levels. This subject is of particular importance with medications known to inhibit or induce metabolism leading to drug interactions.
After the drug has been absorbed, metabolized, and delivered to the site of action, the final step is elimination. There are many pathways for drug elimination that may include the removal of drugs into urine, bile, sweat, saliva, milk, and other body fluids. Total body clearance is the sum of these individual clearance processes.
Clearance is the rate at which drugs get removed from the body. It is a measurement of the volume of plasma containing the amount of drug to be eliminated over a given time.
In an example earlier, we dissolved 100 mg of sugar in an unknown container. Imagine there is a filter pump now connected to the container filtering out sugar and returning the clean water. The filter continues to do this in terms of volume of mL per minute. Each time clean water is pumped back into the container, the concentration of sugar gets diluted further. Because of this, it is challenging to determine clearance by mg/minute as the mg amount will change over time with each dilution. A more consistent method would be to use the volume of fluid per unit of time.
The filter pump’s rate in mL per minute is the clearance of the container. The higher the amount of volume containing the drug removed per unit of time, the better the system (body) is at eliminating the drug (or in this example, the sugar).
Clearance = rate of removal of drug (mg/min)
Plasma concentration of drug (mg/mL)
Current laboratory techniques are not able to detect all drugs in the body, making it difficult to measure clearance based on drug plasma concentrations. An easier and less costly alternative is to use creatinine clearance.
This method determines the kidneys’ clearance of a waste product, creatinine, from the body. Creatinine clearance is also measured in mL/min and is a value that determines how well the kidneys clear the blood plasma of creatinine per unit of time. It is a measurement of renal function and correlates with how well the kidneys eliminate drugs.
Most medications follow two types of elimination models – first order elimination or zero order elimination.
- First-order elimination is the constant decrease in the PROPORTION (e.g. percentage %) of drug eliminated over time
- Zero-order elimination is the constant AMOUNT (e.g. mg) of drug eliminated over time
See an example of the two models below:
“When you FIRST cut a pie into PORTIONS, you have to ZERO in on the AMOUNT of calories per slice”
First-order = PORTIONS (%)
Zero-order = AMOUNT (mg)
The trough is the lowest serum concentration of a drug in the bloodstream collected prior to the administration of the next dose. Trough levels are used to determine the therapeutic effectiveness and toxicity of a medication. Most medications have standard laboratory trough ranges. If a medication requires monitoring and is continued for an extended period, it is essential to measure trough concentrations to determine the drug’s effectiveness and prevent toxicity.
Trough levels must be ordered and drawn correctly to allow for accurate interpretation. If the trough level is drawn too early while the drug is still infusing, it can lead to falsely high readings and vice versa.
The peak is the highest level of a drug in a patient’s bloodstream and is usually measured 30 minutes to 1 hour after the drug has finished infusing. Peak levels help determine the effectiveness of medications that are concentration-dependent. High peak levels can also lead to toxicity in certain medications.
Peak levels must be ordered and drawn appropriately to allow for accurate interpretation. If the peak level is obtained too early while the drug is still infusing, it can result in falsely high levels and vice versa.
Half-life (t ½) is the time required for serum concentration of the drug to decrease by 50%. In other words, after one half-life, the concentration of the drug should be half of the starting dose. After each subsequent half-life, more of the drug gets eliminated until it reaches negligible levels around 4-5 half-lives.
Half-life helps us determine when the next dose should be administered or the dosing interval.
Congratulations on finishing Lesson #1 Important Terminology. Check your understanding by completing the quiz below and see if you can unlock the code that leads to Lesson #2.