Michael A. Militello
Basic understanding of pharmacokinetic and pharmacodynamic concepts is essential to the design of rational, patient-specific pharmacotherapy. The study of pharmacokinetics was first introduced some 40 years ago and is defined as the time course of drug absorption, distribution, metabolism, and elimination. In basic terms, this is described as how the body handles the drug. The concepts of pharmacokinetics can be applied to individual patients in order to maximize efficacy and limit drug toxicities. Drug plasma concentration can help to predict efficacy and toxicity of selected medications. Even though there are limited data for therapeutic drug monitoring for all medications, pharmacokinetic principles can be applied to a wide range of medications.
The primary principle of pharmacodynamics is that a relationship exists between drug concentration at the site of action (receptor) and pharmacologic response. The concentration at the receptor site is most important for elucidating pharmacologic response, with the assumption that serum concentration is directly proportional to receptor concentration. This assumption is not always true. For example, although abciximab has an initial half-life of 10 minutes and second-phase half-life of about 30 minutes, measurement of plasma concentrations of abciximab is not of clinical importance, whereas measurement of platelet activity potentially could be. The focus of this chapter is to review pharmacokinetic and pharmacodynamic concepts and relate them to specific cardiovascular medications. This chapter does not cover current guidelines for use of medications. Please refer to individual chapters in this review book for guideline reference.
PHARMACOKINETICS
Pharmacokinetics refers to the concepts of drug absorption, distribution, metabolism, and elimination (known as “ADME”). Such principles can be applied to drug therapy by such examples as determining loading and maintenance doses of medications, adjusting doses for altered elimination (e.g., renal or hepatic insufficiency), and interpreting plasma drug concentrations. The concepts of ADME are reviewed below.
Absorption
Absorption of medications can occur via multiple routes of administration. Medications administered via the intravenous route are considered to have 100% absorption because the drug is delivered directly into the patient’s circulation. Other routes of administration include oral, transdermal, buccal, sublingual, subcutaneous, intradermal, and rectal. Depending on the type of medication, there are advantages and disadvantages of each of these administration techniques related to absorption. For example, the administration of nitroglycerin via the oral route would provide little systemic effect because of the high degree of presystemic clearance through hepatic metabolism. However, when nitroglycerin is administered intravenously, transdermally, or sublingually, the amount delivered is greatly increased, as presystemic clearance is bypassed.
A number of factors affect the amount of drug absorbed. These include:
Dose administered
Fraction of the administered dose that is “active drug” (S)
Bioavailability of the drug (F)
The equation for amount of drug absorbed is
Amount of drug absorbed = (S) (F) (Dose)
The fraction of administered dose that is “active drug” (S) is typically described as the salt form of a drug and varies with different salts. For example, quinidine sulfate has 82% active drug, and quinidine gluconate has 62%. By using the above equation, you can convert one salt form to another salt, assuming you know the bioavailability (F). For example, quinidine sulfate is 82% quinidine base with a bioavailability of 0.73, and quinidine gluconate is 62% quinidine base with a bioavailability of 0.7. With this information, you can compare the amount of quinidine in each tablet to make your conversion. Below is a comparison of quinidine bases, assuming you have 200-mg tablets of both quinidine sulfate (a) andquinidine gluconate (b).
a. Amount of quinidine base absorbed = 0.82 × 0.7 × 200 → 114.8 mg
b. Amount of quinidine base absorbed = 0.62 × 0.7 × 200 → 86.8 mg
Bioavailability (F) is defined as the fraction of an administered dose that reaches the systemic circulation of a patient. Values of bioavailability can be found in a number of pharmacology texts and drug reference handbooks. Factors that can alter bioavailability include:
Inherent characteristics of the dosage form administered (e.g., tablet dissolution characteristics)
Administration route (e.g., oral versus transdermal versus intravenous). The bioavailability of most parenterally administered drugs is 100% (i.e., F = 1).
Issues related to the gastrointestinal (GI) tract
The bioavailability of orally administered medications can be affected by gastric pH, GI transit time, gut metabolism, and the presence of food. Certain medications may be unstable in low-pH environments and therefore may be enteric coated in order to prevent breakdown in the stomach. Conversely, certain medications, such as itraconazole, require an acid environment for optimal absorption. Likewise, changes in GI motility with promotility agents or patients experiencing diarrhea may have decreased absorption secondary to decreased transit time through the GI tract. Enzymatic metabolism of medications in the GI tract can also alter absorption and can be responsible for drug interactions. A well-described example of this is the fact that administration of grapefruit juice with certain medications may actually enhance bioavailability secondary to preventing GI metabolism of the compound, thereby increasing the amount of drug available for absorption. Finally, the amount of bioavailable drug may be reduced as a result of the extent of metabolism before reaching the systemic circulation. Examples of this include metabolism via GI bacteria (e.g., digoxin) or “first-pass metabolism” by the liver.
Drugs are absorbed from the GI tract into the portal circulation, and certain drugs are extensively metabolized in the liver before reaching systemic circulation. These drugs have a high first-pass effect or high first-pass metabolism, which can significantly decrease the amount of medication reaching the systemic circulation and hence drug bioavailability. Drugs with high first-pass metabolism have much lower intravenous doses compared to oral doses. Examples of medications with high first-pass metabolism are diltiazem, nitroglycerin, propranolol, verapamil, hydralazine, isoproterenol, labetalol, lidocaine, metoprolol, and nifedipine.
Distribution
After absorption, medications distribute to various tissues in the body to produce a pharmacologic effect. Not all distribution sites for a given medication produce a therapeutic effect. In fact, some distribution sites may produce no effect or untoward effects. The volume of distribution (Vd), or apparent volume of distribution, refers to the total amount of drug in the body, assuming that the drug is present at the same plasma drug concentration (Cp) throughout the body. The Vd is expressed in terms of volume (e.g., liters or liters per kilogram) and is a function of the solubility (lipid versus water solubility) and binding (tissue versus plasma protein binding) characteristics of the drug. Actual sites of distribution cannot be determined from the Vd value.
The volume of distribution equation is
Factors that tend to increase Cp will decrease apparent Vd and include drugs that have:
Low lipid solubility
High plasma protein binding
Low tissue binding
Factors that tend to decrease Cp will increase apparent Vd and include drugs that have:
High lipid solubility
Low plasma protein binding
High tissue binding
Volume of distribution can be used to estimate a loading dose needed to achieve a desired plasma concentration rapidly. A medication, such as amiodarone, which has a large volume of distribution (66 L/kg) requires a longer duration (weeks) to load adequately, as there is a large number of distribution sites. In contrast, a person receiving procainamide, which has a volume of distribution of 2 L/kg, can be adequately loaded with a single dose in the appropriate amount. Although a loading dose does not decrease the time to achieve steady-state plasma concentration, it does reduce the time to reach a therapeutic plasma concentration or therapeutic range. For many medications, there is not a target concentration that is defined, and therefore, loading-dose equations are typically not used. In this circumstance, which is true for most drugs, initial and maximal doses are chosen based on dose ranging and randomized studies comparing the expected response to the dose. For instance, early trials of metoprolol tartrate used starting doses of 25 to 50 mg twice daily for hypertension, and these doses produced the clinical response desired to obtain the specified endpoints. Therefore, using both pharmacokinetic and pharmacodynamic data can help to establish appropriate dosing of medications when obtaining serum drug levels is not available.
To determine the loading dose, the following equation is used:
The target plasma concentration for a given drug is often referred to as the therapeutic range, and can be thought of as a range of drug concentrations in which there is a relatively high probability of achieving a desired clinical response and a relatively low probability of developing unacceptable toxicity. Narrow-therapeutic-range drugs are ones in which this desired drug concentration range is small (e.g., lidocaine, procainamide, digoxin, quinidine, etc.) and the therapeutic concentration and toxic concentration are similar. This concept is reviewed later in this chapter under pharmacodynamics.
Metabolism and Elimination
Clearance (Cl) is the intrinsic ability of the body (or eliminating organs such as kidneys or liver) to remove drug, and is expressed in volume per unit of time (e.g., liters per hour). Hepatic metabolism of a drug can lead to formation of active or inactive metabolites. Metabolites may contribute to the therapeutic efficacy or toxicities associated with the parent drug (e.g., procainamide and N-acetylprocainamide).
At steady state, the rate of drug administration (RA, or dose per time) and rate of drug elimination are equal, and the concentration of drug remains constant. Clearance can be thought of in terms of these factors in the following equation, where Cpss refers to steady-state plasma drug concentrations:
The relative clearance of drug is an important factor in calculating the rate of administration or maintenance dose to produce a desired average plasma drug concentration:
Maintenance dose or RA = (Cl)(Cpss)
Another consideration in determining dosing interval is evaluating the half-life of a medication. Half-life (t1/2) refers to the amount of time required for the total amount of drug in the body or the plasma drug concentration to decrease by half. Half-life can be calculated with the following equation:
Half-life can be used to determine the amount of time it will take to reach steady-state plasma concentrations. Typically, three to five half-lives are required to reach steady state. It takes one half-life to reach 50%, two to reach 75%, three to reach 87.5%, four to reach 93.75%, and five half-lives to reach 97% of steady state. Half-life can also be used to determine how long it will take to eliminate drug from the body after the drug has been discontinued. It takes one half-life to eliminate 50%, two to eliminate 75%, and so on.
Metabolism of medications typically occurs in the liver, producing more hydrophilic compounds to allow for elimination through the kidneys. However, many drugs may undergo exclusive renal elimination without any form of biotransformation or metabolism. Biotransformation may also convert prodrugs (precursors to active drug forms) to drugs with biologic activity (e.g., enalapril, losartan). Other routes of drug elimination include biliary routes.
PHARMACODYNAMICS
The main principle of pharmacodynamics is the relationship between drug concentration at the site of action (receptor site) and pharmacologic response. Simply stated, pharmacodynamics is the study of plasma concentration and pharmacologic response. This relationship can be described by the equation
where E is the pharmacologic effect, Emax is the maximum effect the drug can cause (determines efficacy), EC50 is the concentration at which one-half of the maximal response will occur (determines drug potency), and C is the concentration of the drug at the receptor site.
Drugs with low EC50 are considered more potent than the comparison drug (i.e., these drugs elicit the same response at lower concentrations). Drugs with a similar Emax are considered to have similar efficacy (Fig. 60.1). Some medications may have the same EC50 but very different Emax values.
FIGURE 60.1 Potency and efficacy curves. Drug A is considered to have the same efficacy as drug B, because the maximal effect is the same. However, drug A is considered to be more potent, because the EC50 is less than that of drug B.
These same efficacy principles can be applied to toxicity and used to evaluate therapeutic ranges or indexes. The dose that produces toxic effects in 50% of evaluated subjects (typically animals) is called the toxic dose 50 or TD50. The ratio of the TD50 to the ED50 is the typical definition of therapeutic index. As this ratio approaches one, the therapeutic index is considered narrow. The risks versus benefits of the therapy as well as the severity of the disease state determine an acceptable therapeutic index. For example, medications to treat chronic diseases or non–life-threatening diseases typically have therapeutic indexes that are large. In contrast, physicians accept a narrower therapeutic index when treating a disease state that has a high mortality (e.g., certain malignancies).
PHARMACOGENETICS
Pharmacogenetics is the third side of the pharmacology triangle. The other two sides of this triangle, pharmacokinetics and pharmacodynamics, are described above. Drug response may be altered in an individual patient based on their genetic variation. Variations in the genetic code for drug targets (receptors), drug metabolizing enzymes (CYP 450), and drug transport genes can explain in many cases the difference in interindividual response to drug therapy. There are a number of examples of genetic variation that may alter response to drug therapy; these include clopidogrel response and CYP 2C19 activity, warfarin response and CYP 2C9 activity, as well as VKOR (vitamin K epoxide reductase) activity and digoxin levels as it relates to P-glycoprotein activity We are currently limited in our ability to utilize pharmacogenetic information in daily practice because in most cases there are limited data to support improved patient outcomes.
SUGGESTED READINGS
Braunwald E, Zipes DP, Libby P, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 7th ed. Philadelphia: WB Saunders; 2005.
Evans WE, Schentag JJ, Jusko WJ, eds. Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. 3rd ed. Vancouver, WA: Applied Therapeutics; 1992.
McLeod HL, DeVane CL, Haga SB, eds. Pharmocogenomics: Applications to Patient Care. 2nd ed. Lenexa: American College of Clinical Pharmacy; 2009.
Winter ME. Basic Clinical Pharmacokinetics. 4th ed. Baltimore: Lippincott Williams & Wilkins; 2004.
QUESTIONS AND ANSWERS
Questions
1. Which of the following best describes bioavailability?
a. The amount of drug absorbed
b. The amount of drug that reaches systemic circulation
c. The amount of drug that is cleared by the liver upon first-pass metabolism
d. The amount of drug within the tablet
2. Which of the following answers best describes this statement?
Beta-blockers slow ventricular response in patients with atrial fibrillation.
a. Pharmacodynamics of beta blockers
b. Pharmacokinetics of beta blockers
c. Tolerance to beta blockers
d. Pharmacogenetics of beta blockers
3. Amiodarone has a volume of distribution of about 66 L/kg and gentamicin has a volume of distribution of 0.25 L/kg. Based on this information, which answer describes the above statement best?
a. Amiodarone is cleared by the kidneys.
b. Amiodarone distributes only into intravascular volume.
c. Amiodarone is expected to have a short half-life.
d. Amiodarone is expected to have a long half-life.
4. Which of the following angiotensin-converting enzyme inhibitors (ACE-I) needs to undergo biotransformation to become active (i.e., which of the following is a prodrug)?
a. Enalaprilat
b. Lisinopril
c. Captopril
d. Ramipril
5. The average half-life of metoprolol is 6 hours. If you initiated 50 mg three times daily, how long will it take to reach steady state?
a. 12 hours
b. 18 hours
c. 24 hours
d. 30 hours
Answers
1. Answer B: Bioavailability is the amount of drug that reaches the systemic circulation.The amount of drug absorbed is related to the bioavailability; however, if a medication undergoes first-pass effect, some of that medication will not be bioavailable. Answer c also relates to bioavailability but this describes presystemic clearance.
2. Answer A: The pharmacodynamic response to beta-blocker therapy is to decrease heart rate and blood pressure. Pharmacodynamics is the relationship between drug concentration at the site of action (receptor site) and pharmacologic response. Pharmacokinetics is simply the effect that the body has on the medications.This is described in terms of absorption, distribution, metabolism, and elimination (ADME).
3. Answer D: Based on the equation t1/2 = (0.693xVd)/Cl medications that have a large volume of distribution will be expected to have a long half-life.There is a direct relationship with volume of distribution and half-life and an inverse relationship with clearance.The volume of distribution will not give you the mechanism of how the drug is cleared. Finally, you would not expect a medication that has a large volume of distribution to be found only in the intravascular volume and would need to have a great deal of tissue binding.
4. Answer D: Most of the ACE-I are prodrugs and require transformation in the liver to the active compound. Answers a, b, and c are all the active forms and do not require biotransformation.
5. Answer D: In the strictest sense, it takes five half-lives to reach steady state.Thus, 30 hours is the answer. However, the following is true: after one half-life, 50% of steady state is achieved; after two half-lives, 75% of steady state is achieved; after three half-lives, 87.5% of steady state is achieved; and after four half-lives, 93.75% of steady state is achieved.