Chapter 1: General Principles

1.5: Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

David E. Lanfear, MD, MS, FACC Research Grants: Medtronic, Cardioxyl, Amgen, Sanofi-Aventis, Johnson & Johnson; Consulting Fees/Honoraria: Otsuka, Thoratec. James Kalus, PharmD This author has nothing to disclose.
Learner Objectives Upon completion of this module, the reader will be able to: 1. Demonstrate understanding and knowledge of pharmacokinetic drug interactions for common cardiovascular drugs. 2. Describe how principles of pharmacokinetics and pharmacodynamics can influence rational drug prescribing. 3. Define pharmacokinetics and pharmacodynamics as characteristics of medical therapeutics. 4. State principles of pharmacogenetics in cardiovascular drug therapy and cite relevant examples.

Introduction
The ultimate effect a medication has on the body is the complex summation of how it enters, affects, and leaves the body, and these can all vary substantially from one person to another depending on a wide variety of factors. This body-drug interaction can be broken down for better understanding into pharmacokinetics (drug processing) and pharmacodynamics (drug effects), as illustrated in Figure 1, andeach of these broad areas can in turn be affected by an individuals genetic makeup leading to pharmacogenetics (Figure 2). In this module, the authors attempt to breakdown and simplify each focus for better understanding and then reunite them as is best for practical application, using a case example.

Schematic of a Drug Pathway Depicting Transport, Targeting, and Metabolism

Drug Absorption Cell Membrane Transport

X
(Activation)

Inactivation

Metabolite

X-1

Cellular Target
Downstream Signalling

Pharmacokinetics
The term pharmacokinetics refers to the action the body takes on a medication. When a medication is ingested or administered, the medication is absorbed, distributed, metabolized, and eliminated. Key pharmacokinetic parameters exist for all four of these actions. Knowledge of general pharmacokinetic principles can be helpful in understanding the likelihood of adverse effects of a medication, avoiding drug interactions, predicting likely onset or duration of action, or understanding the influence of organ dysfunction on the use of a medication.

Pharmacologic Effects

Figure 1 Schematic of a Drug Pathway Depicting Transport, Targeting, and Metabolism

Absorption
A medication can be absorbed from the gastrointestinal (GI) tract, through the oral mucosa (e.g., sublingual nitroglycerin), through the skin (e.g., transdermal clonidine), or subcutaneously (e.g., enoxaparin). Absorption is not relevant in the setting of intravenous (IV) administration because the drug is administered directly into the bloodstream. Medications that are available as immediate-release dosage forms begin to be absorbed upon ingestion. Some medications are available in formulations that allow for slower release of the medication (i.e., extended-release,

sustained-release, delayed-release). After ingestion, these drugs are slowly made available for absorption, which allows for less frequent dosing. For example, nifedipine is available both as an extended-release and as an immediate-release formulation, with sharp clinical differences between them. The extended-release formulation can be given once daily, whereas the immediaterelease formulation must be administered three times daily and can cause rapid hemodynamic changes, which may contribute to adverse cardiac events. Absorption of a drug may also be affected by a variety of factors including the presence or absence of food, co-administration with other medications (e.g., antacids) that may bind with the
1.5: Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics 1.1.1

Schematic of Background Genetic Variation and Altered Medication-Related Outcomes

No Benet + Toxicity

Another factor that may impact bioavailability is whether or not the drug undergoes first-pass metabolism by the liver. First-pass metabolism refers to rapid metabolism that occurs after absorption, but before the drug has reached the systemic circulation where it will have its effects. A drug that undergoes extensive first-pass metabolism will have relatively lower oral bioavailability than otherwise expected.

All patients with the same diagnosis

+ Benet + Toxicity

Distribution
All medications have an apparent volume of distribution (Vd), a calculated value that relates dose of drug (e.g., millograms) to the concentration achieved in the blood (e.g., millograms per deciliter). Typically, Vd is expressed as a volume (liter) or volume/ body weight (liter per kilogram). For medications where specific drug levels are targeted, knowledge of the typical volume of distribution of a drug can be useful in estimating the concentration that will be achieved with a given dose of the drug. Vd can also assist the clinician in understanding the extent of distribution. For example, amiodarone has one of the largest volumes of distribution of any cardiovascular agent (approximately 50 L/kg). This is notable because amiodarone is well known to cause extracardiac adverse effects and appears to distribute to a variety of tissues. A newer agent, dronedarone, has pharmacologic properties similar to those of amiodarone, yet has fewer extracardiac toxicities and a much smaller volume of distribution (approximately 15 L/kg). In an individual patient, Vd can differ from population estimates due to numerous factors including age, body habitus, disease states, nutritional status, pregnancy, and critical illness. For example, selection of the appropriate bolus dose of lidocaine is based on Vd and can be affected by these factors. Typical loading doses are 1-1.5 mg/kg. The 1 mg/kg dose is often used in the elderly or in patients with heart failure because these patients have a lower volume of distribution than younger patients or those with normal ventricular function. Therefore, a lower dose will be required to achieve an appropriate lidocaine level. Protein binding may also influence Vd, because an increase or decrease in binding of drug to blood proteins can lead to a corresponding alteration in calculated Vd. For example, digoxin loading doses should generally be reduced in patients with severe renal dysfunction (creatinine clearance <20 ml/min) because reduced protein binding in this setting results in a lower Vd and, thus, a smaller initial dose requirement.3

No Benet No Toxicity

+ Benet No Toxicity

Figure 2 Schematic of Background Genetic Variation and Altered Medication-Related Outcomes

medication, or GI tract abnormalities. When a transdermal patch is used, absorption can be altered if the patch has been cut, or by changes in cutaneous blood flow (e.g., a high dose of vasopressors causing reduced cutaneous perfusion).1 The amount of drug available after absorption by a non-IV route, divided by the amount of drug available after IV administration is referred to as bioavailability. All medications have an inherent bioavailability related to efficiency of absorption and other factors. For example, the bioavailability of oral amiodarone is approximately 50% because one-half as much drug is available after oral administration, as compared to IV administration. P-glycoprotein (P-gp) also often plays a role in determining bioavailability. P-gp is an adenosine triphosphate (ATP)-dependent drug transporter that can efflux certain drugs back into the GI tract or kidney after absorption, thereby decreasing absorption. Co-administration of a medication with an inhibitor of P-gp may thus increase bioavailability of the medication. Since P-gp affects or is effected by many medications, it is important to note which drugs are P-gp inhibitors and substrates in order to anticipate these interactions. For example, a clinically relevant P-gp interaction occurs when digoxin and amiodarone are coadministered. P-gp efflux of digoxin into the GI tract is inhibited by amiodarone, leading to a doubling of the digoxin concentration. Therefore, digoxin dose should be decreased by one-half when initiating amiodarone. Other important inhibitors of P-gp are quinidine, verapamil, cyclosporine, tacrolimus, and many of the protease inhibitors.2 It should also be noted that P-gp induction can also occur, although less commonly. One example of a drug interaction that occurs due to P-gp induction is the clinically significant interaction between rifampin (a P-gp inducer) and the new oral anticoagulant, dabigatran, whose bioavailability may be compromised by this.
1.1.2 Chapter 1: General Principles

Metabolism
Drug metabolism occurs primarily through the liver via Phase I (oxidation, hydrolysis, reduction) and Phase II (conjugation) reactions. Phase I reactions include those mediated by the cytochrome P450 (CYP) enzyme system, which is particularly important in drug metabolism, estimated to act on over 90% of all medications.4 Often CYP system actions lead to formation of inactive/ less active metabolites, although it can also activate some medications. Regardless, CYP-mediated drug metabolism leads to many drug interactions via changes in rate of activation or inactivation.

Selected Substrates and Inhibitors of the CYP 450 System

Group/Class Substrates HMG-CoA reductase inhibitors Medication (s) Atorvastatin, lovastatin, simvastatin Fluvastatin Beta-blockers Calcium channel blockers Angiotensin-receptor blockers Antithrombotics Metoprolol All except amlodipine Losartan Warfarin Clopidogrel* Antiarrhythmics Amiodarone Mexilitine Propafenone Immunesuppressives Inhibitors Calcium channel blockers Cyclosporine,tacrolimus Diltiazem Verapamil Gem brozil Proton pump inhibitors Antibiotics Omeprazole, lansoprazole Clarithromycin, erythromycin Fluconazole Ketoconazole, itraconole Selective serotonin reuptake inhibitors Fluoxetine, Paroxetine Cytochrome P450 System 3A4 2C9 2D6 3A4 2C9 2C9 2C19 2C9, 3A4 1A2 2D6 3A4 3A4 3A4 2C8 2C19 3A4 2C9, 3A4 3A4 2D6

Table 1 Selected Substrates and Inhibitors of the CYP 450 System

*Produces active form of agent from prodrug. CYP = cytochrome; HMG-CoA = hydroxy-methyl-glutaryl coenzyme A. Reproduced with permission from R, DR G, ML R, PH V. Digoxin. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. Vancouver, WA: Applied Therapeutics, Inc.; 1992.

The most common CYP enzyme involved with drug interactions is CYP 3A4. Numerous cardiac medications are either inhibitors or substrates of CYP 3A4, including amiodarone, simvastatin, and several calcium channel blockers. When co-administered, these medications can reduce the inactivation of the other and, thus, increase medication exposure, resulting in toxicities. Table 1summarizes important CYP 450 enzyme system substrates and inhibitors. As mentioned previously, CYP enzymes also play an important role in activating certain medications, referred to as prodrugs. For example, CYP 2C19 is a key enzyme in the conversion of clopidogrel (which is an inactive prodrug in its native state) into its active metabolite, which actually causes platelet inhibition. Recently, much attention has been given to a potential drug interaction between omeprazole and clopidogrel. The mechanism of this drug interaction is inhibition of CYP 2C19 by omeprazole, which results in reduced conversion of clopidogrel to its active metabolite, thus reducing clopidogrel effectiveness; however, the

clinical significance of this interaction continues to be debated.5 Medications can also be CYP 450 enzyme inducers. Important CYP enzyme inducers are rifampin (2C9, 3A4), carbamazepine (3A4), tobacco (1A2), phenytoin (3A4), and phenobarbital (3A4). When a CYP 450 enzyme substrate is administered with an inducer of the same enzyme system, there is potential for increased metabolism of the target drug and, therefore, potential reduction in drug concentrations.

Elimination
Elimination refers to how the medication actually exits the body. A few important pharmacokinetic parameters are relevant to drug elimination. The first is half-life, which is the amount of time required for the concentration of drug to be reduced by one-half. When discontinuing a medication, it generally takes 4 to 5 half-lives for the drug to be completely removed from the body. Conversely, when initiating a drug, 4 to 5 half-lives will also be required to achieve steady state concentrations.
1.5: Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics 1.1.3

Steady state is the point at which drug administration is equal to drug elimination.3 All medications are either eliminated from the body unchanged, or if acted upon by drug metabolizing enzymes (as described earlier), they are converted to active or inactive metabolites and subsequently eliminated. The majority of medication/metabolite elimination occurs through renal mechanisms. Patients with renal dysfunction have reduced renal clearance of drugs and are often at greater risk of toxicity of agents that depend on this route. For example, digoxin is eliminated via renal mechanisms, and the frequency of dosing decreases from daily to every other day in severe renal dysfunction. Most often renal elimination occurs via filtration at the glomerulus, although some medications are secreted into the renal tubules. Both mechanisms can mediate alterations of drug clearance and drug interactions. For example, dofetilide is secreted in renal tubules and, thus, may interact with agents that block tubular secretion (e.g., cimetidine, trimethoprim, and ketoconazole), resulting in higher dofetilide levels.

rine), whereas medications that block the action of a receptor are called antagonists (e.g., metoprolol). Antagonists can be either competitive or noncompetitive. Competitive antagonists take the place of a naturally occurring ligand to block activity, whereas noncompetitive antagonists bind elsewhere and, thus, are less affected by the concentration of the usual ligand. Agents that affect the adrenergic system or those that interact with neurotransmitters (e.g., opioids) are good examples of this type of mechanism. Many cardiovascular drugs produce their pharmacodynamic effect by inhibiting the action of cardiac ion channels. Calcium channel blockers inhibit the influx of calcium into the cardiac pacemaker cells, which can limit the inotropic and chronotropic activity of the heart. Vaughan Williams class I antiarrhythmic drugs typically inhibit influx of sodium through sodium channels, whereas class III antiarrhythmics inhibit efflux of potassium through potassium channels. A notable pharmacodynamic effect of the class III antiarrhythmic drugs is prolongation of the QT interval. Concomitant use of more than one medication that prolongs the QT interval could result in a pharmacodynamic drug interaction, increasing the patients risk for developing torsade de pointes. Enzyme inhibition is another important target of many medications. The hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors are an important example of a cardiovascular medication class that produces a pharmacodynamic response through enzyme inhibition. HMG-CoA reductase inhibitors block the enzyme responsible for the final step of cholesterol formation, leading to reductions in intracellular cholesterol levels in the liver, which then cause enhanced reuptake of low-density lipoprotein (LDL) particles from plasma to liver, thus lowering plasma LDL levels. Another example is vitamin K 2,3-epoxide reductase (VKORC1), which is the target of warfarin. Warfarin inhibits VKORC1 from reducing vitamin K and, thus, impairs production of vitamin Kdependent clotting factors. Drugs may also bind to other types of proteins and enhance or impair their physiologic processes. Heparin is a good example of this. Antithrombin is a protein that can inactivate activated thrombin, serving a counter-regulatory function in the coagulation cascade. Heparin enhances antithrombins action, producing an antithrombotic effect due to greater inactivation of thrombin. On the other hand, bivalirudin is a direct thrombin inhibitor; it binds to thrombin and prevents thrombin from converting fibrinogen to fibrin, resulting in the antithrombotic effect. An understanding of pharmacodynamics can be important in drug selection. When selecting a positive inotropic therapy for the treatment of end-stage systolic heart failure, two available options are milrinone or dobutamine. Milrinone and dobutamine both produce increases in intracellular calcium concentrations, increased heart rate, and increased contractility; however, the mechanism by which they achieve this effect is quite different. Dobutamine acts as an agonist for the beta-1 receptors on the myocardium, increasing cyclic adenosine monophosphate

Pharmacodynamics

The term pharmacodynamics refers to the action the drug takes on the body or the biologic response that is elicited by the drug. Medications are generally thought to interact with a particular target in the body, and this interaction alters the function of the target, thus producing the medications effects. The drug target can be a wide variety of macromolecules in the body, such as neurohormonal signaling receptors (e.g., adrenergic receptors), enzymes (e.g., HMG-CoA reductase, vitamin K 2,3-epoxide reductase), ion channels (e.g., calcium channels), and many others in which the medication directly or indirectly alters the function of a biologically active substance. The pharmacodynamic effects of a drug could refer to both the desired therapeutic effects as well as the toxic effects. The term therapeutic index refers to the difference between the minimal therapeutic threshold and the minimal toxic threshold. Some medications have a narrow therapeutic index, meaning there is little difference between doses that produce efficacy and doses that produce toxicity in a given patient. However, most drugs have a broader therapeutic index, where doses much higher than usual therapeutic doses must be given to cause toxicity. Often, drug levels of medications with a narrow therapeutic index can be monitored in order to avoid toxicity (e.g., digoxin, procainamide, lidocaine). When a medication elicits a response by interacting with the drug target, there is often a dose-response pattern that can take different forms. Most medications exhibit a linear dose-response relationship through their therapeutic range, where the pharmacologic effect increases proportionately with number/proportion of occupied targets. Nonlinear dose-response relationships occur as well but are less common at typical doses of most medications. Medications that stimulate a signaling receptor, such as the beta-adrenergic receptor, are called agonists (e.g., epineph-

1.1.4

Chapter 1: General Principles

(cAMP) intracellularly and subsequently increasing calcium influx. Milrinone achieves this action by inhibiting the breakdown of cAMP, bypassing the beta-receptors, yet still increasing cAMP and calcium concentrations. Considering this, in patients requiring inotropic support who have recently taken or are planned for future beta-adrenergic blocking agents, milrinone may be a more sensible choice. Similarly, one might expect milrinone and dobutamine to have synergistic effects (and toxicities) when co-administered because they are both enhancing the same pathway but at different steps. An understanding of the interplay between pharmacokinetics with pharmacodynamics is also important in practice. Aspirin irreversibly inhibits the action of cyclooxygenase (COX) enzyme in the platelets, leading to prevention of platelet activation. While the pharmacodynamic effect of most drugs will not be present 4 to 5 half-lives after discontinuation, the pharmacodynamic effect of aspirin persists long after 4 to 5 half-lives have passed (approximately 12 to 24 hours for aspirin). This is because the irreversible inhibition of the COX enzyme in platelets renders those platelets permanently inactive. Therefore, the antiplatelet effect of aspirin does not resolve until new functional platelets have been generated, which generally takes approximately one week.

The genetic sequence variants of potential interest come in many forms with single nucleotide polymorphisms (SNP) being the most common. There are likely at least 30 million SNPs in the human genome, each of which represents a change of one base-pair to another at a given location in the DNA sequence. This may or may not result in a change in function or amount of the resulting transcript, and thus protein, depending on the nucleotide change and location. SNPs in protein-coding regions can either be synonymous (resulting in no amino acid change) or nonsynonymous, which results in an amino acid alteration, and may impact protein function directly. They can also occur in regulatory sequences such as promoter regions, which despite being noncoding, can impact gene expression. Even more often, SNPs are located in other areas with less certain functional impacts, such as introns or intergenic regions, though functional impact cannot be ruled out based on location alone. Other types of sequence variants that are less common also occur. These include repeats (short or long sequences that occur a variable number of times), and insertion/deletion polymorphisms (one or more base pairs, which are either present or absent). Similar principles regarding location and impact apply to these variants as well (e.g., variants are more likely to have a functional impact if they are within a gene vs. intergenic region). More recently, larger-scale genetic variation has been recognized, which can also impact gene function, for example, copy number variants (i.e., entire gene or larger segments that are duplicated). As science has learned more about the interplay of drugs and genes, genetic sequence variants have helped to explain more of the variation in response between patients; in specific examples, this has ranged widely and as high as 95%. The ultimate goal of pharmacogenetics (both in terms of research and as a clinical tool) is to leverage this knowledge to help physicians provide more rational, efficient, and targeted treatments to their patients (Figure 2).7 On the other hand, due to the fact that one may not always have a perfect understanding of a drug pathwayand with the emergence of high-throughput genotyping technology, genome-wide approaches are now also being used in research, giving birth to pharmacogenomics. As discussed in the previous sections on pharmacokinetics and dynamics, many nongenetic factors (e.g., age, organ function, drug interactions) influence medication response; thus, it is important to view pharmacogenetic factors within this larger framework, supplementing (not supplanting) other more conventional predictors. In this way, pharmacogenetic knowledge will often supplement and interact with ones knowledge about pharmacokinetics and dynamics. Initial applications of pharmacogenetics were limited to medications with very narrow therapeutic indices. A classic example of pharmacogenetics being used clinically is azathioprine and the gene thiopurine methyl transferase (TPMT). Azathioprine is used as an immunosuppressive agent in heart transplantation, as well
1.5: Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics 1.1.5

Pharmacogenetics
Pharmacogenetics is the area of research and medicine that is concerned with understanding how genetic variation impacts drug response. While still largely a research field, it now has burgeoning clinical applications. Important relationships between genetic variation and drug effect have been observed for a growing number of commonly used drugs,6 and ongoing studies should continue to increase the relevance of pharmacogenetics to clinical practice. There are commercially available pharmacogenetic diagnostic tests and a handful of examples with published guidelines for genetically-guided therapy, some of which are relevant to the cardiovascular system (e.g., warfarin). Thus, it is worthwhile to understand this topic conceptually as well as in practical terms. While the average population response for most approved medications is favorable, it is clear that significant interindividual variation exists in the response to most therapeutics. Genetic variants exist throughout the genome, and many such variants reside in genes related to medication response (e.g., drug receptors, drug metabolizing enzymes) and have known functional consequences. Inherited differences in medication response were recognized as early as the 1950s, then focused mainly on drug metabolism.8,9 Since then, as our understanding of pharmacokinetics and dynamics has deepened, many points of genetic influence throughout a drug pathway have come into better focus (Figure 1). This includes variants that impact absorption, distribution, excretion, binding to drug targets, and even downstream effect mediators.6

Summary of Key Cardiovascular Pharmacogenetic Interactions

Drug ACE Inhibitors Aldosterone Antagonists BetaBlockers Gene ACE ACE Variant rs Number Molecular Phenotype Increased ACE level associated with D allele Increased ACE level associated with D allele Arg389 shows greater adenylate cyclase activity Glu27 allele has decreased receptor down-regulation Gly16 allele has greater receptor down-regulation Clinical Phenotype D allele homozygotes with HF had lower event-free survival on low-dose ACE-I therapy Among HF patients, only carriers of the I allele showed improvements in EF, EDV, and ESV with spironolactone treatment Increased survival and LVEF recovery with Arg389Arg Glu27 allele associated with better response to carvedilol Increased risk of death or transplantation Arg16/Gln27 double homozygotes Enhanced bene t of bucindolol in WThomozygotes for mortality or transplantation Leu allele leads to increased survival in AA patients in the absence of beta-blockers Intron 16 I/D rs4646994 Intron 16 I/D rs4646994

ADRB1 ADRB2

Arg389Gly Glu27Gln Gly16Arg

rs1801253 rs1042714 rs1042713

ADRA2C GRK5 Warfarin CYP2C9 VKORC1

Exon 1 I/D Gln41Leu *2, *3

rs61767072 D-allele results in loss of auto-inhibition rs17098707 Leu allele enhances betareceptor desensitization

Decreased enzymatic activity Lower warfarin dose requirements for similar level of anticoagulation Greater warfarin dose requirements for INR Transporter; variant phenotype not well established Increased risk of myopathy or rhabdomyolysis

Simvastatin Clopidogrel

SLCOB1 CYP2C19 *2, *3

Reduced enzymatic activity, Greater residual platelet activity, worse reduced conversion to active outcomes after stenting drug

Table 2 Summary of Key Cardiovascular Pharmacogenetic Interactions

ADRB1 = beta 1 adrenergic receptor gene; LVEF = left ventricular ejection fraction; I/D = insertion/deletion; ADRA2C = adrenergic receptor, alpha 2c; ACE = angiotensin-converting enzyme gene; GRK5 = G-protein coupled receptor kinase 5 gene; AA = African American; HF = heart failure; INR = international normalized ratio; LVH= left ventricular hypertrophy; BP = blood pressure; CYP2C9 = cytochrome P450, family 2, subfamily C, polypeptide 9; EF = ejection fraction; EDV = end-diastolic volume; ESV = end-systolic volume.

as a treatment in some types of cancer. TPMT is responsible for inactivation of azathioprine (actually metabolizing the active metabolite 6-mercaptopurine into an inactive product). Sequence variants in TPMT can disable this enzyme, thus exposing the patient to higher than anticipated levels of the active metabolites and causing toxicity, typically bone marrow suppression. This example also illustrates how a pharmacogenetic interaction operates via alteration of pharmacodynamic or pharmacokinetic factors. The pharmacogenetic impact of TPMT variants would be difficult to appreciate without understanding the pharmacokinetics of azathioprine; furthermore, it suggests the solution-reduced doses of azathioprine in subjects with the alternative alleles. Advances in pharmacogenetics are now showing promise for a broader range of medications, including cardiovascular medications. A well-developed example of pharmacogenetics relevant

to cardiovascular disease is warfarin. Warfarin acts by binding to the vitamin K 2,3-epoxide reductase complex (VKORC1), the enzyme responsible reducing vitamin K into its active form, and genetic variants in this drug target cause resistance to warfarin effects, requiring higher dosing. Warfarin is primarily metabolized by CYP 2C9 (CYP2C9), and genetic variants in this enzyme result in reduced enzyme function and, thus, greater warfarin exposure. Genetic polymorphisms in VKORC1 and CYP2C9 account for roughly 40% of variation in warfarin dose. Many other cardiovascular drugs have been studied and have significant pharmacogenetic interactions but have yet to become clinically applicable. Examples include beta-adrenergic antagonists and adrenergic-receptor gene variants, HMG-CoA reductase inhibitors and the risk of myopathy, and clopidogrel effectiveness with CYP2C19 polymorphisms. These and other examples are summarized in Table 2.

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Chapter 1: General Principles

Principles Applied in a Case Discussion

Pharmacokinetics, pharmacodynamics, and pharmacogenetics can impact medication effects, explain drug interactions, or suggest modifications of dosing. These principles do not act in isolation, but rather clinical application of each is critically dependent on appreciating the others as well. Thus, understanding the interplay of principles is important to optimizing clinical care. The following case discussion is presented to provide an illustrative example of applying these principles together in a case-based setting:

fibrillation with rapid ventricular response. He is admitted and undergoes repeat cardioversion and initiation of amiodarone to attempt maintenance of sinus rhythm.

Discussion (continued)
Several pharmacokinetic drug interactions should be considered when adding amiodarone in this situation. Amiodarone inhibits metabolism of warfarin by CYP2C9. This patient is currently on a stable dose of warfarin, and addition of amiodarone would likely increase the INR unless the warfarin dose is reduced. Typically, warfarin dose is reduced by 30to 50% when initiating amiodarone. Another concern is the use of simvastatin with amiodarone. Simvastatin doses >10 mg are contraindicated in combination with amiodarone due to increased risk of myopathy from simvastatin.10 In this case, the interaction is due to amiodarone inhibition of CYP 450 3A4 metabolism of simvastatin, leading to increased simvastatin concentrations. Interestingly, there are also genetic variants that appear to predispose to statin-induced myopathy. In the case of simvastatin, fairly strong evidence points to a polymorphism in the gene SLCOB1, which is associated with 20% lifetime risk of myopathy in patients treated with simvastatin. Finally, there is an interaction between amiodarone and digoxin. Amiodarone is an inhibitor of P-gp, and digoxin is a substrate of P-gp. Therefore, addition of amiodarone to digoxin without adjustment would likely lead to a doubling of the patients digoxin level, with significant risk of toxic symptoms.

Case Study
A 50-year-old man with a history of hypertension, systolic heart failure, and hyperlipidemia presents to the emergency department with palpitations and shortness of breath, which started today, and he is found to be in atrial fibrillation. Home medications include hydroclorothiazide 25 mg daily, metoprolol XL 100 mg daily, aspirin 81 mg daily, digoxin 0.25 mg daily (last digoxin level = 1.5),and simvastatin 40 mg daily. He is admitted, cardioverted, and warfarin is initiated.

Discussion
Warfarin is a good example of pharmacogenetic interactions operating via both pharmacodynamic and pharmacokinetic aspects of the drug. Recommended algorithms for determining initial warfarin dosing based on genotype have been published; commercial testing is available for genotype; pharmacogenetic dosing is routinely used at some institutions; and it has been associated in multiple studies with more rapidly and more often achieving therapeutic international normalized ratio (INR). CYP2C9 variant alleles (so-called *2 or *3) are associated with reduced enzyme activity, resulting in delayed clearance of warfarin and, thus, lower dose requirements (i.e., a geneticpharmacokinetic effect). On the other hand, VKORC1 variants are associated with increased activity or resistance to warfarins effects, thus requiring greater warfarin dose to achieve a similar effect as compared to a patient with wild type VKORC1 (i.e., a genetic-pharmacodynamic interaction). Testing for genotype can help generate a more accurate initial estimate of stable warfarin dosing. Routine testing for this or other variants to help determine initial warfarin dosing is used at some centers but remains controversial and is the subject of an ongoing National Institutes of Healthmulticenter trial. Pharmacogenetic warfarin dosing is most often currently utilized in patients who are planned in advance for impending warfarin initiation (e.g., joint replacement patients) because of the current turnaround time in genotype testing (several days). In the near future, more rapid testing will be available, which will allow pharmacogenetic dosing to be utilized in a wider variety of patients and indications.

Case Study (continued)

The patient improves and is discharged on amiodarone. He follows up six months later, reports no further episodes of palpations, and is in sinus rhythm. However, he has developed skin discoloration and photosensitivity, and you discontinue amiodarone. You consult the electrophysiology service, who consider dofetilide as an alternative rhythm control strategy.

Case Discussion
The most important issue regarding the initiation of dofetilide in this patient is the current use of hydroclorothiazide. Hydrochlorothiazide is contraindicated for use with dofetilide due to the potential for hydrochlorothiazide to increase dofetilide levels through reduced renal secretion, as well as the potential for hydroclorothiazide to reduce potassium levels predisposing to proarrhythmia. Therefore, hydrochlorothiazide would need to be discontinued prior to initiation of dofetilide.

Key Points
Pharmacokinetics refers to all aspects of drug absorption, transport, and metabolism, which can greatly impact optimal dosing and drug interactions. CYP P450 enzymes in the liver metabolize a large proportion of medications and are a very common reason for cardiovascular drug interactions.

Case Study (continued)

The man is subsequently discharged in sinus rhythm on the same medicines. He is asymptomatic at rest. Three weeks later, he presents again to the emergency department in atrial

1.5: Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

1.1.7

The actions of a medication in the body are known as pharmacodynamic effects, and knowledge of these can aid in avoiding toxicities and anticipating pharmacodynamic drug interactions. Pharmacogenetics seeks to use knowledge of genetic variation and how it affects drug response to better target medications. Current clinically relevant examples of pharmacogenetic impacts on cardiovascular medication use include warfarin, while emerging applications include simvastatin, clopidogrel, and beta-blockers.

4. 5. 6. 7. 8. 9.

Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005;352:2211-21. Depta JP, Bhatt DL. Omeprazole and clopidogrel: Should clinicians be worried? Cleve Clin J Med 2010;77:113-6. Evans WE, McLeod HL. Pharmacogenomicsdrug disposition, drug targets, and side effects. N Engl J Med 2003;348:538-49. Lanfear DE, McLeod HL. Pharmacogenetics: using DNA to optimize drug therapy. Am Fam Physician 2007;76:1179-82. Weinshilboum R. Inheritance and drug response. N Engl J Med 2003;348:529-37. Lehmann H, Ryan E. The familial incidence of low pseudocholinesterase level. Lancet 1956;271:124.

References
1. Dorffler-Melly J, de Jonge E, Pont AC, et al. Bioavailability of subcutaneous low-molecular-weight heparin to patients on vasopressors. Lancet 2002;359:849-50. Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. 2009. Available at: http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664. htm. Accessed 12/12/2011. RH R, DR G, ML R, PH V. Digoxin. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. Vancouver, WA: Applied Therapeutics, Inc.; 1992.

10. Food and Drug Administration. FDA Drug Safety Communication: Ongoing safety review of high-dose Zocor (simvastatin) and increased risk of muscle injury. 2010. Available at: http://www.fda. gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm204882.htm. Accessed 12/12/2011. 11. Shuldiner AR, OConnell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 2009;302:849-57. 12. Lillvis JH, Lanfear DE. Progress toward genetic tailoring of heart failure therapy. Curr Opin Mol Ther 2010;12:294-304.

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Chapter 1: General Principles