1_5 farmacocinetics

7/27/2019 1_5 farmacocinetics

1/8

1.5: Pharmacokinetics, Pharmacodynamics,and Pharmacogenetics 1.1.1

Introduction

The ultimate eect a medication has on the body is the complex

summation o how it enters, aects, and leaves the body, and

these can all vary substantially rom one person to another de-

pending on a wide variety o actors. This body-drug interaction

can be broken down or better understanding into pharmacoki-

netics (drug processing) and pharmacodynamics (drug eects),

as illustrated in Figure 1, and each o these broad areas can in

turn be aected by an individuals genetic makeup leading to

pharmacogenetics (Figure 2). In this module, the authors at-

tempt to breakdown and simpliy each ocus or better under-

standing and then reunite them as is best or practical applica-

tion, using a case example.

Pharmacokinetics

The term pharmacokinetics reers to the action the body

takes on a medication. When a medication is ingested or admin-

istered, the medication is absorbed, distributed, metabolized,

and eliminated. Key pharmacokinetic parameters exist or all

our o these actions. Knowledge o general pharmacokinetic

principles can be helpul in understanding the likelihood o

adverse eects o a medication, avoiding drug interactions, pre-

dicting likely onset or duration o action, or understanding the

inuence o organ dysunction on the use o a medication.

AbsorptionA medication can be absorbed rom 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 o intrave-

nous (IV) administration because the drug is administered directly

into the bloodstream. Medications that are available as immedi-

ate-release dosage orms begin to be absorbed upon ingestion.

Some medications are available in ormulations that allow

or slower release o the medication (i.e., extended-release,

Chapter 1: General Principles

1.5: Pharmacokinetics, Pharmacodynamics,and PharmacogeneticsDavid E. Lanfear, MD, MS, FACC

Research Grants: Medtronic, Cardioxyl, Amgen, Sanof-Aventis, Johnson & Johnson; Consulting Fees/Honoraria:

Otsuka, Thoratec.

James Kalus, PharmD

This author has nothing to disclose.

Learner Objectives

Upon completion o this module, the reader will be able to:

1. Demonstrate understanding and knowledge o pharmacokinetic drug interactions or common cardiovascular drugs.

2. Describe how principles o pharmacokinetics and pharmacodynamics can inuence rational drug prescribing.

3. Defne pharmacokinetics and pharmacodynamics as characteristics o medical therapeutics.

4. State principles o pharmacogenetics in cardiovascular drug therapy and cite relevant examples.

sustained-release, delayed-release). Ater ingestion, these drugs

are slowly made available or absorption, which allows or less

requent dosing. For example, niedipine is available both as anextended-release and as an immediate-release ormulation, with

sharp clinical dierences between them. The extended-release

ormulation can be given once daily, whereas the immediate-

release ormulation must be administered three times daily and

can cause rapid hemodynamic changes, which may contribute

to adverse cardiac events.

Absorption o a drug may also be aected by a variety o actors

including the presence or absence o ood, co-administration

with other medications (e.g., antacids) that may bind with the

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

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

Cell MembraneDrug Absorption

Transport

Inactivation

(Activation)

Metabolite

DownstreamSignalling

Cellular Target

X

X

Y

X-1

Pharmacologic Effects


2/8

1.1.2 Chapter 1: General Principles

medication, or GI tract abnormalities. When a transdermal

patch is used, absorption can be altered i the patch has been

cut, or by changes in cutaneous blood ow (e.g., a high dose o

vasopressors causing reduced cutaneous perusion).1

The amount o drug available ater absorption by a non-IV

route, divided by the amount o drug available ater IV admin-

istration is reerred to as bioavailability. All medications have

an inherent bioavailability related to efciency o absorption and

other actors. For example, the bioavailability o oral amioda-

rone is approximately 50% because one-hal as much drug is

available ater oral administration, as compared to IV adminis-

tration.

P-glycoprotein (P-gp) also oten plays a role in determining bio-

availability. P-gp is an adenosine triphosphate (ATP)-dependent

drug transporter that can eux certain drugs back into the GI

tract or kidney ater absorption, thereby decreasing absorption.

Co-administration o a medication with an inhibitor o P-gp

may thus increase bioavailability o the medication. Since P-gp

aects or is eected 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 co-

administered. P-gp eux o digoxin into the GI tract is inhibited

by amiodarone, leading to a doubling o the digoxin concentra-tion. Thereore, digoxin dose should be decreased by one-hal

when initiating amiodarone.

Other important inhibitors o P-gp are quinidine, verapamil,

cyclosporine, tacrolimus, and many o the protease inhibitors.2

It should also be noted that P-gp induction can also occur,

although less commonly. One example o a drug interaction

that occurs due to P-gp induction is the clinically signifcant

interaction between riampin (a P-gp inducer) and the new oral

anticoagulant, dabigatran, whose bioavailability may be com-

promised by this.

Another actor that may impact bioavailability is whether or not

the drug undergoes frst-pass metabolism by the liver. First-pass

metabolism reers to rapid metabolism that occurs ater absorp-

tion, but beore the drug has reached the systemic circulation

where it will have its eects. A drug that undergoes extensive

frst-pass metabolism will have relatively lower oral bioavailability

than otherwise expected.

DistributionAll medications have an apparent volume o distribution (Vd), a

calculated value that relates dose o 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 specifc

drug levels are targeted, knowledge o the typical volume o

distribution o a drug can be useul in estimating the concentra-

tion that will be achieved with a given dose o the drug.

Vd can also assist the clinician in understanding the extent o

distribution. For example, amiodarone has one o the largest

volumes o distribution o any cardiovascular agent (approxi-

mately 50 L/kg). This is notable because amiodarone is well

known to cause extracardiac adverse eects and appears to

distribute to a variety o tissues. A newer agent, dronedarone,

has pharmacologic properties similar to those o amiodarone,

yet has ewer extracardiac toxicities and a much smaller volume

o distribution (approximately 15 L/kg).

In an individual patient, Vd can dier rom population estimates

due to numerous actors including age, body habitus, disease

states, nutritional status, pregnancy, and critical illness. For

example, selection o the appropriate bolus dose o lidocaine

is based on Vd and can be aected by these actors. Typical

loading doses are 1-1.5 mg/kg. The 1 mg/kg dose is oten used

in the elderly or in patients with heart ailure because these pa-

tients have a lower volume o distribution than younger patients

or those with normal ventricular unction. Thereore, a lower

dose will be required to achieve an appropriate lidocaine level.

Protein binding may also inuence Vd, because an increase

or decrease in binding o 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 dysunction (creatinine clearance


3/8


The most common CYP enzyme involved with drug interactions

is CYP 3A4. Numerous cardiac medications are either inhibitors

or substrates o CYP 3A4, including amiodarone, simvastatin,

and several calcium channel blockers. When co-administered,

these medications can reduce the inactivation o the other and,

thus, increase medication exposure, resulting in toxicities.

Table 1 summarizes important CYP 450 enzyme system sub-

strates and inhibitors. As mentioned previously, CYP enzymesalso play an important role in activating certain medications,

reerred to as prodrugs. For example, CYP 2C19 is a key enzyme

in the conversion o 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

o this drug interaction is inhibition o CYP 2C19 by omeprazole,

which results in reduced conversion o clopidogrel to its active

metabolite, thus reducing clopidogrel eectiveness; however, the

clinical signifcance o this interaction continues to be debated.5

Medications can also be CYP 450 enzyme inducers. Important

CYP enzyme inducers are riampin (2C9, 3A4), carbamazepine

(3A4), tobacco (1A2), phenytoin (3A4), and phenobarbital

(3A4). When a CYP 450 enzyme substrate is administered with

an inducer o the same enzyme system, there is potential or in-

creased metabolism o the target drug and, thereore, potential

reduction in drug concentrations.

EliminationElimination reers to how the medication actually exits the body.

A ew important pharmacokinetic parameters are relevant to

drug elimination. The frst is hal-lie, which is the amount o

time required or the concentration o drug to be reduced by

one-hal. When discontinuing a medication, it generally takes 4

to 5 hal-lives or the drug to be completely removed rom the

body. Conversely, when initiating a drug, 4 to 5 hal-lives will

also be required to achieve steady state concentrations.

Table 1Selected Substrates and Inhibitors of the CYP 450 System

*Produces active orm o agent rom prodrug.

CYP = cytochrome; HMG-CoA = hydroxy-methyl-glutaryl coenzyme A.

Reproduced with permission rom R, DR G, ML R, PH V. Digoxin. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied Pharmacokinetics: Principles o

Therapeutic Drug Monitoring. Vancouver, WA: Applied Therapeutics, Inc.; 1992.

Selected Substrates and Inhibitors of the CYP 450 System

Group/Class Medication (s) Cytochrome P450 System

HMG-CoA reductase inhibitors Atorvastatin, lovastatin, simvastatin 3A4

Fluvastatin 2C9

Beta-blockers Metoprolol 2D6

Calcium channel blockers All except amlodipine 3A4

Angiotensin-receptor blockers Losartan 2C9

Antithrombotics Warfarin 2C9

Clopidogrel* 2C19

Antiarrhythmics Amiodarone 2C9, 3A4

Mexilitine 1A2

Propafenone 2D6

Immunesuppressives Cyclosporine,tacrolimus 3A4

Calcium channel blockers Diltiazem 3A4

Verapamil 3A4

Gembrozil 2C8

Proton pump inhibitors Omeprazole, lansoprazole 2C19

Antibiotics Clarithromycin, erythromycin 3A4

Fluconazole 2C9, 3A4

Ketoconazole, itraconole 3A4

Selective serotonin reuptake Fluoxetine, Paroxetine 2D6inhibitors

Substrates

Inhibitors


4/8


Steady state is the point at which drug administration is equal

to drug elimination.3 All medications are either eliminated rom

the body unchanged, or i acted upon by drug metabolizing

enzymes (as described earlier), they are converted to active or

inactive metabolites and subsequently eliminated.

The majority o medication/metabolite elimination occurs

through renal mechanisms. Patients with renal dysunction have

reduced renal clearance o drugs and are oten at greater risk

o toxicity o agents that depend on this route. For example,digoxin is eliminated via renal mechanisms, and the requency

o dosing decreases rom daily to every other day in severe renal

dysunction. Most oten renal elimination occurs via fltration at

the glomerulus, although some medications are secreted into

the renal tubules. Both mechanisms can mediate alterations o

drug clearance and drug interactions. For example, doetilide

is secreted in renal tubules and, thus, may interact with agents

that block tubular secretion (e.g., cimetidine, trimethoprim, and

ketoconazole), resulting in higher doetilide levels.

Pharmacodynamics

The term pharmacodynamics reers 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

unction o the target, thus producing the medications eects.

The drug target can be a wide variety o macromolecules in the

body, such as neurohormonal signaling receptors (e.g., adren-

ergic 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 unction o a biologically active substance.

The pharmacodynamic eects o a drug could reer to both

the desired therapeutic eects as well as the toxic eects. The

term therapeutic index reers to the dierence between the

minimal therapeutic threshold and the minimal toxic threshold.

Some medications have a narrow therapeutic index, meaning

there is little dierence between doses that produce efcacy

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. Oten, drug levels o 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 thedrug target, there is oten a dose-response pattern that can take

dierent orms. Most medications exhibit a linear dose-response

relationship through their therapeutic range, where the pharma-

cologic eect increases proportionately with number/proportion

o occupied targets. Nonlinear dose-response relationships occur

as well but are less common at typical doses o most medications.

Medications that stimulate a signaling receptor, such as the

beta-adrenergic receptor, are called agonists (e.g., epineph-

rine), whereas medications that block the action o a receptor

are called antagonists (e.g., metoprolol). Antagonists can be

either competitive or noncompetitive. Competitive antagonists

take the place o a naturally occurring ligand to block activ-

ity, whereas noncompetitive antagonists bind elsewhere and,

thus, are less aected by the concentration o the usual ligand.

Agents that aect the adrenergic system or those that interact

with neurotransmitters (e.g., opioids) are good examples o this

type o mechanism.

Many cardiovascular drugs produce their pharmacodynamic

eect by inhibiting the action o cardiac ion channels. Calcium

channel blockers inhibit the inux o calcium into the cardiac

pacemaker cells, which can limit the inotropic and chronotropic

activity o the heart. Vaughan Williams class I antiarrhythmic

drugs typically inhibit inux o sodium through sodium chan-

nels, whereas class III antiarrhythmics inhibit eux o potassium

through potassium channels. A notable pharmacodynamic

eect o the class III antiarrhythmic drugs is prolongation o the

QT interval. Concomitant use o more than one medication that

prolongs the QT interval could result in a pharmacodynamic

drug interaction, increasing the patients risk or developing

torsade de pointes.

Enzyme inhibition is another important target o many medica-

tions. The hydroxy-methyl-glutaryl coenzyme A (HMG-CoA)

reductase inhibitors are an important example o a cardiovascu-

lar medication class that produces a pharmacodynamic response

through enzyme inhibition. HMG-CoA reductase inhibitors block

the enzyme responsible or the fnal step o cholesterol orma-

tion, leading to reductions in intracellular cholesterol levels in

the liver, which then cause enhanced reuptake o low-density

lipoprotein (LDL) particles rom plasma to liver, thus lowering

plasma LDL levels.

Another example is vitamin K 2,3-epoxide reductase (VKORC1),

which is the target o wararin. Wararin inhibits VKORC1 rom

reducing vitamin K and, thus, impairs production o vitamin K-

dependent clotting actors.

Drugs may also bind to other types o proteins and enhance or

impair their physiologic processes. Heparin is a good example o

this. Antithrombin is a protein that can inactivate activated throm-

bin, serving a counter-regulatory unction in the coagulation

cascade. Heparin enhances antithrombins action, producing an

antithrombotic eect due to greater inactivation o thrombin. On

the other hand, bivalirudin is a direct thrombin inhibitor; it binds

to thrombin and prevents thrombin rom converting fbrinogen to

fbrin, resulting in the antithrombotic eect.

An understanding o pharmacodynamics can be important in

drug selection. When selecting a positive inotropic therapy or

the treatment o end-stage systolic heart ailure, two available

options are milrinone or dobutamine. Milrinone and dobuta-

mine both produce increases in intracellular calcium concentra-

tions, increased heart rate, and increased contractility; however,

the mechanism by which they achieve this eect is quite dier-

ent. Dobutamine acts as an agonist or the beta-1 receptors on

the myocardium, increasing cyclic adenosine monophosphate


5/8


(cAMP) intracellularly and subsequently increasing calcium in-

ux. Milrinone achieves this action by inhibiting the breakdown

o 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 or uture beta-adrenergic

blocking agents, milrinone may be a more sensible choice. Simi-

larly, one might expect milrinone and dobutamine to have syner-

gistic eects (and toxicities) when co-administered because theyare both enhancing the same pathway but at dierent steps.

An understanding o the interplay between pharmacokinetics

with pharmacodynamics is also important in practice. Aspirin ir-

reversibly inhibits the action o cyclooxygenase (COX) enzyme in

the platelets, leading to prevention o platelet activation. While

the pharmacodynamic eect o most drugs will not be present

4 to 5 hal-lives ater discontinuation, the pharmacodynamic

eect o aspirin persists long ater 4 to 5 hal-lives have passed

(approximately 12 to 24 hours or aspirin). This is because the

irreversible inhibition o the COX enzyme in platelets renders

those platelets permanently inactive. Thereore, the antiplatelet

eect o aspirin does not resolve until new unctional platelets

have been generated, which generally takes approximately one

week.

Pharmacogenetics

Pharmacogenetics is the area o research and medicine that

is concerned with understanding how genetic variation im-

pacts drug response. While still largely a research feld, it now

has burgeoning clinical applications. Important relationships

between genetic variation and drug eect have been observed

or a growing number o commonly used drugs,6 and ongoing

studies should continue to increase the relevance o pharma-

cogenetics to clinical practice. There are commercially available

pharmacogenetic diagnostic tests and a handul o examples

with published guidelines or genetically-guided therapy, some

o which are relevant to the cardiovascular system (e.g., wara-

rin). Thus, it is worthwhile to understand this topic conceptually

as well as in practical terms.

While the average population response or most approved

medications is avorable, it is clear that signifcant 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 recep-

tors, drug metabolizing enzymes) and have known unctionalconsequences.

Inherited dierences in medication response were recognized

as early as the 1950s, then ocused mainly on drug metabo-

lism.8,9 Since then, as our understanding o pharmacokinetics

and dynamics has deepened, many points o genetic inuence

throughout a drug pathway have come into better ocus

(Figure 1). This includes variants that impact absorption, dis-

tribution, excretion, binding to drug targets, and even down-

stream eect mediators.6

The genetic sequence variants o potential interest come in

many orms with single nucleotide polymorphisms (SNP) being

the most common. There are likely at least 30 million SNPs in

the human genome, each o which represents a change o one

base-pair to another at a given location in the DNA sequence.

This may or may not result in a change in unction or amount

o 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

unction directly. They can also occur in regulatory sequences

such as promoter regions, which despite being noncoding, can

impact gene expression. Even more oten, SNPs are located in

other areas with less certain unctional impacts, such as introns

or intergenic regions, though unctional impact cannot be ruled

out based on location alone.

Other types o sequence variants that are less common also

occur. These include repeats (short or long sequences that occur

a variable number o times), and insertion/deletion polymor-

phisms (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 unctional impact i they are within a gene vs. intergenic

region). More recently, larger-scale genetic variation has been

recognized, which can also impact gene unction, or example,

copy number variants (i.e., entire gene or larger segments that

are duplicated).

As science has learned more about the interplay o drugs

and genes, genetic sequence variants have helped to explain

more o the variation in response between patients; in specifc

examples, this has ranged widely and as high as 95%. The ulti-

mate goal o pharmacogenetics (both in terms o research and

as a clinical tool) is to leverage this knowledge to help physicians

provide more rational, efcient, and targeted treatments to their

patients (Figure 2).7

On the other hand, due to the act that one may not always

have a perect understanding o a drug pathwayand with

the emergence o 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 actors (e.g., age, organ unction, drug interactions)

inuence medication response; thus, it is important to view

pharmacogenetic actors within this larger ramework, supple-

menting (not supplanting) other more conventional predictors.

In this way, pharmacogenetic knowledge will oten supplement

and interact with ones knowledge about pharmacokinetics and

dynamics.

Initial applications o pharmacogenetics were limited to medica-

tions with very narrow therapeutic indices. A classic example o

pharmacogenetics being used clinically is azathioprine and the

gene thiopurine methyl transerase (TPMT). Azathioprine is used

as an immunosuppressive agent in heart transplantation, as well


6/8


as a treatment in some types o cancer. TPMT is responsible or

inactivation o 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 o the

active metabolites and causing toxicity, typically bone marrow

suppression. This example also illustrates how a pharmacoge-netic interaction operates via alteration o pharmacodynamic or

pharmacokinetic actors. The pharmacogenetic impact o TPMT

variants would be difcult to appreciate without understanding

the pharmacokinetics o azathioprine; urthermore, it suggests

the solution-reduced doses o azathioprine in subjects with the

alternative alleles.

Advances in pharmacogenetics are now showing promise or a

broader range o medications, including cardiovascular medica-

tions. A well-developed example o pharmacogenetics relevant

to cardiovascular disease is wararin. Wararin acts by binding

to the vitamin K 2,3-epoxide reductase complex (VKORC1), the

enzyme responsible reducing vitamin K into its active orm, and

genetic variants in this drug target cause resistance to wararin

eects, requiring higher dosing. Wararin is primarily metabo-

lized by CYP 2C9 (CYP2C9), and genetic variants in this enzyme

result in reduced enzyme unction and, thus, greater wararin

exposure. Genetic polymorphisms in VKORC1 and CYP2C9 ac-count or roughly 40% o variation in wararin dose.

Many other cardiovascular drugs have been studied and have

signifcant 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 o myopathy, and clopidogrel

eectiveness with CYP2C19 polymorphisms. These and other

examples are summarized in Table 2.

Table 2Summary of Key Cardiovascular Pharmacogenetic Interactions

ADRB1 = beta 1 adrenergic receptor gene; LVEF = let ventricular ejection raction; I/D = insertion/deletion;

ADRA2C = adrenergic receptor, alpha 2c; ACE = angiotensin-converting enzyme gene;

GRK5 = G-protein coupled receptor kinase 5 gene; AA = Arican American; HF = heart ailure; INR = international normalized ratio;

LVH= let ventricular hypertrophy; BP = blood pressure; CYP2C9 = cytochrome P450, amily 2, subamily C, polypeptide 9;EF = ejection raction; EDV = end-diastolic volume; ESV = end-systolic volume.

Summary of Key Cardiovascular Pharmacogenetic Interactions

D allele homozygotes with HF had lowerevent-free survival on low-dose ACE-I therapy

Among HF patients, only carriers of the Iallele showed improvements in EF, EDV, andESV with spironolactone treatment

Increased survival and LVEF recovery withArg389Arg

Glu27 allele associated with better responseto carvedilolIncreased risk of death or transplantationArg16/Gln27 double homozygotes

Enhanced benet of bucindolol in WT-homozygotes for mortality or transplantation

Leu allele leads to increased survival in AApatients in the absence of beta-blockers

Lower warfarin dose requirements for similarlevel of anticoagulation

Greater warfarin dose requirements for INR

Increased risk of myopathy or rhabdomyolysis

Greater residual platelet activity, worseoutcomes after stenting

Increased ACE levelassociated with D alleleIncreased ACE levelassociated with D allele

Arg389 shows greateradenylate cyclase activityGlu27 allele has decreased

receptor down-regulationGly16 allele has greaterreceptor down-regulationD-allele results in loss ofauto-inhibition

Leu allele enhances beta-receptor desensitizationDecreased enzymatic activity

Transporter; variant pheno-type not well established

Reduced enzymatic activity,reduced conversion to activedrug

rs4646994

rs4646994

rs1801253

rs1042714

rs1042713

rs61767072

rs17098707

Intron 16 I/D

Intron 16 I/D

Arg389Gly

Glu27Gln

Gly16Arg

Exon 1 I/D

Gln41Leu

*2, *3

*2, *3

ACE

ACE

ADRB1

ADRB2

ADRA2C

GRK5

CYP2C9

VKORC1

SLCOB1

CYP2C19

ACE

Inhibitors

Aldosterone

Antagonists

Beta-

Blockers

Warfarin

Simvastatin

Clopidogrel

Drug Gene Variant rs Number Molecular Phenotype Clinical Phenotype


7/8


Principles Applied in a Case Discussion

Pharmacokinetics, pharmacodynamics, and pharmacogenetics can

impact medication eects, explain drug interactions, or suggest

modifcations o dosing. These principles do not act in isolation,

but rather clinical application o each is critically dependent on

appreciating the others as well. Thus, understanding the interplay

o principles is important to optimizing clinical care. The ollowing

case discussion is presented to provide an illustrative example o

applying these principles together in a case-based setting:

Case StudyA 50-year-old man with a history o hypertension, systolic heart

ailure, and hyperlipidemia presents to the emergency depart-

ment with palpitations and shortness o breath, which started

today, and he is ound to be in atrial fbrillation. Home medica-

tions 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, cardio-

verted, and wararin is initiated.

DiscussionWararin is a good example o pharmacogenetic interactions

operating via both pharmacodynamic and pharmacokinetic

aspects o the drug. Recommended algorithms or determining

initial wararin dosing based on genotype have been published;

commercial testing is available or genotype; pharmacogenetic

dosing is routinely used at some institutions; and it has been

associated in multiple studies with more rapidly and more oten

achieving therapeutic international normalized ratio (INR).

CYP2C9 variant alleles (so-called *2 or *3) are associated with

reduced enzyme activity, resulting in delayed clearance o

wararin and, thus, lower dose requirements (i.e., a genetic-

pharmacokinetic eect). On the other hand, VKORC1 variants

are associated with increased activity or resistance to wararins

eects, thus requiring greater wararin dose to achieve a similar

eect as compared to a patient with wild type VKORC1 (i.e., a

genetic-pharmacodynamic interaction).

Testing or genotype can help generate a more accurate initial

estimate o stable wararin dosing. Routine testing or this or

other variants to help determine initial wararin dosing is used

at some centers but remains controversial and is the subject

o an ongoing National Institutes o Healthmulticenter trial.

Pharmacogenetic wararin dosing is most oten currently utilized

in patients who are planned in advance or impending wara-

rin initiation (e.g., joint replacement patients) because o thecurrent turnaround time in genotype testing (several days). In

the near uture, more rapid testing will be available, which will

allow pharmacogenetic dosing to be utilized in a wider variety

o patients and indications.

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

fbrillation with rapid ventricular response. He is admitted and

undergoes repeat cardioversion and initiation o amiodarone to

attempt maintenance o sinus rhythm.

Discussion (continued)Several pharmacokinetic drug interactions should be considered

when adding amiodarone in this situation. Amiodarone inhibits

metabolism o wararin by CYP2C9. This patient is currently on

a stable dose o wararin, and addition o amiodarone would

likely increase the INR unless the wararin dose is reduced.

Typically, wararin dose is reduced by 30to 50% when initiating

amiodarone.

Another concern is the use o simvastatin with amiodarone.

Simvastatin doses >10 mg are contraindicated in combina-

tion with amiodarone due to increased risk o myopathy rom

simvastatin.10 In this case, the interaction is due to amiodarone

inhibition o CYP 450 3A4 metabolism o simvastatin, leading

to increased simvastatin concentrations. Interestingly, there are

also genetic variants that appear to predispose to statin-induced

myopathy. In the case o simvastatin, airly strong evidence

points to a polymorphism in the gene SLCOB1, which is associ-

ated with 20% lietime risk o myopathy in patients treated with

simvastatin.

Finally, there is an interaction between amiodarone and digoxin.

Amiodarone is an inhibitor o P-gp, and digoxin is a substrate o

P-gp. Thereore, addition o amiodarone to digoxin without ad-

justment would likely lead to a doubling o the patients digoxin

level, with signifcant risk o toxic symptoms.

Case Study (continued)The patient improves and is discharged on amiodarone. He

ollows up six months later, reports no urther episodes o pal-

pations, and is in sinus rhythm. However, he has developed skin

discoloration and photosensitivity, and you discontinue amioda-

rone. You consult the electrophysiology service, who consider

doetilide as an alternative rhythm control strategy.

Case DiscussionThe most important issue regarding the initiation o doetilide

in this patient is the current use o hydroclorothiazide. Hydro-

chlorothiazide is contraindicated or use with doetilide due to

the potential or hydrochlorothiazide to increase doetilide levels

through reduced renal secretion, as well as the potential or

hydroclorothiazide to reduce potassium levels predisposing to

proarrhythmia. Thereore, hydrochlorothiazide would need to be

discontinued prior to initiation o doetilide.

Key Points

Pharmacokinetics reers to all aspects o drug absorption,

transport, and metabolism, which can greatly impact

optimal dosing and drug interactions.

CYP P450 enzymes in the liver metabolize a large

proportion o medications and are a very common reason

or cardiovascular drug interactions.


8/8


The actions o a medication in the body are known as

pharmacodynamic eects, and knowledge o these can aid

in avoiding toxicities and anticipating pharmacodynamic

drug interactions.

Pharmacogenetics seeks to use knowledge o genetic

variation and how it aects drug response to better target

medications.

Current clinically relevant examples o pharmacogeneticimpacts on cardiovascular medication use include

wararin, while emerging applications include simvastatin,

clopidogrel, and beta-blockers.

References

1. Dorer-Melly J, de Jonge E, Pont AC, et al. Bioavailability o subcu-

taneous low-molecular-weight heparin to patients on vasopressors.Lancet 2002;359:849-50.

2. Food and Drug Administration. Drug Development and Drug

Interactions: Table o Substrates, Inhibitors and Inducers. 2009.

Available at: http://www.da.gov/drugs/developmentapprovalpro-cess/developmentresources/druginteractionslabeling/ucm093664.

htm. Accessed 12/12/2011.

3. RH R, DR G, ML R, PH V. Digoxin. In: Evans WE, Schentag JJ, JuskoWJ, eds. Applied Pharmacokinetics: Principles o Therapeutic Drug

Monitoring. Vancouver, WA: Applied Therapeutics, Inc.; 1992.

4. Wilkinson GR. Drug metabolism and variability among patients in

drug response. N Engl J Med 2005;352:2211-21.

5. Depta JP, Bhatt DL. Omeprazole and clopidogrel: Should clinicians

be worried? Cleve Clin J Med 2010;77:113-6.

6. Evans WE, McLeod HL. Pharmacogenomicsdrug disposition, drug

targets, and side eects. N Engl J Med 2003;348:538-49.

7. Lanear DE, McLeod HL. Pharmacogenetics: using DNA to optimize

drug therapy. Am Fam Physician 2007;76:1179-82.

8. Weinshilboum R. Inheritance and drug response. N Engl J Med

2003;348:529-37.

9. Lehmann H, Ryan E. The amilial incidence o low pseudocholines-

terase level. Lancet 1956;271:124.

10. Food and Drug Administration. FDA Drug Saety Communica-tion: Ongoing saety review o high-dose Zocor (simvastatin) and

increased risk o muscle injury. 2010. Available at: http://www.da.

gov/Drugs/DrugSaety/PostmarketDrugSaetyInormationorPatient-sandProviders/ucm204882.htm. Accessed 12/12/2011.

11. Shuldiner AR, OConnell JR, Bliden KP, et al. Association o cyto-

chrome P450 2C19 genotype with the antiplatelet eect and clini-

cal efcacy o clopidogrel therapy. JAMA 2009;302:849-57.

12. Lillvis JH, Lanear DE. Progress toward genetic tailoring o heart

ailure therapy. Curr Opin Mol Ther 2010;12:294-304.

Documents

1_5 farmacocinetics