Pharmacogenetics, Drug Interactions, and Cardiotoxicity

Robert E. Benton, MD, FACC

Capital Cardiology Associates

Albany, New York

Pharmacogenetics, Drug Interactions, and Cardiotoxicity

Robert E. Benton, MD, FACC

Capital Cardiology Associates

Albany, New York

Monahan JAMA 1990

Torsade de Pointes

Pharmacogenetics & Toxicity

• Drug Metabolism

• Cardiotoxicity

–Torsade de Pointes

• Grapefruit Juice

Adverse Drug Experiences

• Side Effects

• Therapeutic Failure

• Adverse Reactions– Idiosyncratic (Penicillin)– Excess Pharmacologic Effect

Woosley JAMA 1993

Terfenadine and QuinidineK+ channel blockade potency

Case

• 39 yo wf w/ sinusitis

• Terfenadine 60 bid, cefalcor 250 bid

• Vaginal candidiasis: ketoconazole 200 qd

• 4 episodes of syncope

• QTc 655ms

• Elevated levels of terfenadine and metabolite

Case

• 40 yo wm Gilles de la Tourette’s

• Pimozide for years

• Clarithromycin for Bronchitis

• Sudden death after several episodes of syncope (QTc prolonged)

• Elevated pimozide levels

Case

• 29 yo wm

• Terfenadine 60 bid, 2 glasses GJ

• Sudden death while mowing lawn

• Autopsy: terfenadine levels

PharmacodynamicsWhat the drug does to the body

PharmacokineticsWhat the body does to the drug

Pharmacogenetics

Metabolism/elimination

End organ response/receptors

Major Human P450s

• CYP 1A2

• CYP 2C9 Polymorphic

• CYP 2C19 Polymorphic

• CYP 2D6 Polymorphic

• CYP 2E1

• CYP 3A4

PolymorphicGene frequency > 1%

• Infers survival advantage (increased fitness- number of offspring -situation dependent)

• Advantage for heterozygote

• Disadvantage for homozygote (biological cost)– G6PD- malaria– Cystic fibrosis - ?cholera, diarrheal illness– Chemokine 5- Receptor - HIV (homozygotes)

Biotransformation

Phase I• Oxidation• Reduction• Hydrolysis• Hydration• Dethioacetylation• Isomerization

Phase II• Glucuronidation• Sulfation• Methylation• Acetylation• Amino Acid Conjugation• Glutathione Conjugation• Fatty acid conjugation

Poor MetabolizerFailure of Therapy

Codeine

Morphine

CYP 2D6

Poor MetabolizerToxicity

Phenformin

CYP 2D6

Oxidative Metabolite

Pharmacogenetic Testing

• Genotype- “PCR”

• Phenotype - “probe drugs” measure metabolic ratio– 2D6 Dextromethorphan– 1A2 Caffeine– 3A4 Erythromycin/Midazolam– 2C19 Omeprazole

Pharmacogenetics and Human Disease

• Drug metabolism- adverse reactions– Toxic reaction– Lack of response– Steroid Hormone Metabolism

• Cancer Risk (2D6-breast cancer)

• Atherosclerotic Risk (acetylator phenotype)

• Scleroderma, EMS, Toxic Oil

Acetaminophen

NAPQIToxic Metabolite

CYP 2E1CYP 3A4CYP 1A2

Glucuronidation 60%Sulfation 30%

Non-toxic metabolites

Cytochrome P450 system

• Endoplasmic Reticulum

• Peak absorbance @ 450 nm

• Oxidative Metabolism

• Lipid Soluble Water Soluble

Factors Affecting P450 Activity

• Gender: ?3A4 activity higher in women

• Foods: Grapefruit Juice, Brussel Sprouts

• Alcohol: Induces 2E1

• Smoking: Induces 1A2

• Age: Older lower activity

• Race: More PMs of 2C9 in Asians

• Drugs: Many

Pharmacogenetics

• Genetic determined variations in drug response

• Therapeutic Target Variations -receptor responsiveness in asthma

• Metabolic Pathways– pseudocholinesterase-suxamethonium– G6PD-primaquin– acetylation-isoniazid toxicity

ProcainamideLupus Syndrome

N-Acetyl ProcainamidePotent K+ blockerTorsade de Pointes

N-Acetyl Transferase-2(50% slow acetylators)

Non Cardiac Drugs that Prolong QT

• Terfenadine• Astemizole• Erythromycin• Haloperidol• Cisapride• Pimozide

• Chloroquine• Halofantrine• Pentamidine• Probucol• Terodiline• Tri & Tetracyclics

Cytochrome P450Nomenclature

CYP 450 3A4

Mamalian Species

Family“3”

Subfamily“A”

Gene“4”

P450 ActivityPolymorphic (Bimodal)

0

5

10

15

20

25

30

Metabolic Ratio

UEM

High Activity Low Activity

EM PM

P450 ActivityNon-Polymorphic (Gaussian)

0

5

10

15

20

25

30

Metabolic Ratio

EM

High Activity Low Activity

PM

Acetylation (NAT-2)Polymorphic (Bimodal)

0

5

10

15

20

25

30

Metabolic Ratio

High Activity Low Activity

Slow AcetylatorsRapid Acetylators

Effects of RacePercent “Poor Metabolizers”

2D6 2C9 NAT-2

Caucasian 6 4 50

African 8 - -

Asian 0.7 20 15

Caraco TDM 1998

Inhibitors of P450 EnzymesCYP 1A2 CYP 2C9 CYP 2C19Fluvoxamine Fluconazole Fluoxetine

KetoconazoleOmeprazoleTiclopidine

CYP 2D6 CYP2E1 CYP 3A4FluoxetineParoxetinePropafenoneQuinidine

Disulfiram ErythromycinGrapefruit JuiceItraconazoleKetoconazole

Causes of Variability

• 80% of the variability of 2D6 is due to genetic factors

• 3A4, no genetic variability- variability is probably due to induction (rifampin increases 3A4 activity 20 fold)

Pharmacogenetics

• Pharmakon : Greek for magic charm, drug or poison

• Xenobiotic= Outside the body

• Endobiotic= Inside the body (ie hormone)

• Narrow definition = drugs

CYP 3A4

• Most abundant P450 in the liver (40 % by mass and metabolizes 60% of drugs)

• Liver, small bowel wall

• Not Polymorphic

CYP 3A4

Inducers• Phenobarbital• Rifampin• Prednisone• Carbemazepine• Phenytoin

Substrates• Steroids• Macrolides• CCB• Hormones• Antihistamines• Taxol, Vinblastine• Cisapride

CYP 2C19

Induucers• Rifampin

Inhibitors• Fluvoxamine• Ticlopidine• Fluoxetine

Substrates• Omeprazole• Diazepam• TCAs• Clomipramine• Phenytoin

N-acetyl-transferase-2NAT-2

Inducers• Disulfuram• Prednisone

Inhibitors• Cimetidine• Ketoconazole

Substrates• Caffeine• Hydralazine• Isoniazid• Amrinone• Procainamide

CYP D26

• Polymorphic

• Debrsisoquin hydroxylase- alpha blocker w/ severe hypotension in 5% of patients

• Lactic acidosis w/ phenformin

CYP 2D6

Inducers• ? Pregnancy

Inhibitors• Quinidine

Substrates• TCAs• Propafenone• Sertraline• Propranolol• Metoprolol• Codeine (to activate)• Haloperidol

Grapefruit Juice

• Inhibits metabolism of numerous CYP 3A4 substrates

• First-pass metabolism most prominent

• Mechanism unclear– Flavonoids (nariginen, qercetin)probably not– Decrease CYP 3A4 in the gut wall (?decrease protein

transcription)

Grapefruit Juice Interactions

• Terfenadine• Quinidine• Buspirone• Cyclosporin• Felodipine• Nifedipine• Nisoldipine• Nitrendipine

• Triazolam• Midazolam• Lovastatin• Simvastatin• Saquinavir• Verapamil• Ethinylestradiol• Carbamezapine

Mechanism of Drug Interaction

• Competitive Inhibition– 2 drugs metabolized by the same enzyme– compete for the active enzyme site– Erythromycin/Terfenadine

• Noncompetitive Inhibition– Quinidine inhibits CYP2D6– Quinidine metabolized by CYP 3A4

Grapefruit JuiceCharacteristics of Risky Drugs

• Substrate of 3A4

• Highly cleared by first pass in the gut/liver

• Parent has pharmacodynamic toxicity– Terfenadine/cisapride Torsade de Pointes– Felodipine Hypotension– Lovastatin- Rhabdomyolysis

• ?Useful- Cyclosporin levelslower cost

Grapefruit JuiceHow serious the interaction?

• 8 oz. significantly drug levels

• Interactions resulting in 30-50% increase in bioavailabilty are concerning– Felodipine average 3 (peak 9X) levels– Cyclosporin 3X levels– Nisoldipine 5X (peak 9X) levels– Terfenadine 7-10 X have detectable parent

TerfenadineCardiac Toxicity

• Reports of Syncope 1989

• Torsade de Pointes w/ OD 1989

• Torsade w/ ketoconazole, erythromycin 1990

• “Black Box” 1991

• Withdrawn from US market 1997

Cardiac Toxicity

• Antihypertensives– Calcium Channel Blocker– Beta-Blockers– Carvedilol

• Torsade de Pointes

S(-)Carvedilol

R(+)Carvedilol

Nonselective blocker

Not a blocker

blocker

blocker

2D6

metabolites

metabolites

It can get very complex

Torsade de Pointes

• Congenital (Long QT Syndrome)

• Acquired (Drug Induced)

Torsade de PointesElectrophysiology

• Prolongation of the QT interval– Block potassium channels

• Increases Dispersion of repolarization

• Look for U waves

• Bradycardia, K+ , Mg+2

Cisapride/ClarithromycinInteraction

QTc increasemsec

Cisapride 6

Clarthromycin 3 NS

Combined 23

Cisapride“Black Box Warning”

• Clarithromycin• Erythromycin• Trolandeomycin• Nefazadone• Fluconazole• Itraconazole• Ketoconazole• Indinavir

• Ritonavir• Indinavir• Class IA & III• Other Drugs that increase

QT• Renal Failure

CYP 3A4 Inhibitors

• “zole” drugs

• “mycin” drugs

• All calcium channel blockers

• Some antihistamines

Cardiac Drugs that Prolong QT

• Quinidine• Procainamide• Disopyramide• Amiodarone• Sotalol

• Bretylium• Dofetilide• Bepridil

Pharmacogenetic Variation

Polymorphic• Poor• Extensive• Supermetabolizers

Monogenic• Gaussian• Everybody has the same

gene but differ in activity - GREATLY-

Benton CPT 1996

Lee NEJM 1990

Propafenone, CYP 2D6 and Heart Rate

Woosley NEJM 1978

Procainamide Induced Lupus

Ducharme B J Clin Pharm 1993

Grapefruit Juice and Cyclosporin

Quo Vadis?Pharmacogenetics

• Patients– Rapid, convenient phenotyping and genotyping

• Pharmaceutical Industry– Metabolic Pathways worked out before approval– Drug interactions anticipated

Quo Vadis?Repolarization

• Patients– Rapid, convenient phenotyping and genotyping of

potassium channels

• Pharmaceutical Industry– Effects of drugs on repolarization determined in

vitro- especially non-cardiac drugs

Drug

Metabolite A Metabolite B

90% 10%

2D63A4