Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Transcript of Pharmacogenetics, Drug Interactions, and Cardiotoxicity
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Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Robert E. Benton, MD, FACC
Capital Cardiology Associates
Albany, New York
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Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Robert E. Benton, MD, FACC
Capital Cardiology Associates
Albany, New York
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Monahan JAMA 1990
Torsade de Pointes
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Pharmacogenetics & Toxicity
• Drug Metabolism
• Cardiotoxicity
–Torsade de Pointes
• Grapefruit Juice
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Adverse Drug Experiences
• Side Effects
• Therapeutic Failure
• Adverse Reactions– Idiosyncratic (Penicillin)– Excess Pharmacologic Effect
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Woosley JAMA 1993
Terfenadine and QuinidineK+ channel blockade potency
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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
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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
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Case
• 29 yo wm
• Terfenadine 60 bid, 2 glasses GJ
• Sudden death while mowing lawn
• Autopsy: terfenadine levels
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PharmacodynamicsWhat the drug does to the body
PharmacokineticsWhat the body does to the drug
Pharmacogenetics
Metabolism/elimination
End organ response/receptors
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Major Human P450s
• CYP 1A2
• CYP 2C9 Polymorphic
• CYP 2C19 Polymorphic
• CYP 2D6 Polymorphic
• CYP 2E1
• CYP 3A4
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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)
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Biotransformation
Phase I• Oxidation• Reduction• Hydrolysis• Hydration• Dethioacetylation• Isomerization
Phase II• Glucuronidation• Sulfation• Methylation• Acetylation• Amino Acid Conjugation• Glutathione Conjugation• Fatty acid conjugation
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Poor MetabolizerFailure of Therapy
Codeine
Morphine
CYP 2D6
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Poor MetabolizerToxicity
Phenformin
CYP 2D6
Oxidative Metabolite
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Pharmacogenetic Testing
• Genotype- “PCR”
• Phenotype - “probe drugs” measure metabolic ratio– 2D6 Dextromethorphan– 1A2 Caffeine– 3A4 Erythromycin/Midazolam– 2C19 Omeprazole
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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
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Acetaminophen
NAPQIToxic Metabolite
CYP 2E1CYP 3A4CYP 1A2
Glucuronidation 60%Sulfation 30%
Non-toxic metabolites
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Cytochrome P450 system
• Endoplasmic Reticulum
• Peak absorbance @ 450 nm
• Oxidative Metabolism
• Lipid Soluble Water Soluble
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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
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Pharmacogenetics
• Genetic determined variations in drug response
• Therapeutic Target Variations -receptor responsiveness in asthma
• Metabolic Pathways– pseudocholinesterase-suxamethonium– G6PD-primaquin– acetylation-isoniazid toxicity
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ProcainamideLupus Syndrome
N-Acetyl ProcainamidePotent K+ blockerTorsade de Pointes
N-Acetyl Transferase-2(50% slow acetylators)
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Non Cardiac Drugs that Prolong QT
• Terfenadine• Astemizole• Erythromycin• Haloperidol• Cisapride• Pimozide
• Chloroquine• Halofantrine• Pentamidine• Probucol• Terodiline• Tri & Tetracyclics
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Cytochrome P450Nomenclature
CYP 450 3A4
Mamalian Species
Family“3”
Subfamily“A”
Gene“4”
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P450 ActivityPolymorphic (Bimodal)
0
5
10
15
20
25
30
Metabolic Ratio
UEM
High Activity Low Activity
EM PM
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P450 ActivityNon-Polymorphic (Gaussian)
0
5
10
15
20
25
30
Metabolic Ratio
EM
High Activity Low Activity
PM
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Acetylation (NAT-2)Polymorphic (Bimodal)
0
5
10
15
20
25
30
Metabolic Ratio
High Activity Low Activity
Slow AcetylatorsRapid Acetylators
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Effects of RacePercent “Poor Metabolizers”
2D6 2C9 NAT-2
Caucasian 6 4 50
African 8 - -
Asian 0.7 20 15
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Caraco TDM 1998
Inhibitors of P450 EnzymesCYP 1A2 CYP 2C9 CYP 2C19Fluvoxamine Fluconazole Fluoxetine
KetoconazoleOmeprazoleTiclopidine
CYP 2D6 CYP2E1 CYP 3A4FluoxetineParoxetinePropafenoneQuinidine
Disulfiram ErythromycinGrapefruit JuiceItraconazoleKetoconazole
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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)
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Pharmacogenetics
• Pharmakon : Greek for magic charm, drug or poison
• Xenobiotic= Outside the body
• Endobiotic= Inside the body (ie hormone)
• Narrow definition = drugs
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CYP 3A4
• Most abundant P450 in the liver (40 % by mass and metabolizes 60% of drugs)
• Liver, small bowel wall
• Not Polymorphic
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CYP 3A4
Inducers• Phenobarbital• Rifampin• Prednisone• Carbemazepine• Phenytoin
Substrates• Steroids• Macrolides• CCB• Hormones• Antihistamines• Taxol, Vinblastine• Cisapride
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CYP 2C19
Induucers• Rifampin
Inhibitors• Fluvoxamine• Ticlopidine• Fluoxetine
Substrates• Omeprazole• Diazepam• TCAs• Clomipramine• Phenytoin
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N-acetyl-transferase-2NAT-2
Inducers• Disulfuram• Prednisone
Inhibitors• Cimetidine• Ketoconazole
Substrates• Caffeine• Hydralazine• Isoniazid• Amrinone• Procainamide
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CYP D26
• Polymorphic
• Debrsisoquin hydroxylase- alpha blocker w/ severe hypotension in 5% of patients
• Lactic acidosis w/ phenformin
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CYP 2D6
Inducers• ? Pregnancy
Inhibitors• Quinidine
Substrates• TCAs• Propafenone• Sertraline• Propranolol• Metoprolol• Codeine (to activate)• Haloperidol
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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)
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Grapefruit Juice Interactions
• Terfenadine• Quinidine• Buspirone• Cyclosporin• Felodipine• Nifedipine• Nisoldipine• Nitrendipine
• Triazolam• Midazolam• Lovastatin• Simvastatin• Saquinavir• Verapamil• Ethinylestradiol• Carbamezapine
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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
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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
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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
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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
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Cardiac Toxicity
• Antihypertensives– Calcium Channel Blocker– Beta-Blockers– Carvedilol
• Torsade de Pointes
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S(-)Carvedilol
R(+)Carvedilol
Nonselective blocker
Not a blocker
blocker
blocker
2D6
metabolites
metabolites
It can get very complex
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Torsade de Pointes
• Congenital (Long QT Syndrome)
• Acquired (Drug Induced)
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Torsade de PointesElectrophysiology
• Prolongation of the QT interval– Block potassium channels
• Increases Dispersion of repolarization
• Look for U waves
• Bradycardia, K+ , Mg+2
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Cisapride/ClarithromycinInteraction
QTc increasemsec
Cisapride 6
Clarthromycin 3 NS
Combined 23
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Cisapride“Black Box Warning”
• Clarithromycin• Erythromycin• Trolandeomycin• Nefazadone• Fluconazole• Itraconazole• Ketoconazole• Indinavir
• Ritonavir• Indinavir• Class IA & III• Other Drugs that increase
QT• Renal Failure
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CYP 3A4 Inhibitors
• “zole” drugs
• “mycin” drugs
• All calcium channel blockers
• Some antihistamines
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Cardiac Drugs that Prolong QT
• Quinidine• Procainamide• Disopyramide• Amiodarone• Sotalol
• Bretylium• Dofetilide• Bepridil
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Pharmacogenetic Variation
Polymorphic• Poor• Extensive• Supermetabolizers
Monogenic• Gaussian• Everybody has the same
gene but differ in activity - GREATLY-
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Benton CPT 1996
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Lee NEJM 1990
Propafenone, CYP 2D6 and Heart Rate
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Woosley NEJM 1978
Procainamide Induced Lupus
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Ducharme B J Clin Pharm 1993
Grapefruit Juice and Cyclosporin
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Quo Vadis?Pharmacogenetics
• Patients– Rapid, convenient phenotyping and genotyping
• Pharmaceutical Industry– Metabolic Pathways worked out before approval– Drug interactions anticipated
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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
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Drug
Metabolite A Metabolite B
90% 10%
2D63A4
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