pharmacogenetics, drug interactions, and cardiotoxicity
TRANSCRIPT
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