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Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
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Pharmacogenetics, Drug Interactions, and Cardiotoxicity

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  • 1. Pharmacogenetics, Drug Interactions, and Cardiotoxicity Robert E. Benton, MD, FACC Capital Cardiology Associates Albany, New York
  • 2. Pharmacogenetics, Drug Interactions, and Cardiotoxicity Robert E. Benton, MD, FACC Capital Cardiology Associates Albany, New York
  • 3. Torsade de Pointes
  • 4. Pharmacogenetics & Toxicity
    • Drug Metabolism
    • Cardiotoxicity
      • Torsade de Pointes
    • Grapefruit Juice
  • 5. Adverse Drug Experiences
    • Side Effects
    • Therapeutic Failure
    • Adverse Reactions
      • Idiosyncratic (Penicillin)
      • Excess Pharmacologic Effect
  • 6. Terfenadine and Quinidine K+ channel blockade potency
  • 7. 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
  • 8. 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
  • 9. Case
    • 29 yo wm
    • Terfenadine 60 bid, 2 glasses GJ
    • Sudden death while mowing lawn
    • Autopsy:  terfenadine levels
  • 10. Pharmacodynamics What the drug does to the body Pharmacokinetics What the body does to the drug Pharmacogenetics Metabolism/elimination End organ response/receptors
  • 11. Major Human P450s
    • CYP 1A2
    • CYP 2C9 Polymorphic
    • CYP 2C19 Polymorphic
    • CYP 2D6 Polymorphic
    • CYP 2E1
    • CYP 3A4
  • 12. Polymorphic Gene 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)
  • 13. Biotransformation
    • Phase I
    • Oxidation
    • Reduction
    • Hydrolysis
    • Hydration
    • Dethioacetylation
    • Isomerization
    • Phase II
    • Glucuronidation
    • Sulfation
    • Methylation
    • Acetylation
    • Amino Acid Conjugation
    • Glutathione Conjugation
    • Fatty acid conjugation
  • 14. Poor Metabolizer Failure of Therapy Codeine Morphine CYP 2D6
  • 15. Poor Metabolizer Toxicity Phenformin CYP 2D6 Oxidative Metabolite
  • 16. Pharmacogenetic Testing
    • Genotype- “PCR”
    • Phenotype - “probe drugs” measure metabolic ratio
      • 2D6 Dextromethorphan
      • 1A2 Caffeine
      • 3A4 Erythromycin/Midazolam
      • 2C19 Omeprazole
  • 17. 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
  • 18. Acetaminophen NAPQI Toxic Metabolite CYP 2E1 CYP 3A4 CYP 1A2 Glucuronidation 60% Sulfation 30% Non-toxic metabolites
  • 19. Cytochrome P450 system
    • Endoplasmic Reticulum
    • Peak absorbance @ 450 nm
    • Oxidative Metabolism
    • Lipid Soluble  Water Soluble
  • 20. 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
  • 21. Pharmacogenetics
    • Genetic determined variations in drug response
    • Therapeutic Target Variations
      •  -receptor responsiveness in asthma
    • Metabolic Pathways
      • pseudocholinesterase-suxamethonium
      • G6PD-primaquin
      • acetylation-isoniazid toxicity
  • 22. Procainamide Lupus Syndrome N-Acetyl Procainamide Potent K+ blocker Torsade de Pointes N-Acetyl Transferase-2 (50% slow acetylators)
  • 23. Non Cardiac Drugs that Prolong QT
    • Terfenadine
    • Astemizole
    • Erythromycin
    • Haloperidol
    • Cisapride
    • Pimozide
    • Chloroquine
    • Halofantrine
    • Pentamidine
    • Probucol
    • Terodiline
    • Tri & Tetracyclics
  • 24. Cytochrome P450 Nomenclature CYP 450 3A4 Mamalian Species Family “ 3” Subfamily “ A” Gene “ 4”
  • 25. P450 Activity Polymorphic (Bimodal) Metabolic Ratio UEM High Activity Low Activity EM PM
  • 26. P450 Activity Non-Polymorphic (Gaussian) Metabolic Ratio EM High Activity Low Activity PM
  • 27. Acetylation (NAT-2) Polymorphic (Bimodal) Metabolic Ratio High Activity Low Activity Slow Acetylators Rapid Acetylators
  • 28. Effects of Race Percent “Poor Metabolizers”
  • 29. Inhibitors of P450 Enzymes
  • 30.  
  • 31. 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)
  • 32. Pharmacogenetics
    • Pharmakon : Greek for magic charm, drug or poison
    • Xenobiotic= Outside the body
    • Endobiotic= Inside the body (ie hormone)
    • Narrow definition = drugs
  • 33. CYP 3A4
    • Most abundant P450 in the liver (40 % by mass and metabolizes 60% of drugs)
    • Liver, small bowel wall
    • Not Polymorphic
  • 34. CYP 3A4
    • Inducers
    • Phenobarbital
    • Rifampin
    • Prednisone
    • Carbemazepine
    • Phenytoin
    • Substrates
    • Steroids
    • Macrolides
    • CCB
    • Hormones
    • Antihistamines
    • Taxol, Vinblastine
    • Cisapride
  • 35. CYP 2C19
    • Induucers
    • Rifampin
    • Inhibitors
    • Fluvoxamine
    • Ticlopidine
    • Fluoxetine
    • Substrates
    • Omeprazole
    • Diazepam
    • TCAs
    • Clomipramine
    • Phenytoin
  • 36. N-acetyl-transferase-2 NAT-2
    • Inducers
    • Disulfuram
    • Prednisone
    • Inhibitors
    • Cimetidine
    • Ketoconazole
    • Substrates
    • Caffeine
    • Hydralazine
    • Isoniazid
    • Amrinone
    • Procainamide
  • 37. CYP D26
    • Polymorphic
    • Debrsisoquin hydroxylase- alpha blocker w/ severe hypotension in 5% of patients
    • Lactic acidosis w/ phenformin
  • 38. CYP 2D6
    • Inducers
    • ? Pregnancy
    • Inhibitors
    • Quinidine
    • Substrates
    • TCAs
    • Propafenone
    • Sertraline
    • Propranolol
    • Metoprolol
    • Codeine (to activate)
    • Haloperidol
  • 39. 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)
  • 40. Grapefruit Juice Interactions
    • Terfenadine
    • Quinidine
    • Buspirone
    • Cyclosporin
    • Felodipine
    • Nifedipine
    • Nisoldipine
    • Nitrendipine
    • Triazolam
    • Midazolam
    • Lovastatin
    • Simvastatin
    • Saquinavir
    • Verapamil
    • Ethinylestradiol
    • Carbamezapine
  • 41. 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
  • 42. Grapefruit Juice Characteristics 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 levels  lower cost
  • 43. Grapefruit Juice How 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
  • 44. Terfenadine Cardiac Toxicity
    • Reports of Syncope 1989
    • Torsade de Pointes w/ OD 1989
    • Torsade w/ ketoconazole, erythromycin 1990
    • “ Black Box” 1991
    • Withdrawn from US market 1997
  • 45. Cardiac Toxicity
    • Antihypertensives
      • Calcium Channel Blocker
      • Beta-Blockers
      • Carvedilol
    • Torsade de Pointes
  • 46. S(-)Carvedilol R(+)Carvedilol Nonselective  blocker Not a  blocker  blocker  blocker 2D6 metabolites metabolites It can get very complex
  • 47. Torsade de Pointes
    • Congenital (Long QT Syndrome)
    • Acquired (Drug Induced)
  • 48. Torsade de Pointes Electrophysiology
    • Prolongation of the QT interval
      • Block potassium channels
    • Increases Dispersion of repolarization
    • Look for U waves
    • Bradycardia,  K + , Mg +2
  • 49. Cisapride/Clarithromycin Interaction
  • 50. Cisapride “Black Box Warning”
    • Clarithromycin
    • Erythromycin
    • Trolandeomycin
    • Nefazadone
    • Fluconazole
    • Itraconazole
    • Ketoconazole
    • Indinavir
    • Ritonavir
    • Indinavir
    • Class IA & III
    • Other Drugs that increase QT
    • Renal Failure
  • 51. CYP 3A4 Inhibitors
    • “ zole” drugs
    • “ mycin” drugs
    • All calcium channel blockers
    • Some antihistamines
  • 52. Cardiac Drugs that Prolong QT
    • Quinidine
    • Procainamide
    • Disopyramide
    • Amiodarone
    • Sotalol
    • Bretylium
    • Dofetilide
    • Bepridil
  • 53. Pharmacogenetic Variation
    • Polymorphic
    • Poor
    • Extensive
    • Supermetabolizers
    • Monogenic
    • Gaussian
    • Everybody has the same gene but differ in activity - GREATLY-
  • 54.  
  • 55. Propafenone, CYP 2D6 and Heart Rate
  • 56. Procainamide Induced Lupus
  • 57. Grapefruit Juice and Cyclosporin
  • 58. Quo Vadis? Pharmacogenetics
    • Patients
      • Rapid, convenient phenotyping and genotyping
    • Pharmaceutical Industry
      • Metabolic Pathways worked out before approval
      • Drug interactions anticipated
  • 59. 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
  • 60. Drug Metabolite A Metabolite B 90% 10% 2D6 3A4
  • 61.  

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