Your SlideShare is downloading. ×
Pharmacogenetics, Drug Interactions, and Cardiotoxicity
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×

Introducing the official SlideShare app

Stunning, full-screen experience for iPhone and Android

Text the download link to your phone

Standard text messaging rates apply

Pharmacogenetics, Drug Interactions, and Cardiotoxicity

1,198
views

Published on


0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
1,198
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
61
Comments
0
Likes
1
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide

Transcript

  • 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.