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Introduction to Drug Interactions

Introduction to Drug Interactions. Al Patterson, PharmD. Drug – Drug Interaction. “…phenomena that occurs when the effects (pharmacodynamics) or pharmacokinetics of a drug are altered by prior administration or co-administration of a second drug”

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Introduction to Drug Interactions

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  1. Introduction to Drug Interactions Al Patterson, PharmD

  2. Drug – Drug Interaction “…phenomena that occurs when the effects (pharmacodynamics) or pharmacokinetics of a drug are altered by prior administration or co-administration of a second drug” Hartshorn, EA, Tatro, DS: Drug Interactions, 2003, Facts and Comparisons, St. Louis, MO

  3. Pharmacodynamic Drug Interaction Extension of underlying pharmacology / toxicology • Potentiation • CNS sedation – antihistamines / EtOH • MAOI’s and SSRI’s, Phenylephrine, etc • Digoxin toxicity with diuretic induced potassium wasting • QTc prolongation w/ Amiodarone and clarithromycin • Antagonism • Beta blockers used with terbutaline

  4. Pharmacokinetic Drug Interactions • Absorption • Distribution • Metabolism • Elimination

  5. Absorption • Inhibition of first pass metabolism • CYP 3A4 by erythromycin or grapefruit juice • Inc. concentration of atrovostatin – myopathy • P-Glycoprotein inhibition by clarithromycin • Inc concentration of may drugs • Binding in gut – delayed absorption • Antacids – oral contraceptives

  6. P-GlycoproteinActive Transport Efflux Pump • Biologic protective mechanism against hydrophobic substances (drugs) – linked to CYP • Pumps drugs out of cells • Intestinal transport • Into the gut / prevents absorption • Into the bile • Renal transport • Into the tubule • Blood Brain Barrier • Out of the brain • Principle cause of multi-drug resistance in chemotherapy • Inhibited by many of the same drugs inhibiting 3A4/5 • Cyclosporine, ketoconazole, quinidine

  7. P-Glycoprotein http://www.hanstenandhorn.com/hh-article10-04.pdf

  8. Distribution • Protein binding alterations • Displacement from albumin binding sites by acidic drugs • valproic acid displaces phenytoin – increases free fraction of phenytoin – increasing possibility of toxicity (total phenytoin concentration may appear normal – only free fraction has pharmacodynamic effect) • Aspirin displaces warfarin – increasing warfarin effect by both increasing free fraction and anti-platelet effect of aspirin

  9. Protein Binding – con’t • Displacement from other binding site • Quinidine displaces digoxin from skeletal muscles sites by interfering with PGP increasing serum concentration of digoxin – increases risk of toxicity (as well as quinidine interfering with renal clearance of digoxin) • http://www.hanstenandhorn.com/hh-article10-04.pdf

  10. Metabolism • Most drugs must be lipid soluble to cross cell membranes and reach their site of action • The net effect of drug metabolism is to increase water solubility and facilitate renal excretion • Phase I metabolism primarily involves oxidative metabolism via the Cytochrome P450 (CYP) family of enzymes • Phase II metabolism conjugates the previously oxidized molecule with a water soluble weak acid (glucouronic acid, tauric acid, etc) enhancing overall water solubility

  11. P450 – Phase I Oxidation http://www.qtdrugs.org/medical-pros/education/CERT%20Educational%20Module%201.ppt

  12. Cytochrome P450 Nomenclature,e.g. for CYP2D6 • CYP = cytochrome P450 • 2 = genetic family • D = genetic sub-family • 6 = specific gene • NOTE that this nomenclature is genetically based: it has NO functional implication • Isoforms = variations of the enzyme http://www.qtdrugs.org/medical-pros/education/CERT%20Educational%20Module%201.ppt

  13. Cytochrome P450 Isoforms Relative Importance ofP450s in Drug Metabolism Relative Quantities of P450s in Liver CYP2E1 CYP1A2 CYP1A2 CYP2C ? CYP2C CYP2D6 CYP3A4/5 CYP2E1 CYP3A CYP2D6 CYP3A4/5 Shimada T et al. J Pharmacol Exp Ther 1994;270(1):414.

  14. CYP Inducers • Increase the activity of the enzyme systems – therefore, increases the elimination of drugs that are substrates for that CYP isoform • Rifampin is potent inducer of CYP 3A4 and therefore would be predicted to increase the elimination of cyclosporine (ie. lower the cyclosporine serum concentration – and increase risk of graft rejection)

  15. CYP Inhibitors • Decreases the activity of the CYP isoform leading to reduced clearance of drugs that are metabolized by that CYP isoform • Erythromycin is a potent inhibitor of CYP 3A4 and has been shown dramatically reduce the metabolism of terfenadine (Seldane) which resulted in several deaths due to Torsades De Pointes (QTc prolongation) prompting the FDA to recall terfenadine in 2002

  16. Renal Elimination • Primarily involves interference with active transport of organic acids and bases across the renal tubule • Probably involves P glycoprotien • Probenecid and penicillins (can be used therapeutically – delays PCN clearance • Methotrexate and NSAID’s – delays MTX clearance – increase toxicity • Quinidine and Digoxin –delays digoxin clearnace – increase toxicity

  17. Drug Interaction Resources • Drug Interaction Facts – Facts and Comparisons – quickly outdated • Online – Multum Database – updated daily • http://www.drugs.com/drug_interactions.html • Drugs effecting QTc • University of Arizona Health Sciences • http://www.arizonacert.org • Updated P450 data • http://medicine.iupui.edu/flockhart/table.htm

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