Introduction to Drug Interactions

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Introduction to Drug Interactions

• Al Patterson, PharmD

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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

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Pharmacodynamic Drug Interaction

• Extension of underlying pharmacology / toxicology
• Potentiation
• CNS sedation antihistamines / EtOH
• MAOIs and SSRIs, Phenylephrine, etc
• Digoxin toxicity with diuretic induced potassium
  wasting
• QTc prolongation w/ Amiodarone and clarithromycin
  
• Antagonism
• Beta blockers used with terbutaline

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Pharmacokinetic Drug Interactions

• Absorption
• Distribution
• Metabolism
• Elimination

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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

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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

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

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Protein Binding cont

• 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

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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

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P450 Phase I Oxidation
http//www.qtdrugs.org/medical-pros/education/CERT
20Educational20Module201.ppt
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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
20Educational20Module201.ppt
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Cytochrome P450 Isoforms
Relative Importance ofP450s in Drug Metabolism
Relative Quantities of P450s in Liver
CYP1A2
CYP2E1
CYP1A2
CYP2C
?
CYP2C
CYP2D6
CYP3A4/5
CYP2E1
CYP3A
CYP2D6
CYP3A4/5
Shimada T et al. J Pharmacol Exp Ther
1994270(1)414.
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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)

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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

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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 NSAIDs delays MTX clearance
  increase toxicity
• Quinidine and Digoxin delays digoxin clearnace
  increase toxicity

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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