1. Chapter 6
Drug Interactions 1

2. Drug-Drug Interactions
Basic mechanisms of drug-drug interactions
Clinical significance of drug-drug interactions
Minimizing adverse drug-drug interactions 2

3. Drug-Drug Interactions
Interactions can occur whenever a patient takes more than one drug.
Some interactions are intended and desired or unintended and undesired.
Patients frequently take more than one drug.
Multiple drugs to treat one disorder
Multiple disorders requiring different drugs
OTC meds, caffeine, nicotine, alcohol, etc. 3

4. Consequences of Drug-Drug Interactions
Intensification of effects
Increased therapeutic effects
Increased adverse effects
Reduction of effects
Reduced therapeutic effects
Reduced adverse effects
Creation of a unique response 4

5. Drug-Drug Interactions
Intensification of effects
Increased therapeutic effects
Sulbactam and ampicillin
Increased adverse effects
Aspirin and warfarin 5

6. Drug-Drug Interactions
Reduction of effects
Inhibitory – interactions that result in reduced drug effects
Reduced therapeutic effects
Propranolol and albuterol
Reduced adverse effects
Naloxone to treat morphine overdose 6

7. Drug-Drug Interactions
Creation of a unique response
Alcohol with disulfiram 7

8. Basic Mechanisms of Drug-Drug Interactions
Drugs can interact through four basic mechanisms:
Direct chemical or physical interaction
Pharmacokinetic interaction
Pharmacodynamic interaction
Combined toxicity 8

9. Direct Chemical or Physical Interaction
Never combine drugs in the same container without establishing compatibility.
Most common in IV solution
Precipitate: do not administer 9

10. Basic Mechanisms of Drug-Drug Interactions
Pharmacokinetic interactions
Altered absorption
Altered distribution
Altered renal excretion
Altered metabolism
Interactions that involve P-glycoprotein 10

11. Pharmacokinetic Interactions
Altered absorption
Elevated gastric pH
Laxatives
Drugs that depress peristalsis
Drugs that induce vomiting
Adsorbent drugs
Drugs that reduce regional blood flow 11

12. Pharmacokinetic Interactions
Altered distribution
Competition for protein binding
Alteration of extracellular pH
Altered renal excretion
Drugs can alter
Filtration
Reabsorption
Active secretion 12

13. Pharmacokinetic Interactions
Altered metabolism
Most important and most complex mechanism in which drugs interact
Cytochrome P450 (CYP) group of enzymes
Inducing agents: phenobarbital
2- to 3-fold over 7–10 days
Resolve over 7–10 days after withdrawal
Inhibition of CYP isoenzymes
Usually undesired 13

14. Pharmacokinetic Interactions
Interactions that involve P-glycoproteins (PGPs)
Transmembrane protein that transports a wide variety of drugs out of cells
Reduction or increased PGP
Intestinal epithelium: affects absorption
Placenta: affects drug export from placental cells to maternal blood
Blood-brain barrier: affects drug export from cells of brain capillaries into the blood
Liver: affects drug export from liver into bile
Kidney tubules: affects drug export from renal tubular cells into the urine 14

15. Basic Mechanisms of Drug-Drug Interactions
Pharmacodynamic interactions
At the same receptor
Almost always inhibitory (antagonist/agonist)
At separate sites
May be potentiative (morphine and diazepam) OR
Inhibitory (HCTZ and spironolactone)
Combined toxicity
Drugs with overlapping toxicities should not be used together. 15

16. Clinical Significance of Drug-Drug Interactions
Drug interactions have the potential to significantly impact the outcome of therapy.
Responses may be increased or reduced.
Risk for serious drug interaction is directly proportionate to the number of drugs a patient is taking.
Interactions are especially important in drugs with low therapeutic index.
Many interactions are yet to be identified. 16

17. Minimizing Adverse Drug-Drug Interactions
Minimize number of drugs a patient receives.
Take a thorough drug history.
Be aware of the possibility of illicit drug use.
Adjust the dosage when metabolizing inducers are added or deleted.
Adjust the timing of administration to minimize interference with absorption.
Monitor for early signs of toxicity.
Be especially vigilant when patient is taking a drug with a low therapeutic index. 17

18. Drug-Food Interactions
Impact of food on:
Drug absorption
Decreased absorption
Rate
Extent of absorption (occasionally)
Milk and tetracycline
Fiber and digoxin
Increased absorption
High-calorie meal and saquinavir
Without food, not enough is absorbed. 18

19. Drug-Food Interactions
Drug metabolism
The grapefruit juice effect (not occurring with other citrus fruits or juices)
Inhibits the metabolism of certain drugs
Raises the drugs’ blood levels
406% increase of felodipine
Others – lovastatin, cyclosporine, midazolam, etc. 19

20. Drug-Food Interactions
Impact of food on
Drug toxicity
Monoamine oxidase inhibitors (MAOIs) and tyramine-containing foods
Theophylline and caffeine
Potassium-sparing diuretics and salt substitutes
Aluminum-containing antacids and citrus beverages 20

21. Drug-Food Interactions
Impact of food on
Drug action
Warfarin and foods rich in vitamin K
Timing of drug administration
Some drugs are better tolerated on an empty stomach.
Others should be taken with food, especially for nausea. 21

22. Drug-Herb Interactions
Conventional drugs can interact with herbal preparations.
Interactions with herbal medicines are just as likely as with prescription medications.
Reliable information on drug-herb interactions is lacking.
Example of known interaction:
St. John’s wort induces drug-metabolizing enzymes and reduces blood levels of many drugs. 22