Drug Interactions

1. Chapter 6 Drug Interactions

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

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.

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

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

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

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

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

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

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

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

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

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

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

15. Basic Mechanisms ofDrug-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.

16. Clinical Significance ofDrug-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.

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.

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.

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.

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

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.

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.