Chapter 6 Drug Interactions 1

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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