Drug Interactions

Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Drug Interactions

Chapter 6

2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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


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.


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


Drug-Drug Interactions Intensification of effects

Increased therapeutic effects• Sulbactam and ampicillin

Increased adverse effects• Aspirin and warfarin


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


Drug-Drug Interactions Creation of a unique response

Alcohol with disulfiram


Basic Mechanisms of Drug-Drug Interactions

Drugs can interact through four basic mechanisms:1. Direct chemical or physical interaction2. Pharmacokinetic interaction3. Pharmacodynamic interaction4. Combined toxicity


Direct Chemical or Physical Interaction

Never combine drugs in the same container without establishing compatibility.

Most common in IV solution Precipitate: do not administer


Basic Mechanisms ofDrug-Drug Interactions

Pharmacokinetic interactions Altered absorption Altered distribution Altered renal excretion Altered metabolism Interactions that involve P-glycoprotein


Pharmacokinetic Interactions Altered absorption

Elevated gastric pH Laxatives Drugs that depress peristalsis Drugs that induce vomiting Adsorbent drugs Drugs that reduce regional blood flow


Pharmacokinetic Interactions Altered distribution

Competition for protein binding Alteration of extracellular pH

Altered renal excretion Drugs can alter

• Filtration• Reabsorption• Active secretion


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


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


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.


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.


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.


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.


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.


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


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.


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.

Drug Interactions

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