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Transcript
Chapter 6
Drug Interactions
Copyright © 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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
3
Consequences of
Drug-Drug Interactions

Intensification of effects



Reduction of effects



Increased therapeutic effects
Increased adverse effects
Reduced therapeutic effects
Reduced adverse effects
Creation of a unique response
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
4
Drug-Drug Interactions

Intensification of effects


Increased therapeutic effects
• Sulbactam and ampicillin
Increased adverse effects
• Aspirin and warfarin
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
6
Drug-Drug Interactions

Creation of a unique response

Alcohol with disulfiram
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
7
Basic Mechanisms of
Drug-Drug Interactions

Drugs can interact through four basic
mechanisms:
1.
2.
3.
4.
Direct chemical or physical interaction
Pharmacokinetic interaction
Pharmacodynamic interaction
Combined toxicity
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
9
Basic Mechanisms of
Drug-Drug Interactions

Pharmacokinetic interactions





Altered absorption
Altered distribution
Altered renal excretion
Altered metabolism
Interactions that involve P-glycoprotein
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
11
Pharmacokinetic Interactions

Altered distribution



Competition for protein binding
Alteration of extracellular pH
Altered renal excretion

Drugs can alter
• Filtration
• Reabsorption
• Active secretion
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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

Usually undesired

• Inhibition of CYP isoenzymes
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
19
Drug-Food Interactions

Impact of food on

Drug toxicity
• Monoamine oxidase inhibitors (MAOIs) and tyraminecontaining foods
• Theophylline and caffeine
• Potassium-sparing diuretics and salt substitutes
• Aluminum-containing antacids and citrus beverages
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
22