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Chapter 03 Pharmacotherapeutics for Advanced Practice

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Chapter 3:
Impact of Drug Interactions and
Adverse Events on Therapeutics
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Four Major Categories of Drug
Interactions
• Drug–drug interactions
• Drug–food interactions
• Drug–herb interactions
• Drug–disease interactions
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Pharmacokinetic Factors Affecting Drug
Therapy
• Absorption
• Distribution
• Metabolism
• Excretion
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Pharmacokinetic Drug–Drug Interactions
Involving Absorption
• Acidity (pH): one drug may alter the acidity of the GI
tract
• Adsorption: occurs when one agent binds the other to its
surface to form a complex
• Gastrointestinal motility and rate of absorption: drugs
that affect the GI tract can affect the rate of absorption
instead of amount of drug absorbed
• GI flora: bacteria present in the GI tract are responsible
for a portion of the metabolism of some agents
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Distribution of Drugs in Bloodstream
• Most are bound to plasma proteins such as albumin or
α1-acid glycoprotein.
• Only an unbound drug is free to interact with its target
receptor site and is therefore active.
• The percentage of drug that binds to plasma proteins
depends on the affinity of that drug for the proteinbinding site.
• Clinically significant drug displacement interactions
normally occur only when drugs are more than 90%
protein bound and have a narrow therapeutic index.
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Metabolism
• Main sites of metabolism
– Liver (hepatocytes)
– Small intestine (enterocytes)
– Kidneys, lungs, brain play minor role
• Classification of cytochrome P-450 isoenzymes
– Family (>36% homology in amino acid sequence)
– Subfamily (77% homology)
– Individual gene
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Inhibition of Drug Metabolism:
Competitive and Noncompetitive
• Affinity: the greater the affinity of an inhibiting drug for
an enzyme, the more it blocks binding of other drug
molecules
• Half-life: determines duration of the interaction
• Concentration: threshold concentration must be reached
or exceeded to inhibit an enzyme
• Toxic potential of the object drug
• Efficacy: effectiveness of the object drug
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Question
• A practitioner is prescribing amiodarone for a patient with
cardiac arrhythmia. Which factor affecting the duration of
the drug must a practitioner consider if an adverse
interaction occurs?
A. Efficacy
B. Half-life
C. Concentration
D. Toxic potential
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Answer
• B. Half-life
• Rationale: Along with affinity, the half-life (t½) of the
inhibiting drug determines the duration of the interaction.
The longer the half-life of the inhibiting drug, the longer
the drug interaction lasts. Efficacy refers to the
effectiveness of the drug. Concentration is a factor
contributing to a drug’s ability to inhibit hepatic enzymes.
A threshold concentration must be reached or exceeded
to inhibit an enzyme. Serious toxic potential may cause a
drug to be removed from the market.
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Drug–Drug Interactions Caused by
Induction
• Result of the action of one drug (inducer) stimulating the
metabolism of an object drug (substrate)
• Enhanced metabolism produced by an increase in hepatic
blood flow or an increase in the formation of hepatic
enzymes
• Increases the amount of enzymes available to metabolize
drug molecules, thereby decreasing the concentration
and pharmacodynamic effect of the object drug
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Competitive and Noncompetitive
Inhibition
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Renal Excretion of Drugs
• Drugs are removed from the bloodstream by the kidneys
by filtration or urinary secretion.
• Reabsorption from the urine into the bloodstream may
also occur.
• Absorption may be affected by acidification or
alkalinization of the urine and alteration of secretory or
active transport pathways.
• Although most drugs cross the membrane of the renal
tubule by simple diffusion, some drugs are also secreted
into the urine through active transport pathways.
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Biliary Excretion of Drugs
• Biliary excretion allows for the elimination of drugs and
their metabolites into the feces.
• This route is involved in interactions with drugs that
undergo enterohepatic recirculation.
• Drugs are excreted into the GI tract through the biliary
ducts and have the potential to be reabsorbed through
the intestinal wall into the bloodstream.
• Some of these drugs depend on enterohepatic
recirculation to achieve therapeutic concentrations.
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Question
• A practitioner prescribes a bicarbonate for a patient with
severe heartburn. The practitioner knows that what factor
caused by the drugs plays a key role in its excretion?
A. Enterohepatic recirculation
B. Alteration active transport pathways
C. Alkalinization of the urine
D. Induction of P-glycoprotein
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Answer
• C. Alkalinization of the urine
• Rationale: Administration of bicarbonate can potentially
increase the urine pH. This leads to the increased
excretion of acidic drugs and the increased reabsorption
of basic drugs.
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Pharmacodynamic Interactions
• Pharmacodynamic profile: responses or effects produced
by a drug’s actions.
• Drugs that have a similar characteristic in their
pharmacodynamic profile may produce an exaggerated
response.
• Drugs may also produce opposing pharmacodynamic
effects causing the expected drug response to be
diminished or even abolished.
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Drug–Food Interactions
• Absorption: food can alter extent of drug absorption or
change rate of drug absorption.
• Metabolism: grapefruit juice inhibits the 3A4 subset of
intestinal cytochrome P-450 enzymes and increases the
serum concentration of drugs dependent on these
enzymes for metabolism; food may also induce drug
metabolism and therefore decrease drug efficacy.
• Excretion: ingestion of certain fruit juices can alter the
urinary pH and affect the elimination and reabsorption of
drugs such as quinidine and amphetamine.
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Typical Effects of Food on
Pharmacodynamics
• Food may oppose or potentiate pharmacologic action.
• Warfarin reacts with foods containing vitamin K.
• MAO inhibitors can react with foods containing tyramine.
• Some drugs can deplete nutrients or minerals found in
foods.
• Drug-induced malabsorption can occur in patients with
preexisting poor nutritional status.
• Drugs can change nutrient excretion.
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Question
• A health care practitioner prescribes warfarin for a patient
who Afib. The patient should avoid foods high in:
A. Potassium
B. Tyramine
C. Vitamin C
D. Vitamin K
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Answer
• D. Vitamin K
• Rationale: Warfarin exerts its anticoagulant effects by
inhibiting synthesis of vitamin K–dependent clotting
factors. Vitamin K is required for activation by several
protein factors of the clotting cascade, namely, factors II,
VII, IX, and X. When foods rich in vitamin K are ingested,
they can significantly oppose the anticoagulatory efficacy
of warfarin.
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Pharmacokinetic Drug–Herb Interactions
• Most herbal supplements are not regulated by the FDA.
• Some herbs can prevent absorption of medications and
reduce the effectiveness of those medications.
– Acacia may impair the absorption of amoxicillin.
– Dandelion may reduce effectiveness of quinolones.
– Meadowsweet and black willow may displace highly
protein-bound drugs.
– Certain herbs can be inducers or inhibitors of the
cytochrome P-450 enzyme system.
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Pharmacodynamic Drug–Herb
Interactions
• Some herbs may inhibit platelet activity and/or increase
the INR.
• Kava, lavender, and valerian may potentiate effects of
CNS depressants such as barbiturates and narcotics.
• Kava may interfere with effects of dopamine or dopamine
antagonists and is potentially hepatotoxic.
• Aloe may cause hypoglycemia in patients taking
glibenclamide.
• Bitter orange may interfere with MAO inhibitor action.
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Pharmacokinetic Drug–Disease
Interactions: Absorption
• Absorption depends on the physiologic processes that
maintain normal GI function.
• Vitamin B12 deficiency is common in patients undergoing
stomach surgery.
• Diarrhea, a manifestation of many diseases, can pose a
problem for oral absorption of drugs as well as food and
nutrients.
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Effect of Diseases on Distribution of Drugs
• Conditions that may decrease plasma albumin levels:
– Burns, bone fractures, acute infections, inflammatory
disease, liver disease, malnutrition, and renal disease
• Conditions that may increase plasma albumin levels:
– Benign tumors, gynecologic disorders, myalgia, and
surgical procedures
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Effect of Diseases on Metabolism of Drugs
• Metabolism of drugs can be altered by disease that affect
the functions of the liver (cirrhosis).
• Heart failure is another disease that can cause direct
reduction in ability of liver to metabolize drugs.
• Use of a prodrug in patients with liver dysfunction can
potentially reduce the efficacy of the drug.
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Effect of Diseases on Excretion of Drugs
• Renal function can influence serum drug concentrations.
• Glomerulonephritis, interstitial nephritis, long-term and
uncontrolled diabetes, and hypertension are primary
causes of declining renal function.
• Drugs such as H2 receptor antagonists and
fluoroquinolone antibiotics commonly require dose
adjustments for patients with renal insufficiency.
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Effects of Drugs on Coexisting Disease
• Drugs used to treat one medical condition can exacerbate
the status of another comorbid disease.
– This is particularly important in the elderly who have
multiple concomitant diseases and often take
multiple medications.
– Detected rates of drug–disease interactions range
from 6% to 30% in older adults.
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Patient Factors Influencing Drug
Interactions
• Heredity
• Existing disease state
• Environment
• Smoking
• Diet and nutrition
• Alcohol intake
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Adverse Drug Reactions
• Definition: drug-induced toxic reactions
• Two types of drug reactions
– Type A reactions: exaggeration of the principal
pharmacologic action of the drug
– Type B reactions: unrelated to the principal
pharmacologic action of the drug itself; precipitated
by the secondary pharmacologic actions of the drug
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Medication Errors and Tracking ADRs
• Causes of medication errors: look-alike and sound-alike
drugs, dosage conversions, foreign drugs, illegible
handwriting, unacceptable abbreviations
• Tracking drug interactions and ADRs
– The initial source of documented ADRs comes
primarily from the experience gained while using a
drug during clinical trials
– MedWatch program: enhances the effectiveness of
surveillance of drugs and medical products after they
are marketed and as they are used in clinical practice
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Summary
• As the quantity and types of pharmacologic agents
continue to expand, the likelihood of drug interactions
and adverse reactions increases.
• ADRs present an alarming problem that warrants
significant attention from health care practitioners.
• Not only do ADRs affect morbidity and mortality, they
also dramatically increase health care costs.
• Prescribers must be aware of the mechanisms of drug
interactions and their potential consequences.
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