Transcript Case 1 Mr. L.P. is a 47 year-old man who presents to the E

Drug Interactions
M. E. Blair Holbein, Ph.D.
Clinical Pharmacologist
Presbyterian Hospital of Dallas
Drug Interactions
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Introduction
Concepts
Case examples
Questions
Why study drug interactions?
er
Clinical Significance of Drug Interactions
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Over 2 MILLION serious ADRs and 100,000 deaths yearly
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ADRs 4th leading cause of death ahead of pulmonary disease,
diabetes, AIDS, pneumonia, accidents and automobile deaths
Greater than total costs of cardiovascular or diabetic care
ADRs cause 1 out of 5 injuries or deaths per year to hospitalized
patients
Mean length of stay, cost and mortality for ADR patients are
DOUBLE that for control patients
Account for 6.5% hospital admissions
Nursing home patients ADR rate—50,000 yearly
Ambulatory patients ADR rate—unknown
Ref: Institute of Medicine, National Academy Press, 2000, Lazarou J et al. JAMA 1998;279(15):1200–1205, Gurwitz JH et al.
Am J Med 2000;109(2):87–94.
Johnson JA et al. Arch Intern Med 1995;155(18):1949–1956, Leape LL et al. N Engl J Med
1991;324(6):377–384, Classen DC et al. JAMA 1997;277(4):301–306
Preventable drug interactions are 1/3
of adverse drug events and 1/2 cost.
Definition
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A drug interaction is defined as a measurable modification (in
magnitude or duration) of the action of one drug by prior or
concomitant administration of another substance (including
prescription and nonprescription drugs, food, or alcohol)
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May be harmful: toxicity, reduced efficacy
May be beneficial: synergistic combinations, pharmacokinetic boosting,
increased convenience, reduced toxicity, cost reduction .
Wright JM. 2000. Drug Interactions. In: Carruthers SG, Hoffman BB, et al. , ed. Melmon and Morrelli’s Clinical Pharmacology: Basic
Principles in Therapeutics, 4th ed. New York:McGraw-Hill.
Characterizing Drug Interactions
Mechanism
Pharmacodynamic
Receptor inhibition
Additive effects
Pharmacokinetic
Altered absorption,
distribution, metabolism, or
elimination
Interacting agents
Drug-drug
Prescription
Non-prescription
Illicit, recreational
Food, supplements, herbal products
Clinical Significance
Major
Substantial morbidity and
mortality
Therapy altering
Manageable
Little or no change in therapy
Optimize therapy
Intentional
Additive or synergistic effects
Enhanced pharmacokinetics
Mechanisms of Interactions
Pharmacodynamic
Pharmacokinetic
Receptor
Absorption
Non-receptor
Distribution
Metabolism
Excretion
Pharmacodynamic: Pharmacological
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Interaction at the drug receptor
Activity is function of intrinsic activity and affinity for
receptor
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Agonist and antagonists
• Effect also function of concentration at receptor
Effect can be additive
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Several agents that act via the same receptor
• Example, several agents with anticholinergic activity or side
effects can result in serious anticholinergic toxicity
especially in elderly patients.
Pharmacodynamic: Physiological
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Agents that can act in concert or in opposition via
different cellular mechanisms.
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Both theophylline and b-receptor agonists can cause
bronchiolar muscle relaxation
Sensitization of myocardium to arrhythmogenic action of
catecholamines by general anesthetics.
Combinations of antihypertensive (can be intentional)
Pharmacodynamic: Altered physiology
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Altered cellular environment
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Agents that change the state of the host
• Hypokalemia caused by diuretics increases toxicity of
digoxin.
Pharmacodynamic: Neutralization
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Neutralization systemically in the host (as opposed to
prior to absorption)
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Protamine used to neutralize heparin
Purified antidigoxin Fab fragments used to treat digoxin toxicity
Mechanisms of Interactions
Pharmacodynamic
Pharmacokinetic
Receptor
Absorption
Non-receptor
Distribution
Metabolism
Excretion
Pharmacokinetic: Absorption
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Alters rate that drug enters the system with altered level
or time to peak
Mechanisms:
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Physical interaction, chelation, binding. e.g. tetracyclines and
cations
Altered GI function: changes in pH (ketoconazole), motility,
mucosal function, metabolism, absorption sites, perfusion
Absorption: in the gut
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Sucralfate, some milk
products, antacids, and oral
iron preparations
Block absorption of quinolones,
tetracycline, and azithromycin
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Omeprazole, lansoprazole,
H2-antagonists
Reduce absorption of
ketoconazole, delavirdine
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Didanosine (given
as a buffered tablet)
Reduces ketoconazole
absorption
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Cholestyramine
Binds raloxifene,thyroid
hormone, and digoxin
Interactions: Presystemic Elimination
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Gut transit and metabolism
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Intestinal wall CYP3A4 metabolizes a number of drugs
Inhibition/induction results in altered bioavailability
Ex: grapefruit juice inhibits intestinal CYP3A4
• Results in increased bioavailability of calcium channel
blockers (dihydropyridine), cyclosporin, saquinavir (HIV-1
protease inhibitors), carbamazepine, lovastatin, terazosin,
triazolam and midazolam.
High intrinsic hepatic clearance dependent upon
hepatic blood flow
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Inhibition results in increased bioavailabilty.
Propranolol, metoprolol, labetalol, verapamil, hydralazine,
felodipine, clhlorpromazine, imipramine, amitriptyline, morphine
First-Pass Metabolism after Oral Administration of a Drug, as Exemplified by Felodipine and Its
Interaction with Grapefruit Juice
Fig: First pass metabolism
Wilkinson, G. R. N Engl J Med 2005;352:2211-2221
Consequences of the Inhibition of First-Pass Metabolism, as Exemplified by the Interaction
between Felodipine and Grapefruit Juice
Wilkinson, G. R. N Engl J Med 2005;352:2211-2221
Some Common Drugs with Low Oral
Bioavailability and Susceptibility to
First-Pass Drug Interactions
Wilkinson, G. R. N Engl J Med 2005;352:2211-2221
Monoamine Oxidase Inhibitors
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Intestinal MAO inhibited by nonselective irreversible
agents and inhibit metabolism of dietary tyramine
resulting in increased release of norepi from
sympathetic postganglionic neurons
Less problematic for selective MAO B inhibitor
selegiline and reversible agent moclobemide
Pharmacokinetic: Distribution
Protein-binding displacement
 Relative to :
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Concentration - a high concentration of one drug relative to
another will shift the binding equilibrium
Relative binding affinity - only relatively highly bound drugs will
be effected
Volume of distribution - small Vd allows for greater proportional
effect
Therapeutic index - mostly drugs with a narrow TI are clinically
significant
Alterations in protein-binding capacity
• hypoalbuminemia (acidic drugs)
• .a1-acid glycoprotein (basic drugs)
• acute phase reactants
Pharmacokinetic: Distribution
Protein-binding displacement
 Effect is rapid and transient and usually compensated
by increased elimination
 May result in transient pharmacologic effect
 Overall result is unpredictable
 New steady-state attained
Pharmacokinetic: Distribution
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Cellular distribution interactions
Cellular transport systems
“Promiscuous” and affect several agents requiring
active transport
Best studied example is P-glycoprotein (PGP) an
organic anion transporter system.
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Cyclosporin A, quinidine, verapamil, itraconazole and
clarithromycin inhibit PGP
Some correlation with CYP3A4 affinities
May be significant for some anticancer drugs
Phases of Drug Metabolism
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Phase I
Oxidation/Reduction/Hydrolysis
Phase II
Conjugation
Drug Interactions Due to Hepatic Metabolism
Nearly always due to interaction at Phase I enzymes,
rather than Phase II
i.e. commonly due to interaction at cytochrome P450
enzymes…some of which are genetically variable in
population
Relative Contribution to Drug Metabolism - Phase I
Evans & Relling Science 1999
Hepatic Metabolism
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Cytochrome P450 system responsible for the majority
of oxidative reactions
Significant polymorphism in many.
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Drugs may be metabolized by a single isoenzyme
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CYP2C9, CYP2C19, and CYP2D6—can be even be genetically
absent!
Desipramine/CYP2D6; indinavir/CYP3A4; midazolam/CYP3A;
caffeine/CYP1A2; omeprazole/CYP2C19
Drugs may be metabolized by multiple isoenzymes
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Most drugs metabolized by more than one isozyme
• Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19
If co-administered with CYP450 inhibitor, some isozymes may
“pick up slack” for inhibited isozyme.
Pharmacokinetic: Metabolism
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Interactions can result from increased as well as decreased
metabolism
Clinical relevance is dependent upon timing of interaction,
therapeutic index of affected drug, duration of therapy, metabolic
fate of affected drug, metabolic capacity of host.
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Host factors include age, genetic makeup (acetylation, CYP2D6),
nutritional state, disease state, hormonal milieu, environmental and
exogenous chemical exposure.
P450 isoenzymes are variously affected.
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Isoenzymes characterized
• Substrates
• Inhibiting agents
• Inducing agents
No consistent correlation of substrate versus inhibitor or inducer
Good reference: http://medicine.iupui.edu/flockhart/
Cytochrome P450 Nomenclature
e.g. for CYP2D6
CYP
2
D
6
=
=
=
=
cytochrome P450
genetic family
genetic sub-family
specific gene
NOTE that this nomenclature is genetically based: it has
NO functional implication
Proportion of Drugs Metabolized by
CYP450 Enzymes
CYP2D6
20%
CYP3A4
38%
CYP2C19
8%
CYP1A2
11%
CYP2C9
16%
CYP2E1
4%
CYP2A6
3%
Cytochrome P450 3A4,5,7
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Largest number of drugs metabolized
Present in the largest amount in the liver.
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Not polymorphic
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Present in GI tract
Inherent activity varies widely
Activity has been shown to predominate in the gut.
Responsible for metabolism of:
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Most calcium channel blockers
Most benzodiazepines
Most HIV protease inhibitors
Most HMG-CoA-reductase inhibitors
Cyclosporine
Most non-sedating antihistamines
Cisapride
Cytochrome P450 3A4,5,7 -continued
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Substrates: macrolide antibiotics – clarithromycin, erythromycin;
benzodiazeines- diazepam, midazolam; cyclosporine, tacrolimus,;
HIV Protease Inhibitors – indinavir, ritonavir; chlorpheniramine;
Calcium Channel Blockers – nifedipine, amlodipine; HMG Co A
Reductase Inhibitors – atorvastatin, lovastatin; haloperidol,
buspirone; sildenafil, tamoxifen, trazodone, vincristine
Inhibited by: HIV Protease Inhibitors, cimetidine, clarithromycin,
fluoxetine, fluvoxamine, grapefruit juice, itraconazole,
ketoconazole, verapamil
Induced by: carbamazepine, phenobarbital, phenytoin, rifampin,
St. John’s wort, troglitazone
Common Drug Substrates,
Inhibitors, and Inducers of
CYP3A, According to Drug
Class
Wilkinson, G. R. N Engl J Med 2005;352:2211-2221
Cytochrome P450 2D6
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Second largest number of substrates.
Polymorphic distribution
Majority of the population is characterized as an extensive or
even ultra-extensive metabolizer.
 Approximately 7% of the U.S. Caucasian population and 1-2%
of African or Asian inheritance have a genetic defect in
CYP2D6 that results in a poor metabolizer phenotype.
Substrates include: many beta-blockers – metoprolol, timolol,
amitriptylline, imipramine, paroxetine, haloperidol, risperidone,
thioridazine, codeine, dextromethorphan, ondansetron,
tamoxifen, tramadol
Inhibited by: amiodarone, chlorpheniramine, cimetidine,
fluoxetine, ritonavir
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Common Drug Substrates and Clinically Important Inhibitors of CYP2D6
Wilkinson, G. R. N Engl J Med 2005;352:2211-2221
Cytochrome P450 2C9
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Note: Absent in 1% of Caucasian and AfricanAmericans.
Substrates include: many NSAIDs – ibuprofen,
tolbutamide, glipizide, irbesartan, losartan, celecoxib,
fluvastatin, phenytoin, sulfamethoxazole, tamoxifen,
tolbutamide, warfarin
Inhibited by: fluconazole, isoniazid, ticlopidine
Induced by: rifampin
Cytochrome P450 1A2
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Substrates include: theophylline, imipramine,
clozapine
Inhibited by: many fluoroquinolone antibiotics,
fluvoxamine, cimetidine
Induced by: smoking tobacco
Coffee Intake and Relative Risk of Myocardial Infarction by CYP1A2 Genotype
Cornelis, M. C. et al. JAMA 2006;295:1135-1141.
Copyright restrictions may apply.
Cytochrome P450 2C19
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Note: Absent in 20-30% of Asians, 3-5% of Caucasians
Substrates include: omeprazole, diazepam,
phenytoin, phenobarbitone, amitriptylline,
clomipramine, cyclophosphamide, progesterone
Inhibited by: fluoxetine, fluvoxamine, ketoconazole,
lansoprazole, omeprazole, ticlopidine
Cytochrome P450 2B6
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Substrates include: bupropion, cyclophosphamide,
efavirenz, methadone
Inhibited by: thiotepa
Induced by: phenobarbital, rifampin
Cytochrome P450 2E1
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Substrates include: acetaminophen
Cytochrome P450 2C8
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Substrates; paclitaxel, torsemide, amodiaquine,
cerivastatin, repaglinide
Inhibited by: trimethoprim, quercetin, glitazones,
gemfibrozil, montelukast
Induced by: rifampin
Monoamine Oxidase
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Many interactions
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112 listed for Selegiline!
May be very significant
Used less frequently due to safer agents
Pharmacokinetic: Metabolism
Characteristics of interactions due to INCREASED metabolism
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Induction of metabolizing enzymes
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Timeframe is slow
“Recovery” to basal state is also slow
Mostly in hepatic microsomal enzymes but also in other tissues
Clinical relevance is dependent upon timing of interaction, therapeutic
index of affected drug, duration of therapy.
Most frequently encountered inducing agents:
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Phenobarbital, phenytoin, carbamazepine
Rifampin > rifabutin
Cigarettes and charred or smoked foods
Prolonged and substantial ethyl alcohol ingestion
Isoniazid
Mechanism of Induction of CYP3A4-Mediated Metabolism of Drug
Substrates (Panel A) and the Resulting Reduced Plasma Drug
Concentration (Panel B)
Wilkinson, G. R. N Engl J Med 2005;352:2211-2221
Pharmacokinetic: Metabolism
Characteristics of interactions with DECREASED metabolism
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Inhibition of metabolizing enzymes
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Timeframe is rapid
Duration and extent of effect is dependent upon concentration of agents and
enzyme affinities.
• Maximum effect seen in 4-5 half-lifes
Mostly in hepatic microsomal enzymes (mixed-function oxidases of cytochrome
P450 system)
• Other systems affected; less well characterized
• Conjugation, acetylation, etc.
• P450 isoenzymes are variously affected.
Most important with drugs with narrow TI, brittle hosts, agents with few
alternate metabolic pathways
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Examples: theophylline, antihypertensive agents, hypoglycemic agents,
chemotherapeutic agents, some hormonal agents, HAART agents
The “Usual Suspects” - Inhibitors
Amiodarone
Ketoconazole
Cimetidine
Ciprofloxacin (1A2)
Diltiazem
Erythromycin (3A4)
Ethanol (acute)
Fluconazole (3A4)
Fluoxetine (2C9, 2C19, 2D6)
Fluvoxamine (1A2, 2C19, 3A4)
Grapefruit (3A4)
Isoniazid (2E1)
Itraconazole (3A4)
Ketaconazole (3A4)
Metronidazole
Miconazole (3A4)
Nefazodone (3A4)
Oral contraceptives
Paroxetine (2D6)
Phenylbutazone
Quinidine (2D6)
Sulfinpyrazone
Valproate
Verapamil
The “Usual Suspects” - Inducers
Barbiturates (2B)
Carbamazepine (2C19, 3A4/5/7)
Charcoal-broiled food (1A2)
Dexamethasone
Ethanol (chronic) (2E1)
Griseofulvin
Isoniazid (2E1)
Primidone (2B)
Rifabutin (3A4)
Rifampin (2B6, 2CB, 2C19, 2C9,
2D6, 3A4/5/7)
Tobacco smoke (1A2)
Relative Contribution to Drug Metabolism - Phase II
Evans & Relling Science 1999
Pharmacokinetic: Excretion
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Filtration
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Active secretion
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Renally cleared drugs affected notably digoxin and aminoglycoside
antibiotics
Metabolic products of parent drug
Highly dependent upon GFR of host, elderly of great concern
Two non-specific active transport systems (pars recta)
• Organic acids
• Organic bases
Also digoxin in distal tubule
Reabsorption
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Distal tubule and collecting duct
Dependent on flow, pH
Useful for enhancing excretion of selected agents with inhibition
• Probenecid, drug ingestions
Drug-Disease Interactions
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Liver disease
Renal disease
Cardiac disease (hepatic blood flow)
Acute myocardial infarction?
Acute viral infection?
Hypothyroidism or hyperthyroidism?
SIRS ?
Drug-Food Interactions
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Tetracycline and milk products
Warfarin and vitamin K-containing foods
Grapefruit juice
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Effects of grapefruit juice on felodipine pharmacokinetics and
pharmacodynamics.
Effects of grapefruit juice on felodipine
pharmacokinetics and pharmacodynamics
Dresser GK et al Clin Pharmacol Ther 2000;68(1):28–34
Drug-Herbal Interactions
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St. John’s wort with indinavir
St. John’s wort with cyclosporin
St. John’s wort with digoxin?
Many others
After St. John’s wort
Drug Interactions in a Clinical Setting
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A stepwise approach: Use mnemonic “THOUGHT”
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Take a good medications history:
• “AVOID Mistakes” [Allergies, Vitamins and herbs, Old
drugs/OTC, Interactions, Dependence, Mendel
(polymorphisms)]
High risk patients (multiple meds, old, frail, ill)
Optimize therapy by decreasing number of drugs, use “lowproblem” agents
Use interactions guides (pocket reference, computerized data
banks, experts)
Give counsel about OTC and “herbals”
Have a monitoring plan to look for potential problems
Time, remember some interactions will take time to occur;
some are rapid
Assessing Impact of Inhibition of
Metabolizing Enzymes
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7.
8.
What is the toxic potential and therapeutic index of the
parent compound? (Converse may be true – see #3)
What are the other pathways involved in the
metabolism of the substrate.
What is the role of an active metabolite?
What is the result of inhibition?
Is the inhibitor selective (one CYP) or broad in effect?
Does the subject have an isoform of the enzyme that
makes them a poor or rapid metabolizer?
Do the metabolites have inhibitory effects of their own?
How harmful (or helpful) is the inhibition?
Conclusions
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Drug-drug interactions are part of drug therapy
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Managing drug interactions is often more important than avoiding
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May be beneficial or hazardous
Polypharmacy (therapy with many agents) is often unavoidable
• Estimated that for 5 or more agents the probability of interaction
approaches 100%
Be most cautious with narrow TI agents
Make use of resources
Some interactions are absolutely contraindicated
Drug interactions are significant cause of adverse drug events and
cost billions in additional health care costs.
At-risk patients are most affected, e.g. the elderly, the very young,
the critically ill
Presentation posted on Presbyterian Hospital Internal Medicine
Residency website http://phdres.caregate.net
Summary: Drug Interactions
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Pharmacokinetic drug interactions are defined as those
that alter drug absorption, distribution, metabolism, or
excretion.
Pharmacodynamic drug interactions result in an
alteration of the biochemical or physiological effects of
a drug. Interactions of this type are more difficult to
characterize than pharmacokinetic interactions.
Summary: Drug Interactions
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Drug interactions that alter the rate of absorption are
usually of lesser concern that those that affect the
extent.
Overall outcomes of interactions of agonists and
antagonists at the drug receptor are dependent on the
varying affinities and activities of the different agents
involved.
Summary: Drug Interactions
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Alteration of metabolism of drugs in the liver, gut and
other sites is an important but not singular source of
significant drug interactions.
In general, those drugs that are susceptible to the
effects of induction of metabolism are also subject to
inhibition.
Drug interactions involving induction of metabolism
develop more slowly than those involving inhibition.
Summary: Drug Interactions
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A full profile of the interaction potential of any given
drug generally takes an extended amount of time in the
marketplace to be characterized. Many, but not all,
important drug interactions are described in the official
labeling.
Summary Drug Metabolism
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Polymorphism of CYP gene(s) can result in a “poor
metabolizer” phenotype, but occurs in less than 20% of
the U.S. general population.
Prototypic inhibiting agents include:
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Ciprofloxacin, Erythromycin, Fluconazole, Fluoxetine,
Grapefruit juice, Itraconazole
Prototypic inducing agents include:
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Carbamazepine (2C19, 3A4/5/7)
Rifampin (2B6, 2CB, 2C19, 2C9, 2D6, 3A4/5/7)
Questions?
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Blair Holbein, Ph.D.
• Presbyterian Hospital of Dallas
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Email: [email protected]
Website: http://phdres.caregate.net
Annotated bibliography
Slides
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April 29 :
• Age and Pharmacokinetics: Pediatric and Geriatric
Considerations
May 2:
• Drug Interactions
References
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Wright JM.. Drug Interactions.
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In: Carruthers SG, Hoffman BB, et al. , ed. Melmon and Morrelli’s
Clinical Pharmacology: Basic Principles in Therapeutics, 4th ed.
New York 2000 :McGraw-Hill.
Centers for Education & Research on Therapeutics
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Agency for Healthcare Research and Quality
Dept. Health Human Service
Case Studies
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Illustrate general principles
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Patients at risk
Management versus avoidance
Varied presentations
• Patient demographics
• Interacting agents: drugs, foods, etc.
• Therapeutic decision making
Case 1
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Mr. L.P. is a 47 year-old man who presents to the E.R with rapidly
progressive worsening of his asthma.
He states that he had been at a friend’s home for about 1 hour
when he began to wheeze. He states that the friend has 3 cats and
he is “very” allergic to cats.
He repeatedly used his albuterol inhaler which usually provides
relief. This time he perceived no benefit and quickly became very
short of breath and came to the hospital.
Case 1, continued
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His PMH is significant for his asthma and recently
diagnosed mild hypertension. His medications
include:
• Budesonide 400 mcg twice daily by inhalation
• Albuterol 180 mcg two puffs by inhalation as needed
may repeat in 4 – 6 hours if needed
• Nadolol 40 mg daily
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What accounts for his failure to respond to his
inhaler
What alterations would you make to his drug
therapy?
Case 1, Discussion
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The failure of the b-agonist to produce
bronchodilatation is due to a direct
pharmacodynamic antagonism by the bblocker at the level of the adrenergic b
receptor.
Case 1, Discussion continued
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Non- b-1 selective b-blocker can be hazardous for asthmatic
patients.
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The non-selective agents are more problematic than the b-1 selective
agents.
• Patients can take the b -blocker for some time without incident until
provoked. Fatal asthma attacks have been reported with this
interaction.
Note too that ophthalmic Timolol maleate is sufficiently absorbed to
be included in this class. Ophthalmic solutions of betaxolol may be
an alternative.
Additional reading:
Marshik PL and Kelly HW. Drug-induced pulmonary diseases. In: DiPiro JT et al. Pharmacotherapy: A
Pathophysiologic Approach 4th edition.
Case 2
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Miss J.K. is a 19-year old black female. She calls your
office complaining of drowsiness and says that she
feels dizzy and unsteady on her feet.
Her PMH includes partial seizures treated with 200 mg
sustained release carbamazepine twice daily. She has
been seizure-free for over 5 years and has tolerated the
therapy reasonably well after titration.
Case 2, continued
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After questioning her mother you find out that J.K. had
been seen by a dermatologist three days earlier who
had prescribed itraconazole 200 mg daily for treatment
of onychomycosis of J.K.’s toenails.
What has caused the symptoms in J.K.?
What therapeutic options are appropriate
Case 2, Discussion
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Pharmacokinetic interaction
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Itraconazole inhibits the metabolism of carbamazepine.
J. K.’s symptoms are from carbamazepine toxicity.
Therapeutic alternatives available.
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Newer anti-epileptic medications
• Better tolerability and fewer potential interactions..
The patient has had no seizures for 5 years.
• Consider cautiously discontinuing seizure medication.
Case 2 Discussion, continued
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If the cosmetic value of treating her onychomycosis is
important
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
Closely monitored adjustment of the carbamazepine dose can
be made
Pulse therapy is equally efficacious with decreased cost.
However, this will not eliminate the need to adjust the
carbamazepine dose.
Case 2 Discussion, continued



Constantly review medications for indications and
adjusting accordingly.
In patients receiving drugs with narrow therapeutic
windows, it is imperative that they are aware of the
need to discuss any therapeutic alterations with the
primary physician.
Additional reading:
McNamara JO. Drugs Effective in the Therapy of the epilepsies. In: Hardman JG and
Limbird LE. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th ed.
Verrotti A. Discontinuation of anticonvulsant therapy in children with partial epilepsy.
Neurology 2000;55:1393-5.
Case 3



Mrs. S. V. is an 87-year old Hispanic woman who
resides in a nursing home. The nurse calls you to
report worsening mental status.
Ten days ago your colleague added
Diphenhydramine 50 mg at bedtime as a nonbenzodiazepine sleep aid.
He also added Donepezil 5 mg daily two days
ago after the nurse called reporting a change in
mental status.
Case 3, continued

Medications







Amitriptylline 75 mg at bedtime for post-herpetic neuralgia
Oxybutynin 5 mg three times daily for urinary incontinence
Ipratropium bromide inhaler 2 puffs (36 mg) twice daily for her COPD
Diphenhydramine 50 mg at bedtime
Donepezil 5 mg daily
Can Mrs.. S.V.’s change in mental status be drug-induced? If so,
why?
What should be done in this case?
Case 3 Discussion



Pharmacodynamic interactions acting in concert.
The addition of Diphenhydramine resulted in a delirium
due to additive anticholinergic side effects of her other
medications.
Donepezil, which is a cholinesterase inhibitor, is indicated
for dementia and was erroneously added to try to reverse
the side effects.
Case 3 Discussion, continued



Drug therapy in the elderly requires careful attention to
the alterations in pharmacokinetics of many
medications.
Every medication in a therapeutic regimen requires
careful consideration.
Minimizing the number of medications and using lower
doses is a good strategy in geriatric pharmacotherapy.


Drug metabolism via conjugation better preserved than P450.
Renal clearance proportional to GFR.
Case 3 Discussion, continued




Discontinue the Diphenhydramine and Donepezil.
Evaluate the need for the Amitriptylline and discontinue
if possible.
Reevaluate the need for the Ipratropium and
Oxybutynin.
Additional reading:


Montamont SC and Vestal RE. Management of drug therapy in the elderly. N Engl J Med
1989;321:303-9
Avorn J and Gurwitz JH. Principles of Pharmacology. In Cassel CK et al. Geriatric
Medicine, 3rd Ed.
Case 4



Mr. J. H. is a 59-year old male with a mechanical aortic
valve. He takes anticoagulant medication, Warfarin 10
mg daily, and his INR has been stable at 3.0 for over a
year.
He calls and reports that his gums are bleeding
following routine oral hygiene.
You ask him to come to the clinic.

Lab reports the INR = 6.
Case 4, continued

You question him about any changes in his diet and medications.
He states that nothing has changed except the brand of daily
vitamins that he usually takes.


He changed from One-a-Day Maximum to Centrum Silver.
• He further states that he changed his “heartburn medicine” from
Ranitidine to Cimetidine because of cost.
• Upon further questioning he also admits to starting Ginko
supplements because he is worried about getting Alzheimer’s
Disease.
Is the change in anticoagulation attributable to his change in vitamins,
non-prescription medicines and/or supplements?
What do you need to do to prevent similar problems in the future
Case 4 Discussion

This is both a pharmacodynamic and a pharmacokinetic
interaction.


Non-prescription medications can cause adverse drug
events.
Vitamin K antagonizes the pharmacodynamic effect of
Warfarin
• One-a-Day Maximum (with K) versus Centrum Silver
(without K)
• Many vitamin preparations contain varying amounts of
vitamin K.
• Cimetidine inhibits the metabolism of Warfarin;
Ranitidine does not.
• Ginko has been reported to have an anticoagulant effect
that is either additive or synergistic with Warfarin.
Case 5





Mr. D.N. is a black 64-year old male. He was brought
into the E.R. by his wife. She said that he had become
weak and unable to stand unassisted.
His blood pressure was 78/45 supine. He has a positive
tilt.
His wife reports that he had followed his routine of
taking his medications followed by breakfast. About 2
hours later he said that he began to feel “bad.”
His PMH includes moderate hypertension,
hypercholesterolemia, and benign prostatic hypertrophy.
His breakfast this morning was 8 oz. grapefruit juice and
low-fat cereal with skim milk.
Case 5, continued

His medications include:





Felodipine 5 mg daily for his hypertension
Atorvastatin 10 mg daily for his hypercholesterolemia
Terazosin 5 mg daily for his BPH.
What caused his drop in blood pressure.
What changes in his medications do you need to
make?
Case 5 Discussion

Pharmacokinetic interaction



Enhanced absorption of the felodipine
The intestinal metabolism of a number of medications,
including felodipine and atorvastatin, is a substantial
proportion of the overall metabolism.
Grapefruit juice inhibits intestinal CYP3A4 enzymes
which results in higher blood levels of the drugs.
Case 5 Discussion, continued


The drop in blood pressure in Mr. D.N.is
attributable to the elevated peak in felodipine
levels.
Terazosin is a selective a-1- adrenergic blocker
that can cause orthostatic hypotension.

Pharmacodynamic interaction
• May also account for the symptomatic
hypotension.
Case 5 Discussion, continued




Patients should be warned to avoid grapefruit juice if they are
taking any of the medications known to have interactions.
Consider using an antihypertensive with less orthostatic side
effects and better cardiovascular profile in this patient with
hypercholesterolemia and potential atherosclerosis.
His BPH can be treated with Finasteride as an alternative.
Additional reading:
Kane GC; Lipsky JJ. Drug-grapefruit juice interactions. Mayo Clin Proc
2000;75:933-42.
Case 6



Mr. J. H. is a 64-year old white male. He has mild
chronic heart failure.
In accordance to the U. S. Carvedilol Heart Failure
Study that showed improved survival in heart
failure patients receiving carvedilol, you decide to
start him on carvedilol.
You initiate therapy with carvedilol 3.125 mg twice
daily and expect to titrate upwards to a goal of 50
mg twice daily.
Case 6 continued

His other medications include:
Lovastatin 40 mg daily
Digoxin 0.125 mg daily
Ranitidine 300 mg a.m. and at bedtime for reflux
Aspirin 81 mg daily
Furosemide 20 mg in the morning
Lisinopril 5 mg daily

The pharmacist calls and says that the computerized drug
interaction program “DRUG-REAX® Interactive Drug Interactions”
indicated an class warning of an interaction between digoxin and
beta-blockers with the possibility of inducing heart block and
suggests that you choose an ACE inhibitor instead.

What is your response?
Case 6 Discussion

Your response:

Continue with the therapy prescribed.
• The U. S. Carvedilol Heart Failure Study included patients
receiving digoxin with carvedilol and demonstrated
improved survival.
Case 6 Discussion, continued





Many of the computerized drug-interaction programs will flag
interactions with a complete range of severity and degree of
documentation.
Many will flag a class of drugs without regard to individual agents
within the class. In managing drug therapy it is impossible to
provide optimum drug therapy without occasionally incurring known
drug interactions.
It requires clinical judgment to manage drug interactions while
optimizing therapy.
In the case of carvedilol and digoxin, the class warning is not
sufficient reason to change a therapy with a likelihood of providing
significant survival benefit. Nonetheless, careful attention to the
tolerance of a new therapy is necessary.
Additional reading:
Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in
patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med
1996;334:1349-55.
Case 7


Mr. R.D. is a 15-year old white male whose mother calls your office
asking for an additional pain medication for her son. He had major
orthodonic surgery the day before. The dental surgeon prescribed
Tylenol#3 (Acetaminophen - 300 mg + Codeine Phosphate - 30
mg) to be taken two (2) tablets every 6 hours, as needed.
The mother says that her son is in substantial pain that is
unrelieved by the prescription. When she contacted the oral
surgeon he was concerned about “drug-seeking” by the boy.

What is your response?

What additional information do you need?
Case 7 Discussion



Inactive codeine is metabolized to an active intermediate by
CYP2D6.
Patients with multiple CYP2D6 gene copies metabolize codeine
more rapidly (ultra-rapid metabolism) . 4 to 5% of the United States
population and up to 29% of the population of Ethiopia and Saudi
Arabia.
Patients that lack functional CYP2D6 genes do not metabolize
codeine to morphine and do not experience analgesic effects.



CYP2D6 is absent in 5 to 10% of the Caucasian population.
Your patient may have an altered drug metabolism.
Inquiries about family history for evidence of polymorphism or OTC
medications may be useful.
Case 7 Discussion continued





Your patient may have an altered drug metabolism.
Dextromethorphan is a competitive inhibitor of 2D6
activity. It is also a common ingredient in OTC cough
medications.
Inquiries about OTC medications may be useful.
To avoid these problems, agents with hydrocodone are
a better choice.
Other therapeutic concerns include inadequate dosing.
Patient information should include sufficient information
(weight, height, BMI) for adjusted dosing.