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Drug drug interactions
highlighting P450
Cytochromes
Louis Wu, PA-C
Presented at VAPAA Annual Meeting
March 2, 2017
Financial Disclosures and
Conflicts
I have no financial disclosures nor
conflicts concerning this talk.
You are asking why I am here?
Learning Objectives




Develop a basic understanding of
pharmacodynamics and pharmcokinetics as
it applies to drug interactions
Conceptualize the cytochrome P450 enzyme
system; enzyme inhibition and enzyme
induction
Review potential hazards of drug interactions
in older populations
Be able to access drug interaction resources
on the VA CPRS system as well as online
such as FDA website and publications such
as Medical Letter
Why doesn’t your patient respond
to the medication?







Adherence
Age of the patient
Disease State
Drug-drug and food-drug interactions
Gender
Genetics
Others
Langman and Dasgupta, in Pharmacogenomics in
Clinical Therapeutics, 2012, pp 1-4
People react
differently to drugs
“One size does not fit all …”
Toxic responders
Non-responders
Responders
Patients with drug toxicity
Phenotypes
Patients with non-response to
drug therapy
Patient population
with differing
genotypes
Patients with normal response
to drug therapy
What is the problem with drug-drug
interactions?




Precipitant drug
Object (or substrate) drug
Drug interaction between the two that
increases or decreases the concentration
of the object drug
If significant enough, then the patient
develops a drug toxicity or an inadequate
therapeutic response from the object drug
Hansten, PD.in Levy et al, Metabolic Drug Interactions, 2000, pg 715
Proportionality: Abaporu vs
Still Life with Golden Bream
Pharmacokinetics (PK) &
pharmacodynamics (PD)

PK - What the body does to the drug?


Absorption; distribution, metabolism,
excretion (ADME)
PD - What the drug does to the body?

Drug concentration at the site of action or
in the plasma is related to a magnitude of
effect
Mechanism of drug interaction
1. Pharmacodynamic – one drug affects the
ability of another drug to associate with
its therapeutic target or receptor
Examples:
Methotrexate and
Trimethoprim/sulfamethoxazole
Epinephrine and non selective beta-blockers
Grattagliano, J Fam Prac, 2010 (59) 6: 322-329
Mechanism of drug interaction
2. Pharmacokinetic: from drug absorption to
elimination
D - distribution
A - absorption
M – metabolism (P450 Cytochrome system)
E - elimination
Grattagliano, J Fam Prac, 2010 (59) 6: 322-329
Really fundamental concepts in
drug biotransformation


Lipid soluble drugs are poorly excreted in the
urine. They tend to store in fat and/or
circulate until they are converted (phase I
biotransformation) to more water soluble
metabolites or metabolites that conjugate
(phase II biotransformation) with water soluble
substances.
Water soluble drugs are more readily excreted
in the urine. They may be metabolized, but
generally not by the CYP enzyme systems.
https://courses.washington.edu/chat543/lectures/PowerPointSlides/Biotransformation_07ho.ppt
What is P450 Cytochrome System?



A composite of 30 plus isoenzymes
referred to as CYP (cytochrome P450)
Carries out first phase of
biotransformation for a variety of drugs
(the substrate drugs)
Of significance:
CYP 1A2
CYP 2C9
CYP 2C19
CYP 2D6
CYP 2E1
CYP 3A4
Grattagliano, J Fam Prac, 2010 (59) 6: 322-329
Cytochrome P450 Nomenclature

CYP = cytochrome P450

2 = genetic family

D = genetic sub-family

6 = specific gene

NOTE: This nomenclature is genetically
based; it does not imply chemical specificity
Grattagliano, J Fam Prac, 2010 (59) 6: 322-329
ROLE OF CYP ENZYMES IN HEPATIC DRUG METABOLISM
RELATIVE HEPATIC CONTENT
OF CYP ENZYMES
CYP2D6
2%
% DRUGS METABOLIZED
BY CYP ENZYMES
CYP2E1
7%
CYP 2C19
11%
CYP 2C9
14%
CYP2D6
23%
CYP 2C
17%
OTHER
36%
CYP 1A2
12%
CYP 3A4-5
26%
CYP 1A2
14%
CYP 3A4-5
33%
Slide set, S.P. Markey, NIH, 2006
CYP2E
5%
Drug Interactions (Liver)
CYP Substrate
CYP Inhibitor
CYP Substrate
CYP Inducer
 Substrate
concentration
 Toxicity
 Substrate
concentration
 Efficacy
Inhibitors of P-450
Results in decreased metabolism and
hepatic clearance of the substrate drug

Example: Prolonged warfarin effect
Warfarin as the substrate combined
with Amiodarone as the inhibitor
Lynch and Price, Am Fam Physician. 2007 Aug 1;76(3):391-396.
Inducers of P-450
Results in increased metabolism and
increased hepatic clearance of the
substrate
 Example: Decreased Oral Contraceptive
effect
ethinyl estardiol as the substrate
combined with Tegretol as the inducer
Lynch and Price, Am Fam Physician. 2007 Aug 1;76(3):391-396.
Drug Metabolism
Enzyme
Active drug
(inactivated by enzyme)
Drug
Inactive Metabolite
Prodrug
(needs enzyme to
produce active drug)
Enzyme
Prodrug
Active
Metabolite
Then there are pro-drugs
Pro-Drug
Plus an
inhibitor
Pro-Drug
does not
break down
to active
metabolites
Pro-drug stays
pretty much
unmetabolized
Plus an
inducer
Pro-Drug
breaks down
to active
metabolites
Active
metabolites
are excessive
P-Glycoprotein Drug Transporters
Drug efflux
transporter with
interactions similar to
that of CYP3A4;
notable example is
digoxin as substrate
and carvedilol or
quinidine as P-gp
inhibitors resulting in
prolonged digoxin
effect
The Medical Letter, 2003; (45): 46-48
Enzyme
Potent
Inhibitor**
Potent
Inducer^^
Substrate
CYP1A2
Amiodarone
(Cordarone), cimetidine
(Tagamet), ciprofloxacin
(Cipro), fluvoxamine
(Luvox)
Carbamazepine
(Tegretol),
phenobarbital,
rifampin (Rifadin),
tobacco
Caffeine, clozapine
(Clozaril),
theophylline
CYP2C9
Amiodarone, fluconazole
(Diflucan), fluoxetine
(Prozac), metronidazole
(Flagyl), ritonavir
(Norvir),
trimethoprim/sulfameth
oxazole (Bactrim,
Septra)
Carbamazepine,
phenobarbital,
phenytoin
(Dilantin), rifampin
Carvedilol (Coreg),
celecoxib
(Celebrex), glipizide
(Glucotrol),
ibuprofen (Motrin),
irbesartan (Avapro),
losartan (Cozaar)
**—These will slow down substrate drug metabolism and increase drug effect.
^^—These will speed up substrate drug metabolism and decrease drug effect.
Lynch and Price, Am Fam Physician. 2007 Aug 1;76(3):391-396.
Case 1. Fluconazole and Warfarin
EUROPEAN JOURNALOF EMERGENCYMEDICINE, 2002, 9,175-177




A 75-year-old man on chronic anticoagulation with warfarin
for atrial fibrillation and transient ischaemic attacks
Found to have Candidasis on EGD specimen and
Fluconazole given for 4 weeks.
Five weeks later presented to the emergency department
with complaints of back pain of three days’ duration
radiating to both legs and leg weakness. His INR was
found to be 40
MRI of the thoracic spine demonstrated a posterior
epidural haematoma extending from T3 to T10 and an
emergent laminectomy was performed.
CYP2C9 and Warfarin
If possible,
fluconazole should
not be used for
patients
anticoagulated with
warfarin. Otherwise
close monitoring is
required.
dabigatran (Pradaxa) and
rivaroxaban (Xarelto)
Known
as a direct thrombin inhibitor (dabigatran)
or direct Factor Xa inhibitor (rivaroxaban)
Both are approved to reduce the risk of stroke
and blood clots (systemic embolism) in patients
with non-valvular atrial fibrillation.
XARELTO® is also indicated for the prophylaxis of
deep vein thrombosis (DVT), which may lead to
pulmonary embolism (PE) in patients undergoing
knee or hip replacement surgery.
Drug interactions with p-glycoproteins, CYP34A
Prescriber's Letter 2011; 18(12):271220
Case 2. Simvastatin and Amiodarone
Ann Pharmacother 2006;40:753-7.


A 72-year-old white man presented with thigh
weakness, achiness, and dark urine for 7 days.
Coronary artery bypass had been performed
earlier and Amiodarone 200 mg/day was started
and later simvastatin 80 mg/day was added
Labs included creatine kinase (CK) 19 620 U/L
(reference range 60–224), blood urea nitrogen
50 mg/dL, creatinine 2.6 mg/dL, (AST) 912 U/L
(30–60), (ALT) 748 U/L (30–60), urine
myoglobin 71100 μg/L (<50), and serum
myoglobin 13 877 μg/L (<110).
Rhabdomyolysis
Adapted from: Sinoway L, Li J. J Appl Physiol 2005;99:5–22.
CYP3A4 and Statins
Simvastatin is
metabolized primarily
by CYP3A4, and
amiodarone is a
recognized inhibitor of
this enzyme
Facts about statins



A class of prescription drugs used together with
diet and exercise to reduce blood levels of lowdensity lipoprotein (LDL) cholesterol
Marketed as single-ingredient products, including
Lipitor (atorvastatin), Lescol (fluvastatin), Mevacor
(lovastatin), Altoprev (lovastatin extendedrelease), Livalo (pitavastatin), Pravachol
(pravastatin), Crestor (rosuvastatin), and Zocor
(simvastatin)
Also marketed as combination products, including
Advicor (lovastatin/niacin extended-release),
Simcor (simvastatin/niacin extended-release), and
Vytorin (simvastatin/ezetimibe)
http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm
A word from the FDA
Do not use simvastatin with these medications:
 Itraconazole
 Ketoconazole
 Gemfibrozil
 Cyclosporine
 Danazol
 Posaconazole
 Erythromycin
 Clarithromycin
 Telithromycin
 HIV protease inhibitors
 Nefazodone
http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm
A word from the FDA



Do not use more than 10mg of
simvastatin with these medications:
Verapamil , Diltiazem
(Note: These drugs are contraindicated with
Simcor as Simcor is only available with
20 mg or 40 mg of simvastatin.)
Do not use more than 20mg of
simvastatin with these medications:
Amlodipine, Amiodarone ,
Ranolazine
Avoid large quantities of grapefruit juice
(>1 quart daily)
Lovastatin Dose Limitations
Contraindicated with lovastatin:
 Itraconazole
 Ketoconazole
 Posaconazole
 Erythromycin
 Clarithromycin
 Telithromycin
 HIV protease inhibitors
 Boceprevir
 Telaprevir
 Nefazodone
http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm#hcp
Lovastatin Dose Limitations
Avoid with lovastatin:
 Cyclosporine
 Gemfibrozil
Do not exceed 20 mg lovastatin daily with:
 Danazol
 Diltiazem
 Verapamil
Do not exceed 40 mg lovastatin daily with:
 Amiodarone
Avoid large quantities of grapefruit juice (>1 quart
daily)
Case 3. Tamoxifen and SSRI
Am J Psychiatry 165:10, October 2008




“Ms. B” is a 45-year-old woman who was
diagnosed with major depressive disorder
treated with fluoxetine
One year ago, she was diagnosed with breast
cancer and underwent surgery, followed by
chemotherapy, and then radiation therapy.
Tamoxifen (a selective estrogen receptor
modulator) added to prevent breast cancer
recurrence.
What potential problems do you forsee?
CYP2D6 and Fluoxetine
CYP2D6 is necessary for
conversion of the prodrug
tamoxifen to its primary active
metabolite endoxifen.
Fluoxetine is a strong CYP2D6
inhibitor, and therefore inhibits
the conversion tamoxifen to
endoxifen and compromise the
efficacy of tamoxifen.
Citalopram (Celexa®),
sertraline (Zoloft®), and
venlafaxine (Effexor®) do not
significantly inhibit CYP2D6
http://www.azcert.org/medical-pros/education/index.cfm
Case 4. Plavix and PPIs
Cardiology in Review • Volume 17, Number 4, July/August 2009



A 52-year-old man found to have 80% stenosis
in the right coronary artery and a drug-eluting
stent placed.
On discharge, patient was on metoprolol 25 mg
twice daily, lisinopril 5 mg once daily,
pravastatin 40 mg once daily, aspirin 325 mg
once daily, clopidogrel 75 mg once daily, and
pantoprazole 40 mg once daily (for stress ulcer
prophylaxis during coronary care unit stay).
Should a PPI be continued for gastrointestinal
(GI) ulcer prophylaxis? If so, is there a preferred
PPI to use in this case?
CYP2C19 and Plavix
Clopidogrel (Plavix®) is a
prodrug. Omeprazole
(Prilosec®) is thought to inhibit
the CYP2C19 metabolism of
clopidogrel to its active
metabolite. Concomitant use of
omeprazole and clopidogrel to
be avoided. Unknown to what
extent other PPIs may interact
with clopidogrel. However,
esomeprazole (Nexium®) also
inhibits CYP2C19 and should
also be avoided.
http://www.azcert.org/medical-pros/education/index.cfm
Do you like controversies?


FDA Advisory: “Concomitant use of
clopidogrel and omeprazole should be
avoided … may not get full protective anticlotting effect”
The Medical Letter: “Patients at risk for
upper GI bleeding who take clopidogrel
should also take a PPI, but not
Omeprazole… Pantoprazole would be
reasonable choice”
The Medical Letter, Nov 29, 2010 (52): 93
Do you like controversies?
ACCF / ACG / AHA 2010 Expert
Consensus:
“Pharmacokinetic and pharmacodynamic
studies… suggest that concomitant use of
clopidogrel and a PPI reduces the
antiplatelet effects of clopidogrel …
It is not established that changes in these
surrogate endpoints translate into clinically
meaningful differences”

J. Am. Coll. Cardiology. 2010; (56): 2051-2066
Case 5. Digoxin and Itraconazole
Annals of Int Med, 1992; 116 (6): 525




68 y/o man with chronic atrial fib treated
with Digoxin for rate control
Found to have elbow swelling with positive
fungal culture on aspirate
Treated with ketoconazole with no effect
and switched to itraconazole
Two weeks later, developed nausea and
vomiting which resolved after itraconazole
was stopped
P-Glycoprotein Drug Transporters
Drug efflux
transporter with
interactions similar to
that of CYP3A4;
notable example is
digoxin as substrate
and carvedilol or
quinidine as P-gp
inhibitors resulting in
prolonged digoxin
effect
The Medical Letter, 2003; (45): 46-48
Elderly and Polypharmcy
By some estimates patients 65 and older
average 8 different drugs daily

Frequently used:
Nonnarcotic analgesic
Calcium channel blocker
Diuretics
Antidepressants
ACE inhibitors

Rathore et al, Fam Med (1998); 30: 733-739
Why the elderly are more susceptible
to adverse drug reactions


Aging state: renal clearance diminished,
hepatic drug metabolizing enzyme activity
lessened, and drug sensitivity heightened
Commonly seen: prolonged opioid,
benzodiazepine and CNS depressant
effects and bleeding from anticoagulation;
paradoxically less responsive to beta
adrenergic blockers and agonists
Cooney and Pascuzzi, Clin Geriatr Med, 2009 (25): 221-233
The Beers Criteria (age over 65)
Medications or medication classes that
generally should be avoided due to
ineffectiveness or unnecessarily high
risk when safer alternatives are
available
 Medications should not be used due to
concurrent medical conditions

Fick et al, Arch Int Med 2003; (163): 2716-24
Beers: Drugs to avoid
(with severity rating)
Propoxyphene (Darvon)
Low
Anticholinergics and
antihistamines
HIgh
Indomethacin (Indocin)
High
Diphenhydramine (Benadryl)
High
Pentazocine (Talwin)
High
Meperidine (Demerol)
High
Trimethobenzamide
(Tigan)
High
Non COX selective NSAIDs –
long term use (Feldene, Daypro)
High
Muscle relaxants
High
Daily Fluoxetine (Prozac)
High
Flurazepam (Dalmane)
High
Amiodarone (Cordarone)
High
Amitriptyline (Elavil)
High
Nitrofurantoin (Macrodantin)
High
Doxepin (Sinequan)
High
Mineral Oil
High
Long acting
benozodiazepines
High
Nifedipine – short acting
(Procardia, Adalat)
High
Disopyramide (Norpace)
High
Doxazosin (Cardura)
Low
Beers: Avoid with disease states
Disease state
Drug
Severity rating
Heart failure
Disopyramide (Norpace)
High
Hypertension
Pseudoephedrine
High
Seizure disorder
Chlorpromazine (Thorazine),
Clozapine (Clozaril)
High
Bladder outlet
obstruction
Anticholinergics and
antihistamines
High
Stress incontinence
Alpha blockers (Prazosin), long High
acting benzodiazepines
Arrhythmias
Tricyclic antidepressants
(amitriptyline, doxepin)
High
Insomina
Decongestants, theophylline
High
Parkinson disease
Metoclopramide (Reglan);
tacrine (Cognex)
High
Syncope or falls
Benzodiazepines and tricyclics
High
Estimated Rates of Emergency Hospitalizations for Adverse Drug Events in Older U.S. Adults,
2007–2009.
Budnitz DS et al. N Engl J Med 2011;365:2002-2012
Elderly and Adverse Drug Effects
Four medications or medication classes
were implicated alone or in combination in
67.0% of emergency hospitalizations
 Warfarin (33.3%)
 Insulins (13.9%),
 Oral antiplatelet agents (13.3%), and
 Oral hypoglycemic agents (10.7%)
 High-risk medications were implicated in
only 1.2% hospitalizations.

Common presentation on admission




Acute hemorrhages
Hypoglycemia
Neurologic symptoms (loss of
consciousness, seizures, changes in
mental status).
Electrolyte or fluid-volume disturbances or
nonspecific weakness
NEJM, 2011; 365: 2002-2012
3 drug interactions in elderly
leading to hospitalizations





Population-based case control study of
Canadian residents over age 66
Hospitalization with glyburide, digoxin, or
ACE-I when combined with other drugs
vs similar matched controls
Glyburide + co-trimoxazole
Digoxin + clarithyromycin
ACE-I + potassium sparing diuretic
Juurlink et al., JAMA (2003), 289: 1652-1657
Hypertensive Drug Effects
(especially in the elderly)
Increased effects
Decreased effects
Beta blockers
Cimetidine, Quinidine,
Fluoxetine
NSAIDs, Rifamycins,
Phenobarbital, Antacids
(Al, Ca)
Calcium Channel
Blockers
Cimetidine, Macrolides,
Antifungal Azoles
Grapefruit juice
St. John’s Wort
Rifamycins
Phenytoin
ACE-I and ARB
Diuretics,
Chlorpromazine
NSAIDs
Antacids
Diuretics
Alpha blockers
----------Phosphodiesterase
inhibitors
NSAIDs, steroids,
cholestyramine, colestipol
NSAIDs
Cooney and Pascuzzi, Clin Geriatr Med, 2009 (25): 221-233
Other Drug Interactions
BP drug
Added drug
Effect
Beta blockers
Antihyperglycemics
Non-dihydropyridine
calcium channel blocker
Masks hypoglycemia
Decreased AV conduction
leading to bradycardia
Calcium channel
blockers
Digoxin, carbamazepine,
midazolam, risperidone
Risk of toxicity with nondihydropyridines
ACE-I and ARB
Potassium supplements,
potassium sparing
diuretics, trimethoprim;
Loop diuretics
Hyperkalemia
Lithium
Digoxin
Risk of lithium toxicity
Risk of digoxin toxicity from
diuretic induced hypokalemia
Diuretics
Increased risk hypovolemia
Cooney and Pascuzzi, Clin Geriatr Med, 2009 (25): 221-233
Minimizing Drug Interaction Risks






L – List each drug’s name and dosage
I – Indication and clearly defined therapeutic
goal; discontinue if not
S – Simple regimen as possible with once or
twice a day dosing
T – Treat multiple symptoms with single drug
rather than multiple drugs
E – Educate patients about adverse events and
address all non prescriptions and supplements
N – Narrow therapeutic window drugs, avoid
Werder, J Fam Prac 2005 (4) 5
To Reduce Risk of Adverse Drug
Interactions





Use of alternative noninteracting medications
Adjust dose of object drug: when possible based on
changes in response rather than prophylactically ( to
avoid sub or supra dosing)
Adjust dosing times (object drug two hours before or
six hours after the binding drug)
Monitor for altered response (lab monitoring)
Computerized system to avoid adverse drug
interactions (still patients may have multiple providers
and multiple pharmacies)
Alternative Noninteracting Medications
Drug Class
Interaction
Susceptible
Alternatives
Benzodiazepine
CYP3A4 Inhibition
Alprazolam,
Diazepam,
Midazolam,
Triazolam
Lorazepam,
Oxazepam,
Temazepan
Calcium Channel
Blockers
CYP3A4 Inhibition
Diltiazem,
Verapamil
Dihydropyridine CCB
Coumarin
anticoagulants
CYP2C9 Inhibition
Acenocoumarol,
Warfarin
Phenprocoumon
dabigatran and
rivaroxaban
HMG-CoA reductase
inhibitor
CYP3A4 Inhibition
Lovastatin
Simvastatin
Fluvastatin,
Pravastatin
Hansten, P.D. in Levy et al, Metabolic Drug Interactions, 2000, pg 725
Alternative Noninteracting Medications
Drug Class
Interaction
Susceptible
Alternatives
H2-receptor
antagonists
Various CYP 450
isoenzymes
Inhibition
Cimetidine
Famotidine,
Nizatidine, Ranitidine
Macrolide antibiotics CYP3A4 Inhibition
Clarithromycin,
Erthyromycin
Azithromycin,
Dirithromycin
Quinolone
antibiotics
CYP1A2 Inhibition
Ciprofloxacin,
Enoxacin,
Grepafloxacin
Levofloxacin,
Ofloxacin,
Lovafloxacin,
Sparfloxacin,
Trovafloxacin
Selective serotonin
reuptake inhibitors
CYP2D6 Inhibition Fluoxetine,
Paroxetine
Citalopram,
Fluvoxamine,
Sertraline
Azithromycin and CV deaths
1. FDA Safety Announcement Mar 12,2013
2.Health care professionals should consider the
risk of fatal heart rhythms with azithromycin
when considering treatment options for patients
who are already at risk for cardiovascular events
3.Alternative drugs in the macrolide class, or
non-macrolides such as the fluroquinolones also
have the potential for QT prolongation or other
significant side effects
http://www.fda.gov/Drugs/DrugSafety/ucm341822.htm
Excess Risk of Cardiovascular Death with Azithromycin as Compared with Amoxicillin,
According to Decile of Cardiovascular Risk Score.
Ray WA et al. N Engl J Med 2012;366:1881-1890
Avoiding Drug Interactions for Consumers
http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm096386.htm
Reporting Adverse Drug Effects to
Food and Drug Administration (FDA)
http://www.fda.gov/Safety/MedWatch/HowToReport/
default.htm
General References
1. Cozza, K. Drug Interactions. 2003, American Psychiatric
Publishing Inc
2. www.hanstenandhorn.com (100 Top Drug Interactions)
3. www.drug-interactions.com (P450-mediated interactions)
4. http://medicine.iupui.edu/clinpharm/ddis/
5. https://crediblemeds.org/healthcare-providers/drug-druginteraction/
6. For Simvastatin product information
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019766s085lbl.pdf
http://www.medscape.com/viewarticle/750421
7. www.themedicalletter.com (pay site)
8. www.prescriberletter.com (pay site)
9. www.lexi.com (pay site and apps)
In Summary





Health care providers must pay attention to patients
taking multiple drugs
Significant drug interactions are clinically important if
they retard or accentuate the normal effects of drugs
Consult tables such as the P450 cytochrome system or
your electronic pharmacology software or call your
pharmacist if there is a question about interactions
Elderly patients require special attention
Education of the patient and ongoing education of the
clinician to drug interactions is essential to good care
Questions
Backers of the USS Texas, now a museum, hope to stop further
corrosion to its hull by moving it to dry land.
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