drug interactions pharm 560 2 october 2002 philip d. hansten, pharmd professor, school of pharmacy...
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Drug InteractionsPharm 560
2 October 2002
Philip D. Hansten, PharmDProfessor, School of Pharmacy
University of Washington
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Drugs Removed from the Market Due to Drug-Drug
Interactions•Cerivastatin (Baycol): Rhabdomyolysis
when combined with gemfibrozil•Terfenadine (Seldane): Ventricular
arrhythmias with CYP3A4 inhibitors•Astemizole (Hismanal): Ventricular
arrhythmias with CYP3A4 inhibitors•Cisapride (Propulsid): Ventricular
arrhythmias with CYP3A4 inhibitors•Mebefradil (Posicor): Rhabdomyolysis
when combined with simvastatin
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Hospital Admissions due to Drug Interactions in Elderly
(France)•Prospective study of 1000 patients
> 70 yo admitted to geriatric unit
•538 patients exposed to DDIs
•130 patients developed ADIs
•Most common drugs involved were cardiovascular and psychotropic
Doucet J et al. J Am Geriatr Soc. 1996;44:944-948.
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Severe Cimetidine Adverse Drug Interactions
Are Rare•VA Hospital switched from ranitidine to
cimetidine as cost-saving measure
•Retrospective study of 4570 patients on cimetidine (10% got interacting drugs)
•Only 4 patients had adverse interactions– 2 theophylline (nausea, vomiting,
arrhythmia)– 1 procainamide (arrhythmia)– 1 warfarin (fatal intracerebral hemorrhage)
Scott MA et al. Am J Health-Syst Pharm. 1999;56:1890-91.
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Uncommon Adverse Drug Interactions
For an adverse drug interaction that occurs once in 1000 cases, one would have to study 3000 cases to have a 95% chance of
observing the event.
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David Hume (1711-1776)
•Scientific certainty is not possible using induction–“All swans are white.”
•Absence of proof is not proof of absence–“Bigfoot does not exist.”–“Those drugs do not interact.”
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NO ADR OBSERVED
Drug A + Drug B
Assessing Drug Interactions Using
Induction
25 Patients
Usual Conclusion: This interaction is not clinically important.
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NO ADR OBSERVED
Drug A + Drug B 25
Patients
Correct Conclusion: Available information is insufficient to determine clinical importance.
Assessing Drug Interactions Using
Induction
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Prescriber’s Knowledge
Computer Screening
Pharmacist’s Knowledge
Patient Risk Factors
Patient EducationMonitoring
ADR
Drug Interaction Defenses
Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990
Drug Administration
Pharmacogenetics
Drug A +Drug B
Defenses
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Prescriber’s KnowledgeComputer Screening
Pharmacist’s Knowledge
Latent Failures
Patient Risk Factors
Patient EducationMonitoring
ADR
A + B
Drug Interactions: “When the Holes Line
Up”
Defenses
Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990
Drug Administration
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Prescriber’s Knowledge
Computer Screening
Pharmacist’s Knowledge
Patient Risk Factors
Patient EducationMonitoring
NO ADR
A + B
Drug Interaction Errors
Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990
Drug Administration
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NSAIDs + SSRIs: Increased Risk of Bleeding?
• Case-control study of 1651 incident cases compared to 10,000 matched controls
• “The concurrent use of NSAIDs with SSRIs greatly increases risk of upper GI bleeding”
• SSRIs platelet uptake of serotonin
0
2
4
6
8
10
12
14
16Relative Risk
Neither DrugNSAIDSSRINSAID + SSRI
De Abajo FJ et al. Br Med J 1999;319:1106-1109.
1
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Clarithromycin (Biaxin)-Induced Digoxin Toxicity
•70 YO woman on digoxin 0.25 mg/day for 4 years started on clarithromycin
•After 4 days, hospitalized with nausea, vomiting, weakness, brown spots in vision, ECG abnormalities
•Serum digoxin = 5.4 ng/mLTrevedi S et al. Ann Intern Med 1998;128:604. Letter
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P-glycoprotein (P-gp)
•Efflux pump: exposure to xenobiotics•Found in numerous tissues:
– Intestinal Epithelium– Biliary canaliculi – Renal proximal tubules – Blood-brain barrier – Tumor cells
•Promiscuous: interacts with wide variety of chemical structures
Kovarik JM et al. Clin Pharmacol Ther 1999;66:391-400.
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P-Glycoprotein Actively Transports Drugs Out of Cell
Wall
Inside Cell
Cell Wall
Outside CellEntry via passive diffusion
PGP
= Lipophilic Drug
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P-glycoprotein Involved in Digoxin
Pharmacokinetics P-glycoprotein protects against
digoxin toxicity by:
•Decreasing G.I. absorption
•Increasing biliary excretion
•Increasing renal tubular secretion
•Decreasing access to the brain
Tanigawara Y. Ther Drug Monit 2000;22:137-140.
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Itraconazole Increases Levels of
Methylprednisolone• Randomized
crossover study of 14 subjects, 4 days of itraconazole, then single dose of:– Methylpred. 48mg– Prednisolone 60 mg
• Marked effect on methylprednisolone, but not prednisolone
0
2
4
6
8
Methylprednisolone AUC
Methylprednisolone AloneMethylprednisolone + Itra.
Lebrun-Vignes B. Br J Clin Pharmacol. 2001;51:443-450.
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Prescriber’s Knowledge
Computer Screening
Pharmacist’s Knowledge
Patient Risk Factors
Patient EducationMonitoring
NO ADR
A + B
Drug Interaction Errors
Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990
Drug Administration
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“Asthma Sufferer Wins $28.6 Million Award” (Seattle Times 9/3/94)
“Asthma Sufferer Wins $28.6 Million Award” (Seattle Times 9/3/94)
•24-year-old man on theophylline went into ER with infection, and the ER physician gave him ciprofloxacin
•Theophylline levels doubled, and he was left with permanent brain damage
•Physician was awarded $22.5 million for “damage to his reputation”
•24-year-old man on theophylline went into ER with infection, and the ER physician gave him ciprofloxacin
•Theophylline levels doubled, and he was left with permanent brain damage
•Physician was awarded $22.5 million for “damage to his reputation”
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St. John’s Wort Reduces Simvastatin (Zocor) Levels
• 16 subjects took 10mg simvastatin alone and after St. John’s Wort 900 mg/day X 14 days
• AUC of Simvastatin & its active metabolite substantially reduced
• Induction of CYP3A4 and P-glycoprotein?
• No effect on Pravastatin
0
5
10
15
Simvastatin Alone
Simvastatin + SJ W
Sugimoto K et al. Clin Pharmacol Ther 2001;70:518-24.
Simvastatin Acid AUC
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St. John’s Wort Increases CYP3A4 Activity
• 12 subjects took probe drugs with St. John’s Wort 900mg/d X 14d– Caffeine (1A2)– Tolbutamide (2C9)– Dextromethorphan
(2D6)– Midazolam (3A4)
• Only midazolam was affected (PO > IV)
0
10
20
30
40
50
60
70
80
90
100
Serum Midazolam (% Control)
Midazolam AloneMidazolam IVMidazolam PO
Wang Z et al. Clin Pharmacol 2001;70:317-26.
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Garlic Supplements Decrease Saquinavir (Invirase) Levels
• 9 subjects took 1200 mg saquinavir TID alone and after garlic capsules BID X 20 days
• Allicin content of garlic capsules confirmed
• Garlic associated with 51% decrease in AUC of saquinavir
0
500
1000
1500
2000
2500
3000
3500
Saquinavir AUC
SaquinavirSaquinavir + Garlic
Piscitelli SC et al. 8th Conf. On Retroviruses, 2001, Abst. 743
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Ibuprofen (Advil) Inhibits the Antiplatelet Effects of AspirinIbuprofen (Advil) Inhibits the Antiplatelet Effects of Aspirin
Catella-Lawson F et al. New Engl J Med. 2001;345:1809-17.
• Subjects took 81 mg ASA in AM for 6 days with 3 ibuprofen dosing schedules:– 400 mg 2 hours before ASA ( platelet effect) – 400 mg 2 hours after ASA (No effect on ASA)– 400 mg 2, 7 & 12 h after ASA ( platelet effect)
• Other agents did not reduce platelet effect:– Rofecoxib (Vioxx) 25 mg before or after ASA– Diclofenac DR 75 mg BID (2 & 10 h after ASA)– Acetaminophen 1000 mg before or after ASA
• Subjects took 81 mg ASA in AM for 6 days with 3 ibuprofen dosing schedules:– 400 mg 2 hours before ASA ( platelet effect) – 400 mg 2 hours after ASA (No effect on ASA)– 400 mg 2, 7 & 12 h after ASA ( platelet effect)
• Other agents did not reduce platelet effect:– Rofecoxib (Vioxx) 25 mg before or after ASA– Diclofenac DR 75 mg BID (2 & 10 h after ASA)– Acetaminophen 1000 mg before or after ASA
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Prescriber’s Knowledge
Computer Screening
Pharmacist’s Knowledge
Patient Risk Factors
Patient EducationMonitoring
NO ADR
A + B
Drug Interaction Errors
Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990
Drug Administration
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Rifampin Markedly Reduces Simvastatin Plasma Levels
• 10 subjects took 40 mg simvastatin alone & after rifampin 600 mg/day for 5 days
• Simvastatin acid AUC decreased by 93%
• No effect on half-life of simvastatin; primary effect on first pass metabolism
0
2
4
6
8
10
12
14
16
18
Simvastatin Acid AUC
Simvastatin AloneSimvastatin + Rifampin
Kyrklund et al. Clin Pharmacol Ther 2000;68:592-597..
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Sertraline (Zoloft) Levels Reduced by Enzyme Inducers
(PHT, CBZ)• Sertraline serum
levels compared in 9 patients on phenytoin (PHT) or carbamazepine (CBZ) versus 54 patients on just sertraline
• Concentration/daily dose ratios considerably lower with enzyme inducers
0
20
40
60
80
100
Sertraline Alone
Sertraline + Inducers
Pihlsgard M, Eliasson E. Eur J Clin Pharmacol 2002;57:915-916.
Sertraline C/D Ratio
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Cushing’s Syndrome with Ritonavir + Nasal
Fluticasone• 30 YO HIV (+) man on
ritonavir and nasal fluticasone developed Cushingoid facies
• Positive dechallenge and rechallenge
• Similar case reported by Chen (1998)
0
100
200
300
400
500
600
700
Plasma Cortisol
Fluticasone aloneFluticasone + RitonavirFluticasone alone (3 weeks)
Hillebrand-Haverkort et al. AIDS 1999;13:1803.
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Fluticazone Susceptible to CYP3A4 Inhibitors?
•Fluticasone metabolized by CYP3A4 to inactive metabolite
•Bioavailability of fluticasone after inhalation = 12 to 26%
•CYP3A4 inhibitors theoretically would increase systemic effects of fluticasone
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Prescriber’s Knowledge
Computer Screening
Pharmacist’s Knowledge
Patient Risk Factors
Patient EducationMonitoring
NO ADR
A + B
Drug Interaction Errors
Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990
Drug Administration
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Factors Influencing Drug Interaction Outcomes
CLINICALOUTCOMEOF DRUG
INTERACTIONS
PATIENT FACTORS
DRUGADMINISTRATION
Genetics
Diseases
Diet/Nutrition
Environment
Smoking
Alcohol
Dose
Duration
Dosing Times
Sequence
Route
Dosage FormHIGH VARIABILITY
Adapted from Hansten. Science & Medicine. 1998;5:16-25.
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Fluconazole (Diflucan) + Warfarin (Coumadin)
0
10
20
30
40
50
60
70
1 2 3 4 5 6 7
% Increase in Pro-Time
mean
Patients
•7 people on warfarin given fluconazole 100 mg daily X 7 d
•Marked increase in the PT response (but high variability)
•No bleeding occurred
Crussell-Porter LL et al. Arch Intern Med 1993;153:102-104.
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Fatal Hyperkalemia After Amiloride + ACE Inhibitors
• 5 patients presented to ER with 5 patients presented to ER with severe hyperkalemia (on ACE severe hyperkalemia (on ACE inhibitor with amiloride added 8 to inhibitor with amiloride added 8 to 18 days earlier)18 days earlier)
• All 5 were over 50 & had diabetes All 5 were over 50 & had diabetes and 4 had renal impairmentand 4 had renal impairment
• Potassium levels = 9.4 to 11 mEq/LPotassium levels = 9.4 to 11 mEq/L
• 2 patients died (authors recommend 2 patients died (authors recommend avoiding combination)avoiding combination)
Chiu T-F et al. Ann Emerg Med 1997;30:612-615.
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Hyperkalemia Risk Estimates With Various Combinations of
Drugs
0%
20%
40%
60%
80%
100%
Amiloride(Alone)
Amiloride(+ACEI)
Amiloride(+ACEI + K)
Amiloride(+ACEI + K)
Symtomatic
Hyperkalemia
Normal K
Hypokalemia
Patients Predisposed
to Hyperkalemia
** e.g., Diabetes, Renal impairment, High dietary potassium, etc.