Drug Interactions Pharm 560 2 October 2002 Philip D. Hansten, PharmD Professor, School of Pharmacy...
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Transcript of Drug Interactions Pharm 560 2 October 2002 Philip D. Hansten, PharmD Professor, School of Pharmacy...
Drug InteractionsPharm 560
2 October 2002
Philip D. Hansten, PharmDProfessor, School of Pharmacy
University of Washington
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
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.
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.
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.
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.”
NO ADR OBSERVED
Drug A + Drug B
Assessing Drug Interactions Using
Induction
25 Patients
Usual Conclusion: This interaction is not clinically important.
NO ADR OBSERVED
Drug A + Drug B 25
Patients
Correct Conclusion: Available information is insufficient to determine clinical importance.
Assessing Drug Interactions Using
Induction
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
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
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
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
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
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.
P-Glycoprotein Actively Transports Drugs Out of Cell
Wall
Inside Cell
Cell Wall
Outside CellEntry via passive diffusion
PGP
= Lipophilic Drug
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.
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.
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
“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”
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
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.
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
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
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
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..
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
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.
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
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
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.
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.
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.
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.