7601 Drug Interactions. Part I

Drug Interactions Pharm 560 2 October 2002 Philip D. Hansten, PharmD Professor, 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.” Assessing Drug Interactions Using Induction Drug A + Drug B 25 Patients NO ADR OBSERVED Usual Conclusion: This interaction is not clinically important. Assessing Drug Interactions Using Induction Drug A + Drug B 25 Patients NO ADR OBSERVED Correct Conclusion: Available information is insufficient to determine clinical importance. Drug Interaction Defenses Drug A + Drug B Prescriber’s Knowledge Computer Screening Pharmacist’s Knowledge Patient Risk Factors Pharmacogenetics Drug Administration Patient Education Monitoring Defenses ADR Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990 Drug Interactions: “When the Holes Line Up” A+B Prescriber’s Knowledge Computer Screening Pharmacist’s Knowledge Patient Risk Factors Drug Administration Defenses Latent Failures Patient Education Monitoring ADR Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990 Drug Interaction Errors A+B Prescriber’s Knowledge Computer Screening Pharmacist’s Knowledge Patient Risk Factors Drug Administration Patient Education Monitoring NO ADR Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990 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 Relative Risk 16 14 12 10 8 6 4 2 0 1 Neither Drug NSAID SSRI NSAID + SSRI De Abajo FJ et al. Br Med J 1999;319:1106-1109. 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/mL Trevedi 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 Entry via passive diffusion Outside Cell Cell Wall PGP Inside Cell = 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 Methylprednisolone AUC 8 6 4 2 0 study of 14 subjects, 4 days of itraconazole, then single dose of: – Methylpred. 48mg – Prednisolone 60 mg • Marked effect on methylprednisolone, but not prednisolone Methylprednisolone Alone Methylprednisolone + Itra. Lebrun-Vignes B. Br J Clin Pharmacol. 2001;51:443-450. Drug Interaction Errors A+B Prescriber’s Knowledge Computer Screening Pharmacist’s Knowledge Patient Risk Factors Drug Administration Patient Education Monitoring NO ADR Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990 “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” St. John’s Wort Reduces Simvastatin (Zocor) Levels • 16 subjects took 10mg Simvastatin Acid AUC 15 • • • 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 10 5 0 Simvastatin Alone Simvastatin + SJW Sugimoto K et al. Clin Pharmacol Ther 2001;70:518-24. 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) Serum Midazolam (% Control) 100 90 80 70 60 50 40 30 20 10 0 • Only midazolam was affected (PO > IV) Midazolam Alone Midazolam IV Midazolam PO Wang Z et al. Clin Pharmacol 2001;70:317-26. Garlic Supplements Decrease Saquinavir (Invirase) Levels • 9 subjects took 1200 Saquinavir AUC 3500 3000 2500 2000 1500 1000 500 0 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 Saquinavir Saquinavir + Garlic Piscitelli SC et al. 8th Conf. On Retroviruses, 2001, Abst. 743 Ibuprofen (Advil) Inhibits the Antiplatelet Effects of Aspirin • 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 Catella-Lawson F et al. New Engl J Med. 2001;345:1809-17. Drug Interaction Errors A+B Prescriber’s Knowledge Computer Screening Pharmacist’s Knowledge Patient Risk Factors Drug Administration Patient Education Monitoring NO ADR Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990 Rifampin Markedly Reduces Simvastatin Plasma Levels • 10 subjects took 40 Simvastatin Acid AUC 18 16 14 12 10 8 6 4 2 0 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 Simvastatin Alone Simvastatin + Rifampin Kyrklund et al. Clin Pharmacol Ther 2000;68:592-597.. Sertraline (Zoloft) Levels Reduced by Enzyme Inducers (PHT, CBZ) • Sertraline serum levels Sertraline C/D Ratio 100 80 60 40 20 0 • 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 Sertraline Alone Sertraline + Inducers Pihlsgard M, Eliasson E. Eur J Clin Pharmacol 2002;57:915-916. Cushing’s Syndrome with Ritonavir + Nasal Fluticasone • 30 YO HIV (+) man on Plasma Cortisol 700 600 500 400 300 200 100 0 • • ritonavir and nasal fluticasone developed Cushingoid facies Positive dechallenge and rechallenge Similar case reported by Chen (1998) Fluticasone alone Fluticasone + Ritonavir Fluticasone 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 Drug Interaction Errors A+B Prescriber’s Knowledge Computer Screening Pharmacist’s Knowledge Patient Risk Factors Drug Administration Patient Education Monitoring NO ADR Hansten PD, Horn JR. Modified from: James Reason, Human Error, 1990 Factors Influencing Drug Interaction Outcomes PATIENT FACTORS Genetics Diseases Diet/Nutrition Environment Smoking DRUG ADMINISTRATION Dose CLINICAL OUTCOME OF DRUG INTERACTIONS Duration Dosing Times Sequence Route Alcohol HIGH VARIABILITY Dosage Form Adapted from Hansten. Science & Medicine. 1998;5:16-25. Fluconazole (Diflucan) + Warfarin (Coumadin) • 7 people on warfarin % Increase in Pro-Time 70 60 50 40 30 20 10 0 1 2 3 4 5 6 7 mean given fluconazole 100 mg daily X 7 d • Marked increase in the PT response (but high variability) • No bleeding occurred Patients Crussell-Porter LL et al. Arch Intern Med 1993;153:102-104. Fatal Hyperkalemia After Amiloride + ACE Inhibitors • 5 patients presented to ER with severe hyperkalemia (on ACE inhibitor with amiloride added 8 to 18 days earlier) • All 5 were over 50 & had diabetes and 4 had renal impairment • Potassium levels = 9.4 to 11 mEq/L • 2 patients died (authors recommend avoiding combination) Chiu T-F et al. Ann Emerg Med 1997;30:612-615. Hyperkalemia Risk Estimates With Various Combinations of Drugs 100% Symtomatic Hyperkalemia Normal K 80% 60% Hypokalemia 40% 20% 0% Amiloride (Alone) Amiloride (+ACEI) Amiloride (+ACEI + K) Amiloride (+ACEI + K) Patients Predisposed to Hyperkalemia* * e.g., Diabetes, Renal impairment, High dietary potassium, etc.