Drug Interactions for the Emergency Physician. Lisa Thurgur

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1 Drug Interactions for the Emergency Physician Lisa Thurgur

2 Objectives Why we should care about drug-drug interactions Cases How can we avoid these interactions Short list of culprit drugs

3 Drug-Drug Interaction (DI) Effect of one drug enhanced or diminished by use of another

4 Four Important Characteristics 1. Innumerable 2. Common 3. Clinical consequences not well studied 4. Avoidable

5 Classification Drug level changes Pharmacokinetic vs. Pharmacodynamic Drug level does not change

6 Pharmacodynamic DIs Donepezil (Aricept ) + Gravol Sinemet + olanzapine Narcotics + EtOH + benzodiazepines The Libby Zion story

7 Methadone 200 mg methadone daily

8 Methadone 200 mg methadone daily plus cipro

9 Pharmacokinetic DIs Three mechanisms: or absorption or elimination or metabolism

10 Typical Pharmacokinetic DI new medication ± Toxicity chronic medication ( M/L) } Therapeutic range time

11 Typical Pharmacokinetic DI new medication chronic medication ( M/L) } Therapeutic range ± Loss of effect time

12 Altered absorption H 2 blockers, PPIs absorption of ketoconazole, itraconazole Ca 2+ or Mg 2+ absorption of tetracyclines captopril quinolone antibiotics

13 Altered drug metabolism P450

14 Cytochrome P450 A family of diverse enzymes metabolize different drugs substrates can be inhibited by different compounds inhibitors can be induced by different compounds inducers

15 Cytochrome P450 Major ones CYP 1A2 CYP 2C9 CYP 2C19 CYP 2D6 CYP 2E1 CYP 3A4 / 3A5

16 Cases

17 Case 1 72 y.o. woman with CAD, DM2, HTN Develops symptoms of UTI Rx Septra 2 days later confused upon awakening generalized seizure husband calls 911

18 What happened? Blood glucose = 0.9 mmol/l Patient was on glyburide 10 mg BID metabolized by liver cytochrome P450 (CYP) 2C9 CYP 2C9 inhibited by SMX/TMP

19 CYP 2C9 Drugs metabolized by CYP 2C9 sulfonylureas S-warfarin CYP 2C9 inhibitors SMX/TMP metronidazole fluvoxamine, fluoxetine fluconazole amiodarone

20 Glyburide and SMX-TMP

21 52 y.o. male smoker BMI 35 LDL-C 5.6 mm on simvastatin Case 2 Decides to go on a diet 14 days later presents with severe myalgias strength 4/5 in quads CK = 63,000 IU/L

22

23 What happened? Simvastatin is metabolized by CYP 3A4 Grapefruit blocks CYP 3A4 in gut wall absorption of simvastatin > 10-fold

24 CYP 3A4 The dominant CYP enzyme in man 60% of drugs metabolized by it Inhibited & induced by scores of drugs

25 Location of CYP 3A4 Dresser CMAJ 2004

26 CYP 3A4 Substrates Statins atorvastatin, lovastatin, simvastatin Calcium channel blockers felodipine, nifedipine, amlodipine, diltiazem Miscellaneous carbamazepine cyclosporine, triazolam, alprazolam, diazepam Dresser Can J Clin Pharm 2002

27 CYP 3A4 Inhibitors Macrolides erythromycin, clarithromycin Calcium antagonists verapamil, diltiazem Quinolones norfloxacin, ciprofloxacin Antifungals itraconazole, ketoconazole Amiodarone

28 CYP 3A4 Inducers Anticonvulsants carbamazepine, phenobarbital, phenytoin topiramate Dexamethasone Rifampin Tamoxifen St. John s Wort

29

30 Case 3 64 y.o. with metastatic breast Ca on Codeine Contin 150 mg BID Rx paroxetine for symptoms of depression 2 days later markedly worse bone pain

31 What happened?

32 What happened? Codeine is a prodrug Codeine CYP 2D6 Θ Morphine paroxetine

33 CYP 2D6 Metabolizes 15-20% of drugs Highly polymorphic Poor metabolizers 7 to 8% Extensive metabolizers Ultrarapid metabolizers Prevalence: Italy 10% Greece 12% Saudi 33% Ethiopa 37%

34 CYP 2D6 Interactions CYP 2D6 substrates CYP 2D6 inhibitors donepezil, galantamine carvedilol, metoprolol amiodarone fluoxetine, paroxetine codeine *** tamoxifen *** *** = prodrug

35 62 y.o. man with CLL SOB, cough, fever x 3 days CXR = bilateral pneumonia Day 1 ceftriaxone, clarithromycin, voriconazole codeine 25 mg TID Day 4 Decreased LOC, pco 2 80 mm Hg Rapid reversal with naloxone

36 Lab and Genotyping Codeine CYP 2D6 Morphine CYP 3A4 Normorphine Norcodeine Codeine 6-glucuronide Morphine 3- and 6- glucuronides

37 Lab and Genotyping Clarithro Voriconazole CYP 3A4 Codeine CYP 2D6 Gene duplication x 3 80 µg/l (20 to 80 times expected) Morphine Normorphine Norcodeine Codeine 6-glucuronide 361 µg/l (25% expected) Morphine 3- and 6- glucuronides 10-fold

38 Case 4 92 y.o. woman independent, lives alone PMH atrial fibrillation, penicillin allergy Arrives in emergency feeling unwell x 2d recent Rx for clarithromycin 500 mg BID

39

40 What happened?

41 P-glycoprotein Membrane glycoprotein first identified in cancer cells resistant to multiple chemotherapy drugs Expressed in gut, kidney, bile canaliculi, brain A natural defense mechanism

42 P-glycoprotein Substrates Inhibitors Inducers digoxin macrolides rifampin loperamide amiodarone dexamethasone diltiazem antifungals St. John s wort cyclosporine verapamil protease inhibitors ritonavir chemo (various)

43 Digoxin + Clarithromycin

44 Case 5 72 y.o. man with atrial fibrillation Developed diarrhea after course of amoxicillin Rx metronidazole 500 mg BID Five days later back pain progressively worse

45

46 What happened? (S)-warfarin CYP 2C9 substrate metronidazole inhibits CYP 2C9

47 Amiodarone Antibiotics Interactions with warfarin: The 5 A s sulfamethoxazole / trimethoprim metronidazole Antidepressants Antiplatelets Analgesics NSAIDs acetaminophen

48 Case 6 82 y.o. woman PMH: Meds CAD, HTN, GERD, OA, DM Metoprolol 50 mg BID Aspirin 325 mg OD Lisinopril 20 mg OD Spironolactone 25 OD Rofecoxib 12.5 mg OD Septra DS 1 BID (recent UTI) Arrives in ED with anorexia & malaise x 1/52

49

50

51 Why did this happen? Medications ramipril metoprolol trimethoprim rofecoxib spironolactone Disease diabetes renal insufficiency

52 Hyperkalemia: The Usual Suspects Renal disease ACE Inhibitors ARBs K + supplements Spironolactone Amiloride Triamterene

53 The Unusual Suspects Diabetes NSAIDs Septra -blockers Salt substitutes

54 Co-trimoxazole and K + Co-trimoxazole (SMX-TMP) 1968: Available in Europe 1983: Report of K + (HIV) 1994: K + reported in immunocompetent patients Trimethoprim Amiloride

55 Co-trimoxazole and K + Co-trimoxazole (SMX-TMP) 1968: Available in Europe 1983: Report of K + (HIV) 1994: K + reported in immunocompetent patients

56 Hospitalization for K + in Older Patients Receiving ACE Inhibitors Drug Adjusted OR (95% CI) SMX/TMP 6.7 (4.5 to 10.0) Norfloxacin 0.8 (0.4 to 1.5) Ciprofloxacin 1.4 (0.9 to 2.2) Nitrofurantoin 1.1 (0.6 to 2.0) Amoxicillin (reference) 1.0 Antoniou et al. (in press)

57 Case 7 42 y.o. man PMH depression (citalopram 20 mg / day) Presents 12 hours after starting new medication for exertional LBP O/E: Agitated, sweating, flushed T 38.2 HR 115 SBP 150 Spontaneous and inducible clonus; DTRs 4+

58 Tramadol (Ultram, Zytram, Ralivia) Pharmacology Weak agonist M1 200 x binding affinity Inhibits 5-HT and NE reuptake Marketing Dual mechanism of action Low abuse potential Adverse effects Usual opioid AEs Seizures Serotonin syndrome

59 Tramadol and Serotonin Syndrome Vizcaychipi BJA 2007 Healthy 49 y M with humerus # Morphine 30 mg and tramadol 100 mg 40 minutes later:» Flushing & profuse diaphoresis» HR 136 BP 160/110; GTC seizure Mahlberg Am J Psych y F, mild depression on citalopram 10 mg/d Tramadol 50 mg tremor, restlessness, fever, AMS, hallucinations recurred a year later with 20 mg tramadol

60 Avoiding Drug Interactions in Practice

61 Minimizing Drug Interactions 1. Commit a short list of drugs to memory

62 Common precipitants

63 Minimizing Drug Interactions 1. Commit a short list of drugs to memory 2. Entertain DDI with any new drug, especially esp. in addition to warfarin, digoxin, glyburide, statins, theophylline

64 Minimizing Drug Interactions 1. Commit a short list of drugs to memory 2. Entertain DDI with any new drug, especially esp. in addition to warfarin, digoxin, glyburide, statins, theophylline 3. Encourage patient to use only one pharmacy

65 Minimizing Drug Interactions 4. When possible, use safer alternative

66 Generally safer Drug class Safer Options SSRIs Antibiotics Statins citalopram, sertraline penicillins cephalosporins azithromycin pravastatin, rosuvastatin

67 Minimizing Drug Interactions 4. When possible, use safer alternative 5. Other resources PDAs (epocrates, LexiDrugs, others)

68

69 Minimizing Drug Interactions 4. When possible, use safer alternative 5. Other resources PDAs (epocrates, LexiDrugs, others) A good pharmacist

70 Background Recap Various avoidable DDIs glyburide + SMX-TMP statins + grapefruit juice digoxin + clarithromycin codeine + paroxetine warfarin + metronidazole ACE inhibitors / spironolactone / SMX-TMP tramadol + SSRIs Six common sense strategies to avoid them

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