drug interactions in the emergency department diane lum, pharmd, bcacp emergency medicine clinical...
TRANSCRIPT
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DRUG INTERACTIONS IN THE EMERGENCY DEPARTMENTDIANE LUM, PHARMD, BCACP
EMERGENCY MEDICINE CLINICAL PHARMACIST
STONY BROOK UNIVERSITY HOSPITAL
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OBJECTIVES
Review common and significant drug interactions
Discuss management and monitoring of drug interactions
Identify alternative drug therapy to prevent drug interactions
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DEFINITIONS
Drug-Drug interaction (DDI): “Two or more drugs such that the potency, safety, or efficacy of one drug is significantly modified
by the presence of another drug”
Pharmacokinetic drug interaction: Absorption, distribution, metabolism, excretion
Pharmacodynamic drug interaction: Two drugs with additive or antagonistic effects
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RISK FACTORS FOR DRUG INTERACTIONS
Polypharmacy
Age
Kidney and liver function
Medications with narrow therapeutic index
Pharmacogenetics
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WARFARIN
Mechanism of action: Blocks vitamin K epoxide
Metabolism: Hepatic S-isomer Cytochrome P450 (CYP) 2C9
R-isomer CYP 1A2 and CYP 3A4
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PATIENT CASE
CC is a 75 year old female who presents from home to the ED with rash on leg and fever for 5 days. Patient reports a decrease in overall appetite
PMH: HTN, DM, afib on warfarin, HLD, depression, HIV on HAART
Vitals: Temp 38.2 degrees C, HR 84, RR 18, BP 150/94
Labs: WBC 12, Na 140, K 4.7, Cl 101, Scr 1.1 , INR 3.0
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PATIENT CASE
Medications: Aspirin
Metformin
Pioglitazone
Hydrochlorothiazide
Simvastatin
Sertraline
Tenofovir/emtricitabine (Truvada)
Atazanavir
Ritonavir
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PATIENT CASE
Which of these patient’s home medications interacts with warfarin?
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WARFARIN DRUG INTERACTIONS
Drugs that increase INR Drugs that decrease INR
Drugs that increase bleeding risk
Cimetidine Carbamazepine Anticoagulants
Amiodarone, diltiazem Phenobarbital, phenytoin, primidone
Anti-platelets
Fluoroquinolones, macrolides, sulfamethoxazole/trimethoprim, metronidazole
Rifampin, nafcillin NSAIDs
Protease inhibitors Sucralfate SSRIs
Fibrates Efavirenz SNRIs
Azole antifungals Mesalamine
Steroids St. John’s Wort
Acetaminophen > 2g/day CholestyramineArch Intern Med. 2005;165:1095-1066Ther Drug Monit. 2007;29:687-710
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WARFARIN DRUG INTERACTIONS ANTIBIOTICS
Metronidazole Empirically decrease warfarin dose by 25 to 40% Alternative: clindamycin for anaerobic coverage
Sulfamethoxazole/Trimethoprim Empirically decrease warfarin dose by 25 to 40% Alternative: Community acquired MRSA use doxycycline, UTI use cephalosporins
Azole antifungals Empirically decrease warfarin dose by 25%
Rifampin and rifabutin Empirically increase warfarin dose by 25 to 50% Effects usually seen 1 to 3 weeks after starting rifampin
Ann Intern Med. 1994;121:676-683
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WARFARIN DRUG INTERACTIONS ANTIBIOTICS
Cephalosporins Second or third generation cephalosporins might increase INR
Avoid cefotetan: Can increase INR
Oral cephalosporins that do not interact with warfarin: cefaclor, cefixime, cefpodoxime, cefuroxime
Other antibiotics: Fluoroquinolones (FQ), macrolides (especially erythromycin), tetracyclines
Penicillins: High dose IV penicillin, amoxicillin, amoxicillin/clavulanic acid may increase INR
Oral penicillin G or V, ampicillin do not interact with warfarin
Nafcillin, dicloxacillin decrease INR
Ann Intern Med. 1994;121:676-683
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WARFARIN DRUG INTERACTIONS
Acetaminophen increase INR with doses >2000 mg/day
Amiodarone Anticipated effect: one week
Empiric reduction of warfarin dose 10 to 25% after one week of starting amiodarone therapy
Anticipated offset: may last months after drug is stopped
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FACTORS AFFECTING INR
Increase in INR: Diarrhea, liver disease, poor nutritional state, decrease in vitamin K intake, increase in alcohol
(acute), cranberry and pomegranate juice
Decrease in INR: Increase in vitamin K intake, chronic alcohol intake, cigarette smoking
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PATIENT CASE CONTINUED
Diagnosis: Cellulitis
Medications given in the ED: Sulfamethoxazole/trimethoprim DS
Discharge prescriptions: Sulfamethoxazole/trimethoprim DS 1 tab PO BID x7 days
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PATIENT CASE CONTINUED
Does SMX/TMP interact with warfarin?
What medication would you recommend for fever?
What dose of warfarin would you discharge the patient on? Patient’s home dose is warfarin 5 mg PO once daily
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MONITORING
INR Monitor daily while admitted
Recommend patient to follow up with warfarin/Coumadin clinic at discharge
Counseling points Drug interactions prescription/OTC medications
Vitamin K intake and diet
Alcohol intake
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QTC PROLONGATION AND TORSADES DE POINTES
Prolonged QTc interval >450 milliseconds in males and >470 milliseconds in females
Most common ventricular arrhythmia associated with QTc interval >500 milliseconds is Torsades De Pointes (TdP)
Ther Adv Drug Saf. 2012 Oct; 3(5): 241–253
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DRUGS THAT PROLONG QTC
Drug Class Drugs
Anticonvulsants Fosphenytoin
Antibiotics Macrolides (clarithyromycin, erythromycin, azithromycin), Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin), sulfamethoxazole/trimethoprim
Antifungals Fluconazole, ketoconazole, itraconazole, voriconazole
Anti-arrhythmics Amiodarone, dysopramide, flecainide, ibutilide, procainamide, sotalol, dofetilide
Antidepressants Amitriptyline, desipramine, imipramine, fluoxetine, venlafaxine, doxepin, sertraline
Antipsychotics Chlorpromazine, haloperidol, thioridazine, quetiapine, ziprasidone, risperidone, olanzapine
Antiemetics Ondansetron, prochlorperazine, promethazine
Other Sumatriptan, tizanidine, methadone
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PATIENT CASE
EB is a 44 year old F with a PMH of afib, HTN, HLD, schizophrenia. EB reports vomiting and coughing for 2 days
Vitals: Temp 38.4 degrees C, HR 112, RR 18, BP 135/90
Labs: WBC 14, all other labs WNL
QTc interval: 520
Home medications: amiodarone, lisinopril, diltiazem, simvastatin and ziprasidone
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PATIENT CASE
Which home medications can cause QTc prolongation?
Which medications interact and increase QTc prolongation?
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QTC PROLONGING ANTI-ARRHYTHMIC DRUGS
Class I anti-arrhythmics (quinidine, dysopyramide, procainamide)
Class III anti-arrhythmics (sotalol, dofetilide, ibutilide, amiodarone) Amiodarone lowest TdP risk
Ther Adv Drug Saf. 2012 Oct; 3(5): 241–253N Engl J Med. 2004;350:1013-22
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QTC PROLONGING DRUGS ANTIBIOTICS
Azole antifungals Alternative: micafungin for aspergillosis and candidemia
Fluoroquinolones Moxifloxacin > levofloxacin > ciprofloxacin
Alternative for double gram negative coverage: aminoglycosides
UTI: use beta-lactams
Macrolides Erythromycin > clarithromycin > azithromycin
Alternative for atypical coverage: doxycycline
CID. 2006;43:1603-11
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QTC PROLONGING DRUGS ANTI-EMETICS
Anti-emetics Prochlorperazine > 5H3T antagonists (ondansetron, palonosetron, granisetron)
Alternative: metoclopramide
Ther Adv Drug Saf. 2012 Oct; 3(5): 241–253N Engl J Med. 2004;350:1013-22
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QTC PROLONGING CNS DRUGS
Antipsychotics First generation antipsychotics: Thioridazine, chlorpromazine, haloperidone
Second generation antipsychotics: Ziprasidone > clozapine, olanzapine, risperidone, quetiapine
Antidepressants Tricyclic antidepressants (TCA): amitriptyline, nortriptyline, imipramine, desipramine, doxepin
SSRI: citalopram, escitalopram > sertraline, paroxetine, fluoxetine
SNRI: venlafaxine, desvenlafaxine > duloxetine
TCAs > SSRIs and SNRIs
Ther Adv Drug Saf. 2012 Oct; 3(5): 241–253N Engl J Med. 2004;350:1013-22
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RISK FACTORS FOR QTC PROLONGATION AND TORSADES
Genetic risk factors
Underlying cardiac diseases
Electrolyte abnormalities
Organ dysfunction
Drug interactions Inhibitors of CYP 3A4, 1A2, and 2D6
Ther Adv Drug Saf. 2012 Oct; 3(5): 241–253N Engl J Med. 2004;350:1013-22
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DRUG INTERACTIONS
Enzyme Drug that prolongs QTc Inhibitor
3A4 AmiodaroneErythromycinQuinidineHaloperiodolTacrolimusDofetilideDysopyramideTamoxifen
CimetidineErythromycinProtease InhibitorsAzole antifungals DiltiazemClarithromycin
1A2 Imipramine CimetidineFluvoxamineCiprofloxacin
2D6 ThioridazineImipramineAmitriptylineFlecainideDoxepineTamoxifen
AmiodaroneDiphenhydramineQuinidineFluoxetine
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SEROTONIN SYNDROME
First cases from the 1950s from monoamine oxidase inhibitors (MAOIs)
Complication resulting from excessive effects of serotonin on the CNS
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SEROTONIN SYNDROME SIGNS AND SYMPTOMS
Tachycardia
Shivering
Hypertension
Hyperthermia
Diaphoresis
Delirium
Mydriasis
Muscle rigidity
Tremor or myclonus, hyperreflexia
Hyperactive bowel sounds
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MECHANISM
Inhibition serotonin reuptake
Inhibition of serotonin metabolism by MAO
Increased serotonin release
Stimulation of serotonin receptors
AACN Advanced Critical Care. 2013;24:15-20
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DRUG INDUCED SEROTONIN SYNDROME
SSRIs
TCAs
Opiate analgesics
Antibiotics
Antiemetics
Antimigraine agents
OTC drugs
AACN Advanced Critical Care. 2013;24:15-20
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SEROTONERGIC AGENTS
Drug class Drug
Analgesics Tramadol, meperidine, methadone, codeine, fentanyl
Antibiotics Linezolid
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
Venlafaxine, desvenlafaxine
Serotonin Reuptake Inhibitors (SSRIs)
Citalopram, escitalopram, fluvoxamine, fluoxetine, paroxetine, sertraline
Tricyclic antidepressants (TCAs)
Amitriptyline, nortriptyline, desipramine, imipramine, clomipramine, doxepin
Monamine Oxidase Inhibitors (MAOIs)
Isocarboxazid, phenelzine, rasagiline, selegiline, tranylcypromine
Serotinin Receptor Agonists (5-HT)
Almotriptan, sumatriptan, frovatriptan, rizatriptan, zolmitriptan, naratriptan, buspirone
Over the Counter (OTCs) St. John’s wort, dextromethorphan
Miscellaneous Amphetamines, cocaine, mirtazapine, levodopa, reserpine, methylene blue
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SEROTONINERGIC AGENTS METABOLISM
2D6 3A4
TCAs (amitriptyline, clomipramine, desipramine, imipramine, nortriptyline)
Antidepressants(Imipramine, nefazodone)
Anti-psychotics (Chlorpromazine, clozapine, fluphenazine, haloperidol, perphenazine, risperidone, thioridazine)
Journal of Affective Disorders. 1997;46:59-67
Strong 2D6 inhibitors: bupropion, cinacalcet, fluoxetine, paroxetine, quinidine
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PATIENT CASE
MM is a 60 year old female with PMH of depression who presents to the ED after ingesting unknown amount of venlafaxine 37.5 mg tablets
Vitals: Temp 38.5 degrees C, HR 150, BP 140/90
Labs: Scr 2.5, Na 129, +UA all other labs WNL
Past history of UTI showed VRE
Dx: Overdose of venlafaxine, cystitis UTI
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PATIENT CASE
What antibiotic would you use to treat MM’s UTI?
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SEROTONERGIC AGENTS AND HALF LIFE
Drug Elimination half life
Fluoxetine 5 weeks
Other SSRIs 2 weeks
Venlafaxine 1 week
Duloxetine 5 days
AACN Advanced Critical Care. 2013;24:15-20
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SEROTONERGIC AGENTS
Opioids Alternatives: morphine, hydromorphone
Migraine Alternatives: acetaminophen, NSAIDs, prochlorperazine
Cough suppressant Alternative: guaifenesin
MRSA/VRE coverage Alternative: Daptomycin (Except Pneumonia), vancomycin for MRSA, ampicillin, nitrofurantoin or
fosfomycin for VRE UTI
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SUMMARY
Many drugs are metabolized through Cytochrome P-450
Drug interactions may involve inhibition and/or induction of Cytochrome P-450 or additive pharmacodynamic effects
Recommend close monitoring for drug interactions, alternative drug therapies, dose adjustments