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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