Learning Objectives

After attending this lecture, learners will be able to:

• Recognize the significance of drug-drug interactions (DDIs) in older patients
• Describe potential challenges in preventing DDIs
• Identify clinically significant DDIs involving commonly used antibiotics
• Determine alternative therapeutic options for empiric treatment of uncomplicated urinary tract infections (UTIs) and group A streptococcal (GAS) pharyngitis

Presentation Outline

• Part 1: Adverse Drug Events (ADEs) and Drug-Drug Interactions (DDIs) in Older Patients
• Part 2: Evidence and Management of Clinically Relevant DDIs
• Part 3: Putting It All Together – Case Examples
• Part 4: Conclusion

HOW DO YOU MANAGE DRUG-DRUG INTERACTION ALERTS AND RELATED ISSUES IN YOUR DAY-TO-DAY WORKFLOW AT THE PHARMACY?

Part 1: Adverse Drug Events (ADEs) and Drug-Drug Interactions (DDIs) in Older Patients

Definition

• Adverse drug event (ADE): An injury from medicine or lack of an intended medicine, Includes adverse drug reactions and harm from medication incidents
• Drug-Drug Interactions (DDI): One drug alters the pharmacological effect of another drug upon co-administration, which may or may not result in increased, decreased, synergistic, or new and unanticipated adverse drug event

Significance of drug-drug interactions (DDIs) in older patients

Statistics

• Up to 25% of all hospital admissions and emergency department (ED) visits
  • ↑ risk in seniors
  • ↑ financial burden
    • Ontario 2007: $333 per ED visit; $7528 per hospitalization
    • Estimated annual cost in elderly population alone (> 66 years old): $13.6 million in Ontario and $35.7 million in Canada
  • Up to 70% of these visits are preventable!

Classifications

• Pharmacokinetic (PK): Absorption, distribution, metabolism, and/or excretion (ADME) of one drug is altered by another drug.
• Pharmacodynamic (PD): Response of one drug is altered by another drug without changes in the PK of the original drug

Factors increase susceptibility to DDIs

• Physiological changes ↑ susceptibility to DDIs
  • Body composition ↑ fat mass, ↓ total body water: Lipophilic drug: ↑ Vd, ↑ t1/2, Hydrophilic drug: ↓Vd
  • ↓ renal function: ↓ drug clearance
  • ↓ hepatic blood flow: ↓ drug metabolism

• Other factors that ↑ susceptibility to DDIs
  • Multiple comorbidities
  • Progression of chronic diseases
  • Polypharmacy
    • Bajcar et al. 20105 revealed that Rx claims ↑ 214% for older adults in Ontario between 1997-2006
    • This far exceeded the 18.5% growth in the population of Ontario adults aged 65 years and older

Challenges in preventing DDIs

(1) Detection of DDIs by clinicians is not optimal

• Clinicians identified only: 44% of all DDIs, 54% of all contraindicated DDIs
• 90% of clinicians thought drug alerts would be helpful to identify DDIs
• 55% perceived most significant barrier to alerts was excess non-relevant warnings

(2) Recognition of DDIs by clinical decision support systems is not optimal

• Pharmacy computerized DDI systems may fail to detect up to 1 in 3 DDIs
• Frequent warnings of trivial issues → Operator fatigue → Override of more significant DDIs
• Lack of regular, reliable updates
  • Large, continuously ↑ number of DDIs
  • Delays in turnaround time for knowledge transfer/translation

 (3) Lack of high-quality evidence of clinically significant DDIs

• Most data derived from case reports, volunteer studies, etc
• May contribute to ↓ sensitivity and specificity of computerized drug interaction systems
  • Difficult to determine the clinical significance of DDI alerts, and subsequent actions to manage them

Different approaches to evaluate DDIs…

Pharmacoepidemiologic Studies

• An approach to evaluate DDIs and their clinical relevance
• Population-based studies derived from databases (i.e., prescription and health insurance claims data, hospitalization records, demographic information from provincial and national databases ) linking DDIs with real-world, patient-experienced ADEs → ↑ external validity
• Outcome of interest: Hospitalization → Clinically Relevant DDIs

These clinically significant DDI pairs should be actively screened by community pharmacies!

Part 2: Evidence And Management Of Clinically Relevant DDIs

DDIs involving an antibiotic along with one chronic medication

Why?

• The majority of DDIs identified from pharmacoepidemiological studies involved an antibiotic
• Antibiotics for community-acquired infections are usually required for a relatively short duration
• DDIs involving antibiotics can often be resolved with a different antibiotic(s) from different class(es) → Role for pharmacist intervention.

Uncomplicated UTI

Background

• One of the most common indications for antimicrobial exposure in an otherwise healthy population
  • Second most common infection among community-dwelling older patients
  • Accounts for ~ 25% of all infection in older adults
  • Signs/symptoms: dysuria, polyuria, urinary frequency/urgency, flank pain
• Common Pathogens:
  • Escherichia coli (75-95%)
  • Occasional Enterobacteriaceae (Proteus mirabilis, Klebsiella pneumoniae)
  • Other gram (-) and gram (+) are rare

Treatment

The following are empiric treatment options for uncomplicated UTIs

• First Line
  • TMP/SMX 160/800 mg BID x 3 days
  • Nitrofurantoin monohydrate / macrocrystals 100 mg BID x 5 days
  • Fosfomycin 3 g single dose in 90 120 mL of water
• Second Line
  • Fluoroquinolones x 3 days
    • Ciprofloxacin 250 mg BID
    • Norfloxacin 400 mg BID
  • B lactams x 7 days
    • Cephalexin 500 mg QID
    • Amoxicillin/clavulanate 875/125 mg BID

Trimethoprim/Sulfamethoxazole (TMP/SMX) In The Treatment Of Uncomplicated UTIS

• Septra®, Co-trimoxazole®, Sulfatrim®, Teva-Trimel DS®,TMP-SMX
• Role in treating uncomplicated UTI:
  • Traditional first line agent in uncomplicated UTI
• Mechanism of action:
  • Interferes with bacterial folic acid synthesis
  • Bactericidal, time-dependent kill

DDIS Involving TMP/SMX

ACEI or ARB

Antoniou T et al. Trimethoprim-sulfamethoxazole induced hyperkalemia in patients receiving inhibitors of the renin-angiotensin system. Arch Intern Med 2010; 170(12):1045 9.

 Study outline

Results

Discussion

• Hyperkalemia risk with ACEI alone ~ 10% within 1 year of initiation
  • Risk factors: renal insufficiency, diabetes mellitus, ↓ left ventricular function, advanced age, drugs
• Trimethoprim
  • Structural and pharmacological similarities to K+-sparing diuretic amiloride
  • Amiloride-like inhibition of sodium channels in the luminal membrane of the distal tube → ↓ K+ excretion by ~ 40%

Conclusion

Among older patients treated with ACEI or ARB, use of TMP/SMX is associated with ~ 7-fold increased risk of hyperkalemia-associated hospitalization. Consider using alternative antibiotic therapy whenever possible.

Spironolactone

Antoniou T et al. Trimethoprim-sulfamethoxazole induced hyperkalemia in elderly patients receiving spironolactone: nested case-control study. BMJ 2011;343:d5228.

Study Outline

Results

Discussion

• Hyperkalemia occurs in up to 1/3 of patients on spironolactone
  • Regular monitoring of electrolytes
  • Caution/avoidance of other medications that can cause hyperkalemia
• Trimethoprim
  • Structural and pharmacological similarities to K+-sparing diuretic amiloride
  • ↓ K+ excretion by ~ 40%

Conclusion

Among older patients treated with spironolactone, use of TMP/SMX is associated with ~ 12-fold increased risk of hyperkalemia-associated hospitalization.
Nitrofurantoin is also associated with a ~2-fold increased risk.
Consider using alternative antibiotic therapy whenever possible.

Warfarin

Fischer HD et al. Hemorrhage during warfarin therapy associated with cotrimoxazole and other urinary tract anti-infective agents. Arch Intern Med 2010; 170(7):617-21.

Study outline

Results

Discussion

• Many antibiotics interact with warfarin
  • Antibiotics disrupt gut flora → ↓ intestinal vitamin K synthesis → ↑ warfarin effect
• TMP/SMX inhibits CYP 2C9
  • • CYP 2C9 metabolizes more biologically active S-enantiomer of warfarin → ↑ warfarin effect

Conclusion

Among older patients treated with long-term warfarin, use of TMP/SMX is associated with ~ 4-fold increased risk of hospitalization for UGI hemorrhage. Ciprofloxacin is also associated with ~ 2-fold increased risk. Consider using alternative antibiotic therapy whenever possible.

Glyburide

Juurlink DN et al.Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA 2003; 289(13)1652 8.

Study Outline

Results

Discussion

• Mechanism not fully understood
• Hypotheses:
  • Inhibition of sulfonylurea metabolism (glyburide) by sulfonamides (SMX)
  • Displacement of sulfonylureas from protein binding sites → ↑ free fraction of sulfonylureas

Conclusion

• Among older patients treated with glyburide, use of TMP/SMX is associated with ~ 6-fold increase in risk of hospitalization for hypoglycemia.
• Recommend close blood glucose monitoring during concomitant therapy – dose adjustments may be necessary.

Phenytoin

Antoniou T et al. Trimethoprim-sulfamethoxazole-induced phenytoin toxicity in the elderly: a population based study. Br J Clin Pharmacol 2011; 71(4):544 9.

Study Outlet

Results

Discussion

• Phenytoin
  • Saturable, non-linear pharmacokinetics → unpredictable serum concentrations
  • Metabolized by CYP 2C9, 2C8, 2C19
• Trimethoprim
  • Potent inhibitor of CYP 2C8 → can ↑ phenytoin concentration
  • Small PK study demonstrated phenytoin clearance was ↓ by 30% when combined with TMP

Conclusion

Among older patients treated with phenytoin, use of TMP/SMX is associated with ~ 2-fold increased risk of phenytoin toxicity requiring hospitalization. Consider using alternative antibiotic therapy whenever possible.

Uncomplicated UTIs Treatment Alternatives To Reduce The Risk Of Hospitalization

Pharyngitis

Background

• Etiology
  • 30-65% idiopathic
  • 30-60% viral
  • 5-10% bacterial
    • Most common is Group A streptococcus (GAS) aka “strep throat”
    • A significant cause of community-associated infections
• Typical signs and symptoms: Very sore throat, Fever (T > 38.5°C)

Treatment

• The following are empiric treatment options for GAS pharyngitis:
• Penicillin VK 300 mg TID x 10 days
  • [For children] Amoxicillin 500 mg BID x 10 days
• Cephalexin 500 mg BID x 10 days
• Azithromycin 500 mg daily x 1 day, then 250 mg daily x 4 days
• Clarithromycin 250 mg BID x 10 days

 

Macrolides

Mechanism Of Action

 

• Mechanism of action:
  • Interferes with bacterial protein synthesis
  • Bacteriostatic, time-dependent kill
    • May be bactericidal, depending on concentration and pathogen

Comparisons

DDIs Involving Macrolides

Digoxin

Gomes T et al. Macrolide induced digoxin toxicity: a population-based study. Clinical Pharmacology and Therapeutics 2009; 86(4): 383-6.

Study Outline

Results 

Discussion

• Digoxin: High affinity substrate for multidrug efflux transporter P-glycoprotein (P-gp)
• Macrolides inhibit P-gp : ↑ risk of digoxin toxicity

Conclusion

• Among older patients treated with digoxin, use of clarithromycin is associated with ~ 15-fold increased risk of digoxin toxicity requiring hospitalization.
• Erythromycin and azithromycin are also associated with ~ 4-fold increased risk.
• Consider using alternative antibiotic therapy whenever possible.

CCBs

Wright A et al.The risk of hypotension following co-prescription of macrolide antibiotics and calcium-channel blockers. CMAJ 2011; 183(3): 303-7.

Study outline

Results

Discussion

• Calcium channel blockers: Substrates for CYP 3A
• Erythromycin and clarithromycin inhibit CYP 3A4
  • ↑ CCB effect
  • Bailey DG et al. found erythromycin use associated with ↑ felodipine levels by ~ 300% in 12 patients

Conclusion

Among older patients treated with CCB therapy, use of erythromycin is associated with ~ 6-fold increased risk of hypotension or shock requiring hospitalization. Clarithromycin is also associated with a ~ 4-fold increased risk. Consider azithromycin when macrolide therapy is necessary.

Treatment Alternatives To Reduce The Risk Of Hospitalization

Patient receiving

long-term therapy with:

Switch macrolide:

SCENARIO A

 

• ST, a 68-year-old female, walks into your community pharmacy and states that she has been experiencing increased frequency and a burning sensation upon urination for the past 2
• She presents you with the following prescription:
• As you begin processing her prescription, you notice she is currently on several chronic medications, which include:
  • Amlodipine 5 mg daily
  • Digoxin 0.0625 mg daily
  • Glyburide 5 mg BID
  • Hydrochlorothiazide 25 mg daily
  • Metformin 500 mg TID cc
  • Salbutamol MDI 1-2 puffs QID prn

ST is at risk of experiencing a drug-drug interaction.

True or False?

ST is at risk of experiencing a drug-drug interaction.

• Which drug pair may potentially cause an adverse effect resulting in hospitalization?
• TMP/SMX and Amlodipine
• Amlodipine and Digoxin
• TMP/SMX and Hydrochlorothiazide
• Glyburide and TMP/SMX
• Glyburide and Digoxin
• Which drug pair may potentially cause an adverse effect resulting in hospitalization?
• TMP/SMX and Amlodipine
• Amlodipine and Digoxin
• TMP/SMX and Hydrochlorothiazide

(e) Glyburide and Digoxin

• What clinically relevant adverse outcome may be of concern when TMP/SMX is given with glyburide?
• Hyperglycemia with ↑ risk of diabetic ketoacidosis
• Hypoglycemia symptoms with blood glucose < 4 mmol/L
• Unresolved UTI due to ↓ efficacy of TMP/SMX
• Skin rash due to ↑ sensitivity to sulfa medications
• B and C
• What clinically relevant adverse outcome may be of concern when TMP/SMX is given with glyburide?

(a) Hyperglycemia with ↑ risk of diabetic ketoacidosis

• Unresolved UTI due to ↓ efficacy of TMP/SMX
• Skin rash due to ↑ sensitivity to sulfa medications
• B and C

What is ST’s actual or potential

drug therapy problem?

ST is at risk of experiencing hypoglycemia (weakness, confusion, tremors, headache) secondary to concomitant use of glyburide and TMP/SMX and would benefit from reassessment of therapy for uncomplicated UTI.

• ST’s recent bloodwork shows normal renal What is/are appropriate

therapeutic recommendation(s) for ST?

• Ciprofloxacin 500 mg BID x 3 days
• Nitrofurantoin 100 mg BID x 5 days
• Patient self-monitoring of blood glucose
• A or B and C
• B and C

• ST’s recent bloodwork shows normal renal What is/are appropriate

therapeutic recommendation(s) for ST?

• Ciprofloxacin 500 mg BID x 3 days
• Nitrofurantoin 100 mg BID x 5 days
• Patient self-monitoring of blood glucose
• A or B and C

What is an appropriate monitoring plan for ST?

 

• PA, a 65-year-old female with NKDA, walks into your pharmacy stating that she has been feeling terrible for the past She woke up this morning with a fever of 38.3°C (axilla) and “the worst throat ache” she has ever experienced.
• She states that her doctor’s diagnosis is “strep throat,”

and gives you a prescription:

• As you begin processing her prescription, you notice she is currently on several chronic medications, which include:
  • Diltiazem ER 240 mg once daily
  • Ramipril 5 mg once daily
  • Metformin 1000 mg BID CC
  • Warfarin 3 mg once daily (last INR 2 weeks ago: 8)
  • Lorazepam 1 mg QHS prn

PA is at risk of experiencing a drug-drug interaction.

True or False?

PA is at risk of experiencing a drug-drug interaction.

• Which drug pair may potentially cause an adverse effect resulting in hospitalization?
  • Diltiazem and Clarithromycin
  • Diltiazem and Metformin
  • Clarithromycin and Ramipril
  • Warfarin and Diltiazem
  • Clarithromycin and Lorazepam
• Which drug pair may potentially cause an adverse effect resulting in hospitalization?
• Diltiazem and Metformin
• Clarithromycin and Ramipril
• Warfarin and Diltiazem
• Clarithromycin and Lorazepam
• What clinically relevant adverse outcome may be of concern when clarithromycin is given with diltiazem?
• Hypotension
• Bradycardia
• Syncope
• Shock
• All of the above
• What clinically relevant adverse outcome may be of concern when clarithromycin is given with diltiazem?
• Hypotension
• Bradycardia
• Syncope
• Shock
• What is/are appropriate therapeutic recommendation(s)?
• Azithromycin 250 mg daily x 5 days
• Erythromycin ethyl succinate 400 mg Q6H x 10 days
• Amoxicillin 500 mg daily x 10 days
• Penicillin VK 300 mg TID x 10 days
• A and D
• What is/are appropriate therapeutic recommendation(s)?
• Azithromycin 250 mg daily x 5 days
• Erythromycin ethyl succinate 400 mg Q6H x 10 days
• Amoxicillin 500 mg daily x 10 days

(e) A and D

• What is/are appropriate monitoring parameter(s)?
• Phonophobia
• Throat ache severity
• Neck stiffness/rigidity
• Photophobia
• B and C

SCENARIO B – ANSWER #5

 

• What is/are appropriate monitoring parameter(s)?

(a) Phonophobia

• Neck stiffness/rigidity
• Photophobia
• B and C

CONCLUSION

 

• DDIs are preventable adverse drug events that are associated with significant

morbidity and mortality

• Research has demonstrated an association between specific drug-drug interaction pairs with hospitalization in older patients
• Healthcare practitioners are encouraged to familiarize themselves with these drug- drug interaction pairs to prevent clinically significant adverse drug events