To provide the knowledge required to identify, prevent and resolve predictable drug-drug interactions to optimize patient outcomes.
Explain the mechanisms of common drug interactions.
Determine potential drug interactions.
Develop an understanding of how to prevent or clinically manage drug-drug interactions that may occur in practice.
Definitions
Drug Interaction: The phenomenon of two or more drugs interacting in such a manner that the effectiveness or toxicity of one or more drugs is altered (frequency varies ~10%).
Precipitant drug: The drug causing the altered action on another drug.
Object drug: The drug whose action is being altered by the interaction.
Pharmacokinetics and Pharmacodynamics
Pharmacokinetics (What the body does to a drug):
Absorption
Distribution
Metabolism
Excretion
Pharmacodynamics (How the body reacts to a drug):
Drug concentrations at the site of action and effect
Effects of receptor binding, post-receptor effects
Mechanisms of Drug Interactions
Synergistic
Additive
Antagonistic
Decreased drug absorption (GI)
Protein-binding displacement
Enzyme induction
Enzyme inhibition
Modified drug excretion
Case 1
Mr. GS, 59yr male, A.Fib, Diabetes-type 2 (diet controlled) is looking for something to treat his occasional heartburn (1-2x/month).
Medications: digoxin 0.125mg po daily, warfarin 5mg po daily (last INR 2.4), ciprofloxacin 500mg po bid + clindamycin 450mg po qid for a resolving diabetic foot infection.
Options:
A. Mg/Al combo? Maalox? Diovol?
B. Alginic acid (Gaviscon)?
C. Ca based product (Tums)?
D. H2Blocker (Ranitidine or Famotidine)?
E. PPI (OTC omeprazole)?
Which option(s) could result in adverse effects due to a drug interaction?
Approach to a potential Drug Interaction
Complete Medication History (Incl. recent stopped meds)
Determine Mechanism of Interaction (Utilize resources)
Determine Clinical Significance
Theoretical vs. Clinical effect Likely occurrence? Significance? Any data/evidence? Will patient likely experience harm?
Clinical Intervention
Do nothing + monitor?
Separate Timing?
Stop drug / Avoid (if possible)?
Document
Drug Level
Patient Level
Patient + Drug
Clinical Action
Recall… oral medication absorption
Dissolves (stomach acid)
Drug in solution (ionized/un-ionized molecules)
Absorption from small intestine (un-ionized drug crosses GI wall)
↓Drug Absorption Overview
Drug binding
-adsorption
-chelation/complexes
∆ in GI motility
- gastric emptying
- gastric emptying (extent vs. rate of absorption)
∆ in GI pH
∆ in Intestinal flora
Drug metabolism in the intestinal wall
Drug Transporters
↓Drug Absorption: Drug Binding
Adsorption
Chelation/Complexation
↓Drug Absorption: ∆ in GI motility
GI motility
GI motility (extent vs rate of absorption)
↓Drug Absorption: ∆ in GI pH
Weak acids in acidic pH are more likely to be in the lipid-soluble form.
Weak bases in an acidic pH are more likely to be in an ionized form.
↓Drug Absorption: Intestinal flora
enterohepatic circulation
cleaving of bonds
↓Drug Absorption: Drug metabolism in the intestinal wall
Monoamine oxidase enzyme
CYP 3A4
Drug Transporters
P-gp (efflux pump)
OATP (influx pump)
Intestinal Wall Drug Metabolism and Transporters
Lumen
Intestinal Enterocyte
P-gp
3A4
OATP
MAO
Portal vein
Management of ↓ Drug Absorption Interactions
Binding interaction
Give object drug 2 hours before precipitant drug
GI motility interaction
Separation of doses not usually effective. May be useful to give after precipitant drug has worn off
∆’es in GI pH
Adjust dosing times (antacids pH transiently). H2 blockers given qHS – give object drug mid-day
Intestinal flora
Adjustment of dosing times not effective (∆ in gut flora takes time to occur and recover)
Intestinal wall metabolism and drug transport
Separate drugs?- poor data, but theoretically may work
Case 1 Discussion
The potential DI’s = cipro and mg/al/ca
Recall… a “Drug Interaction” is not one of the 7 types of DTP’s! (Hint: what would the PATIENT experience?)
Case 2
Mr. SZ has a complex history of seizures. He had been well controlled for several years with phenytoin 300mg po daily. Over the past 6 months, he has had multiple seizures. He is compliant with his medication.
His neurologist plans on switching him over to valproic acid by cross-tapering (adding valproic acid, tapering up, while slowly tapering phenytoin down).
Mr. SZ has started valproic acid 500mg po daily in addition to his phenytoin 300mg po daily for ~ 7 days. He returns to clinic complaining of drowsiness and dizziness.
What is the likely cause of these symptoms?
Protein Binding Displacement
Absorption of drug
Distributed through the body
free drug ∆ bound drug (only free drug exerts effect)
Protein Binding Displacement Continued
Drugs highly bound are more likely to have a clinically significant effect. E.g. Drug 99% protein bound vs. 60% protein bound
Drug with > affinity displaces drug with lesser affinity.
Highly protein-bound drugs:
Warfarin, amiodarone
Methotrexate
phenytoin, valproic acid
Sulfonamides
Ertapenem
Fluoxetine, sertraline, nortriptyline
Protein Binding Displacement Bottomline
Protein binding displacement interactions rarely result in clinical significance.
Watch for in drugs with
high protein binding PLUS narrow therapeutic index
Management:
Monitor levels - Measure free (unbound) object drug
Metabolism
Primary Function?
Helps the body breakdown substances for easier elimination
Phase I
CYP P450
3A4, 1A2, 2D6, etc
Phase II
Enzyme Induction
Enzyme Inhibition
Concepts: Substrate, Inducer, Inhibitor
Enzyme Induction
Involves CYP 450 system (many enzymes) - 3A4 is “inducible”
High (>70%): Alprazolam, amlodipine, dexamethasone, quetiapine
Conclusions: Clinically Significant Drug Interactions More Likely When
Drugs with narrow therapeutic range
Drugs with high plasma drug concentrations
Drugs undergoing extensive 1st pass metabolism
Drugs highly protein bound
Case 5
BP is a 27-year-old female with a history of Bipolar affective disorder. She is brought to the emergency department after falling off her bicycle following a collision with a car.
The physician asks you to dispense meperidine 150mg IM to the nurse for administration to BP for her pain.
Allergies: Codeine
Current medications:
Phenelzine 15mg po daily
Vitamin C 500mg po daily
Naproxen 225mg po daily prn
TriCyclen 28 1 tab po daily
Is there a drug interaction? If so, what is the DTP?
Pharmacodynamic Drug Interactions
Synergistic
SSRI’s and St John’s Wort Serotonin Syndrome
Additive
K+ sparing diuretics and ACEI’s Elevated K levels
ACEI’s and B-blockers enhanced BP lowering
Antagonistic
Morphine and naloxone reversal of pain relief
Vitamin K and Warfarin reversal of inability to clot quickly
Time frame – rapid onset/offset
Easy to detect
Case 5 Discussion
The relevant meds are Phenelzine (MAOI) and Meperidine
Pharmacodynamic Interaction
Meperidine is contraindicated with MAOIs due to risk of serotonin syndrome.
Common Pharmacodynamic Interactions
Cumulative anticholinergic load
Bleed risk
Miscellaneous concepts
Prodrugs
QT prolongation
Case 6
SN is a 72-year-old male who recently (4 days ago) experienced a STEMI. He underwent PCI and had 2 stents inserted.
Allergies: none
Medications on discharge from hospital:
Clopidogrel 75mg po daily
EC ASA 81mg po daily
Omeprazole 40mg po daily
Ramipril 5mg po daily
Metoprolol 25mg po bid
Atorvastatin 40mg po qhs
Is there a drug interaction here? If so, what is the DTP?
Prodrugs
Drugs that need to be metabolized to become activated
Thus, effects on metabolism will either increase or decrease the amount of ‘activated’ drug
E.g. Clopidogrel requires metabolization via CYP450 2C19 to an active metabolite that is actually responsible for all its efficacy.
Case 6 - Discussion
The relevant meds are Clopidogrel and Omeprazole.
Omeprazole inhibits CYP2C19, the enzyme responsible for activating clopidogrel. Using them together may reduce the effectiveness of clopidogrel.
Case 7
AR is a 75-year-old female who was diagnosed at a local walk-in clinic with pneumonia. She presents to you a new prescription for Levofloxacin 750mg po daily x5days. Baseline QT interval is 453 msec.
Allergies: None
Current medications:
EC ASA 81mg po daily
Amiodarone 200mg po bid
Atorvastatin 20mg po qhs
Furosemide 40mg po QAM
Metoprolol 25mg po bid
Ramipril 5mg po daily
Is there a drug interaction? If so, what is the DTP?
Hypokalemia or hypomagnesemia (can be caused by drugs too)
Heart failure
Bradycardia
Ischemia
Congenital
QT prolongation can lead to torsade de pointes (TdP)
Considered prolonged if QTc Interval is > 450 msec (men); >460 msec (women)
Interactions can be Pharmacokinetic or Pharmacodynamic to increase QT
Drug-induced QT prolongation - How to manage?
Although the risk for a single agent may be very low
Risk increases with PK interactions which increase an object drug into supratherapeutic levels;
Risk increases significantly with PD interactions with multiple agents each prolonging QT
Avoid combinations (if possible)
Select drugs less associated with QT prolongation
Risk vs. Benefit
Stop medication if prolonged QTc (>450 msec (men), >460 msec (women)) or if prolonged by more than 60 msec from baseline
(* AHA/ACCF guidelines suggest stopping if QTc >500ms (in hospital setting))
ECG at baseline + repeat when the drug is at steady-state
Case 7 - Discussion
Levofloxacin and Amiodarone both increase QT interval.
The patient's baseline QT is already prolonged, and adding levofloxacin increases the risk of torsades de pointes (TdP).
Case 8
BR is a 66-year-old female who presents to your clinic with presumed low-risk, outpatient treatable CAP. They receive a prescription for clarithromycin 500mg po bid x7 days.
PMHx
generally healthy except had an unprovoked DVT – discovered last month
Allergies: beta-lactams and ciprofloxacin.
Medications:
Edoxaban 60mg po daily (started ~ 1 month ago)
Multivitamin 1 tablet po daily
Assuming the antibiotic prescription was appropriate, what would be the best course of action?