Drug Interactions Notes

Drug Interactions

Objectives

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”
Time frame – slow onset/offset
Dose-related

CYP 3A4 Inducers

Anticonvulsants
- Carbamazepine, phenytoin, phenobarbital
Rifampin
St. John’s Wort
Dexamethasone
Tobacco smoke
Chronic alcohol consumption
Etc.

Enzyme Inhibition

Involves CYP 450 system
Competitive inhibition of object drug isoenzyme
Involves 1A2, 2C9, 2D6, 2E1, 3A4 etc!
Time frame – quick onset/offset
Dose related

CYP 3A4 Inhibitors

Macrolides
- Erythromycin
- Clarithromycin
Calcium Antagonists
- Verapamil, diltiazem
Older quinolones
- cipro
Antifungals
- Itraconazole
- ketoconazole
Amiodarone
Antiretrovirals
- Indinavir, nelfinavir, saquinavir etc.

Common CYP 3A4 Substrates

Statins (some)
- Atorvastatin, lovastatin, simvastatin
DOACs (some)
- Apixaban, Rivaroxaban
Colchicine
Estradiol, oral contraceptives
Methadone, hydrocodone, fentanyl, oxycodone
Sertraline, paroxetine
Risperidone, quetiapine
Tacrolimus
Sildenafil, tadalafil
Verapamil
Warfarin

CYP 1A2 Substrates, Inhibitors, and Inducers

Substrates: Caffeine, Clopidogrel, Estradiol, Methadone, Theophylline, Warfarin
Inhibitors: Ciprofloxacin, Fluvoxamine, Fluconazole, Amiodarone, Verapamil
Inducers: Carbamazepine, Phenobarbital, Rifampin, Smoking

Case 3

72-year-old female with CAD, DM2, HTN
Develops symptoms of UTI
Rx’d Septra
2 days later:
- Confused upon awakening
- Generalized seizure

Case 3 Continued

Blood glucose = 0.9mmol/L
Patient takes glyburide 10 mg po bid
Metabolized by CYP 2C9
CYP 2C9 inhibited by SMX/TMP

CYP 2C9 Substrates, Inhibitors, and Inducers

Substrates: Sulfonylureas, Warfarin, Fluvastatin, Methadone, Warfarin
Inhibitors: SMX/TMP, Metronidazole, Fluvoxamine, Fluoxetine, Fluconazole, Amiodarone
Inducers: Carbamazepine, phenobarbital, phenytoin, Rifampin, St. John’s Wort, Phenobarbital, phenytoin

CYP 2D6 Substrates and Inhibitors

Substrates: Codeine, Carvedilol, Metoprolol, Haloperidol, Risperidone
Inhibitors: Amiodarone, SSRI’s, Haloperidol, Bupropion, Ritonavir

Modified Drug Excretion

Renal excretion:
- Glomerular filtration – non-protein-bound drugs
- Active tubular secretion – acidic and basic drugs
- Passive tubular reabsorption - non-ionized drugs

Modified Drug Excretion - Clinically significant interactions are more likely to occur if:

Drug is excreted unchanged e.g. lithium
Narrow therapeutic window e.g. digoxin, cyclosporine, theophylline etc.
High plasma concentration of drug – precipitant drug pushes levels into toxic range
- Bottomline: Overall, this mechanism is an uncommon cause of clinically significant drug interactions.

Drug Transporters

P-glycoprotein (P-gp)
Organic Anion Transporting Polypeptide (OATP)

Case 4

92-year-old female with A. Fib, penicillin allergy
Independent, lives alone
digoxin 0.125mg po daily
Arrives at the Emergency feeling unwell x 2 days
Recent Rx for Clarithromycin (Biaxin) 500mg po bid x 7days for cellulitis

P-Glycoprotein (P-gp)

Transporter protein in the brush border of the intestinal wall
Pumps “out” toxins to ensure saturation of intestinal wall enzymes (eg. CYP 3A4) does not occur

P-Glycoprotein Substrates, Inhibitors, and Inducers

Substrates: Digoxin, Loperamide, Diltiazem, Midazolam, Cyclosporine, Chemo (various), Cyclosporine, Colchicine
Inhibitors: Macrolides, Amiodarone, Antifungals, Quinidine, Protease inhibitors, Verapamil, Ritonavir
Inducers: Rifampin, Dexamethasone, St. John’s Wort

Organic Anion Transporting Polypeptide (OATP)

Family of influx transporters expressed in various tissues (intestine, liver, kidney, other)
Pumps drugs “into” a cell – often to be excreted
Though effect will vary depending on location of OATP.
Inhibiting OAPT in the liver or kidney will increase drug level (most common)
(Inhibiting OAPT in the GI tract, will decrease drug level)

OATP Substrates and Inhibitors

Substrates: Statins, Angiotensin Receptor Blockers, Ciprofloxacin, Erythromycin, Montelukast, Fexofenadine
Inhibitors: Clarithromycin, Cyclosporine, Erythromycin, Gemfibrozil, Grapefruit, Ketoconazole, Rifampin, Protease Inhibitors

Grapefruit Juice

Inhibits CYP 3A4 in the intestinal wall (not hepatic) thereby ’ing 1st pass metabolism
Result = higher bioavailability,  plasma concentrations
Drugs with steep conc/response curves, narrow therapeutic index, if [plasma] doubles.

CYP 3A4 Substrates and bioavailability

Very low (
Low (10%-30%): Atorvastatin, felodipine
Intermediate (30% to 70%): Amio, CBZ, CyA, diazepam, diltiazem, nifedipine Silendafil, triazolam
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?

Drug-induced QT prolongation

Drug-associated:
- Antiarrhythmic agents
  - Particularly Class 1A (Quinidine, procainamide)
  - Class 3 (Sotalol > amiodarone)
- Antidepressants (TCAs)
- Antipsychotics (Haloperidol, thioridazine, quetiapine)
- Antimicrobials (Quinolones, macrolides)
- Antifungals (ketoconazole)
- Prokinetic agents (domperidone)
- Methadone
- Tamoxifen
Non-drug risk factors
- Female
- Advanced age
- 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?

DOAC Drug Interaction Mechanisms

$Dabigatran$ :
- CYP450: -
- P-gp: Substrate -(weak inhibitor)
- OATP: -
$Rivaroxaban$ :
- CYP450: 3A4 (50% metabolized) (3A5, 2J2)
- P-gp: Substrate
- OATP: Substrate of OAT3
$Apixaban$ :
- CYP450: 3A4 (20-25% metabolized)
- P-gp: Substrate
- OATP: -
$Edoxaban$ :
- CYP450: 3A4 (minor – 4%)
- P-gp: Substrate - (Weak inhibitor)
- OATP: -

DOAC Enzyme Inhibitor Interaction Management

$Dabigatran$ :
- P-gp Inhibitor (macrolides, amiodarone, ketoconazole, quinidine, cyclosporine, verapamil, ritonavir): ↓ dose or avoid
$Rivaroxaban$ :
- STRONG 3A4 inhibitor + P-gp inhibitor (itraconazole, ketoconazole, ritonavir): Avoid
$Apixaban$ :
- STRONG 3A4 inhibitor + P-gp inhibitor (itraconazole, ketoconazole, ritonavir): ↓ dose or avoid
$Edoxaban$ :
- P-gp Inhibitor (macrolides, amiodarone, ketoconazole, quinidine, cyclosporine, verapamil, ritonavir)
  - Afib – continue dose
  - VTE Tx - ↓ dose

Case 8 - Discussion

Edoxaban is a substrate of P-gp, and Clarithromycin is a P-gp inhibitor.
Coadministration can increase Edoxaban levels, increasing bleeding risk.
For VTE treatment, reduce the dose to edoxaban 30mg po daily while on clarithromycin

Drug Interaction Resources

Hansten + Horn
- Drug Interactions
- Top 100 Drug Interactions – A guide to Patient Management
Stockley’s Drug Interactions
Electronic:
- MICROMEDEX
- Lexi-Comp
- eCPS (powered by Lexi-comp)
CPOE – most will utilize a drug database with interaction checker (e.g. FDB)

Other Drug Interaction Resources

HIV
- Toronto General HIV (Immunodeficiency)Clinic Handbook/Charts (www.hivclinic.ca)
- UCSF database of HIV Interactions (arv.ucsf.edu)
- University of Liverpool (www.hiv-druginteractions.org)
Indiana University School of Medicine (Dr. David Flockhart) (www.drug-interactions.com)
QT prolongation interactions (www.crediblemeds.org)
For patients: FDA – Drugs – Resources for you Series (http://www.fda.gov/Drugs/ResourcesForYou/ucm163354.htm)
Handbook on Drug and Nutrient Interactions